Comparative Effectiveness of Drug Therapy for Rheumatoid ...
Evidence Table 1. Randomized controlled trials and observational studiesStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Askling et al., 2005 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUz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ADDIN EN.CITE.DATA 1Country, Setting:Sweden; registries Funding:Swedish Cancer Society; AFA Insurance Company; Wyeth-Ayerst; Schering-Plough; Abbott Immunology; Bristol-Myers Squibb; King Gustav V; ?sterlund and Kock Foundations; Reumatikerf?r-bundet Research Objective:The risk of TB pts with RAStudy Design:Retrospective cohort study Overall N:36,115 w/ RA Study Duration: 467,770 PYInclusion Criteria:Diagnosed with RA according to ACR criteriaRA inpatient btwn 1964 to 2001Exclusion Criteria:Psoriatic arthritis, SLE, or AS diagnosisInterventions, dose:D1: RA inpatientD2: Early RAD3: TNF treated RAN:D1: 31,185D2: 2430D3: 2500Mean age, yrs:D1: 0-39: 19.08%;40-59: 40.80%;60-79: 35.90%;80+: 4.22%D2: 0-39: 15.80%;40-59: 38.40%;60-79: 41.60%;80+: 4.20%D3: 0-39: 18.40%;40-59: 49.44%;60-79: 30.52%;80+: 1.64%Sex, % female:D1: 73.4D2: 70.2D3: 73.4Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: NAD2: 3.6D3: 5.8HAQ:D1: NAD2: 0.8D3: 1.84TB cases: D1: 27D2: 21987 to 2001 RA inpatient vs. General RR 3.9 (95% CI,3.1-5.0)RA inpatient vs. General inpatient RR 1.6 (95% CI,1.3-1.9)1999 to 2001RA inpatient vs. General were at increased risk of TB RR 2.0, (95% CI,1.2-3.4)TNF treated RA had a 4-fold increased risk of TB RR 4.0, (95% CI,1.3-12) vs. RA inpatientNAOverall Attrition Rate, %:NAITT Analysis:NA Quality Rating:GoodAuthor, yr:Askling et al., 2005 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE.DATA 2Country, Setting:Sweden,Multicenter Funding:Swedish Cancer Society; insurance company AFA; Wyeth Ayerst, Schering-Plough, Abbott, Bristol Myer Squibb; Swedish National Board of Health and Welfare Research Objective:Cancer pattern of contemporary pts with RA and risk of solid cancer after TNF Study Design: Retrospective cohort study Overall N:60,930 Study Duration: NRInclusion Criteria:Inpatient Register RA cohort: inpts > 16 yrs or age ever discharged with an RA diagnosis between January 1990 and December 31 2003Early RA cohort: pts diagnosed within 1 yr with RA from 1995 through 2003. TNF antagonist cohort: pts with RA treated with ETA, INF, or ADA from a Swedish registry of pts treated with anti-TNF medicationsExclusion Criteria:Pregnant or lactatingInpatient Register RA cohortPts discharged with SLE, AS, or PsAObserved and expected cancers during the 1st yr of follow upInterventions, dose:D1: Inpatient RA CohortD2: Early Arthritis RA CohortD3: TNF antagonist cohortN:NRMean age, yrs:NRSex, % female:D1: 71.4D2: 69.9D3: 74.8Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: NRD2: 3.5D3: 5.5% age 45-74 yrs:D1: 56.3D2: 65.4D3: 71.8Inpatient RA cohort:Based on 3379 observed solid cancers, this cohort had minimally increased overall risk of solid cancer (SIR: 1.05, 95% CI,1.01 to 1.08)Overall RR was 1.19 (95% CI,1.13 to 1.26, N:1311) among men and 0.97 (95% CI,0.93 to 1.02, N:2068) among womenGI cancer risk (SIR: 0.85, 95% CI,0.78 to 0.93); Lung cancers (SIR: 1.48, 95% CI,1.33 to 1.65); (SIR: 1.66, 95% CI,1.50 to 1.84);Early Arthritis cohort:138 solid cancers (SIR: 1.1, 95% CI,0.9 to 1.3), women (SIR: 0.87, 95% CI,0.67 to 1.11, n:64) Men (SIR: 1.42, 95% CI,1.12 to 1.79, n:74)TNF cohort67 solid cancers observed (SIR: 0.9, 95% CI,0.7 to 1.2)Women (SIR: 0.87, 95% CI,0.63 to 1.16, N:45) Men 1.06 (95% CI,0.67 to 1.61, N:22)Risk of colorectal cancer (SIR: 1.2 lung cancer (SIR: 1.8), breast cancer (SIR: 0.4), NMSC ( SIR: 3.6)NAOverall Attrition Rate, %:NRITT Analysis:NA: retrospective cohortQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Askling, 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw
MTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4zPC9zdHls
ZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MjAxMjwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjVmeHR3MmV0NnR2cmZ3ZTB6cHM1MnByZno5
YXg5dGFmeHBkNSI+MjAxMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy
bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+
QXNrbGluZywgSi48L2F1dGhvcj48YXV0aG9yPkZvcmVkLCBDLiBNLjwvYXV0aG9yPjxhdXRob3I+
QmFlY2tsdW5kLCBFLjwvYXV0aG9yPjxhdXRob3I+QnJhbmR0LCBMLjwvYXV0aG9yPjxhdXRob3I+
QmFja2xpbiwgQy48L2F1dGhvcj48YXV0aG9yPkVrYm9tLCBBLjwvYXV0aG9yPjxhdXRob3I+U3Vu
ZHN0cm9tLCBDLjwvYXV0aG9yPjxhdXRob3I+QmVydGlsc3NvbiwgTC48L2F1dGhvcj48YXV0aG9y
PkNvc3RlciwgTC48L2F1dGhvcj48YXV0aG9yPkdlYm9yZWssIFAuPC9hdXRob3I+PGF1dGhvcj5K
YWNvYnNzb24sIEwuIFQuPC9hdXRob3I+PGF1dGhvcj5MaW5kYmxhZCwgUy48L2F1dGhvcj48YXV0
aG9yPkx5c2hvbG0sIEouPC9hdXRob3I+PGF1dGhvcj5SYW50YXBhYS1EYWhscXZpc3QsIFMuPC9h
dXRob3I+PGF1dGhvcj5TYXhuZSwgVC48L2F1dGhvcj48YXV0aG9yPktsYXJlc2tvZywgTC48L2F1
dGhvcj48YXV0aG9yPkZlbHRlbGl1cywgTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5DbGluaWNhbCBFcGlkZW1pb2xvZ3kgVW5pdCwgRGVwYXJ0bWVudCBv
ZiBNZWRpY2luZSwgS2Fyb2xpbnNrYSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBTdG9ja2hvbG0sIFN3
ZWRlbi4gam9oYW4uYXNrbGluZ0BtZWRrcy5raS5zZTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp
dGxlPkhhZW1hdG9wb2lldGljIG1hbGlnbmFuY2llcyBpbiByaGV1bWF0b2lkIGFydGhyaXRpczog
bHltcGhvbWEgcmlzayBhbmQgY2hhcmFjdGVyaXN0aWNzIGFmdGVyIGV4cG9zdXJlIHRvIHR1bW91
ciBuZWNyb3NpcyBmYWN0b3IgYW50YWdvbmlzdHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5u
IFJoZXVtIERpczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp
dGxlPkFubmFscyBvZiB0aGUgUmhldW1hdGljIERpc2Vhc2VzPC9mdWxsLXRpdGxlPjxhYmJyLTE+
QW5uLiBSaGV1bS4gRGlzLjwvYWJici0xPjxhYmJyLTI+QW5uIFJoZXVtIERpczwvYWJici0yPjwv
cGVyaW9kaWNhbD48cGFnZXM+MTQxNC0yMDwvcGFnZXM+PHZvbHVtZT42NDwvdm9sdW1lPjxudW1i
ZXI+MTA8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5
d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFudGly
aGV1bWF0aWMgQWdlbnRzLyBhZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk
PjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5L2VwaWRlbWlvbG9n
eTwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFJlc3BvbnNlIE1vZGlmaWVycy8gYWR2ZXJz
ZSBlZmZlY3RzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5FcGlkZW1pb2xvZ2lj
IE1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlbWF0
b2xvZ2ljIE5lb3BsYXNtcy8gY2hlbWljYWxseSBpbmR1Y2VkL2VwaWRlbWlvbG9neTwva2V5d29y
ZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TGV1a2VtaWEvY2hlbWljYWxseSBp
bmR1Y2VkL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5d29yZD5MeW1waG9tYS9jaGVtaWNhbGx5
IGluZHVjZWQvZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydCwgTm9u
LVUuUy4gR292JmFwb3M7dDwva2V5d29yZD48a2V5d29yZD5Td2VkZW4vZXBpZGVtaW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPlR1bW9yIE5lY3Jvc2lzIEZhY3Rvci1hbHBoYS8gYW50YWdvbmlzdHMg
JmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA1PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+T2N0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGFjY2Vz
c2lvbi1udW0+MTU4NDM0NTQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20xPkk8
L2N1c3RvbTE+PGN1c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9tMz5PQUU8L2N1c3RvbTM+PGN1c3Rv
bTQ+MzwvY3VzdG9tND48Y3VzdG9tNz5HRyAxMC00IChMTCA5LTEzKTwvY3VzdG9tNz48L3JlY29y
ZD48L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA 3Country, Setting:Sweden, Registry dataFunding:AFA Insurance Company, Pharmas: Swedish National Board of Health and Welfare; Swedish Cancer SocietyResearch Objective:Risks of hemapoetic malignancies, especially those with associtaed with TNF Study Design:Retrospective cohort studyOverall N:Prevalent Cohort (inpatient): 53,067Study Duration: 4 yrsInclusion Criteria:Age: Prevalence: 16+Diagnosed with RA according to ACR criteriaPrevalence: 1987Exclusion Criteria:Prevalence: discharged with systemic lupus, AS, or PsAInterventions, dose:D1: PrevalenceD2: IncidenceD3: TNF AntagonistN:D1: 53,067D2: 3,703D3: 4,160Mean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRSee AEsHaematopoetic malignancnies:D1: SIR: 1.7 (1.5-1.8)D2: SIR: 1.6 (0.9-2.6)D3: 2.1 (1.1-3.8)Overall Attrition Rate, %:ITT Analysis:NARating:Fair Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableAskling et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM2
NzI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij40PC9zdHls
ZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MzY3MjwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjU5YXN4c3h2eWZ4eHh2ZWUwMnBwYXh3Zndm
MGZzZnoyOTV2OSI+MzY3Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJHZW5l
cmljIj4xMzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkFza2xpbmcs
IEouPC9hdXRob3I+PGF1dGhvcj52YW4gVm9sbGVuaG92ZW4sIFIuIEYuPC9hdXRob3I+PGF1dGhv
cj5HcmFuYXRoLCBGLjwvYXV0aG9yPjxhdXRob3I+UmFhc2Nob3UsIFAuPC9hdXRob3I+PGF1dGhv
cj5Gb3JlZCwgQy4gTS48L2F1dGhvcj48YXV0aG9yPkJhZWNrbHVuZCwgRS48L2F1dGhvcj48YXV0
aG9yPkRhY2toYW1tYXIsIEMuPC9hdXRob3I+PGF1dGhvcj5GZWx0ZWxpdXMsIE4uPC9hdXRob3I+
PGF1dGhvcj5Db3N0ZXIsIEwuPC9hdXRob3I+PGF1dGhvcj5HZWJvcmVrLCBQLjwvYXV0aG9yPjxh
dXRob3I+SmFjb2Jzc29uLCBMLiBULjwvYXV0aG9yPjxhdXRob3I+TGluZGJsYWQsIFMuPC9hdXRo
b3I+PGF1dGhvcj5SYW50YXBhYS1EYWhscXZpc3QsIFMuPC9hdXRob3I+PGF1dGhvcj5TYXhuZSwg
VC48L2F1dGhvcj48YXV0aG9yPktsYXJlc2tvZywgTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250
cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1lZGljaW5lIFNvbG5hLCBLYXJv
bGluc2thIFVuaXZlcnNpdHkgSG9zcGl0YWwgYXQgU29sbmEgYW5kIEthcm9saW5za2EgSW5zdGl0
dXRldCwgU3RvY2tob2xtLCBTd2VkZW4uIGpvaGFuLmFza2xpbmdAa2kuc2U8L2F1dGgtYWRkcmVz
cz48dGl0bGVzPjx0aXRsZT5DYW5jZXIgcmlzayBpbiBwYXRpZW50cyB3aXRoIHJoZXVtYXRvaWQg
YXJ0aHJpdGlzIHRyZWF0ZWQgd2l0aCBhbnRpLXR1bW9yIG5lY3Jvc2lzIGZhY3RvciBhbHBoYSB0
aGVyYXBpZXM6IGRvZXMgdGhlIHJpc2sgY2hhbmdlIHdpdGggdGhlIHRpbWUgc2luY2Ugc3RhcnQg
b2YgdHJlYXRtZW50PzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgUmhldW08L3Nl
Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BcnRocml0aXMg
YW5kIFJoZXVtYXRpc208L2Z1bGwtdGl0bGU+PGFiYnItMT5BcnRocml0aXMgUmhldW0uPC9hYmJy
LTE+PGFiYnItMj5BcnRocml0aXMgUmhldW08L2FiYnItMj48YWJici0zPkFydGhyaXRpcyAmYW1w
OyBSaGV1bWF0aXNtPC9hYmJyLTM+PC9wZXJpb2RpY2FsPjxwYWdlcz4zMTgwLTk8L3BhZ2VzPjx2
b2x1bWU+NjA8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFn
ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbC8gYWR2ZXJzZSBlZmZl
Y3RzL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BbnRpcmhldW1hdGljIEFnZW50
cy9hZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhy
aXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5L2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5
d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5Eb3NlLVJlc3BvbnNlIFJlbGF0
aW9uc2hpcCwgRHJ1Zzwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcvIGFkdmVyc2UgZWZmZWN0
cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3JkPjxr
ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG90cmV4YXRlL2FkdmVyc2UgZWZmZWN0
cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+
PGtleXdvcmQ+TmVvcGxhc21zLyBlcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0
b3JzLCBUdW1vciBOZWNyb3NpcyBGYWN0b3IvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3
b3JkPlJlZ2lzdHJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9r
ZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5Td2VkZW4vZXBp
ZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48a2V5d29y
ZD5UdW1vciBOZWNyb3NpcyBGYWN0b3ItYWxwaGEvIGFudGFnb25pc3RzICZhbXA7IGluaGliaXRv
cnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVz
PjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDQtMzU5MSAoUHJp
bnQpJiN4RDswMDA0LTM1OTEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE5ODc3MDI3
PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20y
Pkk8L2N1c3RvbTI+PGN1c3RvbTQ+S1EgMyAvIGZhaXI8L2N1c3RvbTQ+PC9yZWNvcmQ+PC9DaXRl
PjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 4Swedish Biologics RegisterCountry and settingSwedenSource of fundingSwedish Cancer Society; Stockholm County CouncilResearch objectiveTo assess the risk of cancer in RA patients treated with anti-TNF therapyStudy designObservationalOverall N6366 (first time anti-TNF users)Duration of study25,693 person-yrsInclusion CriteriaRA patients, older than 16 yrsStarting treatment with TNF antagonistsExclusion CriteriaComparisons (dosage and frequency)D1: ETN: dose NRD2: ADA: dose NRD3: INF: dose NRNumber in groupD1: 2287D2: 937D3: 3380Overall: 6604Mean age (years)D1: 54D2: 55D3: 55Overall: 55Sex, % femaleD1: 77D2: 77D3: 74Overall: 75Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 10.7D2: 11.9D3: 10.1Overall: 10.6TJC, meanD1: 9.1D2: 8.4D3: 8.6Overall: 8.7SJC, mean D1: 9.8D2: 9.1D3: 9.4Overall: 9.5Corticosteroid use, %D1: 57D2: 56D3: 45Overall: 51DMARD use, %: D1: 64.3D2: 76.9D3: 90.7Overall: 80MTX na?ve, %: D1: 44.3D2: 31.9D3: 12.9Overall: 27Treatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreD1: 5.6D2: 5.4D3: 5.5Overall: 5.5Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallNRSerious adverse events:NRMalignancies:Skin?cancer (basal cell?or squamous cell)?(n): D1: 7D2: 2D3: 23Overall: 32Respiratory cancer: D1: 9D2: 2D3: 25Overall: 36GI cancer: D1: 8D2: 4D3: 19Overall: 31Reproductive cancerD1: 25D2: 10D3: 40Overall: 75Urogenital cancer: D1: 8D2: 1D3: 6Overall: 15Hematopoeietic cancer: D1: 8D2: 4D3: 16Overall: 28Other cancer: D1: 5D2: 3D3: 14Overall: 22Respiratory events:NROther infections:NRGI:NROther:Other AEs?1 (n): RR of first primary cancer compared to biologic naive patients: D1: 0.78 (0.61 to 1.00) D2: 1.09 (0.91 to 1.30)D3: 1.32 (0.87 to 1.98)Overall: 1.00 (0.86 to 1.15, P=0.034)Any other AEs: RR of first primary cancer in RA patients first starting anti-TNF therapy versus starting biologic-naive patients: 1.00 (0.87 to 1.17)RR of first primary cancer in RA patients first starting anti-TNF therapy versus starting MTX therapy: 0.99 (0.79 to 1.24)RR of first primary cancer in RA pts first starting anti-TNF therapy versus starting DMARD combination therapy: 0.97 (0.69 to 1.36)Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Baecklund et al2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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 EN.CITE.DATA 5Country, Setting:Sweden, inpatient Funding:Swedish Rheumatism Society; Lions Cancer Research Foundation of Uppsala; AFA InsuranceSwedish Cancer SocietyResearch Objective:To investigate which RA pts are at highest risk of lymphoma, and whether antirheumatic txt is hazardous or protectiveStudy Design:CohortOverall N:756Study Duration: 1964 to 1995Inclusion Criteria:Age: ≥ 16 RA and lymphomaAll pts receiving inpatient care in Sweden discharged with a diagnosis of RA (ICD)Randomly selected as potential controls 3 individuals from underlying RA cohortFrom potential controls, we included first of 3 whose medical record could be identified and who fulfilled ACR criteria for RAExclusion Criteria:NRInterventions, dose:NRMTXSSZOther?: steroidsN:756378 cases378 controlsMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRisk of developing lymphoma is increased in subset of RA with severe disease.(Cases vs. controls)Inflammatory activity Low inflammatory activity: 94 (25%) vs. 278 (74%) OR 1 (referent) Medium: 196 (52%) vs. 94 (25%) OR 7.7 (95% CI,4.8-12.3) High: 86 (23%) vs. 4 (1%) OR 71.3 (95% CI,24.1-211.4) Functional class I 34 (9) vs. 138 (37) OR 1 (referent) II 185 (49) vs. 204 (54) OR 3.9 (95% CI,2.4-6.3) III 105 (28) vs. 31 (8) OR 13.8 (95% CI,7.2-26.2) IV 52 (14) vs. 3 (1) OR 67.5 (95% CI,18.9-239.8) DMARD OR 0.9 (95% CI,0.6-1.2)MTX crude OR 0.8 (95% CI,0.4-1.4); adjusted OR 0.7 (95% CI,0.3-1.6)SSZ; crude OR 0.6 (95% CI,0.4-1.0); adjusted OR 0.6 (95% CI,0.3-1.1)Oral steroids (adjusted OR 0.6 [95% CI,0.4-0.9]) and intraarticular steroids (adjusted OR 0.4 [95% CI,0.2-0.6]), calculated with adjustment for disease activity and DMARD useNAOverall Attrition Rate, %:NAITT Analysis:NA: Case contol studyQuality Rating:GoodStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Txt CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Bathon et al., 2000PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg0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ADDIN EN.CITE.DATA 6; Genovese et al., 2002 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE.DATA 7;Kosinski et al., 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY5
NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjg8L3N0eWxl
PjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj42OTQ8L3JlYy1udW1iZXI+PGZvcmVp
Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1Znh0dzJldDZ0dnJmd2UwenBzNTJwcmZ6OWF4
OXRhZnhwZDUiPjY5NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFs
IEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S29z
aW5za2ksIE0uPC9hdXRob3I+PGF1dGhvcj5LdWphd3NraSwgUy4gQy48L2F1dGhvcj48YXV0aG9y
Pk1hcnRpbiwgUi48L2F1dGhvcj48YXV0aG9yPldhbmtlLCBMLiBBLjwvYXV0aG9yPjxhdXRob3I+
QnVhdHRpLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+V2FyZSwgSi4gRS4sIEpyLjwvYXV0aG9yPjxh
dXRob3I+UGVyZmV0dG8sIEUuIE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh
dXRoLWFkZHJlc3M+UXVhbGl0eU1ldHJpYywgSW5jLCBMaW5jb2xuLCBSSSAwMjg2NSwgVVNBLiBt
a29zaW5za2lAcW1ldHJpYy5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5IZWFsdGgt
cmVsYXRlZCBxdWFsaXR5IG9mIGxpZmUgaW4gZWFybHkgcmhldW1hdG9pZCBhcnRocml0aXM6IGlt
cGFjdCBvZiBkaXNlYXNlIGFuZCB0cmVhdG1lbnQgcmVzcG9uc2U8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+QW0gSiBNYW5hZyBDYXJlPC9zZWNvbmRhcnktdGl0bGU+PHNob3J0LXRpdGxlPkhlYWx0
aC1yZWxhdGVkIHF1YWxpdHkgb2YgbGlmZSBpbiBlYXJseSByaGV1bWF0b2lkIGFydGhyaXRpczog
aW1wYWN0IG9mIGRpc2Vhc2UgYW5kIHRyZWF0bWVudCByZXNwb25zZTwvc2hvcnQtdGl0bGU+PC90
aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW1lcmljYW4gSm91cm5hbCBvZiBNYW5hZ2Vk
IENhcmU8L2Z1bGwtdGl0bGU+PGFiYnItMT5BbS4gSi4gTWFuYWcuIENhcmU8L2FiYnItMT48YWJi
ci0yPkFtIEogTWFuYWcgQ2FyZTwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFnZXM+MjMxLTQwPC9w
YWdlcz48dm9sdW1lPjg8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48a2V5d29yZHM+PGtleXdv
cmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbnRpcmhl
dW1hdGljIEFnZW50cy8gdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRp
cywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5LyBwc3ljaG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk
PkNvbXBhcmF0aXZlIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPkNvc3Qgb2YgSWxsbmVzczwva2V5
d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxr
ZXl3b3JkPkltbXVub2dsb2J1bGluIEcvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29y
ZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvdHJleGF0ZS8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBhaW4gTWVhc3Vy
ZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+UXVlc3Rpb25uYWlyZXM8L2tleXdvcmQ+PGtleXdvcmQ+
UmVjZXB0b3JzLCBUdW1vciBOZWNyb3NpcyBGYWN0b3IvIHRoZXJhcGV1dGljIHVzZTwva2V5d29y
ZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0LCBOb24tVS5TLiBHb3YmYXBvczt0PC9rZXl3b3Jk
PjxrZXl3b3JkPlNpY2tuZXNzIEltcGFjdCBQcm9maWxlPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0
bWVudCBPdXRjb21lPC9rZXl3b3JkPjxrZXl3b3JkPlVuaXRlZCBTdGF0ZXM8L2tleXdvcmQ+PC9r
ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1hcjwvZGF0
ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxhY2Nlc3Npb24tbnVtPjExOTE1OTczPC9hY2Nlc3Npb24t
bnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+
PGN1c3RvbTM+SFJDVDwvY3VzdG9tMz48Y3VzdG9tND4yPC9jdXN0b200PjxjdXN0b203PkxNIDgt
MTQgKFNXKSBnb2VzIHdpdGggODQ8L2N1c3RvbTc+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY5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=
ADDIN EN.CITE.DATA 8; Genovese et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE.DATA 9;ERA Country, Setting:US, clinicsFunding:ImmunexResearch Objective:To compare ETA and MTX in pts with early RAStudy Design:RCTOverall N:632 (468 extension)Study Duration: 12 mos (1 year open label extension; 2 more years, total of 5 yrs)Inclusion Criteria:Age: 18+Diagnosed with RA according to ACR criteriaDuration of condition: < 3 yrsPositive serum test for RF or at least 3 bone erosions evident on radiographs of hands, wrists, or feetAt least 10 swollen joints and at least 12 tender or painful jointsESR ≥ 28 mm per hourSerum CRP concentration of at least 2.0 mg per deciliterMorning stiffness that lasted at least 45 minutesStable doses of NSAIDS and PRE allowedExclusion Criteria:Prior txt with MTXNo other important concurrent illnessesInterventions, dose:D1: MTX (19 mg/wk)D2: ETA (10 mg twice wkly)D3: ETA (25 mg twice wkly)N:D1: 49D2: 50D3: 51Mean age, yrs:D1: 49D2: 50D3: 51Sex, % female:D1: 75D2: 75D3: 74Race, % white:D1: 88D2: 84D3: 86Mean disease duration, yrs:D1: 12 mosD2: 11 mosD3: 12 mosTJC, mean:D1: 30 (16.1)D2: 31 (15.5)D3: 31 (15.8)SJC, mean:D1: 24 (11.9)D2: 24 (11.7)D3: 24 (11.9)DMARD use, %:NRCorticosteroid use, %D1: 41D2: 42D3: 39MTX naive, %:D1: 100D2: 100D3: 100Txt resistant, %:NRPts with Early RA (≤3 yrs):D1: 100D2: 100D3: 100Baseline DAS, mean:NRFirst 12 weeksMean changes in SF-36, HAQ, and ASHI significantly better in with ETA vs. MTX (P < 0.0001)16 to 52 weeksNo significant difference in SF-36, HAQ, and ASHI scores between groupsAt 6 monthsSignificantly more pts on ETA (25 mg) than on MTX achieved ACR50 and ACR70 responses (data NR, P < 0.05)At 12 monthsACR 20 response rates, %: D1: 65 D3: 72 (P = 0.16)Mean increase in Sharp score D1: 1.00 D3: 1.59 (P = 0.11) Erosion score changeD1: 1.03 D3: 0.47 (P = 0.002) Despite improvement, QoL measures remained below general population (P < 0.0001); at start QoL measures were significantly below that of general population (P < 0.0001)24 month open-label extension: ACR20,%D1: 59 D3: 72 (P = 0.005);ACR50, % D1: 49 D3: 42ACR 70,% D1: 29 D2: 24 HAQ improvement of at least 0.5 units, %:D1: 55 D2: 37 (P < 0.001)Total modified Sharp score changeD1: 1.3 D3: 3.2 (P = 0.001) Erosion score changeD1: 0.7 D3: 1.9 (P = 0.001) At year 2SAEs:20.6Cardiovascular Events:1.8 MIMalignancies: 3% overall Total events: 18 Breast: 3Prostate: 3Colon: 3Lung: 12Malignant melanoma: l2 Leukemia: 1Kidney: 1Hodgkins: 1 Adenocarcinoma: 1 URTI:Pnuemonia 2Overall SAE rate of 0.093 events per pt-year comparable to rate observed in first year of efficacy study, events per pt-year MTX: 0.109 ETA: 0.091 Overall Attrition Rate, %:19ITT Analysis:YesQuality Rating: FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Bergstrom, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjk2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjk2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ADDIN EN.CITE.DATA 10Country, Setting:US, 5 practicesFunding:NRResearch Objective:To assess if pts who were treated with TNF antagonists have a higher risk of developing coccidioido-mycosisStudy Design:Retrospective cohort studyOverall N:985Study Duration: 3 yrsInclusion Criteria:Pts with RA, reactive arthritis, PsA, JRAOther meds were allowedExclusion Criteria:NAInterventions, dose:D1: INF D2: Other Anti-TNF alphaD3: controlN:D1: 7D2: 4D3: 974Mean age, yrs:D1: 64.8D2: 64D3: 57.8Sex, % female:D1: 71D2: 75D3: 77Race, % white:D1: 86D2: 75D3: NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 100D2: 50D3: 50Pts treated with INF are at higher risk for developing symptomatic coccidioidomycosis7 of 247 pts receiving INF and 4 of 738 pts receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54-17.71; P < 0.01)NAOverall Attrition Rate, %:NAITT Analysis:NA: Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableBernatsky et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3045</RecNum><DisplayText><style face="superscript">11</style></DisplayText><record><rec-number>3045</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3045</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Bernatsky, S.</author><author>Hudson, M.</author><author>Suissa, S.</author></authors></contributors><auth-address>Division of Clinical Epidemiology, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada. sasha.bernatsky@mail.mcgill.ca</auth-address><titles><title>Anti-rheumatic drug use and risk of serious infections in rheumatoid arthritis</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology</full-title><abbr-1>Rheumatology (Oxford).</abbr-1><abbr-2>Rheumatology (Oxford)</abbr-2></periodical><pages>1157-60</pages><volume>46</volume><number>7</number><keywords><keyword>Aged</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/microbiology</keyword><keyword>Bacterial Infections/ complications</keyword><keyword>Case-Control Studies</keyword><keyword>Cyclophosphamide/therapeutic use</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Glucocorticoids/therapeutic use</keyword><keyword>Humans</keyword><keyword>Logistic Models</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Tumor Necrosis Factor-alpha/antagonists & inhibitors</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1462-0324 (Print)</isbn><accession-num>17478469</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>11Country and settingCanada (Province of Quebec), phDacy and hospital (discharge) databasesSource of fundingNot reportedResearch objectiveAssess risk of severe infections associated with use of traditional DMARDs and glucocorticoid agentsStudy designCohort Study – Nested AnalysisOverall N23,733 (RA cohort) For each case of hospitalization for infection that occurred in cohort, they randomly selected 10 controlsDuration of studyJanuary 1, 1980 and December 31, 2003Quality rating FairInclusion CriteriaRegistered in phDacy claims database of Re?gie d’assurance maladie du Que?bec (RAMQ) and Ministry of Health’s Maintenance et exploitation des donne?es pour l’e?tude de la cliente` le hospitalie`re (MEDECHO). Diagnosis of RA using physician billing codes (ICD-9 code 714) Were dispensed at least 1 DMARD after January 1, 1980.Exclusion CriteriaRecord of a hospitalization for infection at any time prior to cohort entry date.Interventions, DoseD1: MTX: Dosage NRLEF: Dosage NRSSZ: Dosage NRHydroxychlorquine: Dosage NRETN: Dosage NRIFX: Dosage NRGlucocorticoids: Dosage NRD2: MTX: Dosage NRLEF: Dosage NRSSZ: Dosage NRHydroxychlorquine: Dosage NRETN: Dosage NRIFX: Dosage NRGlucocorticoids: Dosage NRNumber in groupOverall: 23,733Mean age (years)Overall: 61.7Sex, % femaleOverall: 69.9Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NRTreatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %Overall: Drug exposures at cohort entry for RA subjects (n/%): MTX 7044 (29.7)Anti-malarial agent: 9415 (39.7)Anti-TNF agents: 261 (1.1)All other DMARDs: 6180 (26.0).MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Avera age at cohort entryOverall: 61.7 yrs% FemaleOverall: 69.9. Average followup:Overall: 6.3 year follow upAfter average of 6.3 yrs followupMean age, Cases: 71.0 yrsMean age, Controls: 71.5 yrs % Male, Overall: 65.5 Average yearly number of physician visits: Cases: 5.5Controls: 5.1Events occurred at a mean time of 5.5 (S.D. 4.7) yrs after cohort entry.ACR NRHAQ, NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallOverall adverse events reported, n: Overall: 1991 from entire RA cohortSerious adverse eventsNRMalignanciesNRRespiratory eventsPneumonia, n: Overall: 1,315Other infectionsNRGINROtherAny other AEs: Entire RA cohort generated 156,520 person-yrs of follow-up time, for an average follow-up of 6.3 yrs. During this time, 1970 cases of serious infection occurred, for an incidence rate of 129.1 events per 10 000 person-years. Of these infections, most common event was pneumonia with 1315 cases, for an incidence rate of 83.4 per 10 000 person-years. There were only 21 cases of TB recorded. Risk for all infections requiring hospitalization appeared to be most elevated with current exposures to systemic glucocorticoid agents (RR: 2.6, 95% CI: 2.3 - 2.9)Similar effects were seen with pneumonia as outcome (RR 2.1 (2.4-3.1). For MTX, there was a trend towards increased risk for all infections (RR 1.10 (0.98-1.2), and a moderate increased risk for pneumonia (RR: 1.2, 95% CI: 1.0 - 1.3). For HCQ (and chloroquine) RR 1.1 (0.94-1.2)Anti-TNF 1.9 (0.7-5.3); and for other DMARDs 0.9 (0.8-1.05). Limiting sample to subjects aged 65 yrs and older, estimates were similar, but with suggestion of slightly more pronounced effects, noted particularly for MTX (adjusted RR: 1.3; 95% CI: 1.1-1.5).Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Boers et al., 1997PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx
MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjEyPC9zdHls
ZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTEyPC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJmejlh
eDl0YWZ4cGQ1Ij4xMTI8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJv
ZXJzLCBNLjwvYXV0aG9yPjxhdXRob3I+VmVyaG9ldmVuLCBBLiBDLjwvYXV0aG9yPjxhdXRob3I+
TWFya3Vzc2UsIEguIE0uPC9hdXRob3I+PGF1dGhvcj52YW4gZGUgTGFhciwgTS4gQS48L2F1dGhv
cj48YXV0aG9yPldlc3Rob3ZlbnMsIFIuPC9hdXRob3I+PGF1dGhvcj52YW4gRGVuZGVyZW4sIEou
IEMuPC9hdXRob3I+PGF1dGhvcj52YW4gWmViZW4sIEQuPC9hdXRob3I+PGF1dGhvcj5EaWprbWFu
cywgQi4gQS48L2F1dGhvcj48YXV0aG9yPlBlZXRlcnMsIEEuIEouPC9hdXRob3I+PGF1dGhvcj5K
YWNvYnMsIFAuPC9hdXRob3I+PGF1dGhvcj52YW4gZGVuIEJyaW5rLCBILiBSLjwvYXV0aG9yPjxh
dXRob3I+U2Nob3V0ZW4sIEguIEouPC9hdXRob3I+PGF1dGhvcj52YW4gZGVyIEhlaWpkZSwgRC4g
TS48L2F1dGhvcj48YXV0aG9yPkJvb25lbiwgQS48L2F1dGhvcj48YXV0aG9yPnZhbiBkZXIgTGlu
ZGVuLCBTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVu
aXZlcnNpdHkgSG9zcGl0YWwgTWFhc3RyaWNodCwgVGhlIE5ldGhlcmxhbmRzLjwvYXV0aC1hZGRy
ZXNzPjx0aXRsZXM+PHRpdGxlPlJhbmRvbWlzZWQgY29tcGFyaXNvbiBvZiBjb21iaW5lZCBzdGVw
LWRvd24gcHJlZG5pc29sb25lLCBtZXRob3RyZXhhdGUgYW5kIHN1bHBoYXNhbGF6aW5lIHdpdGgg
c3VscGhhc2FsYXppbmUgYWxvbmUgaW4gZWFybHkgcmhldW1hdG9pZCBhcnRocml0aXM8L3RpdGxl
PjxzZWNvbmRhcnktdGl0bGU+TGFuY2V0PC9zZWNvbmRhcnktdGl0bGU+PHNob3J0LXRpdGxlPlJh
bmRvbWlzZWQgY29tcGFyaXNvbiBvZiBjb21iaW5lZCBzdGVwLWRvd24gcHJlZG5pc29sb25lLCBt
ZXRob3RyZXhhdGUgYW5kIHN1bHBoYXNhbGF6aW5lIHdpdGggc3VscGhhc2FsYXppbmUgYWxvbmUg
aW4gZWFybHkgcmhldW1hdG9pZCBhcnRocml0aXM8L3Nob3J0LXRpdGxlPjwvdGl0bGVzPjxwZXJp
b2RpY2FsPjxmdWxsLXRpdGxlPkxhbmNldDwvZnVsbC10aXRsZT48YWJici0xPkxhbmNldDwvYWJi
ci0xPjxhYmJyLTI+TGFuY2V0PC9hYmJyLTI+PC9wZXJpb2RpY2FsPjxwYWdlcz4zMDktMTg8L3Bh
Z2VzPjx2b2x1bWU+MzUwPC92b2x1bWU+PG51bWJlcj45MDc0PC9udW1iZXI+PGtleXdvcmRzPjxr
ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50cy8g
YWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5
d29yZD5BbnRpcmhldW1hdGljIEFnZW50cy8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2Fk
dmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMsIFJoZXVtYXRvaWQvIGRy
dWcgdGhlcmFweS9yYWRpb2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVk
eTwva2V5d29yZD48a2V5d29yZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPkRydWcgVGhlcmFweSwgQ29tYmluYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RmVt
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3
b3JkPjxrZXl3b3JkPk1ldGhvdHJleGF0ZS8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL2Fk
dmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5
d29yZD5QcmVkbmlzb2xvbmUvIGFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNlIGVm
ZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydCwgTm9uLVUuUy4gR292JmFw
b3M7dDwva2V5d29yZD48a2V5d29yZD5TdWxmYXNhbGF6aW5lLyBhZG1pbmlzdHJhdGlvbiAmYW1w
OyBkb3NhZ2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRj
b21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTc8L3llYXI+PHB1Yi1kYXRl
cz48ZGF0ZT5BdWcgMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxhY2Nlc3Npb24tbnVtPjky
NTE2MzQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1
c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9tMz5IUkNUPC9jdXN0b20zPjxjdXN0b200PjEsMiwzPC9j
dXN0b200PjxjdXN0b203PlBUIDktMjYgKEtEIDgtMTYpIGdvZXMgd2l0aCA3MzY8L2N1c3RvbTc+
PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA 12; Landewe et al., 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcz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ADDIN EN.CITE.DATA 13;COBRA studyCountry, Setting:Netherlands and Belgium, multicenterFunding:NetherlandResearch Objective:Comparing efficacy and radiographic outcomes of combination of SSZ, MTX and PNL with SSZ aloneStudy Design:RCTOverall N:155 (148)Study Duration: 56 wks; (5 yr followup)Inclusion Criteria:Age: 18 to 69Diagnosed with RA according to ACR criteriaDuration of condition < 2 yrsNSAID txt at least 3 mos, 6 or more active inflamed joints AND presence of 2 or more (9 or more tender joints, morning stiffness 45 min or more, EST of 28 or more in first hourExclusion Criteria:Pregnant or lactating: adequate contraceptionPrior txt with: DMARDS except HCQ or steroidsPast TBImpaired renal or hepatic system serious comorbidity surgery in past 3 mosUnable to comply with protocolAllergy to study medAlcohol or substance abuseInterventions, dose:D1: Combined txt (SSZ, MTX, PNL)D2: SSZ OnlySSZ: 2g/dMTX: 7.5 mg/wk, weaned after 40 wksPNL: 60 mg/d wk 140 mg/d wk 225 mg/d wk 320 mg/d wk 415 mg/d wk 510 mg/d wk 6then 7.5 mg/d until wk 28 then weaned offN:D1: 76D2: 79Mean age, yrs:NRSex, % female:D1: 66%D2: 52%Race, % white:NRMean disease duration, yrs:D1: 4 mosD2: 4 mosTJC, mean:NRSJC, mean:NRAntimalarial use (%):D1: 21D2: 24Corticosteroid use, %NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRErosions on hand or foot xrays, %:D1: 74D2: 79At week 28Mean pooled indexD1: - 1.4 (95% CI, 1.2-1.6)D2: - 0.8 (95% CI, 0.6-1.0) (P < 0.0001)ACR20, %:D1: 72D2: 49 (P = 0.006)ACR50, %:D1: 49D2: 27 (P = 0.007)DAS median change:D1: -2.1 (SD 1.2)D2: -1.3 (SD 1.2) (P < 0.0001)HAQ mean change:D1: -1.1 (SD 0.8)D2: -0.6 (SD 0.6) (P < 0.0001)Sharp mean change: D1: 1 D2: 4 (P < 0.001)At week 56Mean pooled index:D1: 1.1 (SD 0.8)D2: 0.9 (SD 0.8) (P = 0.20)DAS median change:D1: 1.4 (SD 1.2)D2: 1.3 (SD 1.4) (P = 0.78)HAQ mean change:D1: 0.8 (SD 0.8)D2: 0.6 (SD 0.7) (P < 0.06)Sharp mean change: D1: 2 D2: 6 (P < 0.004)At week 80Sharp mean change:D1: 4 D2: 12 (P < 0.01)Five yr follow up Sharp score mean change:D1: 5.6 (95% CI, 4.3, 7.1)(P = 0.001)D2: 8.6 (95%CI, 6.2-11) (P = 0.001)Time averaged DAS28, points/yr: D1: -0.07D2: -0.17 Overall: D1: 72.3D2: 62.0SAEs:D1: 2.6D2: 7.6Infections:D1: 15.8D2: 7.6Cardiovascular Events:D1: 7.9D2: 5.1Hepatotoxicity:D1: 2.6D2: 0Overall Attrition Rate, %:3.2ITT Analysis:YesQuality Rating:Good Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableBrassard et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2434</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>2434</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2434</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Brassard, P.</author><author>Lowe, A. M.</author><author>Bernatsky, S.</author><author>Kezouh, A.</author><author>Suissa, S.</author></authors></contributors><auth-address>Division of Clinical Epidemiology, McGill University Health Center, Montreal, Quebec, Canada. paul.brassard@clinepi.mcgill.ca</auth-address><titles><title>Rheumatoid arthritis, its treatments, and the risk of tuberculosis in Quebec, Canada</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>300-4</pages><volume>61</volume><number>3</number><keywords><keyword>Aged</keyword><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/immunology</keyword><keyword>Canada/epidemiology</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunocompromised Host</keyword><keyword>Immunosuppressive Agents/ adverse effects</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword><keyword>Tuberculosis/ epidemiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>19248128</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>14Country and settingCanada, hospital (inpatient) or outpatient settingSource of fundingMentions support by Canadian career award and institutesNot reportedResearch objectiveDetermine risk of TB and assess whether this risk is associated with exposure to DMARDsStudy designCohort – Case / ControlOverall NCohort consisted of 24,282 patients with RA; 70.1% were women. mean (SD) subject age at time of cohort entry was 61.7 (14.6) years.Duration of study1980-2003 for cohort and 1992-2003 for TB incidence ratesQuality rating Fair: Confounding and potential bias in population characteristics (older population). Use of case definitions to validate diagnosis of TB and RA conditions.Inclusion CriteriaPatients registered in provincial phDacy claims database, which covers residents age ≤ 65 years, those who receive social assistance, and those who do not have private drug insurance through their employer. ≥ 1 occurrence of diagnosis of RA using physician billing code for RA (ICD-9 code 714) during inpatient or outpatient visit. Cohort subjects further restricted to those who were dispensed ≥ 1 prescription for DMARD therapy. Cohort entry was defined by date of first DMARD prescription after 1 year of eligibility in provincial health insurance system. TB as a primary hospitalization diagnosis (ICD-9 codes 010-018) or if TB was part of a medical claim.Had at least 2 classes of usual first-line anti-TB medications prescribed (isoniazid, rifampin, pyrazinamide, or ethambutol)Treatment lasted at least 6 months.Exclusion CriteriaTB cases that occurred before date of cohort entry were excluded from cohort.Interventions, DoseD1: MTX: dosage and frequency NRLEF: dosage and frequency NROther: Corticosteroids: dosage and frequency NRAll DMARDs included MTX, HCQ, chloroquine, SSZ, azathioprine, LEF, cyclophosphamide, cyclosporine, gold compounds, minocycline, or penicillamineD2: MTXDosage NRLEF: dosage and frequency NROther: Corticosteroids: dosage and frequency NRNumber in groupD1: 50D2: 1500Overall: 1550Mean age (years)D1: 65D2: 67P =.06Sex, % femaleD1: 50D2: 70P = 0.002Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 18D2: 8.1P = 0.03DMARD use, %D1: 72D2: 45.6P = 0.0004MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %Other comorbid clinical conditions and risk factors:D1: 2.0D2: 1.9Overall: : P = ?0.62Diabetes:D1: 12.0D2: 10.1P = 0.67Use of COX-2 inhibitors:D1: 8.0D2: 5.7P = 0.53Use of NSAIDS:D1: 56.0D2: 49.9P = 0.39ACR NRHAQ, NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROverallNR Overall adverse events reported, n: NRSerious adverse eventsNR MalignanciesNRRespiratory eventsNROther infectionsNRGINR OtherAny other AEs: RR of TB associated with any nonbiologic DMARD exposure in year prior to index date is 3.0 (95% CI 1.6-5.8). Current use of corticosteroids was also significantly associated with occurrence of TB (adjusted RR 2.4, 95% CI 1.1-5.4). There were 50 cases of TB identified during followup period. overall sex and age-standardized rate of TB in RA cohort for period 1992-2003 was 45.8 cases per 100,000 person-years of followup compared with 4.2 cases per 100,000 person-years in general population of Quebec (SIR 10.9, 95% CI 7.9-15.0). Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableBrassard, P., et al.; 2006; Antirheumatic Drugs and Risk of TB ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3151</RecNum><DisplayText><style face="superscript">15</style></DisplayText><record><rec-number>3151</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3151</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Brassard, P.</author><author>Kezouh, A.</author><author>Suissa, S.</author></authors></contributors><auth-address>Department of Medicine, McGill University, Montreal, QC, Canada. paul.brassard@mcgill.ca</auth-address><titles><title>Antirheumatic drugs and the risk of tuberculosis</title><secondary-title>Clin Infect Dis</secondary-title></titles><periodical><full-title>Clinical Infectious Diseases</full-title><abbr-1>Clin. Infect. Dis.</abbr-1><abbr-2>Clin Infect Dis</abbr-2></periodical><pages>717-22</pages><volume>43</volume><number>6</number><keywords><keyword>Adrenal Cortex Hormones/therapeutic use</keyword><keyword>Adult</keyword><keyword>Antibodies, Monoclonal/ adverse effects/therapeutic use</keyword><keyword>Antirheumatic Agents/ adverse effects/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/drug therapy</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/ adverse effects/therapeutic use</keyword><keyword>Interleukin 1 Receptor Antagonist Protein</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Receptors, Tumor Necrosis Factor/therapeutic use</keyword><keyword>Risk Factors</keyword><keyword>Sialoglycoproteins/ adverse effects/therapeutic use</keyword><keyword>Tuberculosis/ epidemiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep 15</date></pub-dates></dates><isbn>1537-6591 (Electronic)</isbn><accession-num>16912945</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>15Country and settingCanada; Medical and phDaceutical claims data from PhDetrics Patient-Centric Database were reviewed.Source of fundingNot reportedResearch objectiveQuantify rate of Mycobacterium TB and assess whether independent use of DMARDs is associated with risk of developing TBStudy designCohort Study with Nested Case / ControlOverall Nn:?112,300 patients from which a nested case-control was selected (386 cases, 38,600 controls)Duration of studySeptember 1998 - December 31, 2003Quality rating FairInclusion CriteriaPatients aged 18 years or older with 1 or more occurrence of a diagnosis of RA Dispensed 1 or more prescriptions for any anti-RA drug during study period were inlcuded in cohort. Cases were those patients who were diagnosed with TB during study period. For each case, 100 controls were matched on date of cohort entry and confirmation that they were at risk for TB at time case occurred.Exclusion CriteriaPatients who had TB prior to cohort entry were excluded from being cases.Interventions, DoseD1: MTX: dosage and frequency NRLEF: dosage and frequency NRSSZ: dosage and frequency NRHCQ: dosage and frequency NRETN: dosage and frequency NRIFX: dosage and frequency NRANK: dosage and frequency NROther: auronofin, cyclosporin, penacillamine, and cyclophosphamide: dosage and frequency NRD2: MTX: dosage and frequency NRLEF: dosage and frequency NRSSZ: dosage and frequency NRHCQ: dosage and frequency NRETN: dosage and frequency NRIFX: dosage and frequency NRANK: dosage and frequency NROther: auronofin, cyclosporin, penacillamine, and cyclophosphamide: dosage and frequency NRNumber in groupD1: 386D2: 38,600Mean age (years)D1: 54D2: 56P =.01Sex, % femaleD1: 77.2D2: 73.7P =.12Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 46.6D2: 31.2P =.001DMARD use, %D1: biologic DMARDs 17.4%; Traditional DMARDs 50.8%D2: biologic DMARDs 11.8% (P = ?.008); Traditional DMARDs 44.1% (P = ?.008)MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Diabetes 19.9%; Other comorbid condition (silicosis, chronic renal failure/hemodialysis, solid organ transplantation, and carcinoma) 3.8%; use of corticosteroids 46.6%D2: Diabetes 15% (P = ?.007)Other comorbid condition (silicosis, chronic renal failure/hemodialysis, solid organ transplantation, and carcinoma) 1.9% (P = ?.007); Use of corticosteroids 31.2% (P = ?0.001)ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference NROverallOverall attrition/withdrawal, n: NAOverall adverse events reported, n:D1: 386D2: 0Serious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNRAny other AEs: Crude and Adjusted rate ratio (RR) of developing TB, according to antirheumatoid arthritis medications use (cases:?386, controls:?38,600)Use of biologic DMARDs, crude RR:?1.5, adjusted RR:?1.5 (1.1 - 1.9); Infliximib, crude RR:?1.7, adjusted RR:?1.6 (1.0 - 2.6); ETN, crude RR:?1.4, adjusted RR:?1.2 (0.9 - 1.8); ANK, crude RR:?1.5, adjusted RR:?1.3 (0.8 - 2.1); Use of traditional DMARDs, crude RR:?1.3, adjusted RR 1.2 (1.0 - 1.5); study inlcudes a subanalysis of corticosteroid use among cases; crude and adjusted rate ratio (RR) of developing tuberulosis associated with anti-rheumatoid arthritis medication use stratified by current use of corticosteroids (noncurrent users among cases:?313, current users among cases:?73); For noncurrent users on any biologic DMARDs, crude RR:?1.8, adjusted RR:?1.7 (1.3 - 2.3); noncurrent users on IFX, crude RR:?2.0, adjusted RR:?1.8 (1.1 - 3.0); noncurrent users on ETN, crude RR:?1.5, adjusted RR:?1.3 (0.9 - 2.0); noncurrent users on ANK, crude RR:?1.7, adjusted RR:?1.7 (1.1 - 2.8)For noncurrent users on traditional DMARDs, crude RR:?1.5, adjusted RR:?1.4 (1.1 - 1.8)For current users also on any biologic DMARDs, crude RR:?0.7, adjusted RR:?0.7 (0.3 - 1.3); for current users also on IFX, crude RR:?0.9, adjusted RR:?1.1 (0.3 - 3.6), for current users also on ETN, crude RR:?0.9, adjusted RR:?0.9 (0.4 - 2.0), for current users also on ANK rates were not estimable; for current users on traditional DMARDs crude RR:?0.6, adjusted RR:?0.6 (0.4 - 1.0).Study Characteristics 140: Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Breedveld et al. 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE0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ADDIN EN.CITE.DATA 17, Maini et al. 2004 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc5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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc5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==
ADDIN EN.CITE.DATA 18 and Smolen et al. 2005 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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ADDIN EN.CITE.DATA 19Country, Setting:MultinationalMulticenterFunding:CentocorResearch Objective:To examine the impact of INF + MTX on the progression of structural damage in pts with early RA. Subanalyses of ATTRACT, early RA and in non-responders.Study Design:RCTOverall N?=?428 and 61 of these had available radiographsStudy Duration: 102 wksInclusion Criteria:Previous use of DMARDs: current MTX6 or more swollen and tender joints ESR ≥ 28 mm/hour; CRP ≥ 2mg/dlExclusion Criteria:NRInterventions (dose):D1: AllD2: Early RAD3: Responders placebo/INFD4: Nonresponders placebo/INFMTXINF: 3 mg/kg every 4 or 8 wks and 10 mg/kg every 4 or 8 wksPlaceboN?=?D1: 428D2: 82D3: 15/176D4: 73/164Mean age (yrs):D1: 54D2: 50D3: 49.7/50.6D4: 51.2/55.2Sex (% female):D1: 78D2: 79D3: 67/77D4: 82/77Race (% white):NRMean disease duration (yrs):D1: 8.4D2: 1.7D3: 9.9/9.5D4: 10.8/11.2TJC (mean):D1: 31D2: 30D3: 32.5/32.5D4: 30.4/32.5SJC (mean):D1: 20D2: 20D3: 21.2/22.6D4: 21.5/22.7DMARD use (%):NRCorticosteroid use (%)NRMTX na?ve (%):NRTxt resistant (%):NRPatients with Early RA (≤3 yrs):NRBaseline DAS (mean):NRErosion score:D1: 23.5D2: 8.9JSN score: D1: 28.3D2: 10.0Early RA at 102 wks-Erosion scores meanPlacebo + MTX 12.21 (13.32)vs. INF + MTX -0.49 (3.89) P?<?0.001JSNPlacebo + MTX 12.82 (15.73) vs. INF + MTX -0.05 (4.30) P?<?0.001Responders vs. non-respondersRadiographic progression was much greater in pts receiving MTX + placebo than in pts receiving INF + MTX, (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX + placebo-treated group, vs. 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the INF + MTX-treated group (P?<?0.01)HAQ median change MTX 0.1 vs. all INF 0.4 P?≤?0.006 SF-36 median change MTX 2.8 vs. all INF 6.4 P?≤?0.011SAEs:D1: 33D2: 33D3: 23D4: 29/32Serious Infections:D1: 13D2: 11D3: 13D4: 13/10Malignancies:D1: 1D2: 1D3: 0D4: 3/6Overall Attrition Rate (%):428 randomised, 259 entered 2nd yr and 216 completed.ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Breedveld et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE0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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE0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=
ADDIN EN.CITE.DATA 16PREMIER studyCountry, Setting:Multinational (Europe, North America, Australia), multicenter (133) Funding:Abbott LaboratoriesResearch Objective:To compare efficacy and safety of ADA + MTX vs. MTX or ADA in pts with early, aggressive RA (RA) who had not previously received MTX txtStudy Design:RCTOverall N:799Study Duration: 2 yrsInclusion Criteria:Age: 18+Diagnosed with RA according to ACR criteriaDuration of condition: 3 yrs or lessMTX naive pts > 8 swollen joints, > 10 tender joints, and an erythrocyte sedimentation rate of > 28Folic acid only other med allowedExclusion Criteria:Prior txt with: MTX, cyclophosphamide, cyclosporine, azathioprineInterventions, dose:D1: MTX (20 mg/wk)D2: ADA (40 mg/biwkly)D3: ADA (40 mg/biwkly) + MTX (20 mg/wk)N:D1: 257D2: 274D3: 268Mean age, yrs:D1: 52D2: 52.1D3: 51.9Sex, % female:D1: 73.9D2: 77.4D3: 72Race, % white:NRMean disease duration, yrs:D1: .8 D2: .7D3: .7TJC, mean:D1: 32.3 D2: 31.8D3: 30.7SJC, mean:D1: 22.1 D2: 21.8D3: 21.1DMARD use, %:NRCorticosteroid use, %D1: 35.4 D2: 36.5D3: 35.8MTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs): NRBaseline DAS, mean:D1: 6.3 D2: 6.4D3: 6.3HAQ:D1: 1.5 D2: 1.6D3: 1.5Erosion score: D1: 13.6 D2: 11.3D3: 11.0At 6 monthsRadiographic progression; change in Sharp scores:D1: 3.5D2: 2.1 (P < 0.001) At 1 yr Radiographic progression; change in Sharp scores:D1: 5.7D2: 3.0 (P < 0.001) HAQ DI improvement, mean units +/- sd: D1: -0.8 +/- 0.7 D2: -0.8 +/- 0.6D3: -1.1 +/- 0.6 D2 vs. D1, P = NR D3 vs. D1: P < 0.001 D3 vs. D2: P = 0.002)At 2 yrsACR50 response, %: D1: 43 D2: 37D3: 59 D3 vs. D2 or D1: P < 0.001D1 vs. D2: P= NSClinical remission, %: D1: 25 D2: 25D3: 49 (both P < 0.001)Radiographic progression; change in Sharp scores: D1: 10.4D2: 5.5 (P < 0.001)Withdrawal because of lack of efficacy, %: D1: 18D2: 19D3: 4.9HAQ DI improvement, mean units +/- sd: D1: -0.9 +/- 0.6 D2: -0.9 +/- 0.7D3: -1.0 +/- 0.7 D2 vs. D1, P = NR D3 vs. D1; P < 0.05 D3 vs. D2; P = 0.058% with HAQ DI score of zero: D1: 19 D2: 19D3: 33 D3 vs. D2, P < 0.001 D3 vs. D1: P < 0.001% with HAQ DI improvement of ≥ 0.22 units from baseline: D1: 63 D2: 58D3: 72 D3 vs. D2, P < 0.05 D3 vs. D1: P < 0.05SAEs:D1: 18.5D2: 21.1D3: 15.9Infections:D1: 123D2: 110D3: 119Serious Infections:D1: 2.9D2: 0.7D3: 1.6Malignancies:D1: 0.4D2: 0.9D3: 0.9Withdrawal because of adverse events:D1: 7% D2: 10% D3: 12% Overall Attrition Rate, %:32%ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Brown, 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE1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ADDIN EN.CITE.DATA 20Country, Setting:US, NAFunding:Authors are from FDA and National Cancer InstituteResearch Objective:Occurrence of lympho-proliferative disorders in pts treated with ETA and INFStudy Design:Database analysis; AERS systemOverall N:26 casesStudy Duration: NAInclusion Criteria:MedWatch reports submitted to FDA for biologic products ETA and INF. All reports citing neoplasms, benign or malignant, were reviewed. Any report with a keyword of lymphoma or mentioned lymphoma in text was investigated further. Cases reported to MedWatch through December 2000 comprise basis for current summaryExclusion Criteria:NAInterventions, dose:D1: ETA (various)D2: INF (various) N:D1: 18D2: 8Mean age, yrs:D1: 64D2: 62Sex, % female:D1: 61.1D2: 25.0Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 72.2D2: 25ETA19 cases per 100,000 treated personsINF6.6 cases per 100,000 treated personsIn general, diffuse large B cell lymphoma (non-Hodgkin’s) were most common form(21 of 26 were non-Hodgkin’s lymphomas)Treated person rates of lymphomas in ETA and INF users is probably an underestimate based on underreporting, according to authors (Age adjusted rate of lymphomas in US from 1992-1998 18.3 per 100,000 people)Median time to lymphoma diagnosis was 8 wks (range 2-52 wks) for ETA and 6 wks (range 2-44 wks) for INFNAOverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableBurmester, B. R. et al., 2007ReActPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 21Country and settingMultinational, multicenterSource of fundingNRResearch objectiveEvaluate safety and effectiveness of ADA alone or in combination with standard DMARDs fortreatment of RA.Study designOpen – label ObservationalOverall N6610Duration of study12 weeks for main study, 5 years totalQuality rating FairInclusion CriteriaTreatment resistant defined as treatment failure with at least one traditional DMARDMen and women ≥ 18 years of age with active, adult-onset RA in accordance with1987 revised criteria ofACRDisease duration ≥?3 mosDAS based on ESR and an evaluation of 28 joints (DAS28) of greater than or equal to 3.2.Exclusion CriteriaCurrent pregnancy or breast feedingAny persistent or severe infection within 30 days of baselinePrevious treatment with other TNF antagonists up to 2 mos before enrollmentTreatment with alkylating agentsTotal lymphoid irradiation, IV immunoglobulin or any investigational biologic agentHistory of active arthritis other than RAAny uncontrolled medical conditionHistory or signs of demyelinating diseaseActive TB or histoplasmosis, malignancy (except for completely treated squamous or basal cell carcinoma)Interventions, doseD1: ADA: 40 mg every other weekD2: MTX LEFSSZADA: 40 mg every other weekAntimalarialsNumber in groupD1: 1731D2: 4879 1 DMARD 4004 2 DMARDs 769 ≥ 3 DMARDs 106 MTX only 2794 LEF only 842SSZ only 133 AM only 148 1 other DMARD 84 MTX+LEF 180 MTX+AM 269 MTX+SSZ 182 MTX+SSZ+AM 76Overall: 6610Mean age, years (SD)D1: 55 (13)D2: 55 (13)1 DMARD 53 (13) 2 DMARDs 53 (13) ≥ 3 DMARDs 52 (12)MTX only 53 (13)LEF only 54 (12)SSZ only 56 (13)AM only 56 (12)1 other DMARD 55 (13)MTX+LEF 53 (13) MTX+AM 52 (13)MTX+SSZ 52 (13)Sex, % femaleD1: 82D2: 80 1 DMARD 81 2 DMARDs 75 ≥ 3 DMARDs 76 MTX only 82 LEF only 82 SSZ only 81 AM only 83 1 other DMARD 79 MTX+LEF 79 MTX+AM 75 MTX+SSZ 70 MTX+SSZ+AM 78Overall: 81Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 12 (9)D2: 10 (8) 1 DMARD 10 (8) 2 DMARDs 9 (7) ≥ 3 DMARDs 10 (9) MTX only 10 (8)LEF only 11 (9)SSZ only 11 (8)AM only 8 (7)1 other DMARD 13 (9) MTX+LEF 10 (8)MTX+AM 8 (7)MTX+SSZ 9 (8)MTX+SSZ+AM 9, SPatients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100Overall: 100Tender Joint Count, meanD1: 14 (7)D2: 13 (7)1 DMARD 13 (7)2 DMARDs 13 (7)≥ 3 DMARDs 13 (7)MTX only 13 (7)LEF only 13 (7)SSZ only 14 (8)AM only 15 (7)1 other DMARD 14 (7)MTX+LEF 13 (7)MTX+AM 14 (7)MTX+SSZ 13 (7)MTX+SSZ+AMSwollen Joint Count, mean D1: 11 (6)D2: 10 (6)1 DMARD 10 (6)2 DMARDs 11 (6)≥ 3 DMARDs 12 (7)MTX only 10 (6)LEF only 11 (6)SSZ only 11 (6)AM only 10 (6)1 other DMARD 11 (5)MTX+LEF 11 (6)MTX+AM 10 (6)MTX+SSZ 11 (6)MTX+SSZ+AMCorticosteroid use, %D1: 70D2: 72 1 DMARD 71 2 DMARDs 75 ≥ 3 DMARDs 67 MTX only 70 LEF only 73 SSZ only 63 AM only 78 1 other DMARD 81 MTX+LEF 81 MTX+AM 74 MTX+SSZ 69 MTX+SSZ+AM 66Overall: 71DMARD use, %D1: Prior: 3.1 (2.1)D2: Prior: 2.9 (1.7)1 DMARD 2.8 (1.7)2 DMARDs 3.3 (1.5)≥ 3 DMARDs 3.8 (1.2)MTX only 2.7 (1.7)LEF only 3.3 (1.7)SSZ only 3.1 (1.8)AM only 2.8 (1.8)1 other DMARD 4.1 (2.1)MTX+LEF 3.5 (1.6)MTX na?ve, %NRBaseline DAS scoreD1: 6.2 (1.1)D2: 6.0 (1.1)1 DMARD 6.0 (1.1)2 DMARDs 6.0 (1.1)≥ 3 DMARDs 5.9 (1.1)MTX only 6.0 (1.1)LEF only 6.0 (1.1)SSZ only 6.1 (1.1)AM only 6.2 (1.0)1 other DMARD 6.3 (1.0)MTX+LEF 6.1 (1.0)MTX+AM 6.0, SRequired treatment for latent TBD1: NRD2: NROverall: 835Other population characteristics, %,?(CI/SD/P value)D1: HAQ DI: 1.73 (0.68)D2: HAQ DI: 1.60 (0.68)1 DMARD 1.61 (0.68)2 DMARDs 1.55 (0.69)≥ 3 DMARDs 1.68 (0.65)MTX only 1.61 (0.68)LEF only 1.58 (0.68)SSZ only 1.70 (0.71)AM only 1.62 (0.69)1 other DMARD 1.87 (0.69)MTX+LEF 1.55 (0.64)MTX+AM 1.52 (0.70)MTX+SSZ 1.57 (0.70)MTX+SSZ+AM 1.669 (0.66)Overall: HAQ DI: 1.64 (0.68)ACR mean difference/ absolute differenceResponse at 12 weeks with ADA+MTX as comparison group, OR (CI):ACR 20:D1: 0.52 (0.45-0.60), P?<?0.0001D2: LEF only 0.69 (0.58-0.82), P?<?0.0001, SSZ only 0.61 (0.41-0.89), P?=?0.0ACR 50:D1: 0.61 (0.53-0.70), P?<?0.0001D2: LEF only 0.72 (0.61-0.86), P?=?0.0002, SSZ only 0.76 (0.52-1.22), P?=?0.1555, AM only 1.14 (0.81-1.63), P?=?0.4503; 1 other DMARD 092 (0.57-1.48), P?=?0.7280, MTX+LEF 0.70 (0.50-0.97), P?=?0.0307, MTX+AM 0.94 (0.72-1.23), P?=?0.6590, MTX+SSZ 1.0 (0.73-1.36), P?=?0.9822, MTX+SSZ+AM 0.97 (0.59-1.57), P?=?0.8849ACR 70:D1: 0.74 (0.62-0.87), P?=?0.0004D2: LEF only 0.67 (0.54-0.84), P?=?0.0006, SSZ only 0.76 (0.46-1.26), P?=?0.2817, AM only 1.11 (0.73-1.68), P?=?0.6397, 1 other DMARD 1.08 (0.61-1.94), P?=?0.7871, MTX+LEF 0.72 (0.47-1.11), P?=?0.1387, MTX+AM 0.89 (0.64-1.24), P?=?0.4860, MTX+SSZ 0.99 (0.67-1.44), P?=?0.9438, MTX+SSZ+AM 1.11 (0.62-2.0), P?=?0.7208HAQ, D1: Abs change from baseline to 12 weeks: -0.47 (0.63D2: Abs change from baseline to 12 weeks: -0.56 (0.60, 1 DMARD -0.56 (0.60, 2 DMARDs -0.56 (0.60, ≥ 3 DMARDs -0.56 (0.57, MTX only -0.58 (0.60, LEF only -0.49 (0.59, AM only -0.72 (0.63, SSZ only -0.52 (0.62, 1 other DMARD -0.55 (0.55, MTX+LEF -0.54 (0.58, MTX+AM -0.63 (0.66, MTX+SSZ -0.55 (0.52, MTX+SSZ+AM -0.58 (0.59Overall: Abs change from baseline to 12 weeks: -0.54 (6.1DAS (CI)Abs change from baseline to 12 weeks:D1: -1.9 (1.4, DAS28<2.6 OR for achieving a response at week 12 (ADA+MTX as comparison group): 0.59 (0.49-0.71), P?<?0.0001D2: -2.2, SD 1.3; 1 DMARD -2.2, SD 1.3; 2 DMARDs -2.3, SD 1.3; ≥ 3 DMARDs -2.3, SD 1.3; MTX only -2.3, SD 1.3; LEF only -2.0, SD 1.3; AM only -2.4, SD 1.4; SSZ only -2.1, SD 1.3; 1 other DMARD -2.2, SD 1.2; MTX+LEF -2.2, SD 1.3; MTX+AM -2.4, SD 1.3; MTX+SSZ -2.4, SD 1.3; MTX+SSZ+AM -2.4, SD 1.3; DAS28<2.6 OR for achieving a response at week 12 (ADA+MTX as comparison group): LEF only 0.75 (0.6-0.93), P= 0.0103; SSZ only 1.51 (0.97-2.36), P= 0.0694; AM only 1.03 (0.65-1.62), P= 0.9107; 1 other DMARD 0.93 (0.48-1.81), P= 0.8365; MTX+LEF 0.82 (0.53-1.25), P= 0.3491; MTX+AM 0.97 (0.69-1.34), P= 0.8310; MTX+SSZ 1.01(0.68-1.48), P= 0.9729; MTX+SSZ+AM 1.61 (0.91-2.84), P= 0.1006SF-36, mean difference/absolute differenceNRRadiographic measures, mean difference/absolute differenceNRQuality of life scales, mean difference/absolute differenceNROthers, (please name) Moderate EULAR OR for achieving a response at week 12 (ADA+MTX as comparison group): D1: 0.45 (0.38-0.53), P?<?0.0001 D2: LEF only 0.68 (0.54-0.84), P?=?0.0004, SSZ only 0.72 (0.44-1.16), P?=?0.1756, AM only 0.81 (0.51-1.30), P?=?0.3859, 1 other DMARD 0.79 (0.42-1.46), P?=?0.4446, MTX+LEF 0.92 (0.59-1.45), P?=?0.7183, MTX+AM 1.33 (0.87-2.03), P?=?0.1922, MTX+SSZ 1.36 (0.82-2.24), P?=?0.2366, MTX+SSZ+AM 2.89 (1.04-8.01), P?=?0.0411 Good EULAR OR for achieving a response at week 12 (ADA+MTX as comparison group): D1: 0.53 (0.46-0.62), P?<?0.0001D2: LEF only 0.77 (0.64-0.93), P?=?0.0058, SSZ only 0.95 (0.63-1.43), P?=?0.8142, AM only 0.99 (0.67-1.44), P?=?0.9420, 1 other DMARD 0.97 (0.57-1.65), P?=?0.9157, MTX+LEF 0.72 (0.50-1.02), P?=?0.0673, MTX+AM 0.99 (0.75-1.32), P?=?0.9493, MTX+SSZ 0.94 (0.67-1.32), P?=?0.7336, MTX+SSZ+AM 1.24 (0.74-2.09), P?=?0.4180Attrition/withdrawalNR by arm Serious adverse events, nD1: 126D2: 260Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Cannon et al., 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE3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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE3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==
ADDIN EN.CITE.DATA 22Country, Setting:US, claims databaseFunding:Aventis Pharmaceuticals;Veterans AffairsResearch Objective:The incidence of serious adverse events during txt of RA with DMARDs, focusing on LEFStudy Design:Retrospective cohort studyOverall N:40594Study Duration: 2 yrsInclusion Criteria:Age: 18 and olderDiagnosed with RA according to ACR criteria: ICD 9 code (rx for LEF-surrogate marker), 90 d observation period prior to entryExclusion Criteria:Impaired renal or hepatic system: if on DMARD other than LEF-hepatic event 90 ds prior to entering cohort unable to determine sex or date of birthInterventions, dose:NRHCTMTXLEFSSZETAINFN:NRMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRates of AE in LEF group, alone and combined with MTX, were lower than or comparable to AE rates seen with MTX and other agents. LEF monotherapy had lowest rate of hepatic events in DMARD monotherapy groupsAll AE rates: LEF monotherapy (94 events/1000 PY, 95%CI, 84.4-104.8 ), MTX monotherapy (145 events/1000 PY, 95%CI,136.3-154.3), other DMARD (143 events/1000 PY, 95%CI,137.4-150.3), no DMARD (383 events/1000 PY, 95%CI,365.8-399.6) (P < 0.001). LEF + MTX (42.8/1000 PY, 95%CI, 32.8-55.9), LEF + other DMARD (58.7/1000 PY, 95%CI, 52.0-66.2), DMARD + MTX (69.5/1000 PY, 95%CI, 65.0-74.3; P = 0.002)Overall (rate per 1000 PY adjusted for age, sex, and comorbidities): D1: 94.1 D2: 145.0D3: 143.7D4: 42.8Hepatotoxicity (adjusted rate per 1000 PY):D1: 4.1 D2: 6.9D3: 4.2D4: 4.6Overall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Capell, 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1955</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>1955</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1955</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Capell, Hilary</author><author>Madhok, Rajan</author><author>Porter, Duncan</author><author>Munro, Robin</author><author>McInnes, Iain</author><author>Hunter, John</author><author>Steven, Malcolm</author><author>Zoma, Asad</author><author>Morrison, Elaine</author><author>Sambrook, Martin</author><author>Poon, Fat Wui</author><author>Hampson, Rosemary</author><author>McDonald, Fiona</author><author>Tierney, Ann</author><author>Henderson, Neil</author><author>Ford, Ian</author></authors></contributors><titles><title>Combination therapy with sulphasalazine and methotrexate is more effective than either drug alone in rheumatoid arthritis (ra) patients with a suboptimal response to sulphasalazine: Results from the double blind placebo controlled mascot study</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>235-41</pages><volume>66</volume><number>2</number><edition>2006 Aug 22</edition><dates><year>2007</year><pub-dates><date>Feb</date></pub-dates></dates><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>GG 10-4 (LL 9-13)</custom7><electronic-resource-num>10.1136/ard.2006.057133</electronic-resource-num></record></Cite></EndNote>23Country, Setting:Scotland, 8 NHS sitesFunding:Wyeth and Pharmacia -drugsArthritis Research CampaignResearch Objective: If a combination of SSZ and MTX is superior to either alone in RA pts with supoptimal response to 6 mos of SSZStudy Design:RCTOverall N:165 Study Duration: Phase I: 6 mos; Phase 2: 12 additional mos for those with DAS > 2.4 after 6 mosInclusion Criteria:Age: 18 to 80Duration of condition: < 10 yrsActive disease defined by DAS > 2.4 after 6 mos SSZ txt were eligble for phase IINSAIDs and other medications were continuedIntra-articular or intramuscular corticosteroid was permitted but not within 1 mo of 6, 12, & 18 mo assessmentsExclusion Criteria:Pregnant or lactatingPrior txt with: MTX or SSZImpaired renal or hepatic system: creatinine > 150 mmol/dl, ALT, aspertate aminotransferase > 80 IU/l, alkaline phosphatase > 700 IU/l, gamma GT x3Other: abnormal white cell count (< 4 x 10*9/l)Pre-existing pulmonary fibrosisUse of oral steroids > 7.5 mg/dKnown SSZ allergiesInterventions, dose:D1: SSZ + MTXD2: SSZ + placeboD3: MTX + placebo Phase IMTX: 7.5 mg/w (3 x 2.5 mg) increasing by 2.5 mg/mo until max of 25 mg or toxicitySSZ: enteric coated 500 mg/d increased by 500 mg/wkly until 40 mg/kg per d to a max of 4g/d for initial 6 mosPlacebo: Folic Acid 5 mg/wk given 3 days after MTX and MTX + placeboN:D1: 56 D2: 55D3: 54Overall: 687Mean age, yrs:D1: 56 D2: 55D3: 53Overall: 55Sex, % female:D1: 75 D2: 75D3: 79Overall: 77Race, % white:NRMean disease duration, yrs:D1: 1.9D2: 1.6 D3: 1.8TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %NRMTX naive, %:AllTxt resistant, %:AllPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 3.63D2: 3.67 D3: 3.5Sharp: D1: 17.0D2: 14.0D3: 12.0Median change 18 mos:DAS:D1: -0.67D2: -0.30 D3: -0.26(D1 vs. D2; P = 0.039)(D1 vs. D3; P = 0.023)(D2 vs. D3; P = 0.79)HAQ: D1: -0.50D2: -0.25 D3: -2.00(D1 vs. D2; P = 0.51)(D1 vs. D3; P = 0.57)(D2 vs. D3; P = 0.99)SJC: D1: -3.00D2: -3.00 D3: -2.00(D1 vs. D2; P = 0.94)(D1 vs. D3; P = 0.81)(D2 vs. D3; P = 0.74)ACR20, %?:D1: 29D2: 18 (OR 1.25 (95% CI, 0.56-2.79)?; P = 0.68)D3: 15 (OR 2.01 (95% CI, 0.85-4.76), P = 0.14) ACR50, %: D1: 11D2: 6 (OR 1.43 (95% CI, 0.43-4.81), P = 0.76)D3: 7 (OR 1.79 (95% CI, 0.49-6.49), P = 0.53)ACR70, %: D1: 4D2: 2 (OR 1.50 (95% CI, 0.24-9.34), P = 1.00)D3: 2 (OR 3.00 (95% CI, 0.30-29.78), P = 0.62)NROverall Attrition Rate, %:28.5687 pts entered phase I (6 mos)At 6 mos, 165 were not eliglbe to enter phase II (discontinued SSZ because of side effects: 19%, did not attend: 3.6%, died: 0.4%)Another 191 were not randomized because DAS score was < 2.4ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Chakravarty, 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE.DATA 24Country, Setting:US, multicenterFunding:Bristol-Myers-SquibbResearch Objective:Rates of NMSC (non-melanoma skin camcer) in a large cohort of pts with RA or OA and to evaluate the role of immunosuppressive medications on the development of NMSCStudy Design:Retrospective cohort studyOverall N:15,789 (RA); 3,639 (OA)Study Duration: NRInclusion Criteria:Participants in National Data Bank for Rheumatic Diseases (NDB)Recruited from 908 US rheumatologists; pts who returned at least 2 questionnaires between January 1999 and January 2003Exclusion Criteria: NRInterventions, dose:D1: pts with RAD2: pts with OAPREMTXLEFTNF inhibitors N:D1: 15789D2: 3639Mean age, yrs:D1: 62D2: 67Sex, % female:D1: 77D2: 83Race, % white:D1: 91D2: 94Mean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRSkin cancer before NDB:D1: 3.8D2: 5.8History of smoking: D1: 56D2: 46A total of 738 pts with RA reported new cases of NMSC during followup within the NDB; crude incidence rate: 18.1 / 1000 PY (95% CI, 16.8 -19.4 / 1000 PY)After excluding prevalent cases of NMSC, incidence rate was 15.2 / 1000 PY (95% CI, 14.1 -16.5)Based on multivariate Cox proportional hazard analysis restricted to pts with RAUse of PNL was associated with an increased hazard ratio (HR) (HR: 1.28, P = 0.014) for development of NMSCNo association found with use of LEF or MTX aloneUse of any anti-TNF (ETA, INF, and ADA) alone showed a slightly increased riskAn approximately 2-fold HR for development of NMSC was found among pts with RA using both MTX and any TNF inhibitor (HR 1.97, P = 0.001)NAOverall Attrition Rate, %:After initial assessment, ~ 8% of pts decline to participate each yrITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableChoy et al., 2008PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG95PC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaG95PC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj
TnVtPjI5Njc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4y
NTwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI5Njc8L3JlYy1udW1i
ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJw
cGF4d2Z3ZjBmc2Z6Mjk1djkiPjI5Njc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt
ZT0iR2VuZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D
aG95LCBFLiBILjwvYXV0aG9yPjxhdXRob3I+U21pdGgsIEMuIE0uPC9hdXRob3I+PGF1dGhvcj5G
YXJld2VsbCwgVi48L2F1dGhvcj48YXV0aG9yPldhbGtlciwgRC48L2F1dGhvcj48YXV0aG9yPkhh
c3NlbGwsIEEuPC9hdXRob3I+PGF1dGhvcj5DaGF1LCBMLjwvYXV0aG9yPjxhdXRob3I+U2NvdHQs
IEQuIEwuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+U2ly
IEFsZnJlZCBCYXJpbmcgR2Fycm9kIENsaW5pY2FsIFRyaWFscyBVbml0LCBBY2FkZW1pYyBEZXBh
cnRtZW50IG9mIFJoZXVtYXRvbG9neSwgS2luZyZhcG9zO3MgQ29sbGVnZSBTY2hvb2wgb2YgTWVk
aWNpbmUsIFdlc3RvbiBFZHVjYXRpb24gQ2VudHJlLCBDdXRjb21iZSBSb2FkLCBMb25kb24gU0U1
IDlSSiwgVUsuIGVybmVzdC5jaG95QGtjbC5hYy51azwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRp
dGxlPkZhY3RvcmlhbCByYW5kb21pc2VkIGNvbnRyb2xsZWQgdHJpYWwgb2YgZ2x1Y29jb3J0aWNv
aWRzIGFuZCBjb21iaW5hdGlvbiBkaXNlYXNlIG1vZGlmeWluZyBkcnVncyBpbiBlYXJseSByaGV1
bWF0b2lkIGFydGhyaXRpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gUmhldW0gRGlzPC9z
ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uYWxzIG9m
IHRoZSBSaGV1bWF0aWMgRGlzZWFzZXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5Bbm4uIFJoZXVtLiBE
aXMuPC9hYmJyLTE+PGFiYnItMj5Bbm4gUmhldW0gRGlzPC9hYmJyLTI+PC9wZXJpb2RpY2FsPjxw
YWdlcz42NTYtNjM8L3BhZ2VzPjx2b2x1bWU+Njc8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48
a2V5d29yZD5BZ2VkLCA4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BbnRpcmhldW1hdGlj
IEFnZW50cy8gdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhl
dW1hdG9pZC8gZHJ1ZyB0aGVyYXB5L3JhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkN5Y2xv
c3BvcmluZS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1l
dGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3
b3JkPjxrZXl3b3JkPkRydWcgVGhlcmFweSwgQ29tYmluYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+
RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvb3QgSm9pbnRzL3JhZGlvZ3JhcGh5PC9rZXl3b3Jk
PjxrZXl3b3JkPkdsdWNvY29ydGljb2lkcy8gdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3
b3JkPkhhbmQgSm9pbnRzL3JhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5
d29yZD48a2V5d29yZD5Mb2dpc3RpYyBNb2RlbHM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5
d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3
b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByZWRuaXNvbG9uZS90aGVyYXBldXRp
YyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+UXVhbGl0eSBvZiBMaWZlPC9rZXl3b3JkPjxrZXl3b3Jk
PlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8
L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXk8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi
bj4xNDY4LTIwNjAgKEVsZWN0cm9uaWMpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3NzY4MTczPC9h
Y2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8
L2N1c3RvbTI+PGN1c3RvbTM+Q1Q8L2N1c3RvbTM+PGN1c3RvbTQ+S1EgMSwgMiwgMyAvIGdvb2Q8
L2N1c3RvbTQ+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA 25Country and settingEngland/Wales multicenterSource of fundingMedical Research Council, UKResearch objectiveTest hypothesis that combining MTX with glucocorticoids and/or ciclosporin in early RA reducesproportion of pts developing new erosions within 2 yrsStudy designControlled TrialsOverall N467Duration of study2 yrsQuality rating Good Inclusion CriteriaEarly RAActive RA by ACR criteria of less than 24 mos with three offollowing: >3 swollen joints, >6 tender joints, >45 min morning stiffnessESR >28 mm/h, informed consent and aged >18 years.Exclusion CriteriaOther inflammatory arthropathies (e.g., psoriatic arthritis)Current oral glucocorticoidsSerious medical disorders (e.g., hepatic or cardiac failure)Women of child-bearing potential without adequate contraceptive protectionContraindications for trial drugsInterventions, doseD1: MTX: open-label MTX 7.5 mg weekly, increasing incrementally to target dose of 15 mg/weekD2: MTX: open-label MTX 7.5 mg weekly, increasing incrementally to target dose of 15 mg/weekCiclosporin: started 3 mos after MTX, initial dose 100 mg/day, increased gradually to target dose of 3 mg/kg dailyD3: PNL: step-down PNL started with MTX, 60 mg/day initially, reduced to 7.5 mg at 6 weeks, 7.5 mg daily from 6 to 28 weeks, stopped by 34 weeksMTX: open-label MTX starting 7.5 mg weekly, increasing incrementally to target dose of 15 mg/weekD4: PNL: same as in arm 3MTX: same as in other armsCyclosporin: same as in arm 2Number in groupD1: 117D2: 119 D3: 115D4: 116Overall: 467Mean age, years (SD)D1: 54D2: 53D3: 54D4: 55Overall: NRSex, % femaleD1: 67D2: 65D3: 66D4: 67Overall: 70Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 2.7 mos (3.8)D2: 4.2 (5.7)D3: 5.1 (5.8)D4: 3.9 (5.2)Patients with early RA, three years or less, %D1: 100D2: 100D3: 100D4: 100Treatment resistant, %NRTender Joint Count, mean (CI)D1: NRD2: NRD3: NRD4: NROverall: 11.8 (11.1 - 12.5)Swollen Joint Count, mean (CI)D1: NRD2: NRD3: NRD4: NROverall: 9.9 (9.3 - 10.4)Corticosteroid use, %NRDMARD use, %D1: 12D2: 14D3: 14D4: 16Overall: 14MTX na?ve, %NRBaseline mean DAS28 score, mean (SD)D1: 5.8 (1.2)D2: 5.9 (1.3)D3: 5.8 (1.4)D4: 5.6 (1.3)Required treatment for latent TBNRErosive changes on X-ray, %:D1: 32D2: 37D3: 30D4: 34Median Larsen score (IQR): D1: 7 (3, 15)D2: 8 (3, 23)D3: 6 (2, 20)D4: 5 (2, 14)HAQ score, mean (SD):D1: 1.5 (0.7)D2: 1.7 (0.7)D3: 1.6 (0.7)D4: 1.6 (0.7)SF-36 PCS, median (IQR): D1: 30 (9)D2: 29 (8)D3: 30 (10)D4: 30 (9) ACR mean difference/ absolute differenceNRHAQ, mean change, at 2 years (SD)D1: -0.29 (0.07)D2: -0.20 (0.06)D3: -0.28 (0.07)D4: -0.50 (0.06) Overall: NR/ P = ?0.02/P = ?0.35/P = ?0.01DAS, mean change, at 2 years (SE)D1: -1.42 (0.17) D2: -1.34 (0.15) D3: -1.37 (0.15) D4: -1.67 (0.15)Overall: NR/P = ?0.19/ P = ?0.13/P = ?0.06SF-36, mean change, at 2 years (SE)D1: 5.8 (1.0)D2: 3.9 (1.1)D3: 3.5 (1.0) D4: 8.0 (1.2)Overall: NR/ P = ?0.22/P = ?0.46/P = ?0.001Radiographic measures at 2 yearsCases with new erosions (primary outcome), %:D1: 34 (29)D2: 19 (17)D3: 19 (16)D4: 15 (13)Mean change in Larsen score (SE):D1: 7.41 (0.99) D2: 4.53 (0.88)D3: 4.70 (0.69)D4: 2.99 (0.51)Overall: 95% CI: NR (0.36, 0.96), P = ?0.03/ (0.33,0.88), P = ?0.01, P = ?0.32/ (5.47,9.33), P = ?0.003, P = ?0.008, P = ?0.45Quality of life scales, mean difference/absolute differenceNROverallOverall attrition/withdrawal, n:D1: 49D2: 62D3: 54D4: 55Overall: 220Withdrawals due to adverse events, n:D1: 8D2: 9D3: 14D4: 23Overall: 71Withdrawals due to lack of efficacy, n:D1: 13D2: 8D3: 10D4: 7Overall: 71Other attrition:n's for various arms reported as "exclusively withdrew for toxicity and lack of effect", but n:?71 totals for each reported intext. Withdrawals from toxicity:D1: 12D2: 21D3: 22D4: 33 Withdrawals lack of effect:D1:19D2: 17D3: 13D4: 15NNH for any adverse event leading to withdrawal was 20 (95% CI 8, 1280) with added ciclosporin and 14 (95% CI 6, 65) with added PNL. Estimated NNH for triple therapy, based only on data from patients receiving this therapy was 6 (95% CI 3,23).Overall adverse events reported, n:D1: 21D2: 18D3: 19D4: 23Overall: 81Serious adverse eventsDeath, n:D1: 1D2: 1D3: 1D4: 2Overall: 5Myocardial infarctions, angina, strokes, n:D1: 1D2: 2D3: 2D4: 4Overall: 9Hepatotoxicity/elevated liver enzymes?n:D1: 5D2: 23D3: 4D4: 35Overall: 67Malignancies, nD1: 5D2: 2D3: 0D4: 1Overall: 8Respiratory eventsTuberculosis: NR Pneumonia n:D1: NRD2: NRD3: NRD4: NROverall: 3Upper respiratory infection,?n:D1: 54D2: 51D3: 49D4: 55Overall: NROther infectionsUpper GI, n:D1: 1D2: 2D3: 0D4: 1Overall: 4GINausea or vomiting,?n:D1: 15D2: 31D3: 20D4: 10Overall: 76Abdominal pain, n:D1: 7D2: 3D3: 9D4: 7Overall: 26GI bleed or ulcer, n:D1: 5D2: 16D3: 4D4: 14Overall: 39OtherHeadache, n:D1: 6D2: 17D3: 10D4: 15Overall: 48Dizziness, n:D1: 4D2: 14D3: 6D4: 5Overall: 29Diarrhea , n:D1: 5D2: 10D3: 10D4: 3Overall: 28Paraesthesia, n:D1: 3D2: 5D3: 8D4: 11Overall: 27Cough, n:D1: 7D2: 5D3: 11D4: 4Overall: 27Elevated blood pressure, n:D1: 1D2: 11D3: 8D4: 17Overall: 37Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Chung, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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 EN.CITE.DATA 26Country, Setting:US, University clinics (32 centers)Funding:CentocorResearch Objective:To assess effectiveness and safety of INF in pts with moderate to severe congestive heart failureStudy Design:RCTOverall N:150Study Duration: 28 wksInclusion Criteria:Age: 18+Stable New York Heart Association (NYHA) class III or IV heart failure Exclusion Criteria:Prior txt with txt within 3 mos of INF or other therapeutic agents that could interfere with actions of TNF (eg, ETA, pentoxifylline, thalidomide, or D2E7)History of TB: had latent TB or had had TB within 3 yrsNSAID other than aspirin; experienced a serious infection within 2 mosDocumented HIV infectionInterventions, dose:D1: placeboD2: INF 5mg/kgD3: INF 10mg/kgN:D1: 49D2: 50D3: 51Mean age, yrs:D1: 60D2: 62D3: 62Sex, % female:D1: 24D2: 14D3: 16Race, % white:D1: 88D2: 88D3: 84Mean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NR10 mg/kg INF group were more likely to die or be hospitalized for heart failure than placebo (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P = 0.043 using log-rank test);Pts in the 10 mg/kg INF group were more likely to be hospitalized for heart failure or for any reason than pts in the placebo or 5 mg/kg INF groupsOverall: D1: 83.3D2: 92.2D3: 84SAEs:D1: 29.2D2: 23.5D3: 44Serious Infections:D1: 2.1D2: 5.9D3: 8Dizziness:D1: 4.2D2: 31.4D3: 20Overall Attrition Rate, %:NRITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableCohen et al., 2006, TrialPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE.DATA 27 ; Keystone et al. , 2008PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXlzdG9uZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXlzdG9uZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+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ADDIN EN.CITE.DATA 28; Keystone et al., 2009PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXlzdG9uZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXlzdG9uZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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ADDIN EN.CITE.DATA 29 REFLEXCountry and settingMulitnational, multicenterSource of fundingHoffman-La Roche, Biogen Idee, and GenentechNIH grantResearch objectiveDetermine efficacy and safety of tx with RIT + MTX in pts with inadequate responses to anti-tumor necrosis factor therapiesStudy designControlled TrialsOverall N520517 received treatment and were analyzed as part of "safety population." 499 were analyzed as ITT population. (3 never received treatment, some were treated prior to randomization, and others were participants at a center where blinding of the assessor was potentially compromised).Duration of studyResults presented are at 24 weeksREFLEX trial is a 2-year trial.Quality rating Fair Inclusion CriteriaTreatment resistantHad RA for at least 6 mosHad active disease (8 or more tender joints, 8 or more swollen joints, a CRP level of 1.5 or more, or an erythrocyte sedimentation rate of 28 mm/hour or greater, and radiographic evidence of at least 1 joint with a definite erosion attributable to RA)Had to be taking MTX (10 - 25 mg/week) for at least 12 weeks prior to screening with last 4 weeks at stable doseExperienced an inadequate response to previous or current treatment with anti-TNF agents inflixumab, adalimuman, or ETNWere intolerant to at least 1 administration of these agents.Exclusion CriteriaHistory of rheumatic autoimmune disease other than RA (except secondary Sjorgen's syndrome)Significant systematic involvement secondary to RAACR functional class IV diseaseInterventions, doseD1: MethylPNL: 100 mg, 30 minutes before each infusionPREDoral: 60 mg on days 2 - 7, 30 mg on days 8 – 14MTX: 10 - 25 mg/week orally or parenterallyPlaceboFolate: 5 or more mg/weekD2: MethylPNL: 100 mg, 30 minutes before each infusionPRED oral: 60 mg on days 2 - 7, 30 mg on days 8 – 14MTX: 10 - 25 mg/week orally or parenterallyRIT: 2 infusions of 1,000 mg eachFolate: 5 or more mg/weekNumber in groupD1: 201D2: 298Mean age, years (SD)D1: 52.8 (12.6)D2: 52.2 (12.2)Based on safety populationSex, % femaleD1: 81D2: 81Based on safety populationRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsNote: These data are based on safety population, n:D1: 11.7 (7.7) D2: 12.1 (8.3)Overall: 517Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100Tender Joint Count, mean, (SD)68 joints assessedD1: 33.0 (15.6)D2: 33.9 (15.1)Swollen Joint Count, mean (SD)66 joints assessedD1: 22.9 (12.7)D2: 23.4 (11.8)Corticosteroid use, n (%)D1: 127 (61)D2: 200 (65)Previous DMARD use, n (%)D1: 2.4 (1.8)D2: 2.6 (1.8)MTX na?ve, %NRBaseline DAS28 score, mean (SD)D1: 6.8 (1.0)D2: 6.9 (1.0)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Baseline characteristics are reported for safety population, N:?517 - Placebo group, N:?209) HAQ-D, mean score (SD): D1: 1.9 (0.5)D2: 1.9 (0.6)Total Genant-modified Sharp radiographic score D1: 47.9 (36.0)D2: 48.3 (34.9)Previous anti-TNF agents taken (no (%) of patients): Inflixumab D1: 169 (81) D2: 219 (71)ADA D1: 38 (18)D2: 71 (23)ETN D1: 104 (50)D2: 168 (55)Previous anti-TNF agents taken (mean (±SD)) D1: 1.5 (0.67)D2: 1.5 (0.67)Inadequate efficacy of anti-TNF agents (%) D1: 90D2: 92ACR ACR 20:D1: 18D2: 51P = 0.0001ACR 50:D1: 5D2: 27P = 0.0001ACR 70:D1: 1D2: 12P = 0.0001HAQ NRDAS D1: -0.4D2: -1.9P = 0.0001SF-36 NRRadiographic measures D1: N:?177D2: N:?268 Total Genant-modified Sharp radiographic score, mean change from baseline (SD): D1: 1.2 (3.3)D2: 0.6 (1.9)No worsening of erosions, n (%): D1: 106 (60%)D2: 176 (66%)Quality of life scales NREULARModerate Response, %:D1: 20D2: 50Good Response, %: D1: 2D2: 15Low disease, %:D1: 2D2: 15Remission, %:D1: 0D2: 9Attrition/withdrawalOverall, n:D1: 97D2: 57Withdrawals due to adverse events, n:D1: 2D2: 8Withdrawals due to lack of efficacy, n:Required rescue therapy D1: 80D2: 1Adherent/compliant, n:D1: 112D2: 254Serious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NR Other infectionsNRGINROther AEsFor safety population (N:?517)Any adverse event, n: 183 (88)Severe adverse event, n: 49 (23)Related adverse event, n: 77 (37)Serious adverse event, n: 21 (10)Death, n: 0 (0) Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Combe et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2007</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>2007</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2007</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Combe, B. G.</author><author>Codreanu, C.</author><author>Fiocco, U.</author><author>Gaubitz, M.</author><author>Geusens, P. P.</author><author>Kvien, T. K.</author><author>Pavelka, K.</author><author>Sambrook, P. N.</author><author>Smolen, J.</author><author>Wajdula, J.</author><author>Fatenejad, S.</author></authors></contributors><auth-address>CHU Lapeyronie, France.</auth-address><titles><title>Double-blind comparison of Etanercept and Sulphasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving Sulphasalazine</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><dates><year>2006</year><pub-dates><date>Apr 10</date></pub-dates></dates><accession-num>16606651</accession-num><urls></urls><custom1>I</custom1><custom2>B</custom2><custom3>HRCT</custom3><custom6>RA</custom6><custom7>PT 10-9 (KD 9-13)</custom7></record></Cite></EndNote>30Country, Setting:Europe, multicenterFunding:WyethResearch Objective:To compare efficacy and safety of ETA and SSZ, alone and in combination, in pts with active RA despite SSZ txt Study Design:RCTOverall N:260Study Duration: 24 wksInclusion Criteria:Age > 18Diagnosed according to ACR criteria; Functional class of: I-IIIPrevious use of DMARDs: 2 to 3g SSZ/d for ≥ 4, w/o toxicityDuration of condition < 20 yrsStable doses of oral corticosteroids (10 mg/d of PRE or equivalent), one NSAID, simple analgesics with no anti-inflammatory action or daily doses of aspirin (300 mg)Exclusion Criteria:Prior txt with: (1) ETA or other TNF antagonists or (2) received a DMARD other than SSZ within 3 mos. Or any biologic or cyclophosphamide within 6 mos, corticosteroids within 4 wksPresence of relevant comorbidity, including active infectionsInterventions, dose:D1: SSZ (2,2.5, or 3 g /d) + placeboD2: ETA (25 mg SC twice wkly) + placeboD3: ETA (25 mg SC twice wkly) + SSZ (2,2.5, or 3 g /d)N:D1: 50D2: 103D3: 101Overall: 254Mean age, yrs:D1: 53.3D2: 51.3D3: 50.6Overall: 51.4Sex, % female:D1: 82.0D2: 78.6D3: 80.2Overall: 79.9Race, % white:NRMean disease duration, yrs:D1: 5.6 (sd 4.4)D2: 7.1 (sd 5.2)D3: 6.5 (sd 5.1)TJC, mean:D1: 14.0D2: 14.7D3: 14.1SJC, mean:D1: 11.1D2: 10.1D3: 10.4DMARD use, %:D1: 58.0D2: 69.9D3: 58.4Corticosteroid use, %D1: 40.0D2: 59.2D3: 44.6MTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.0D2: 5.1D3: 5.2At 24 weeksACR20, %:D1: 28.0 D2: 73.8D3: 74.0 (P < 0.01)ACR50, %:D1: 14.0 D2: 46.6D3: 52.0 (P < 0.01)ACR70, %:D1: 2.0 D2: 21.4D3: 25.0 (P < 0.01)In groups receiving ETA, significant differences in ACR core components were observed by wk 2 compared with those receiving SSZ alone (P < 0.01)DAS improvement, %:D1: 19.6 D2: 48.2D3: 49.7 (P < 0.01)Mean HAQ improvement, %:D1: 9.2D2: 35.3D3: 40.2 (P < 0.01)Mean % improvement EuroQOL VAS D2: 64.6D3: 67.6(P = NS, NR)No meaningful clinical advantage to use of ETA in combination with SSZInfections:D1: 13D2: 47D3: 31Infusion or injection reaction:D1: 3D2: 38D3: 21Abdominal Pain:D1: 0D2: 7D3: 8Headache:D1: 4D2: 5D3: 15Nausea:D1: 3D2: 3D3: 12URTI:D1: 5D2: 10D3: 11Overall Attrition Rate, %:13ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableCombe et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 31; add ADDIN EN.CITE <EndNote><Cite><Author>Combe</Author><Year>2006</Year><RecNum>2007</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>2007</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2007</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Combe, B. G.</author><author>Codreanu, C.</author><author>Fiocco, U.</author><author>Gaubitz, M.</author><author>Geusens, P. P.</author><author>Kvien, T. K.</author><author>Pavelka, K.</author><author>Sambrook, P. N.</author><author>Smolen, J.</author><author>Wajdula, J.</author><author>Fatenejad, S.</author></authors></contributors><auth-address>CHU Lapeyronie, France.</auth-address><titles><title>Double-blind comparison of Etanercept and Sulphasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving Sulphasalazine</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><dates><year>2006</year><pub-dates><date>Apr 10</date></pub-dates></dates><accession-num>16606651</accession-num><urls></urls><custom1>I</custom1><custom2>B</custom2><custom3>HRCT</custom3><custom6>RA</custom6><custom7>PT 10-9 (KD 9-13)</custom7></record></Cite></EndNote>30 from old reportCountry and settingMultinational, multicenterSource of fundingWyeth ResearchResearch objectiveDetermine efficacy and safety of ETN and ETN + SSZ versus SSZStudy designControlled TrialsOverall N260Duration of study2 yearsQuality rating Fair Inclusion CriteriaTreatment resistant SSZ18 years or olderDisease duration of 20 years or less with active adult onset of RAPrevious use of DMARDs: 2 to 3g SSZ/d for ≥ 4, w/o toxicityStable doses of oral corticosteroids (10 mg/d of PRE or equivalent), one NSAID, simple analgesics with no anti-inflammatory action or daily doses of aspirin (300 mg)Received stable dose of SFS for four mos or more before screeningFunctional class of: I-IIIExclusion CriteriaPrior txt with: (1) ETA or other TNF antagonists or (2) received a DMARD other than SSZ within 3 mos. Or any biologic or cyclophosphamide within 6 mos, corticosteroids within 4 wksPresence of relevant comorbidity, including active infectionsInterventions, doseD1: ETN: 25mg by sub-cutaneous injection twice dailyPlaceboOther: Patients in ETN discontinued SSZD2: SSZ: 2g, 2.5g or 3g daily PlaceboD3: SSZ: 25mg by subcutaneous injection twice daily ETN: 2g, 2.5g or 3g dailyNumber in groupD1: 103D2: 50D3: 101 Interventions, dose:D1: SSZ (2,2.5, or 3 g /d) + placeboD2: ETA (25 mg SC twice wkly) + placeboD3: ETA (25 mg SC twice wkly) + SSZ (2,2.5, or 3 g /d)N:D1: 50D2: 103D3: 101Overall: 254Mean age, yrs:D1: 53.3D2: 51.3D3: 50.6Overall: 51.4Sex, % female:D1: 82.0D2: 78.6D3: 80.2Overall: 79.9.Race, % whitePopulation described as predominantly white.Race, % blackNREthnicity, LatinoNRMean disease duration, yearsNRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanNRSwollen Joint Count, mean NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS scoreNRRequired treatment for latent TBNRACR At Week 2ACR 20:D1: 67D2: 77D3: 34P = 0.01 (ETA vs. SSZ)At Week 8ACR 50:P = ?0.01 At Week 12ACR 70:P = ?0.01 HAQ achieved, by % patientsD1: 76D2: 78D3: 40P = 0.01 (combination or ETN)DAS mean change at 2 yearsD1: 2.3D2: -2.7D3: -0.6P = ?0.05 for ETA vs. SFSDAS, %:?2.4 at 2 yearsD1: 45.6D2: 4.0D3: 57.0DAS2.8 vs. 4.5 vs. 2.5 P = ?0.01SF-36 NRRadiographic measures, mean difference/absolute differenceNRQuality of life scalesNRAttrition/withdrawalOverall, n:D1: 38D2: 34D3: 24Overall: 96Withdrawals due to adverse events, n (%):D1: 8D2: 9D3: 10Overall: NRWithdrawals due to lack of efficacy, n (%):D1: 52D2: 6D3: 6P = 0.001Overall adverse events reported, n: D1: 166D2: 53D3: 140Overall: 359Serious adverse eventsDeath, n: Overall: 223 patients receiving combination, 27 receiving ETN and 2 receiving SSZ had one or more serious adverse event (SAE). Non-infectious SAE were significantly greater in patients receiving ETN (20.8% for the combination and 20.4% for ETN alone) compared with 4% for patients receiving SSZ (P = ?0.01).MalignanciesLymphoma or leukemia, n: D1: 1D2: 0D3: 0Overall: 1Skin?cancer (basal cell?or squamous cell), n: D1: 1D2: 0D3: 0Overall: 1Respiratory eventsTuberculosis: NRPneumonitis, n: D1: 1D2: 0D3: 0Overall: 1Pharyngitis/laryngitis, n: D1: 24D2: 2D3: 10P = 0.01 (combination vs. SFS)Sinusitis, n:D1: 12D2: 0D3: 3Other infectionsAny treatment-emergent infection, n:D1: 76D2: 21D3: 60BronchitisD1: 21D2: 4D3: 12Gingival/dental infection:D1: 7D2: 2 D3: 12GINausea or vomiting, n:D1: 7D2: 5D3: 19Overall: 31Abdominal pain, n: D1: 14D2: 1D3: 12Overall: 27Dyspepsia, n: D1: 14D2: 2D3: 12Overall: 28Diarrhea, n:D1: 11D2: 0D3: 6Overall: 17OtherInfusion/injection site reactions, n: D1: 34D2: 2D3: 2Overall: 57Hemorrhage:D1: 9D2: 3D3: 14Overall: 26Skin rashes/miscellaneous skin infections, n: D1: 15/19D2: 3/0D3: 8/12Overall: 31Headache, n: D1: 11D2: 4D3: 25Overall: 40Back pain, n: D1: 9D2: 5D3: 20Overall: 34Parathesia , n: D1: 4D2: 1D3: 11Overall: 16Flu syndrome, n: D1: 18D2: 2D3: 12Overall: 32Leuccopenia, n: D1: 2D2: 0D3: 8Overall: 10Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableCurtis et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 32Country and settingUnited States, Hospital and administrative claims dataSource of fundingMaryland Chapter of Arthritis Foundation, Agency for Healthcare Research and Quality and NIH National Institute of Arthritis and Musculoskeletal and Skin DiseasesResearch objectiveEvaluate risk of serious bacterial infections associated with TNFα antagonistsStudy designRetrospective CohortOverall Nn:?5,326 (obtained and abstracted 187 records for analysis)Duration of study67 months (May 1998 to December 2003), median follow up time 17 months; 3,894 person-years for RA patients receving TNFα antagonists and 4,846 person-years for RA patients receiving MTX.Quality rating FairInclusion CriteriaRA patients older than 18 years with 2 ICD9 codes for RAEither received an infusion or filled a prescription for a TNFα antagonist or filled at least 3 prescriptions for MTX.Exclusion CriteriaIndividuals with HIV, who had an organ transplant, diagnosed with a malignancyInterventions, DoseD1: MTX, ETN, IFX, ADA, patients may have been using more than one biologic and/or other nonbiologic DMARDs or glucocorticoids in addition to a biologicD2: MTXOther (describe)patients may have been using other nonbiologic DMARDs or glucocorticoids in addition to MTXNumber in groupD1: 2393D2: 2933Mean age (years)D1: 50D2: 55 P = 0.0001Sex, % femaleD1: 73D2: 73Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: 100 (inferred)D2: NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Mean PRED equivalent dosage: None (referrent), 1,061 (44%) less than or equal to 5mg/day, 252 (10%)5 - 10 mg/day, 348 (15%)> 10 mg/day, 732 (31%)Selected medical conditions and drug usage (only that those there were different between groups are abstracted, groups are similar with respect to other conditions investigated): Severe RA (defined by claims for rheumatoid lung disease, rheumatoid carditis, inflammatory eye disease, or Felty's symdrome), 76 (3%)Joint surgery or deformity, 64 (3%)Coronary artery disease (inlcuding CABG, angioplasty), 285 (12%)Number of comorbidities, 0.7 ±1Anti TNFα use: IFX 792 (33%)ETN 1,201 (50%)ADA 118 (5%)≥ 1 anti TNFα 282 (12%)MTX use 1,677 (70%);D2: Mean PRED equivalent dosage: None (referrent), 1,290 (44%) less than or equal to 5mg/day, 294 (10%)5 - 10 mg/day, 418 (14%)> 10 mg/day, 931 (32%)Selected medical conditions (only those that were different between groups are abstracted, groups are similar with respect to other conditions investigated): Severe RA (defined by claims for rheumatoid lung disease, rheumatoid carditis, inflammatory eye disease, or Felty's symdrome), 59 (2%) (P = ?0.01)Joint surgery or deformity, 37 (1%) (P = ?0.001)Coronary artery disease (inlcuding CABG, angioplasty), 43 (15%) (P <0.01)Number of comorbidities, 0.9 ±1.2 (P = ?0.0001). MTX use 2,933 (100%) (P = ?0.0001)ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallOverall attrition/withdrawal, n: D1: 17 records for individuals in exposed Dcould not be accessed, therefore they were not abstracted. number of exposed out of total number of records (217) identified to be abstracted is not given, so a percentage cannot be determinedWithdrawals due to adverse events, n: NRWithdrawals due to lack of efficacy, n: NRAdherent/compliant, n: NROverall adverse events reported, n:D1: 86 (total infections)D2: 82 (total infections)Serious adverse eventsDeath, n: NRCardiovascular events (specify), n: NRHepatotoxicity/elevated liver enzymes, n: NRMalignanciesLymphoma or leukemia, n: NRSkin?cancer (basal cell?or squamous cell), n: NROther cancer (specify), n: NRRespiratory eventsTuberculosis: NR Pneumonia, n:D1: 25D2: 23Upper respiratory infection, n: NROther infectionsUrinary tract infection, n: kidney/UTID1: 8D2: 10Other infections (specify), n: NRGINausea or vomiting, n:NRAbdominal pain, n: NRGI bleed or ulcer, n: NRBowel obstruction, n: NROther GI symptoms (specify), n: NROther AEs, n:Cellulitis/soft tissue, n:D1:?23 D2: 17Bacteremia/sepsis, n:D1: 7D2: 8Postoperative, n:D1: 7D2: 5Device associated, n:D1: 6D2: 4Septic Arthritis:D1: 4D2: 4Gastroenteritis:D1: 1D2: 5Abdominal abscess:D1: 1D2: 2Osteomyelitis exposed: D1: 1D2: 3Bacterial sinusitis:D1: 3D2: 0Diverticulitis:D1: 0D2: 0Summary results: 65 infections out of 2,393 exposed individuals (2.7%)58 infections among 2,933 unexposed individuals (2.0%)In first 6 months after index date, there were 32 infections in exposed D(incidence of 2.9 infections per 100 person -years) compared with 19 infections in unexposed D(incidence rate of 1.4 infections per 100 person-years)After mulitvariate adjustment, hazard ratios for "risk of hospitilization with a bacterial infection" for those receiving TNF-alpha antagonists was 1.94 (95% CI, 1.32 - 2.83)Factors Associated hospitalization with a "definite" bacterial infection (hazard ratio and 95% CI): Anti TNFα treatment crude HR:?1.39 (0.97 - 1.98), Adjusted HR:?1.94 (1.32 - 2.83)Age (5 year increments)Crude HR:?1.22 (1.14 - 1.31), Adjusted HR:?1.14 (1.03 - 1.27)Insurance Type, Medicare, Age:?65 years Crude HR:?2.82 (1.42 - 5.61), Adjusted HR:?2.88 (1.41 - 5.86), Age > 65 years Crude HR:?2.83 (1.89 - 4.22), Adjusted HR 1.88 (1.01 - 3.32)Number of Face to Face physician visits Crude HR:?1.07 (1.05 - 1.10), Adjusted HR:?1.04 (1.01 - 1.07)Prior Infection Crude HR:?1.98 (1.19 - 3.31), Adjusted HR:?1.46 (0.85 - 2.51)Chronic Obstructive Pulmonary Disease Crude HR:?2.68 (1.71 - 4.18)Adjusted HR:?1.90 (1.19 - 3.04)Diabetes mellitus Crude HR:?2.60 (1.66 - 4.06), Adjusted HR:?1.75 (1.10 - 2.78)Kidney Disease crude HR:?6.84 (3.01 - 15.5), Adjusted HR:?3.23 (1.35 - 7.73Decubitus Ulcer crude HR:?6.35 (3.22 - 12.52), Adjusted HR:?3.05 (1.50 - 6.19)Number of comorbidities crude HR:?1.50 (1.31 - 1.68), Adjusted HR:?NSMean PRED equivalent doasage > 10 mg per day Crude HR:?1.92 (1.26 - 2.91), Adjusted HR 1.85 (1.21 - 2.85) Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableCurtis et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE.DATA 33; subanalysis of Curtis et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 32Country and settingNRSource of fundingSupported by Maryland Chapter of Arthritis Foundation, Agency for Healthcare Research and Quality (grant HS-10389), NIH (grant K24-AR-052361-01 from National Institute of Arthritis and Musculoskeletal and Skin Diseases and grant T32-ARResearch objectiveEvaluate comparative effects of antibody-based and non-antibody-based TNFα antagonists on risk of hospitalizization with a bacterial infectionStudy designCohort StudyOverall N5195Duration of studyGreater than 6 months (specific duration not provided); Person-years: IFX:?372, ETN:?602, MTX:?1197Quality rating FairInclusion CriteriaAt least 2 International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for RA (714.x, excluding 714.3), receiving either IFX, ADA, ETN or MTX without a TNFα antagonistAll patients exposed to TNFα antagonist were new users, defined as having at least 6 months of nonexposure to these drugs prior to first filled prescription.Exclusion CriteriaPatients who were exposed to multiple TNFα antagonists during same window of risk were excluded (within 90 days of most recent filled prescription for drug of interest).Interventions, DoseD1: IFX: dose NRD2: ETN: dose NRD3: MTXNumber in groupD1: 850D2: 1412D3: 2933Overall: 5195Mean age (years)D1: 47.8D2: 53.4D3: 54.9Sex, % femaleNRRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Physician encounters in 6 months prior to therapy:?8.2D2: Physician encounters in 6 months prior to therapy:?7.0D3: Physician encounters in 6 months prior to therapy:?6.9Overall: NRACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallOverall attrition/withdrawal, n: NRWithdrawals due to adverse events, n: NRWithdrawals due to lack of efficacy, n: NRAdherent/compliant, n: NRAttrition information is not reported as they utilized person-years in their analyses. INF:?372 person-yrs, ETN:?602 person-yrs, MTX:?1197 person-yrs.Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsD1: Bacterial Infection::?6 months, n:?16, IR/100 person-yrs:?4.30, 95% CI (2.46 - 6.98), adjusted IRR:?2.40, 95% CI (1.23-4.68); > 6 months, n:?10, IR/100 person-yrs:?1.61, 95% CI (0.77-2.97), adjusted IRR:?1.14, 95% CI (0.55-2.24);D2: Bacterial Infection::?6 months, n:?12, IR/100 person-yrs:?1.99, 95% CI (1.03-3.48), adjusted IRR:?1.61, 95% CI (0.75-3.47); > 6 months, n:?19, IR/100 person-yrs:?1.34, 95% CI (0.81-2.10), adjusted IRR:?1.37, 95% CI (0.74-2.53)D3: Bacterial Infection::?6 months, n:?20, IR/100 person-yrs:?1.67, 95% CI (1.02-2.58), adjusted IRR:?referent; > 6 months, n:?34, IR/100 person-yrs:?1.55, 95% CI (1.11-2.22), adjusted IRR:?referentOverall: Bacterial Infection::?6 months, n:?48, > 6 months, n:?63, IR/100 person-yrs:?NRGINROtherNR Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableCurtis et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+Q3VydGlzPC9BdXRob3I+PFll
YXI+MjAwNzwvWWVhcj48UmVjTnVtPjI5MTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZh
Y2U9InN1cGVyc2NyaXB0Ij4zNDwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVt
YmVyPjI5MTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1
OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3ZjBmc2Z6Mjk1djkiPjI5MTU8L2tleT48L2ZvcmVpZ24t
a2V5cz48cmVmLXR5cGUgbmFtZT0iR2VuZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+
PGF1dGhvcnM+PGF1dGhvcj5DdXJ0aXMsIEouIFIuPC9hdXRob3I+PGF1dGhvcj5LcmFtZXIsIEou
IE0uPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW4sIEMuPC9hdXRob3I+PGF1dGhvcj5TYWFnLCBLLiBH
LjwvYXV0aG9yPjxhdXRob3I+UGF0a2FyLCBOLjwvYXV0aG9yPjxhdXRob3I+U2hhdGluLCBELjwv
YXV0aG9yPjxhdXRob3I+QnVyZ2VzcywgTS48L2F1dGhvcj48YXV0aG9yPlhpZSwgQS48L2F1dGhv
cj48YXV0aG9yPkJyYXVuLCBNLiBNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48
YXV0aC1hZGRyZXNzPkNlbnRlciBmb3IgRWR1Y2F0aW9uIGFuZCBSZXNlYXJjaCBvbiBUaGVyYXBl
dXRpY3Mgb2YgTXVzY3Vsb3NrZWxldGFsIERpc29yZGVycywgVGhlIFVuaXZlcnNpdHkgb2YgQWxh
YmFtYSBhdCBCaXJtaW5naGFtLCBCaXJtaW5naGFtLCBBTCwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0
aXRsZXM+PHRpdGxlPkhlYXJ0IGZhaWx1cmUgYW1vbmcgeW91bmdlciByaGV1bWF0b2lkIGFydGhy
aXRpcyBhbmQgQ3JvaG4mYXBvcztzIHBhdGllbnRzIGV4cG9zZWQgdG8gVE5GLWFscGhhIGFudGFn
b25pc3RzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJoZXVtYXRvbG9neSAoT3hmb3JkKTwvc2Vj
b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlJoZXVtYXRvbG9n
eTwvZnVsbC10aXRsZT48YWJici0xPlJoZXVtYXRvbG9neSAoT3hmb3JkKS48L2FiYnItMT48YWJi
ci0yPlJoZXVtYXRvbG9neSAoT3hmb3JkKTwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFnZXM+MTY4
OC05MzwvcGFnZXM+PHZvbHVtZT40Njwvdm9sdW1lPjxudW1iZXI+MTE8L251bWJlcj48a2V5d29y
ZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25h
bC9hZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGly
aGV1bWF0aWMgQWdlbnRzLyBhZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3Jk
PjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxr
ZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkNyb2huIERpc2Vhc2UvIGRy
dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVh
cnQgRmFpbHVyZS8gY2hlbWljYWxseSBpbmR1Y2VkL2VwaWRlbWlvbG9neTwva2V5d29yZD48a2V5
d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy9hZHZlcnNlIGVm
ZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBUdW1vciBOZWNy
b3NpcyBGYWN0b3IvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlR1bW9yIE5lY3Jv
c2lzIEZhY3Rvci1hbHBoYS8gYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48
a2V5d29yZD5Vbml0ZWQgU3RhdGVzL2VwaWRlbWlvbG9neTwva2V5d29yZD48L2tleXdvcmRzPjxk
YXRlcz48eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Tm92PC9kYXRlPjwvcHViLWRh
dGVzPjwvZGF0ZXM+PGlzYm4+MTQ2Mi0wMzI0IChQcmludCk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+
MTc5MzgxMzg8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+
PGN1c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9tMz5PPC9jdXN0b20zPjxjdXN0b200PktRIDMgLyBm
YWlyPC9jdXN0b200PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+Q3VydGlzPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA 34Country and settingUSASource of fundingFDA CBER Award #223-02-1420 Task Order #1, Maryland chapter of Arthritis Foundation, grant HS10389 from AHRQ, K24 AR052361-01 from National Institute of Arthritis and Musculoskeletal and Skin Diseases, and T32 AR47512-03 from NIHResearch objectiveInvestigate a possible association between TNF-antagonist use and incident heart failureStudy designObservationalOverall N2121 with RADuration of studyMedical and phDacy administrative claims from January 1998 to December 2002 (5 years), with medical record review for identified casesQuality rating FairInclusion CriteriaAt least two ICD9-CM diagnosis codes for RA (714.X) or CD (555.X) during study period, received an infusion or filled a prescription for a TNF- antagonist or filled at least three prescriptions for one of several selected immunosuppressive drugs.Exclusion CriteriaHIV, organ transplantation, or malignancy in 6 mos prior to index dateInterventions, DoseD1: IFX: dose NRD2: ETN: dose NRD3: Unexposed arm had to fill at least three prescriptions for MTX.Number in groupD1: 330D2: 808D3: 983Mean age (years)D1: 40 D2: 38 D3: 39 Sex, % femaleD1: 70D2: 75D3: 75Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)NRSJC, mean (SD) NRCorticosteroid use, %D1: 53D2: 45D3: 42DMARD use, %D1: non anti-TNF alpha DMARD use 83%D2: non anti-TNF alpha DMARD use 85%D3: non anti-TNF alpha DMARD use 100%MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Exposed D(IFX)N = 330Age 40 ± 8 yearsWomen N = 230 (70%)Duration of health plan enrollment 15 ± 10 mosNumber of physician visits 23 ± 23Proportion of patients hospitalized N = 36 (11%)Comorbidities in 6 mos prior to index date: extra-articlar disease, N = 27(8%)Joint deformity, N = 16 (5%)Joint surgery, N = 20 (6%)Coronary artery disease, N = 3 (1%)Medication use in 6 mos prior to index date(mean ± SD of infusions or filled prescriptions): MTX, 9 ± 11Glucocorticoid use, N = 176 (53%)NSAID use, N = 266 (81%)Non anti-TNF-alpha DMARD use, N = 274 (83%)As above, or glucocorticoids, N = 309 (94%)D2: Exposed Drug (ETN)N = 808Age 38 ± 10 yearsWomen N = 608 (75%)Duration of health plan enrollment 21 ± 16 mosNumber of physician visits 24 ± 32Proportion of patients hospitalized N = 95 (12%)Comorbidities in 6 mos prior to index date: extra-articlar disease, N = 36(4%)Joint deformity, N = 39 (5%)Joint surgery, N = 68 (7%)Coronary artery disease, N = 12 (1%)Medication use in 6 mos prior to index date (mean ± SD of infusions or filled prescriptions): MTX, 5 ± 10Glucocorticoid use, N = 365 (45%)NSAID use, N = 711 (88%)Non anti-TNF-alpha DMARD use, N = 684 (85%)As above, or glucocorticoids, N = 730 (90%)D3: Unexposed GroupN = 983Age 39 ± 10 yearsWomen N = 742 (75%)Duration of health plan enrollment 17 ± 14 mos (P < 0.001)Number of physician visits 19 ± 26 (P < 0.0001)Proportion of patients hospitalized N = 59 (6%) (P < 0.0001)Comorbidities in 6 mos prior to index date: extra-articlar disease, N = 27(3%)(P < 0.01)Joint deformity, N = 27 (3%) (P = < 0.05)Joint surgery, N = 31 (3%) (P = < 0.0001)Coronary artery disease, N = 6 (1%) (NS)Medication use in 6 mos prior to index date (mean + or - SD of infusions or filled prescriptions): MTX, 13 ± 13 (P < 0.01)Glucocorticoid use, N = 412 (42%) (P < 0.01)NSAID use, N = 874 (89%) (P < 0.05)Non anti-TNF-alpha DMARD use, N = 983 (100%)(P < 0.001)As above, or glucocorticoids, N = 983 (100%) (P < 0.001) - Note: P-values compare pooled IFX and ETN RA patients with unexposed RA patients.ACR mean difference/ absolute difference (CI/SD/P Value)ACR 20: NRACR 50: NRACR 70: NRHAQ, mean difference/ absolute difference NRDAS, mean difference/absolute difference NRSF-36, mean difference/absolute difference NRRadiographic measures, mean difference/absolute difference NRQuality of life scales, mean difference/absolute difference NROthers, (please name); mean difference/absolute difference NRSerious adverse eventsCardiovascular events (specify), n:D1: Definite and possible heart failure; N = 1 (in IFX group)D2: Definite and possible heart failure; N = 4 (in ETN group)D3: Definite and possible heart failure; N = 1 (in unexposed group)Any other AEs: Exposed group: patients receiving TNF-alpha antagonistsUnexposed Group: patients not receiving TNF-alpha antagonists, these patients did receive MTX, 6-mercaptopurine, azathioprine, or PRED. Cumulative incidence of HF among exposed patients: 4.4 cases per 1000 personsCumulative incidence of HF among unexposed patients: 1.0 case per 1000 persons in unexposed group. RA exposed compared with RA unexposed, RR = 4.3 (ns)RA exposed (ETN) compared to RA unexposed, RR = 4.9 (ns)RA exposed (IFX) compared to RA unexposed, RR = 3.0 (ns)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:De Bandt et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE.DATA 35Country, Setting:France, clinical reportsFunding:NRResearch Objective:To report cases and incidence of anti-TNF-induced SLE from a French national surveyStudy Design:Case seriesOverall N:10,700 (22 cases)Study Duration: variedInclusion Criteria:Pts in France given INF or ETA; cases of SLE-like illness during anti-TNF txt were sought; retrospective survey of French rheumatologists and internists between June and October 2003All French hospital centres prescribing anti-TNF txts (ETA and INF at that time) were surveyedExclusion Criteria:Improper diagnosis of lupusInterventions, dose:D1: Limited skin lupusD2: Complete lupusETA: variedINF: variedN:D1: 10D2: 12Mean age, yrs:D1: of RA onset 39D2: 36Sex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRINF/ETA:D1: 6 / 4D2: 9 / 3Incidence 15/7700: 0.19% with INF and 7/3800: 0.18% with ETA32 initially reported, 10 were ruled out leaving 22 cases10 pts only had anti-DNA antibodies and skin manifestations 1 could classify as 'limited skin lupus' or 'toxidermia' in a context of autoimmunity, and 12 pts had more complete drug-induced lupus with systemic manifestations NAOverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableden Broeder et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE.DATA 36Country and settingThe Netherlands, hospitalSource of fundingNRResearch objectiveIdentify risk factors for SSI in RA pts with special attention for anti-TNF txStudy designObservationalOverall N1219Duration of studyJanuary 1997 (at Sint Maartenskliniek, January 2001; Radboud University Nijmegen Medical Centre, January 1997) through September 2004Quality rating Fair: cohort baseline differences and number of patients between groups 1 and 2 decrease quality in strength of studyInclusion CriteriaAll RA patients that underwent elective orthopedic surgery between introduction of TNF inhibitors.Exclusion CriteriaPatients with no known follow up exceeding 1 yearPatients with another principal diagnosisPatients with multiple operations who developed more than one SSIProcedures where an infection was present at start of surgery.Interventions, DoseD1: anti-TNF-naive patients (1)D2: stopped anti-TNF treatment (2A)D3: patients that continued anti-TNF treatment (2B)Number in groupD1: 1023D2: 104D3: 92Overall: 1219Mean age (years)D1: 61D2: 54D3: 57Overall: 60Sex, % femaleD1: 77D2: 75D3: 82Overall: 77Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 17 yrs (11)D2: 16 (9)D3: 17 (8)Overall: 17 (11)Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)NRSJC, mean (SD) NRCorticosteroid use, %D1: 30D2: 40D3: 42Overall: 32DMARD use, %D1: NRD2: NRD3: NROverall: 16MTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P?value)D1: Concomitant MTX (%): 34>?1 DMARD (%): 11D2: Concomitant MTX (%): 37>?1 DMARD (%): 54D3: Concomitant MTX (%): 38>?1 DMARD (%): 46ACR mean difference/ absolute difference (CI/SD/P?Value)NRHAQ, mean difference/ absolute difference (CI/SD/P?Value)NRDAS, mean difference/absolute difference (CI/SD/P?Value)NRSF-36, mean difference/absolute difference (CI/SD/P?Value)NRRadiographic measures, mean difference/absolute difference (CI/SD/P?Value)NRQuality of life scales, mean difference/absolute difference (CI/SD/P?Value)NROthers, (please name); mean difference/absolute difference (CI/SD/P?Value)NROverallSeventeen cases in cohort 2 were excluded because documentation of anti-TNF treatment was incomplete (9 IFX, 5 ETN, 3 ADA), percentage of missing values was 3%. Due to a logistical error, data on prior SSI/skin infections were missing for cohort 1 patients from Maartenskliniek. For cohort 2, data were complete.Overall adverse events reported, n:D1: Total noninfectious complications: 115D2: Total noninfectious complications:6D3: Total noninfectious complications:13Overall: Total noninfectious complications:134Serious adverse eventsDeath, n:D1: 4D2: 0D3: 0Overall: 4Cardiovascular events (specify), n:NRHepatotoxicity/elevated liver enzymes, n:NRMalignanciesNRRespiratory eventsNROther infectionsD1: Surgical site infections: 41D2: Surgical site infections: 6D3: Surgical site infections: 8 Overall: Surgical site infections: 55 (22 were backed by positive cultures)GINROtherPerioperative continuation of anti-TNF was not associated with a significant increase of SSI risk, according to entry model (OR, 1.56, 95% CI, 0.52-4.66) and when corrected for potential confounders (OR, 1.50, 95% CI, 0.43-5.2). Wound dehiscence occurred more frequently in patients that continued anti-TNF compared to patients that temporarily discontinued anti-TNF treatment (OR, 11.2, 95% CI, 1.4-90). Risk of wound dehiscence was, however, very low in patients that stopped anti-TNF treatment. Compared with anti-TNF-naive patients OR for wound dehiscence was lower but still significant (RR 2.4, 95% CI, 1.1-5.0).Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Dixon et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1951</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>1951</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1951</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dixon, W. G.</author><author>Watson, K.</author><author>Lunt, M.</author><author>Hyrich, K. L.</author><author>Silman, A. J.</author><author>Symmons, D. P.</author></authors></contributors><auth-address>British Society for Rheumatology Biologics Register Control Centre Consortium.</auth-address><titles><title>Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2368-2376</pages><volume>54</volume><number>8</number><dates><year>2006</year><pub-dates><date>Jul 25</date></pub-dates></dates><accession-num>16868999</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>PT 9-28 (DJ 8-23)</custom7></record></Cite></EndNote>37 Country, Setting:BritainMulticenterFunding:Schering Plouogh, Wyeth, Abbott, and Amgen all fund The British Society for Rheumatology Biologics Register (BSRBR) Research Objective:The rate of serious infection anti-TNF-pts compared with RA pts treated with traditional DMARDsStudy Design:Prospective cohort studyOverall N:8,973Study Duration: 11,220 PYInclusion Criteria: ANTI-TNF cohort: diagnosed by physician w/ RATreated with ETA, INF, or ADA as first anti-TNF drug, at least 6 mos of followup by September 2005Comparison cohort: physician diagnosis of RA, active disease (guideline DAS28 >4.2), current txt with a DMARD, and no previous use of biologic drugs. Comparison pts also completed at least 6 mos of followup by September 2005. Exclusion Criteria: Anti-TNF cohort: pts who had been registered >6 mos after start of biologic therapyInterventions, dose:D1: DMARDD2: All anti-TNFD3: ETAD4: INFD5: ADAN:D1: 1354D2: 7664D3: 3596D4: 2878D5: 1190Mean age, yrs:D1: 60D2: 56D3: 56D4: 56D5: 57Sex, % female:D1: 71D2: 76D3: 77D4: 76D5: 74Race, % white:NRMedian disease duration, yrs:D1: 6D2: 12D3: 12D4: 12D5: 11TJC (median):D1: 6D2: 16D3: 16D4: 16D5: 15SJC (median):D1: 5D2: 11D3: 11D4: 12D5: 12DMARD use, %:NRCorticosteroid use, %:D1: 22D2: 47D3: 47D4: 48D5: 44MTX naive, %: NRTxt resistant %: NRPts with Early RA (≤3 yrs): NRBaseline DAS mean:D1: 5.1D2: 6.6 D3: 6.6D4: 6.6 D5: 6.6 Diabetes %:D1: 5.5D2: 5.4D3: 6.0D4: 4.6D5: 5.5COPD/asthma %: D1: 20D2: 13D3: 14D4: 12D5: 13:In pts with active RA, anti-TNF therapy was not associated with increased risk of overall serious infection compared with DMARD txt, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissuesSerious Infections:D1: N:56 (41 events/1000 PY)D2: N:525 (53 events/1000 PY)UTI:D1: N:3 (2.2 events/1000 PY)D2: N:45 (4.6 events/1000 PY)Overall Attrition Rate, %:NAITT Analysis:NA: Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableDixon et al., 2006,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXhvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXhvbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl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=
ADDIN EN.CITE.DATA 38 British Society for Rheumatoid Biologics RegisterCountry and settingUK, hospitals/general practiceSource of fundingFinancial support to BSRBR comes indirectly from following: UK companies marketing biologic agents in UK: Schering Plough, Wyeth Laboratories, Abbott Laboratories, and Amgen.The resources used to fund BSRBR are received under contractResearch objectiveTo compare rates of serious infection in RA patients treated with anti-TNF to those treated with traditional DMARDsStudy designObservationalOverall N9018Duration of studyDecember 2001 to September 2005Quality rating FairInclusion CriteriaAnti-TNF cohort: patients registered with BSRBR who had been diagnosed by a physician as having RA and who had been treated with ETN, IFX, or ADA as their first anti-TNF drug. Patients had to have completed at least 6 mos of followup by September 2005Comparison cohort: biologic naive, a physician diagnosis of RA, current treatment with a DMARD. Comparison patients also had to have completed at least 6 mos of followup by September 2005.Exclusion CriteriaIn order to limit problems associated with recall and left censorshipPatients who had been registered > 6 mos after start of biologic therapy were excluded.Interventions, DoseD1: Other: NR (traditional DMARDs)D2: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRNumber in groupD1: 1354D2: 7664Overall: 9018Mean age (years)D1: 60D2: 56Sex, % femaleD1: 71D2: 76Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 6 yrs (IQR = 1 - 15)D2: 12 yrs (IQR = 6 - 19)Overall: 100Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)D1: median = 6 (IQR = 3 - 13)D2: median = 16 (IQR = 10 - 22)SJC, mean (SD) D1: median = 5, (IQR = 2 - 9)D2: median = 11 (IQR = 7 -16)Corticosteroid use, %D1: 22D2: 47DMARD use, %D1: 100D2: 100MTX na?ve, %NRBaseline DAS score, mean (SD)D1: 5.1D2: 6.6Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: HAQ score, mean: 1.5Extraarticular disease: 21%Current smoker: 26%Former smoker: 39%Never a smoker: 35%Diabetes: 5.5%COPD/asthma: 20%D2: HAQ score, mean: 2.1Extraarticular disease: 30%Current smoker: 22%Former smoker: 38%Never a smoker: 40%Diabetes: 5.4%COPD/asthma: 13%ACR mean difference/ absolute difference (CI/SD/P Value)ACR 20: ACR 50: ACR 70: HAQ, mean difference/ absolute difference (CI/SD/P Value)DAS, mean difference/absolute difference (CI/SD/P Value)SF-36, mean difference/absolute difference (CI/SD/P Value)Radiographic measures, mean difference/absolute difference (CI/SD/P Value)Quality of life scales, mean difference/absolute difference (CI/SD/P Value)Others, (please name); mean difference/absolute difference (CI/SD/P Value)Adverse events reported, n:Urinary tract infection, n:D1: 3; Incidence rate/1,000 person-years: 2.2 (0.5 - 6.5)D2: 45; Incidence rate/1,000 person-yeears: 4.6 (3.3 - 6.1) Other infections (specify), n:D1: All serious infections: n = 56Rate of infections/1,000 person-years (95% CI) = 41.4 (31.4 - 53.5)D2: All serious infections: n = 525Rate of infections/1,000 person-years (95% CI) = 53.2 (48.9 - 57.8)Overall: All serious infections, IRR, DMARD = ref, adjusted for age and sex: 1.47 (1.07 - 2.01)Adjusted for aged, sex, disease severity, comorbidity, extraarticular manifestations, steroid use, and smoking: 1.03 (0.68 - 1.57)D1: Lower respiratory tract: 36Incidence rate/1,000 person-years: 26.6 (18.7 - 36.7)D2: Lower respiratory tract: 203Incidence rate/1,000 person-years: 20.6 (17.9 - 23.6)D1: Skin and soft tissue: 4; Incidence rate/1,000 person-years: 3.0 (0.8 - 7.6)D2: Skin and soft tissue: 118; Incidence rate/1,000 person-years: 12.0 (9.9 - 14.3)D1: Bone and joint: 4; Incidence rate/1,000 person-years: 3.0 (0.8 - 7.6)D2: Bone and joint: 68; Incidence rate/1,000 person-years: 6.9 (5.4 - 8.7)D1: Bacterial intrcellular infections: 0D2: Bacterial intrcellular infections: 19 (10 Mycobacterium TB, 2 Legionella pneumophila, 3 Listeria monocytogenes, 1 Mycobacterium fortuitum, and 3 Salmonella)Subanalysis: No. of infections: DMARD = 56, ETN = 209, IFX = 255, ADA = 61;Rate of infections/1,000 person-years (95% CI): DMARD = 41.4 (31.4-53.5), ETN = 51.3 (44.7-58.5), IFX = 55.2 (48.8-62.2), ADA = 51.9 (39.9-66.2); Adjusted IRR (DMARD = ref): ETN = 0.97 (0.63-1.50), IFX = 1.04 (0.68-1.61), ADA = 1.07 (0.67-1.72); TB, crude IR: ETN = 0.5, IFX = 1.5, ADA = 0.9; adjusted IRRs for TB (ETN = ref): IFX = 4.9 (95% CI, 0.5-49.8) and ADA = 3.5 (0.3-47.3)Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableDixon et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE.DATA 38; British Society for Rheumatology Biologics Register (BSRBR).Country and settingUnited Kingdom (UK)Source of fundingBritish Society for Rheumatology is indirectly funded by Schering-Plough, Whety Laboratories, Abbot Laboratories, and AmgenResearch objectiveDetermine whether incidence of myocardial infarction (MI) was lower in pts treated with anti-TNFα than traditional DMARDs; to explore impact of response to tx on rates of MI in anti-TNFalpha cohortStudy designProspective Cohort StudyOverall NN:?10,755; 74 individuals switched groups during course of study and were counted in both DMARDs and anti-TNFalpha groups.Duration of studyAnti-TNFalpha Drepresented 13,233 person-years of follow up. DMARDs Drepresented 2,893 person-years of follow up. Median follow up for anti-TNFalpha cohort was 1.66 years; median follow up for DMARDs cohort was 1.34 years.Quality rating Fair: Drug specific data not reportedInclusion CriteriaRegistered with BSRBRDiagnosed with RAFollowed up for more than 6 months by July 31, 2006Anti-TNFalpha cohort: treated with an anti-TNFalpha drugRegistered with BSRBR within 6 months of starting biologic therapy. UK national guidelines require that patients to whom anti-TNFa drugs are prescribed have a Disease Activity Score in 28 joints >?5.1 despite previous therapy with at least 2 DMARDs, one of which must have been MTX.DMARDs cohort: never taken biologic agents, diagnosed as having active RA (guideline DAS more than 4.2).Exclusion CriteriaNRInterventions, DoseD1: Unspecified DMARDs: dose and frequency NRD2: ETNIFXADAIn anti-TNFalpha group, 3,844 pts received ETN, 2,944 pts received infliximib, and 1,871 pts received ADA. Dosages and frequencies were not reported.Number in groupD1: 2,170D2: 8,659Mean age (years)D1: 60D2: 56Sex, % femaleD1: 72D2: 76Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 7 years (IQR, 1 - 15)D2: 12 years (IQR, 6 - 19)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 19.3D2: 43.7DMARD use, %D1: 100%D2: NRMTX na?ve, %D1: NRD2: 0 (inferred)Baseline DAS score, mean (SD)D1: 5.0 (SD 1.4)D2: 6.6 (SD 1.0)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: BMI, mean ±SD kg/m2:?26.9 (5.7)Smoking History, no. (%), current smoker 537 (25), Former Smoker 849 (39), Never Smoked 767 (35)Prior MI, no (%), 116 (5.3)Angina, no (%), 183 (8.4)Hypertension, no (%), 672 (31.0)Diabetes, no. (%), 132 (6.1)Corticosteriods, no. (%), 418 (19.3)Lipid-lowering Drugs, no. (%), 338 (15.6)Antiplatelet Drugs. no (%), 291 (13.4)NSAIDs, no. (%), 1344 (61.9)D2: BMI, mean ±SD kg/m2:?26.7 ± 5.8)Smoking History, no. (%), current smoker 1886 (22), Former Smoker 3298 (38), Never Smoked 3431 (40)Prior MI, no (%), 250 (2.9)Angina, no (%), 381 (4.4)Hypertension, no (%), 2581 (29.8)Diabetes, no. (%), 470 (5.4)Corticosteriods, no. (%), 3793 (43.7)Lipid-lowering Drugs, no. (%), 768 (8.9)Antiplatelet Drugs. no (%), 648 (7.5)NSAIDs, no. (%), 5705 (65.9)A sub-analysis was done of non-responders and respondersAnti-TNFalpha Nonresponders, N:?1,638Mean Age (Y), 57Sex, female (%), 79Race, white (%), NRRace, black (%), NREthnicity, Latino (%) NRDisease Duration (mean & SD), 11 (IQR, 6-19)DMARD use (%), NRCorticosteroid use (%) 45.3MTX na?ve (%), 0 (inferred)Treatment resistant (%) NRPatients with early RA, three years or less, (%), NRBaseline DAS score, mean (SD), 6.4 (SD 1.1)Tender joint count, NRSwollen joint count, NRRequired treatment for latent TB, NROtherBMI, mean ±SD kg/m2:?26.9 (6.2)Smoking History, no. (%)Current smoker 382 (23)Former Smoker 625 (38)Never Smoked 621 (38)Prior MI, no (%), 48 (2.9)Angina, no (%), 85 (5.2)Hypertension, no (%), 506 (30.9)Diabetes, no. (%), 110 (6.7)Corticosteriods%ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallOverall attrition/withdrawal, n: In general for BSRBR only 2.2% of all patients enrolled > 12 months before July 31, 2006 had no returned rheumatologist questionnaires and 17.2% had no returned patient diaries. Only 0.6% had no follow up information from either source. Patients with no returned information from rheumatologist were not included in this analysis.Overall adverse events reported, n:D1: 17D2: 63; In subanalysis, nonresponders had 17 AEs and responders had 35 AEs.Serious adverse eventsCardiovascular events (specify), n:D1: MI, 17D2: MI, 63; In subanalysis, nonresponders had 17 MIs (n:?1,638), and responders had 35 MIs (n:?5,877).MalignanciesNRRespiratory eventsNROther infectionsNRGINROtherIn DMARD group, Person-years, 2893Number of Reported MIs:?17Rate of MIs per 1000 person-years (95% CI):?5.9 (3.4-9.4)Incident rate ratio, referentIncidence rate ratio adjusted for age and sex, referentIncidence rate ratio multivariate analysis, referentIn anti-TNFalpha DPerson-years, 13323Number of Reported MIs, 63Rate of MIs per 1000 person-years (95% CI), 4.8 (3.7 - 6.1)Incident rate ratio, 0.81 (0.47 - 1.38)Incidence rate ratio adjusted for age and sex, 1.13 (0.65 - 1.96)Incidence rate ratio multivariate analysis, 1.44 (0.56 - 3.67)In subanalysis, results among nonresponders, Person-years 1,815, Number of reported MIs:?17, rate of MIs per 1,000 person years was 9.4 (95% CI, 5.5 - 15.0), Incident rate ratio, referentIncidence rate ratio adjusted for age and sex, referentIncidence rate ratio multivariate analysis, referentAmon responders, Person-years 9,886, Number of reported MIs:?35, rate of MIs per 1,000 person-years (95% CI):? 3.5 (2.5 - 4.9), Incident rate ratio, 0.38 (2.5 - 4.0)Incidence rate ratio adjusted for age and sex, 0.38 (0.21 - 0.68)Incidence rate ratio multivariate analysis, 0.36 (0.19 - 0.69), incidence rate ratio by sex, multivariate analysis (male) 0.31 (0.12 - 0.81), (female) 0.46 (0.20 - 1.06).Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableDixon WG et al., 2010PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXhvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaXhvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl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ADDIN EN.CITE.DATA 39British Society for Rheumatology Biologics Register (BSRBR)Country and settingUKSource of fundingthe University of ManchesterResearch objectiveTo compare directly the risk between drugs, to explore time to event, site of infection and the role of ethnicity.Study designObservationalOverall N13739Duration of studyTotal follow-up time (person-yrs): DMARD: 7345Anti-TNF: 34025Median duration of follow-up/patient (yrs): DMARD: 2.30 Anti-TNF: 3.21Inclusion CriteriaPatient with doctor's dx of RAAt least 1 returned consultant follow-up questionnaire before 3/31/08Anti-TNF cohort the anti-TNF drug must have been their first biolgical drugDMARD cohort they must have been biologic naiveExclusion CriteriaNAComparisons (dosage and frequency)D1: Non-biologic DMARDs: Dosage and frequency NRD2: All anti-TNF: Dosage and frequency NRD3: ETN: Dosage and frequency NRD4: INF: Dosage and frequency NRD5: ADA: Dosage and frequency NRNumber in groupD1: 3232D2: 10712D3: 3913D4: 3295D5: 3504Mean age (years)D1: 60D2: 56D3: 56D4: 56D5: 57Overall: DMARD vs. All anti-TNF, P<0.001; Between the three anti-TNF drugs, P=0.012Sex, % femaleD1: 72D2: 76D3: 77D4: 76D5: 75Overall: DMARD vs. All anti-TNF, P<0.001; Between the three anti-TNF drugs, P=0.108Race, % whiteD1: 78D2: 83D3: 82D4: 82D5: 84Overall: DMARD vs. All anti-TNF, P<0.001Between the three anti-TNF drugs, P=0.363Race, % blackD1: Non-white: 2D2: Non-white: 3D3: Non-white:3D4: Non-white: 4D5: Non-white: 3Ethnicity, LatinoNRMean disease duration, yearsD1: 6 (1-15)D2: 11 (6-19)D3: 12 (6-19)D4: 12 (6-19)D5: 10 (5-18)Overall: DMARD vs. All anti-TNF, P<0.001; Between the three anti-TNF drugs, P<0.001TJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %: D1: 100MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): 205 patients switched from the DMARD cohort to the anti-TNF cohortACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): OverallNRSerious adverse events:NRMalignancies:NRRespiratory events:Tuberculosis?(n): D1: 0D2: 40 (118/100,000 pys; 95% CI, 84-160)D3: 8 (53/100,000 pys; 95% CI, 23-105)D4: 12 (123/100,000 pys; 95% CI, 64-215) D5: 20 (217/100,000 pys; 95% CI, 132-335)Rates of TBD1: NRD2: NRD3: 39 events/100,000 person-yrsD4: 136 events/100,000 person-yrsD5: 144 events/100,000 person-yrsIRR for active TBNon-white vs. white patients=6.5 (2.8-15.3). UK population rate of TB: 12.3-14.7 events/100,000 person-yrs from 2001-2005).Other infections:NRGI:NROther:NRQuality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year:Doran et al., 2002 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>330</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>330</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">330</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Doran, M. F.</author><author>Crowson, C. S.</author><author>Pond, G. R.</author><author>O'Fallon, W. M.</author><author>Gabriel, S. E.</author></authors></contributors><auth-address>Beaumont Hospital, Dublin, Ireland.</auth-address><titles><title>Predictors of infection in rheumatoid arthritis</title><secondary-title>Arthritis Rheum</secondary-title><short-title>Predictors of infection in rheumatoid arthritis</short-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2294-300</pages><volume>46</volume><number>9</number><keywords><keyword>Adrenal Cortex Hormones/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ complications/drug therapy</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Forecasting</keyword><keyword>Hospitalization</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Infection/ complications/epidemiology/etiology/therapy</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Minnesota/epidemiology</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Research Support, U.S. Gov't, P.H.S.</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2002</year><pub-dates><date>Sep</date></pub-dates></dates><accession-num>12355476</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>PT 10-9 (KD 9-13)</custom7></record></Cite></EndNote>40Country, Setting:US, Minnessota cohortFunding:Immunnex;NIHResearch Objective:Identify predictors of serious infections amnong pts with RAStudy Design:Retrospective CohortOverall N:609Study Duration: 39 yrsInclusion Criteria:Diagnosed with RA according to ACR criteriaExclusion Criteria:NRInterventions, dose:DMARDSN:NRMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRAge, /10-yr increment OR 1.49 95% CI,1.33-1.67 P < 0.001 Alcoholism OR 2.00 95%CI,1.27-3.16 P = 0.003 Leukopenia OR 2.17 95%CI,1.58-2.98 P < 0.001 Organic brain disease OR 2.94 95%CI,2.08-4.16 P < 0.001 DM OR 2.45 95%CI,1.84-3.27 P < 0.001 Chronic lung disease OR 2.83 95%CI,2.15-3.72 P < 0.001 Extraarticular RA OR 3.22 95%CI,2.17-4.77 P < 0.001 RF OR 1.65 95%CI,1.24-2.20 P < 0.001 RA nodules OR 1.76 95%CI,1.32-2.33 P < 0.001 Functional capacity OR 1.87 95%CI,1.49-2.35 P < 0.001 ESR OR 1.63 95%CI,1.25-2.13 P < 0.001 Chemo OR 5.02 95%CI,2.44-10.3 P < 0.001 Cyclophosphamide OR 6.14 95%CI,3.12-11.8 P < 0.001 Cyclosporine OR 1.99 95%CI,1.25-3.16 P = 0.004 Corticosteroids OR 1.90 95%CI,1.47-2.47 P < 0.001 NAOverall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Dougados et al., 1999 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1617</RecNum><DisplayText><style face="superscript">41</style></DisplayText><record><rec-number>1617</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1617</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dougados, M</author><author>Combe, B</author><author>Cantagrel, A</author><author>Goupille, P</author><author>Olive, P</author><author>Schattenkirchner, M</author><author>Meusser, S</author><author>Paimela, L</author><author>Rau, R</author><author>Zeidler, H</author><author>Leirisalo-Repo, M</author><author>Peldan, K</author></authors></contributors><titles><title>Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components</title><secondary-title>Annals of the rheumatic diseases</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>220-5</pages><volume>58</volume><number>4</number><keywords><keyword>CN-00164143</keyword></keywords><dates><year>1999</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>PT 9-28 (DJ 8-16) goes with 1520 (5 year follow up)</custom7></record></Cite></EndNote>41 and Maillefert et al., 2003 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1520</RecNum><DisplayText><style face="superscript">42</style></DisplayText><record><rec-number>1520</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1520</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maillefert, J F</author><author>Combe, B</author><author>Goupille, P</author><author>Cantagrel, A</author><author>Dougados, M</author></authors></contributors><titles><title>Long term structural effects of combination therapy in patients with early rheumatoid arthritis: five year follow up of a prospective double blind controlled study</title><secondary-title>Annals of the rheumatic diseases</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>764-6</pages><volume>62</volume><number>8</number><keywords><keyword>CN-00439296</keyword></keywords><dates><year>2003</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2</custom4><custom7>PT 9-28 (DJ 8-16) goes with 1617</custom7></record></Cite></EndNote>42Country, Setting:Finland, France, Germany (France only for 5 yr), multicenterFunding:Pharmacia UpjohnResearch Objective:Clinical benefit of MTX + SSZ compared to either drug alone early, active RA pts fulfilling some criteria of poor potential long term outcomeStudy Design:RCTOverall N:209 (146)Study Duration: 52 wks (5 yrs)Inclusion Criteria:Diagnosed according to ACR criteriaDuration < 1 yrPresence of active disease as defined by DAS ≥ 3 (calculation based on Ritchie articular index, 44 SJC, and ESR) and presence of RF and/or HLA DR 1/4Concommitant drugs allowed were analgesics and NSAIDSExclusion Criteria:Prior txt with steroids, DMARDS, or any drugs to treat RA other than analgesic or NSAIDSPts with contraindications to use of SSZ or MTXInterventions, dose:D1: SSZ + placeboD2: MTX + placeboD3: SSZ + MTXMTX: 7.5 mg wkly (2.5 mg 3 times per wk). After wk 16, could be increased to 15 mg wkly if efficacy inadequateSSZ: increased to 2 grams daily by d #9. Could be increased to 3 grams daily after wk 16 of study if efficacy was inadequateOther?: combo MTX + SSZN:D1: 68D2: 69D3: 68Mean age, yrs:D1: 52D2: 50D3: 52Sex, % female:D1: 71D2: 74D3: 77Race, % white:NRMean disease duration, yrs:D1: 2.9 mos since diagnosis, 10.8 since onsetD2: 2.3 mos from diagnosis, 18.4 from onsetD3: 3.4 mos from diagnosis, 10.6 from onsetTJC, mean:NRSJC, mean:D1: 10.5 D2: 9.4D3: 9.4DMARD use, %:All groups: 0Corticosteroid use, %All groups: 0MTX naive, %:All groups: 100Txt resistant, %:NRPts with Early RA (≤3 yrs):All groups: 100DAS change:D1: -1.15 D2: -0.87 D3: -1.26 (P = 0.019 from inter-group comparisons using analysis of variance)RAI changes:D1: -7.1D2: -4.2D3: -9.4 (P = 0.001) ACR response, %:D1: 59D2: 59D3: 65 (P = NR)At 5 yearsTxt of pts with early RA with combination therapy of MTX and SSZ during first yr did not result in any long term differences in disease activity, quality of life, or structural damage compared to monotherapy with either drug used aloneMean DAS (SD): D1 or D2: 2.2 (1) D3: 2.2 (1)Overall: (P = 0.9)HAQ: D1 or D2: 0.6 (0.7) D3: 0.6 (0.6) Overall: (P = 0.9)Overall: D1: 75D2: 75D3: 91Abdominal Pain:D1: 9D2: 6D3: 13Dizziness:D1: 6D2: 1D3: 3Headache:D1: 9D2: 4D3: 12Nausea:D1: 32D2: 23D3: 49Overall Attrition Rate, %:27% (28.8)ITT Analysis:YesQuality Rating:Fair Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableDuclos, 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE.DATA 43Country and settingMonocenter French tertiary-referral rheumatology unitSource of fundingNot reportedResearch objectiveEvaluate TNF blocker retention rates and their predisposing factors in daily practice.Study designRetrospective CohortOverall N770 (142 patients received more than one TNF blocker for 975 treatment courses)Duration of study1997 to December 15, 2004Quality rating Fair: single referral center population, different baseline population characteristicsInclusion CriteriaReceived a TNF blockerExclusion CriteriaNRInterventions, DoseD1: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRD2: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRNumber in groupD1: 440D2: 290Overall: 770Mean age (years)D1: 55.1D2: 41.6Overall: 49.3Sex, % femaleD1: 80.5D2: 29.7Overall: 60.4Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 13.5 yrs (9.5)D2: 13.6 (10.0)Overall: 13.4 (9.7)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NR Overall: 16.1 (21.5)DMARD use, %NR Overall: 3.0 (2.1)MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR NRHAQ, DAS SF-36 Radiographic measures Quality of life scales Others, (please name); mean difference/absolute difference (CI/SD/P Value)OverallPercentage of patients who did not interrupt treatment due to inefficacy or intolerance was 82.5% ± 1.3 at 6 months, 64.0% ± 1.8 at 12 months, 50.3% ± 2.1 at 24 months, and 39.4% ± 2.4 at 36 months. Retention rates were similar for 3 TNF blockers. At 1 year, rates were 63.2% ± 2.9, 63.9% ± 2.6, and 68.2% ± 4.6, and at 2 years, rates were 47.5% ± 3.2, 50.8% ± 3.0, and 60.2% ± 5.6 for IFX, ETN, and ADA, respectively (P = ?0.48). Analyses according to reason for interruption did not find any difference in efficacy between 3 agents (P = ?0.33), but showed a trend for a better tolerance with ETN and ADA versus with IFX (P = ?0.06)Overall adverse events reported, n: Serious adverse eventsNRMalignanciesNR Respiratory eventsNR Other infectionsNR GINROtherNRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEdwards et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2936</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>2936</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2936</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Edwards, C. J.</author><author>Cooper, C.</author><author>Fisher, D.</author><author>Field, M.</author><author>van Staa, T. P.</author><author>Arden, N. K.</author></authors></contributors><auth-address>University of Southampton, and Southampton General Hospital, Southampton, UK. cedwards@soton.ac.uk</auth-address><titles><title>The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1151-7</pages><volume>57</volume><number>7</number><keywords><keyword>Antirheumatic Agents/adverse effects/ therapeutic use</keyword><keyword>Arthritis, Infectious/ etiology</keyword><keyword>Arthritis, Rheumatoid/ complications/ drug therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Methotrexate/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Penicillamine/adverse effects/therapeutic use</keyword><keyword>Prednisolone/adverse effects/therapeutic use</keyword><keyword>Risk Assessment</keyword><keyword>Sulfasalazine/adverse effects/therapeutic use</keyword></keywords><dates><year>2007</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>17907232</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>44Country and settingUnited Kingdom, primary care database (GPRD)Source of fundingProctor & Gamble PhDaceuticalsGovernment or non-profit organization- please list name.Medical Research Council and Southhampton Rheumatology TrustResearch objectiveEvaluate effect of DMARDs on the likelihood of pts with RA developing septic arthritis (SA)Study designCohortOverall N136,997 (34,250 patients with RA, 102,747 controls)Duration of studyJune 1987-April 2002Quality rating FairInclusion CriteriaDiagnosis of RA (ICD-9 code 714.0)At least 3 control subjects without RA, matched by age (within 5 years), sex, and practice, were defined for each RA case.Exclusion CriteriaPatients with RA who were first diagnosed subsequent to a diagnosis of SAInterventions, DoseD1: PNL: Dosage NRMTX: Dosage NRLEF: Dosage NRSSZ: Dosage NRHydroxychlorquine: Dosage NROther: Any combinationD2: PNL: Dosage NRMTX: Dosage NRLEF: Dosage NRSSZ: Dosage NRHydroxychlorquine: Dosage NROther: Any combinationNumber in groupD1: 102,747D2: 34,250Mean age (years)D1: 55.3D2: 55.6P =.001Sex, % femaleD1: 71.4D2: 71.4P =1.0Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: NRD2: 40Overall: NRDMARD use, %D1: NRD2: 50Overall: NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Smoking (ever vs. never), %:D1: 37.5D2: 41.6P = 0.001Diabetes %:D1: 5.55D2: 5.50 P = 0.7Hypertension %:D1: 23.5D2: 22.8 P = 0.01Heart Failure: D1: 6.39D2: 9.38 P = 0.001Renal Failure %:D1: 0.86D2: 1.83 P = 0.001BMI IQR in kg meters squared: D1: 25.2 (22.7-28.2)D2: 24.9 (22.3-28.0) P = 0.001ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherSA incidence (1992-1997): 0.29 (95% confidence interval [95% CI] 0.27– 0.31) per 1,000 person-years for entire population studied (including RA cases and controls) and 0.11 (95% CI 0.09–0.12) per 1,000 person-years for control population. In RA population, SA incidence was increased at 1.31 (95% CI 1.22–1.41) per 1,000 person-years. incidence rate of SA was 12.9 times greater among patients with RA than among RA controls (95% CI 10.1–16.5, P = ?0.001). A diagnosis of RA, hypertension, heart failure, or renal failure significantly increased risk of future SA, and incidence of SA was significantly higher while experiencing one or more of these risk factors than while not. SA incidence rate while receiving a DMARD or PNL was 2.17 (95% CI 1.68–2.80, P = ?0.001) times greater than while receiving no drugs,even after adjustment for RA. Incident rate of SA in patients with RA receiving DMARDs was 2.14 (95% CI 1.64–2.78, P = ?.001) times greater than in patients with RA not receiving DMARDs, and corresponding rate ratio for RA controls was 2.80 (95% CI 1.03–,P = ?0.045). Incident rate ratios (IRRs) for developing SA while receiving DMARDs compared with receiving no DMARDs were different for different medications: SSZ (adjusted IRR 1.74, 95% CI 1.04–2.91, P 0.03), and PNL (adjusted IRR 2.94, 95% CI 1.93–4.46, P = ?0.001) were associated with an increased incidence of SA when compared with not receiving any DMARD. use of other DMARDs including MTX showed no such effect; adjusted IRR HCQ 0.59 (0.08-4.25); LEF no events; MTX 1.01 (0.44-2.34).Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Emery, 2000 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1579</RecNum><DisplayText><style face="superscript">45</style></DisplayText><record><rec-number>1579</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1579</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Emery, P</author><author>Breedveld, F C</author><author>Lemmel, E M</author><author>Kaltwasser, J P</author><author>Dawes, P T</author><author>Gomor, B</author><author>Van Den Bosch, F</author><author>Nordstrom, D</author><author>Bjorneboe, O</author><author>Dahl, R</author><author>Horslev-Petersen, K</author><author>Rodriguez De La Serna, A</author><author>Molloy, M</author><author>Tikly, M</author><author>Oed, C</author><author>Rosenburg, R</author><author>Loew-Friedrich, I</author></authors></contributors><titles><title>A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology</full-title><abbr-1>Rheumatology (Oxford).</abbr-1><abbr-2>Rheumatology (Oxford)</abbr-2></periodical><pages>655-65</pages><volume>39</volume><number>6</number><keywords><keyword>CN-00298162</keyword></keywords><dates><year>2000</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>DJ 10-2 (LL 8-8)</custom7></record></Cite></EndNote>45Country, Setting:Multinational, 117 centersFunding:NRResearch Objective:To compare both short and long-term (up to 2 yr) clinical efficacy and safety of LEF and MTX for txt of RAStudy Design:RCTOverall N:999Study Duration: 1 yr, optional second yrInclusion Criteria:Age: 18+Diagnosed with RA according to ACR criteria: Active DiseasePrevious use of DMARDs: only if discontinued 28 ds before trialDuration of condition: for at least 4 mos, but no longer than 10 yrsNSAIDs and steroids were allowed provided a stable dose of NSAIDs or steroid (≤ 10 mg/d) PNL for at least 28 ds prior to study entryWomen of childbearing age were required to use adequate contraceptionExclusion Criteria:Pregnant or lactatingPrior txt with: Intra-articular corticosteriod injections w/in 6 wks of efficacy assessmentInterventions, dose:D1: LEF Yr 1D2: MTX Yr 1D3: LEF Yr 2D4: MTX Yr 2MTX: 7.5 to 15 mg/wkLEF: loading dose of 100 mg/d for 3 ds, followed by maintenance dose 20/ mg/dN:D1: 501D2: 498D3: 292D4: 320Mean age, yrs:D1: 58.3D2: 57.8D3: 57.7D4: 57.0Sex, % female:D1: 70.7D2: 71.3D3: 71.2D4: 71.3Race, % white:NRMean disease duration, yrs:D1: 3.7 D2: 3.8D3: 3.5D4: 3.8TJC, mean:NRSJC, mean:NRDMARD use, %:D1: 66.3D2: 66.9D3: 64.7D4: 66.9Corticosteroid use, %D1: 36.3 D2: 33.5D3: 14.0 D4: 11.3MTX naive, %:NRDMARD Txt resistant, %:D1: 1.1 D2: 1.1D3: 1.0 D4: 1.1Pts with Early RA (≤ 3 yrs):NRAt year 1ACR20: D1: 50.5%D2: 64.8% (P < 0.001)HAQ improvement: Minimal quantitative difference between groups, but statistically significant (shown in figure only; P < 0.05)Radiograph change, Larsen Scores: D1 and D2: 0.03 increase (P = NS, NR)Primary clinical efficacy endpoints: TJC:D1: -8.3 D2: - 9.7SJC: D1: -6.8D2: -9.0 Physician global assessment: D1: -0.9 D2: -1.2 Pt global assessment:D1: -0.9 D2: -1.2 At year 2ACR20, %: D1: 64.3D2: 71.7 (P = NS, NR)SAEs:D1: 7%D2: 8%Headache:D1: 6.2D2: 4.8Hepatotoxicity:D1: 5.4D2: 16.3D3: 2.7D4: 5.9Nausea:D1: 11.2D2: 15.7URTI:D1: 5.2D2: 5.0D3: 4.5D4: 5.6DeathsMTX: 2Overall Attrition Rate, %:26.3% (263/999) during yr 1 Combined 2 yrs, attrition 50.3% (502/999) of those initially starting study at baseline During yr 2, attrition 18.8% (115/612) of those agreeing to continue study for 2nd yr ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEmery et al., 2006, DANCER trialPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE.DATA 46Country and settingMultinational, multicenterSource of fundingRoche primarily, also support from Genentech and Biogen IdecResearch objectiveExamine efficacy and safety of different RIT doses + MTX with or without glucocorticoids in pts resistant to DMARDs, including biologicsStudy designControlled TrialsOverall N465 (Note: 465 pts were randomizedadverse event and baseline data analyses usewhole population, efficacy analyses use an "ITT efficacy population" of N:?367.ITT population is limited toRF+ pts who were not exlcuded (13 RF+ pts were excluDuration of study24 weeksQuality rating Fair Inclusion CriteriaTreatment resistant, outpatients between ages of 18 - 80 years who had presented at least 6 mos prior to randomization with severe RA despite ongoing treatment with MTX for at least 12 weeksMust have failed prior treatment with at least 1 but not more than 5 DMARDs (other than MTX) and/or biologic response modifiersPts taking glucocorticoids were included ifdosage had been stable for at least 4 weeks before trial entryPts who received intraarticular or parenteral glucocorticoids were included if most recent administration was more than 4 weeks before screening.Exclusion CriteriaSignificant systematic involvement secondary to RAEvidence of significant other illness or laboratory adnormalitiesHistory of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodiesPrevious treatment with RIT or any lymphocyte-depleting therapiesHistory of recurrent significant infection.Interventions, doseD1: MethylPNL Placebo methylPNL IV: 30 - 60 minutes before infusion on days 1 and 15 - or - premed methylPNL 100 mg IV on days 1 and 15 - or - premed methylPNL 100 mg IV on days 1 and 15 plus 60 mg of oral PRED on days 2 - 7 and 30 mg on days 8 – 14PRED see "methylPNL" MTX: weekly regimen 10 - 25 mg orallyPlacebo placebo RIT: on days 1 and 15Folate: dosage and frequency NRD2: MethylPNL Placebo methylPNL IV: 30 - 60 minutes before infusion on days 1 and 15 - or - premed methylPNL 100 mg IV on days 1 and 15 - or - premed methylPNL 100mg IV on days 1 and 15 plus 60 mg of oral PRED on days 2 - 7 and 30 mg on days 8 – 14PRED see "methylPNL"MTX: weekly regimen: 10 - 25 mg orallyRITIn RF+ positive patients: 500 mg on days 1 and 15Other: folate: dosage and frequency NRD3: MethylPNL Placebo methylPNL IV: 30 - 60 minutes before infusion on days 1 and 15 - or - premed methylPNL 100 mg IV on days 1 and 15 -or - premed methylPNL 100mg IV on days 1 and 15 plus 60 mg of oral PRED on days 2 - 7 and 30 mg on days 8 – 14PRED see "methylPNL"MTX: weekly regimen: 10 - 25mg orallyRITIn RF+ pts: 1,000 mg on days 1 and 15; In RF- pts: 1,000 mg on days 1 and 15Other: folate: dosage and frequency NRNumber in groupD1: 122D2: 123D3: 122Mean age, years (%)51.1Sex, % female80Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years10.8Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100D3: 100Tender Joint Count, meanD1: 35D2: 33D3: 32Swollen Joint Count, mean D1: 21D2: 22D3: 22Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS scoreD1: 6.8D2: 6.8D3: 6.7Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1:Data presented in table above are baseline disease characteristics for ITT efficacy D (N:?367). Other population characteristics as follows are for "safety population" N:?465: (D1) Age, mean years:?51.1 %Female:?80, Duration of RA, mean years:?9.3, Previous DMARDs, mean number:?2.2 prior anti-tnf alpha treatment:?26%, MTX dose, mean mg/week:?15.6 D2:Data presented in table above are baseline disease characteristics for ITT efficacy D (N:?367). Other population characteristics as follows are for "safety population" N:?465: (D2) Age, mean years:?51.4 %Female:?83, Duration of RA, mean years:?11.1, Previous DMARDs, mean number:?2.5 prior anti-tnf alpha treatment:?33, MTX dose, mean mg/week:?16 D3:Data presented in table above are baseline disease characteristics for ITT efficacy D (N:?367). Other population characteristics as follows are for "safety population" N:?465: Prior anti-tnf alpha treatment:?28%, MTX dose, mean mg/week:?14.9 ACR mean difference/ absolute difference ACR 20:D1: 28D2: 55 (P ≤ 0.001)D3: 54 (P ≤ 0.001)ACR 50:D1: 13D2: 33 (P ≤ 0.001)D3: 34 (P ≤ 0.001)ACR 70:D1: 5D2: 13 (P = ?0.029)D3: 20 (P = ?0.0001HAQ-DI, mean change from baselineD1: -0.16D2: -0.43D3: -0.49DAS (P Value)Adjusted mean change:D1: -0.67D2: -1.79 (P = ?0.0001)D3: -2.05 (P = ?0.0001)SF-36, mean difference/absolute differenceNRRadiographic measures, mean difference/absolute differenceNRQuality of life scales NREULAR (%)No response: D1: 63D2: 28D3: 34Moderate/good response:D1: 37D2: 73D3: 67Good response:D1. 4%D2: 14%D3: 28%P = ?0.0001 for D2 and D4 vs. D1.Attrition/withdrawalOverall, n:D1: 52D2: 11D3: 27Withdrawals due to adverse events, n:D1: 0D2: 3D3: 6Withdrawals due to lack of efficacy, n:D1: 46D2: 8D3: 16Adherent/compliant, n: NR13 RF+ pts (out of 380) were exlcuded from analyses because of unblinding, drug dispensing errors, and unverifiable data.Serious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NR Other infectionsNRGINROtherData are from Safety Population N:?465Adverse events affecting 5% or more of patients in any one Dare reported, values are %. D1: All Events:?105, Exacerbations of RA:?44, Headache:?19, Nausea:?13, URI:?9, Nasopharyngitis:?8, Arthralgia:?5, Diarrhea:?8, Fatigue:?8, Hypertension:?4, Rigors:?3, Dizziness:?6, Serious noninfection adverse events:?2, Serious infections:?2; Arm 2: All Events:?100, Exacerbations of RA:?21, Headache:?14, Nausea:?8, URI:?10, Nasopharyngitis:?7, Arthralgia:?5, Diarrhea:?7, Fatigue:?5, Hypertension:?5, Rigors:?5, Dizziness:?4, Serious noninfection adverse events:?9, Serious infections:?0; Arm 3 All Events:?164, Exacerbations of RA:?27, Headache:?21, Nausea:?19, URI:?12, Nasopharyngitis:?10, Arthralgia:?11, Diarrhea:?6, Fatigue:?8, Hypertension:?12, Rigors:?13, Dizziness:?10, Serious noninfection adverse events:?9, Serious infections:?4Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEmery et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3551</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>3551</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3551</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Emery, P.</author><author>Kosinski, M.</author><author>Li, T.</author><author>Martin, M.</author><author>Russell, A. S.</author><author>et al.,</author></authors></contributors><auth-address>Univ Leeds, Dept Rheumatol & Rehabil, 36 Clarendon Rd, Leeds LS2 9N2, W Yorkshire, England p.emery@leeds.ac.uk</auth-address><titles><title>Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life</title><secondary-title>Journal of Rheumatology</secondary-title></titles><periodical><full-title>Journal of Rheumatology</full-title><abbr-1>J. Rheumatol.</abbr-1><abbr-2>J Rheumatol</abbr-2></periodical><pages>681-689</pages><volume>33</volume><number>Apr</number><keywords><keyword>Abatacept--arthritis-</keyword><keyword>Methotrexate--arthritis-</keyword><keyword>Anti inflammatory agents--methotrexate</keyword><keyword>Combined therapy--abatacept and methotrexate</keyword><keyword>Combined therapy--methotrexate and abatacept</keyword><keyword>Immunostimulant agents--abatacept</keyword><keyword>Quality of life--methotrexate</keyword><keyword>Quality of life--abatacept</keyword><keyword>Arthritis--abatacept</keyword><keyword>Toxicity--abatacept</keyword><keyword>Arthritis--methotrexate</keyword><keyword>Toxicity--methotrexate</keyword><keyword>Outcomes--clinical</keyword></keywords><dates><year>2006</year><pub-dates><date>04/01/</date></pub-dates></dates><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>CT</custom3><custom4>KQ 2 / fair</custom4></record></Cite></EndNote>47Country and settingUK, US, CanadaSource of fundingBristol-Myers SquibbResearch objectiveExamine effect of ABA on HRQOLStudy designControlled TrialsOverall N339Duration of study1 yearQuality rating Fair Inclusion CriteriaAmerican Rheumatism Association criteria for RA while meeting functional class I, II, or III according to revised criteria of ACRHave?>?10 swollen,?>?12 tender joints, and CRP level?>?1 mg/dl signifying active diseaseHave been treated with MTX for at least 6 mos and on a stable dose for 28 days prior to enrollmentBe washed-out of all DMARD other thanExclusion CriteriaNRInterventions, DoseD1: MTX: 15.8 (SD 4.1)Abatacept: 2 mg/kg administered at baseline, every two weeks for first month, then monthly thereafterD2: MTX: 15.8 (SD 4.8)Abatacept: 10 mg/kg administered at baseline, every two weeks for first month, then monthly thereafterD3: MTX: 15.0 (SD 4.4)Placebo Number in groupD1: 105D2: 115D3: 119Overall: 339Mean age (years)D1: 54.4D2: 55.8D3: 54.7Sex, % femaleD1: 62.9D2: 74.8D3: 66.4Race, % whiteD1: 86.7D2: 86.9D3: 87.4Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 9.7 (8.1)D2: 9.7 (9.8)D3: 8.9 (8.3)Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)D1: 28.2D2: 30.8D3: 29.2SJC, mean (SD) D1: 20.2D2: 21.3D3: 21.8Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: All reported characteristics were similar at baseline including mean MTX dose and HRQOL scoreD2: All reported characteristics were similar at baseline including mean MTX dose and HRQOL scoreD3: All reported characteristics were similar at baseline including mean MTX dose and HRQOL scoreACR NRHAQ NRDAS NRSF-36, mean Changes in 8 categories of SF-36 scale PF (SE)Physical functioningD1: 4.7 (0.9)D2: 7.2 (0.8)D3: 2.1 (0.8)Role limitations due to physical health (RP):D1: 5.3 (1.1)D2: 8.2 (1.0)D3: 4.1 (1.0)Bodily pain (BP):D1: 6.5 (0.9)D2: 9.3 (0.8)D3: 3.5 (0.8)General health perceptions (GH):D1: 4.1 (0.7)D2: 5.8 (0.7D3: 2.3 (0.7)Vitality (VT):D1: 3.5 (0.8)D2: 7.9 (0.8)D3: 2.1 (0.8)Social functioning (SF):D1: 4.6 (1.0)D2: 7.6 (0.9)D3: 3.6 (0.9)Role limitations due to emotional health (RE):D1: 5.0 (1.4)D2: 6.8 (0.9)D3: 3.8 (1.0)Mental health (MH):D1: 3.5 (0.9)D2: 5.3 (0.8)D3: 2.6 (0.8)Mean Changes in SF-36 summary measures, physical summary measure (SE)Physical summary measure (PCS):D1: 5.2 (0.8)D2: 8.0 (0.8)D3: 2.6 (0.7)Mental summary measure (MCS): D1: 3.5 (1.0)D2: 5.7 (0.9)D3: 2.8 (0.9)Radiographic measures NRQuality of life scales D1: See SF-36 resultsD2: See SF-36 resultsD3: See SF-36 resultsOverall: See SF-36 resultsOthers, (please name) Differences in Mean Change Scores in 8 categories of SF-36 scale: Placebo vs. Abatacept 2mg/kg - Physical Functioning (PF)?=?2.6 (P?=?0.05)Role limitations due to physical health (RP)?=?1.2Bodily pain (BP)?=?3.0 (P?=?0.05)General health perceptions (GH)?=?1.8Vitality (VT)?=?1.4Social functioning (SF)?=?1.0Role limitations due to emotional health (RE)?=?1.8Mental health (MH)?=?0.9Differences in Mean Change Scores in SF-36 summary measures: Physical summary measure (PCS)?=?2.6 (P?=?0.05)Mental summary measure (MCS)?=?0.7Difference in Mean Change Score in SF-36 Utility Index: SF-6D?=?0.00 - - Abatacept 2mg/kg vs. Abatacept 10 mg/kg - Physical Functioning (PF)?=?2.5 (P?=?0.05)Role limitations due to physical health (RP)?=?2.9 (P?=?0.05)Bodily pain (BP)?=?2.8 (P?=?0.05)General health perceptions (GH)?=?1.7Vitality (VT)?=?4.4 (P?=?0.001)Social functioning (SF)?=?3.0 (P?=?0.05)Role limitations due to emotional health (RE)?=?1.8Mental health (MH)?=?1.8Differences in Mean Change Scores in SF-36 summary measures: Physical summary measure (PCS)?=?2.8 (P?=?0.05)Mental summary measure (MCS)?=?1.9Difference in Mean Change Score in SF-36 Utility Index: SF-6D?=?0.05 (P?=?0.05) - - Placebo vs. Abatacept 10 mg/kg - Physical Functioning (PF)?=?5.1 (P?=?0.0001)Role limitations due to physical health (RP)?=?4.1 (P <0.01)Bodily pain (BP)?=?5.8 (P <0.0001)General health perceptions (GH)?=?2.5 (P?=?0.001)Vitality (VT)?=?5.8 (P?=?0.0001)Social functioning (SF)?=?4.0 (P?=?0.01)Role limitations due to emotional health (RE)?=?3.0 (P?=?0.001)Mental health (MH)?=?2.7 (P?=?0.05)Differences in Mean Change Scores in SF-36 summary measures: Physical summary measure (PCS)?=?5.4 (P?=?0.0001)Mental summary measure (MCS)?=?2.9 (P?=?0.05)Difference in Mean Change Score in SF-36 Utility Index: SF-6D?=?0.05 (P?=?0.001)OverallOverall attrition/withdrawal, n:D1: 31D2: 25D3: 48Overall: 104Overall adverse events reported, n: NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEmery et al., 2008, COMETPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 48Country and settingMultinational, multicenterSource of fundingWyeth ResearchResearch objectiveCompare remission and radiographic non-progression in pts treated with MTX monotherapy or MTX + ETNStudy designControlled TrialsOverall N542Duration of study52 weeksQuality rating Fair Inclusion CriteriaMTX Na?veEarly RA defined as at least 3 mos but less than 2 yrsAge 18 years or older with diagnosis of adult-onset RADisease duration of at least 3 mos but not more than 2 yearsDAS28 of 3·2 or moreEither Westergren ESR of 28 mm/h or more or CRP of 20 mg/L or more.Exclusion CriteriaPrevious treatment with MTX, ETN, or another TNF antagonist at any timeHad received treatment with other DMARDs or corticosteroid injections in4 weeks before baseline visits.Important concurrent medical diseases and/or other relevant comorbidities.Interventions, doseD1: MTX: 7.5 mg orally once a week Placebo ETN-matching placebo injections subcutaneously: once a week for 52 weeks Other: In patients with tender or swollen joints, dose was titrated up over 8 weeks to a maximum of 20 mg a weekD2: MTX: 7.5 mg orally once a week ETN: 50 mg by subcutaneous injection once a week for 52 weeks Other: In patients with tender or swollen joints, dose was titrated up over 8 weeks to a maximum of 20 mg a weekNumber in groupD1: 263D2: 265Overall: 528Mean age, years (SD)D1: 52.3D2: 50.5Overall: 51.4Sex, % femaleD1: 73D2: 74Overall: 73Race, % whiteD1: 88D2: 87Overall: 88Race, % blackNREthnicity, LatinoNRMean disease duration, monthsD1: 9.3 (0.4)D2: 8.8 (0.4)Overall: 9.0 (0.3)Patients with early RA, three years or less, %D1: 100D2: 100Overall: 100 Treatment resistant, %NRTender Joint Count, meanD1: 24.8 (14.5)D2: 25.1 (14.6)Overall: 25.0 (14.5)Swollen Joint Count, mean D1: 17.6 (10.0)D2: 17.1 (10.5)Overall: 17.3 (10.2)Corticosteroid use, %D1: 50D2: 49Overall: 49DMARD use, %D1: 24D2: 18Overall: 21MTX na?ve, %D1: 100D2: 100Overall: 100Baseline DAS28 mean (SD)D1: 6.5 (1.0)D2: 6.5 (1.0)Overall: 6.5 (1.0)Required treatment for latent TBNRHAQ mean?(SD)D1: 1.6 (0.7) D2: 1.7 (0.7)Overall: 1.7 (0.7)ACR mean difference/ absolute difference?(%)Week 52:ACR 20:D1: 67 (61-73)D2: 86 (82-90)Overall: Week 52: P = ?.0001ACR 50:D1: 49 (43-55)D2: 71 (66-76)P =.0001ACR 70:D1: 28 (22-34)D2: 48 (41-55)P =.0001HAQ, Week 52 difference:D1: 0.7D2: 1.0P = 0.0001Remission DAS28:?2.6 (CI)At week 52:D1: - 73 [28%] of 263 (23-33%) D2: -132 [50%] of 265 (44-56%) Overall: Week 4: DAS 44- effect difference 9.07% (95% CI 4.84-13.31%, P = ?0·0001) Week 52: DAS 28 22.05%, 95% CI 13.96-30.15%, P <0.0001)/ Week 52: DAS 44: effect difference-23.56% (95% CI: 15.47-31.66%)SF-36 NRRadiographic measures (CI)Week 52: mTSS change from baseline D1: - 2.44 (1.45 -3.43)D2: - 0.27 (-0.13- 0.68) Overall: mTSS-effect difference 20.98%, (12.97-29.09%, P = ?0.0001)Quality of life scales NRMean DAS 28 swollen joint count- Week (CI/SD/P Value)D1: 8D2: 10.6P = 0.0108Radiographic nonprogression: mTSS::?0.5 (%)D1: 59 (53-65)D2: 80 (75-85), P = ?0.0001Attrition/withdrawalOverall, n:D1: 79D2: 53Withdrawals due to adverse events, n:D1: 34D2: 28Withdrawals due to lack of efficacy, n:D1: 24D2: 9Adherent/compliant, n:D1: 221D2: 189Overall adverse events reported, n:D1: 246D2: 247Overall: 493Serious adverse eventsDeath, n: NR Overall: 1Cardiovascular events (specify), n:D1: 2D2: 2Overall: 4Hepatotoxicity/elevated liver enzymes, n:D1: 0D2: 3Overall: 3MalignanciesLymphoma or leukemia, n:D1: CLL: 0D2: CLL: 1Overall: CLL: 1Skin?cancer (basal cell?or squamous cell), n:D1: 0D2: 4Overall: 4Breast cancer, n:D1: 3D2: 0Overall: 3Prostate cancer:D1: 0D2: 1Overall: 1Respiratory eventsTuberculosis: NRPneumonia, n:D1: 1D2: 1Overall: 2Upper respiratory infection, n:D1: 44D2: 45Overall: 99Other infectionsNot specified, n:D1: 8D2: 5Overall: 14Opportunistic Herpes Zoster: D1:1D2: NRGINausea or vomiting, n:D1: 50D2: 53Overall: 103Not specified, n:D1: 4D2: 1Overall: 5OtherInfusion/injection site reactions, n:D1: 1D2: 2Overall: 3Demyelenation or multiple sclerosis, n:D1: 0D2: 0Overall: 0Worsening of RA, n:D1: 5D2: 2Overall: 7Cholelithiasis, n:D1: 0D2: 2Overall: 2Intervertebral disc protrusion, n:D1: 0D2: 2Overall: 2Osteoarthritis, n:D1: 2D2: 0Overall: 2Any other AEs: Interstitial lung disease (2 incombined-treatment group) and hip arthroplasty (2 in MTX group).Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEmery el al., 2008, RADIATE StudyPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE.DATA 49Country and settingMultinational multicenterSource of fundingHoffmann-La Roche Ltd, Chugai Pharma KKResearch objectiveExamine safety and efficacy of Tocilizumab in pts refractory to TNF antagonist therapyStudy designControlled TrialsOverall N499Duration of study24 weeksQuality rating Fair Inclusion CriteriaTreatment resistant inadequate response to 1 or more TNF antagonist withinpast year18 years old or older with moderate to severe RA for 6 mos or moreSwollen joint count of 6 or moreCRP of more than 1.0 mg/dl or ESR of more than 28 mm/hTreatment with MTX for 12 weeks or moreExclusion CriteriaTreatment with cell depleting agentsUncontrolled medical conditionsHistory of other inflammatory diseases or functional class 4 RAHistory of malignancies or recurrent infectionsPrimary or secondary immunodeficiencyHemoglobin less than 8.5 g/dlLeucopeniaNeutropeniaThrombocytopeniaAbnormal liver functionTtriglycerides greater than 10 mmol/lRecognized active TB, hepatitis B, or hepatitis CInterventions, doseD1: MTX: 10-25 mg/weekTocilizumab: 8 mg/kg every 4 weeksD2:MTX: 10-25 mg/weekTocilizumab: 4 mg/kg every 4 weeksD3: MTX10-25 mg/weekPlacebo every 4 weeksNumber in groupD1: 170D2: 161D3: 158Overall: 498Mean age, years (SD)D1: 53.9D2: 50.9D3: 53.9Sex, % femaleD1: 84D2: 81D3: 79Overall: 79.5Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 12.6 (9.3)D2: 11.0 (8.5)D3: 11.4 (9.2)Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100D3: 100Overall: 10Tender Joint Count, meanD1: 31.7 (15.4)D2: 31.3 (15.1)D3: 30.4 (16.8)Swollen Joint Count, mean D1: 18.9 (10.9)D2: 19.5 (10.4)D3: 18.9 (11.1)Corticosteroid use, %Receiving oral steroids: D1: 52D2: 58D3: 58Overall: 54.6DMARD use, %D1: 100D2: 100D3: 100Overall: 100MTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS scoreD1: 6.79 (0.93)D2: 6.78 (0.97)D3: 6.80 (1.06)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: HAQ-D1: 1.7 (0.6)D2: 1.7 (0.6)D3: 1.7 (0.6)ACR mean difference/ absolute difference (P Value)ACR 20:D1: 50D2: 30.4D3: 10.1 (P = ?0.001)ACR 50:D1: 28.8 (P = ?0.001)D2: 16.8 (P = ?0.001)D3: 3.8ACR 70:D1: 12.4 (P = ?0.001)D2: 5.0 (P = ?0.1)D3: 1.3HAQ D1: -0.39 (P = ?0.001)D2: -0.31 (P = ?0.003)D3: -0.05DAS (%)Low disease activity (DAS:?3.2):D1: 51.2D2: 15.2D3: 4.9%Remission (DAS:?2.6): D1: 30.1% (P = ?0.001)D2: 7.6% (P = ?0.053)D3: 1.6%SF-36, mean difference/absolute differenceNRRadiographic measures Swollen joint count:D1: -7.8 (P = ?0.001)D2: -6.8 (P = ?0.001)D3: -0.5Tender joint count: D1: -14.8 (P = ?0.001)D2: -10.5 (P = ?0.001)D3: -0.3Quality of life scales, mean difference/absolute differenceNRGood or moderate EULAR responsesD1: 67.7% (P = ?0.001)D2: 46.5% (P = ?0.001)D3: 16.5%Attrition/withdrawalOverall, n:D1: 23D2: 25D3: 33Overall: 82Withdrawals due to adverse events, n:D1: 11D2: 10D3: 10Overall: 31Withdrawals due to lack of efficacy, n:D1: 4D2: 6D3: 19Overall: 291 control withdrew after randomization but before receiving study treatment due to latex allergyPatients received rescue therapy (8 mg/kg of tocilizumab plus MTX at week 16 in case of treatment failure defined as less than 20% improvement in both SJC and TJC): D1:20D2:30D3: 63 Overall adverse events reported, n:D1: 147D2: 142D3: 129Overall: 418Serious adverse eventsDeath, n:D1: 0D2: 0D3: 0Overall: 0Myocardial infarction, n:D1: 0D2: 0D3:1Overall: 1Hepatotoxicity/elevated liver enzymes, n:D1: 4D2: 0 4D3: 0 1Overall: 0 9MalignanciesNRRespiratory eventsTuberculosis: NROther infectionsInfections:D1: 86D2: 76D3: 66Overall: 228Serious infections:D1: 8D2: 3D3: 5Overall: 16GIOther GI event (not specified), n:D1: 64D2: 53D3: 31Overall: 90OtherInfusion/injection site reactions, n:D1: 15D2: 15D3: 10Overall: 40HDL > 60 mg/dl, n:D1: 29D2: 22D3: 6Overall: 57LDL > 160 mg/dl, n:D1: 21D2: 25D3: 6Overall: 52Severe AE (resulting in inability to work or perform daily activities), n:D1: 24D2: 22D3: 31Overall: 77Serious AE (primarily related to complications of RA), n:D1: 11D2: 12D3: 18Overall: 41AE leading to discontinuation, n: D1: 10D2: 10D3: 8AE leading to dose modification, n: D1: 12D2: 24D3: 1Note that AE occurring in those receiving rescue therapy excluded from AE analysisStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableEmery et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE.DATA 50Country and settingMultinational; multicenterSource of fundingCentocor Research and Development; Schering-Plough Research InstituteResearch objectiveTo assess the safety and efficacy of GOL in MTX-naive patients with active RA.Study designRCTOverall N637Duration of study24 wksQuality rating Fair Inclusion CriteriaMTX na?veAdults with ACR diagnosis of RA for at least 3 mosNot received more than 3 wkly doses of MTX as RA tx≥ 4 swollen and tender jointsmet ≥ 2 of the following criteria: (1) CRP of 1.5 mg/dl or more or ESR of 28 mm/hr or greater; (2) morning stiffness lasting 30 minutes or longer (3) bone erosion by radiography and/or MRI prior to tx initiation with study agent; (4) anti-cyclic citrullinated peptide antibody positivity or rheumatoid factor positivity; met prespecified TB screening criteriaExclusion CriteriaPrevious use of INF, ETN, ADA, RTX, natalizumab, or cytotoxic agentsInterventions, DoseD1: MTX: 10 mg/wk escalated to 20 mg/wkPlaceboD2: GOL: 100 mg every 4 wksPlaceboD3: MTX: 10 mg/wk escalated to 20 mg/wkGOL: 50 mg every 4 wksD4: MTX: 10 mg/wk escalated to 20 mg/wkGOL: 100 mg every 4 wksNumber in groupD1: 160D2: 159D3: 159D4: 159Mean age (years)D1: 48.6D2: 48.2D3: 50.9D4: 50.2Overall: NRSex, % femaleD1: 83.8D2: 84.3D3: 84.9D4: 78.6Overall: NRRace, % whiteD1: 71.3D2: 69.8D3: 74.8D4: 73.6Overall: NRRace, % blackD1: 3.8D2: 2.5D3: 0.6D4: 0.6Overall: NREthnicity, LatinoD1: NRD2: NRD3: NRD4: NROverall: NRMean disease duration, yearsD1: 2.9 (4.8)D2: 4.1 (5.6)D3: 3.5 (5.65)D4: 3.6 (6.09)Overall: NRPatients with early RA, three years or less, %: D1: 72.5D2: 63.5D3: 73.0D4: 69.8Overall: NR Treatment resistant, %: NRTender Joint Count, meanD1: 27.3 (16.16)D2: 27.3 (15.4)D3: 29.2 (26.0)D4: 27.4 (14.7)Overall: NRSwollen Joint Count, mean D1: 14.9 (10.01)D2: 15.2 (10.08)D3: 16.0 (9.98)D4: 15.8 (10.34)Overall: NRCorticosteroid use, %D1: 68.1D2: 63.5D3: 69.8D4: 65.4Overall: NRDMARD use, %: D1: 51.9D2: 58.5D3: 50.3D4: 57.2Overall: NRMTX na?ve, %: 100Baseline DAS scoreUsing CRPD1: 5.0 (1.01)D2: 5.2 (0.98)D3: 5.1 (0.99)D4: 5.1 (1.0)Overall: NRUsing ESRD1: 6.2 (1.17)D2: 6.3 (1.10)D3: 6.3 (1.11)D4: 6.3 (1.11)Overall: NRRequired treatment for latent TBNROther population characteristics: ACR:ACR 20: ITT popD1: 49.4D2: 51.6D3: 61.6 (P = 0.028)D4: 61.6 (P = 0.028)ACR 50: ITT popD1: 29.4D2: 32.7D3: 40.3 (P = 0.042)D4: 36.5 (P = 0.177)mITT popD1: 29.4D2: 33.1D3: 40.5 (P = 0.038)D4: 36.5 (P = 0.177)ACR 70: ITT popD1: 15.6D2: 13.8D3: 23.9 (P = 0.064)D4: 18.2 (P = 0.535)HAQ: DAS: SF-36: Radiographic measures: Quality of life scales: Others: OverallOverall attrition/withdrawal (n): D1: 10D2: 11D3: 9D4: 8Withdrawals due to adverse events?(n): UnclearWithdrawals due to lack of efficacy?(n): UnclearAdherent/compliant?(n): UnclearOther attrition related comments? Figure 1 describes the number of patients that discontinued a study agent and stratifies by SC and oral agents. The lists are not mutually exclusive, so it is unclear how many of the total withdrawals were due to adverse events or for reasons of efficacy.Overall adverse events reported (n): D1: 116D2: 107D3: 129D4: 121Serious adverse events:Death (n):D1: 0D2: 0D3: 1D4: 1Cardiovascular events (specify)?(n): HTND1: 3D2: 4D3: 8D4: 6Hepatotoxicity/elevated liver enzymes?(n): ALTD1: 10D2: 7D3: 20D4: 12ASTD1: 6D2: 6D3: 13D4: 10Malignancies:Lymphoma or leukemia?(n): D1: 0D2: 0D3: 0D4: 1Skin?cancer (basal cell?or squamous cell)?(n): D1: 1D2: 0D3: 0D4: 0Other cancer (specify)?(n): MalignancyD1: 2D2: 0D3: 1D4: 1Breast cancerD1: 1D2: 0D3: 1D4: 0Respiratory events:Tuberculosis?(n): D1: 0D2: 0D3: 1D4: 0Pneumonia (n): D1: NRD2: NRD3: NRD4: 2Upper respiratory infection?(n): D1: 14D2: 9D3: 13D4: 19Other infections:InfectionsD1: 52D2: 55D3: 54D4: 50Serious infectionsD1: 3D2: 2D3: 2D4: 7GI:NauseaD1: 16D2: 11D3: 22D4: 24VomitingD1: 3D2: 2D3: 4D4: 7Abdominal pain (n): D1: 1D2: 6D3: 9D4: 5DyspepsiaD1: 7D2: 5D3: 10D4: 8Other:Infusion/injection site reactions?(n): D1: 3D2: 17D3: 7D4: 14Skin rash (n): D1: 7D2: 6D3: 8D4: 5Headache?(n): D1: 10D2: 7D3: 6D4: 11Dizziness (n): D1: 1D2: 3D3: 7D4: 3Serious AEsD1: 11D2: 5D3: 10D4: 10 Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableEmery, 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUw
NTE8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41MTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjUwNTE8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjUwNTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5FbWVyeSwg
UC48L2F1dGhvcj48YXV0aG9yPkJyZWVkdmVsZCwgRi48L2F1dGhvcj48YXV0aG9yPnZhbiBkZXIg
SGVpamRlLCBELjwvYXV0aG9yPjxhdXRob3I+RmVycmFjY2lvbGksIEcuPC9hdXRob3I+PGF1dGhv
cj5Eb3VnYWRvcywgTS48L2F1dGhvcj48YXV0aG9yPlJvYmVydHNvbiwgRC48L2F1dGhvcj48YXV0
aG9yPlBlZGVyc2VuLCBSLjwvYXV0aG9yPjxhdXRob3I+S29lbmlnLCBBLiBTLjwvYXV0aG9yPjxh
dXRob3I+RnJldW5kbGljaCwgQi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1
dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIExlZWRzLCBMZWVkcywgVUsuIHAuZW1lcnlAbGVlZHMu
YWMudWs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Ud28teWVhciBjbGluaWNhbCBhbmQg
cmFkaW9ncmFwaGljIHJlc3VsdHMgd2l0aCBjb21iaW5hdGlvbiBldGFuZXJjZXB0LW1ldGhvdHJl
eGF0ZSB0aGVyYXB5IHZlcnN1cyBtb25vdGhlcmFweSBpbiBlYXJseSByaGV1bWF0b2lkIGFydGhy
aXRpczogYSB0d28teWVhciwgZG91YmxlLWJsaW5kLCByYW5kb21pemVkIHN0dWR5PC90aXRsZT48
c2Vjb25kYXJ5LXRpdGxlPkFydGhyaXRpcyBSaGV1bTwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz
PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFydGhyaXRpcyBhbmQgUmhldW1hdGlzbTwvZnVsbC10
aXRsZT48YWJici0xPkFydGhyaXRpcyBSaGV1bS48L2FiYnItMT48YWJici0yPkFydGhyaXRpcyBS
aGV1bTwvYWJici0yPjxhYmJyLTM+QXJ0aHJpdGlzICZhbXA7IFJoZXVtYXRpc208L2FiYnItMz48
L3BlcmlvZGljYWw+PHBhZ2VzPjY3NC04MjwvcGFnZXM+PHZvbHVtZT42Mjwvdm9sdW1lPjxudW1i
ZXI+MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDIvMjc8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3
b3JkPkFudGlyaGV1bWF0aWMgQWdlbnRzL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8gdGhl
cmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1
ZyB0aGVyYXB5L3JhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJvZ3Jlc3Np
b248L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29y
ZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgVGhl
cmFweSwgQ29tYmluYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3
b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHLyBhZG1pbmlzdHJh
dGlvbiAmYW1wOyBkb3NhZ2UvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8
L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG90cmV4YXRlLyBhZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3Nh
Z2UvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y
ZD48a2V5d29yZD5SZWNlcHRvcnMsIFR1bW9yIE5lY3Jvc2lzIEZhY3Rvci8gYWRtaW5pc3RyYXRp
b24gJmFtcDsgZG9zYWdlL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UcmVhdG1l
bnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxw
dWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyOS0w
MTMxIChFbGVjdHJvbmljKSYjeEQ7MDAwNC0zNTkxIChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9u
LW51bT4yMDE4NzEzNTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+STwvY3Vz
dG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b200PktRIDEsIDIsIDMgLyBmYWlyPC9jdXN0
b200PjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDAyL2FydC4yNzI2OCBbZG9pXTwvZWxl
Y3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08L3JlbW90
ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0Np
dGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE.DATA 51 COMET trial (do not combine with other COMET REF IDs)Country and settingmultinational; multicenterSource of fundingWyeth Pharmaceuticals; PfizerResearch objectiveTo evaluate how continuation of and alterations to initial year 1 combination ETN + MTX therapy and MTX monotherapy regimens affect long-term remission and radiograhic progression in early active RAStudy designRCTOverall N411Duration of studytotal of 2 yrs (results from this study from wk 52 to wk 104)Inclusion CriteriaEarly RADisease duration of 3-24 mosIncluded in year 2 of studyCompleted COMET trial by end of year 1Exclusion CriteriaPrevious treatment with MTX, ETN, or another TNF antagonist at any timeHad received treatment with other DMARDs or corticosteroid injections in4 weeks before baseline visitsImportant concurrent medical diseases and/or other relevant parisons (dosage and frequency)D1: MTX: avg. of 16.2 mg once weeklyETN: 50 mg once weekly(ETN+MTX in year 1)D2: ETN: 50 mg once weekly(ETN+MTX in year 1)D3: MTX: avg. 17.8 mg once a weekETN: 50 mg once weekly(MTX in year 1)D4: MTX: avg.18.0 mg once weekly (MTX in year 1)Number in groupD1: 108D2: 108D3: 88D4: 94Overall: 398Mean age (years)D1: 52.4D2: 52.2D3: 55.6D4: 53.2Overall: 53.2Sex, % femaleD1: 72.2D2: 75.9D3: 59.1D4: 81.9Overall: 72.6Race, % whiteD1: 87.0D2: 88.0D3: 88.6D4: 88.3D5Overall: 87.9Race, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 8.4 mos (5.7)D2: 9.1 mos (5.6)D3: 9.1 mos (6.0)D4: 8.7 mos (5.4)Overall: 8.8 mos (5.7)TJC, meanD1: 3.9 (7.3)D2: 3.7 (7.9)D3: 6.5 (10.2)D4: 6.1 (7.9)Overall: 4.9 (8.4)SJC, mean D1: 2.7 (6.1)D2: 1.5 (3.1)D3: 3.9 (6.4)D4: 3.1 (4.4)Overall: 2.7 (5.2)Corticosteroid use, %NRDMARD use, %: D1: 100D2: 100D3: 100D4: 100Overall: 100MTX na?ve, %: 0Treatment resistant, %: NRPatients with early RA, three years or less, %: 100 Baseline DAS scoreD1: 2.7 (1.2)D2: 2.6 (1.2)D3: 3.3 (1.4)D4: 3.4 (1.4)Overall: 3.0 (1.4)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: D1: 86 (P<0.001 compared to MTX/MTX)D2: 80 (P=0.004, compared to MTX/MTX)D3: 81D4: 61ACR 50: D1: 70 (P<0.001 compared to MTX/MTX)D2: 64 (P=0.007 compared to MTX/MTX)D3: 66D4: 46ACR 70: D1: 57 (P<0.001 copmared to MTX/MTX)D2: 44 (P=0.034 compared to MTX/MTX)D3: 48D4: 32HAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): Diff from wk 104 and wk 52 D1: 0.00 D2: -0.5 (P<0.001 versus MTX/MTX)D3: 0.5 (P<0.05 versus ETN + MTX/ETN + MTX)D4: 0.1SF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): SHS change from wk 52 to wk 104, mean (95% CI)D1: -0.02 (-0.32 to 0.29; P=0.006 vs ETN + MTX/ETN)D2: 0.11 (-0.54 to 0.77)D3: 0.78 (-0.06 to 1.61)D4: 2.07 (0.42 to 3.72)Quality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallOverall attrition/withdrawal (n): D1: 7D2: 18D3: 16D4: 23Overall: 64Withdrawals due to adverse events?(n): D1: 3D2: 5D3: 7D4: 9Overall: 24Withdrawals due to lack of efficacy?(n): D1: 0D2: 7D3: 1D4: 7Overall: 15Overall adverse events reported (n): D1: 91D2: 89D3: 71D4: 79Overall: 330Serious adverse events:Death (n): D1: 0D2: 0D3: 0D4: 1Overall: 1Malignancies:MalignancyD1: 0D2: 1D3: 5D4: 3Overall: 9Respiratory events:NROther infections:Serious InfectionsD1: 1D2: 2D3: 1D4: 2Overall: 6GI:NROther:NRQuality rating for efficacy/effectiveness? FairQuality rating for observational studies NRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableEmery et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx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ADDIN EN.CITE.DATA 52 SERENECountry and settingmultinational; multicenterSource of fundingHoffmann-La Roche, Genentech, Biogen IdecResearch objectiveTo study the efficacy and safety of RTX 2 x 500 mg and 2 x 1000 mg with MTX in active RA patients who had inadequate response to MTX and no prior biologic treatmentStudy designControlled TrialsOverall N511Duration of study48 wksInclusion CriteriaTreatment resistant resistant to 10-25 mg MTX/wk for 12 wks or more18-80 yrs oldRA according to ACR (SJC and TJC of both at least 8CRP at least 0.6 mg/dl or ESR at least 28 mm/h) for 6 mos or moreAbsolute neutrophil count of 1500 mcg/mcl or moreHemoglobin of 8 g/dl or moreIgM of 40 mg/dl or moreIgG of 500 mg/dl or moreExclusion CriteriaPrevious treatment with biologicComparisons (dosage and frequency)D1: MTX: 10-25 mg/wkPlaceboD2: MTX: 10-25 mg/wkRTX: 500 mg IV infusion on day 1 and 15D3: MTX: 10-25 mg/weekRTX: 1000 mg IV infusion on day 1 and 15Number in groupD1: 172D2: 167D3: 170Mean age (years)D1: 52.16D2: 51.91D3: 51.30Sex, % femaleD1: 85.5D2: 79.6D3: 81.2Race, % whiteD1: 82.6D2: 80.2D3: 80.6Race, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 7.48 (7.642)D2: 7.10 (6.969)D3: 6.61 (7.294)TJC, meanD1: 30.2 (15.94)D2: 27.1 (14.10)D3: 28.7 (14.98)SJC, mean D1: 20.9 (11.26)D2: 18.6 (9.62)D3: 19.5 (10.32)Corticosteroid use, %D1: 47.7D2: 47.9D3: 39.4DMARD use, %: NRMTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreDAS28-ESRD1: 6.54 (1.015)D2: 6.40 (0.951)D3: 6.49 (1.061)DAS28-CRP D1: 5.95 (0.972)D2: 5.81 (0.912)D3: 5.86 (0.967)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: Wk 24D1: 23.3D2: 54.5 (P<0.0001)D3: 50.6 (P<0.0001) Wk 48: D1: NRD2: 55.7D3: 57.6 (P=NR)ACR 50: Wk 24D1: 9.3D2: 26.3 (P<0.0001)D3: 25.9 (P<0.0001)Wk 48D1: NRD2: 32.9D3: 34.1(P=NR)ACR 70: Wk 24D1: 5.2D2: 9.0 (P=NR)D3: 10.0 (P=NR)D1: NRD2: 12.6D3: 13.5(P=NR)HAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): DAS28-ESRWk 24D1: -0.75D2: -1.76 (P<0.0001)D3: -1.69 (P<0.0001)Wk 48D1: NRD2: -1.96 (P=NR)D3: -2.02 (P=NR)SF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): Remission (DAS28-ESR<2.6)Wk 24D1: 4 D2: 16 (P<0.01)D3: 16 (P<0.01) Wk 48D1: NRD2:15 (P=NR)D3: 19 (P=NR)OverallOverall attrition/withdrawal (n): D1: 13D2: 6D3: 6Withdrawals due to adverse events?(n): D1: 2D2: 2D3: 3Other attrition related comments? Reported for 24 wksWithdrawals due to AE exclude RA flareStudy reports that over 90% of patients completed 48 wks of study.Overall adverse events reported (n): D1: 128D2: 128D3: 138Serious adverse events:Death (n): D1: 0D2: 0D3: 0Any Cardiac Disorder EventsD1: 4D2: 5D3: 7Serious Cardiac Disorder EventsD1: 2D2: 2D3: 1Malignancies:MalignancyD1: 1D2: 1D3: 2Respiratory events:NROther infections:Any InfectionD1: 74D2: 69D3: 61Serious InfectionD1: 4D2: 1D3: 2GI:Any lower GI eventsD1: 20D2: 16D3: 16Any serious GI EventsD1: 3D2: 1D3: 1Other:Infusion/injection site reactions?(n): Day 1D1: 24D2: 31D3: 42Day 15D1: 14D2: 12D3: 10Any other AEs: Reported AEs only up to 24 wksQuality rating for efficacy/effectiveness? FairQuality rating for observational studies NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, yr:Feltelius et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM4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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM4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ADDIN EN.CITE.DATA 53Country, Setting:Sweden, Swedish Society of Rheumatology databaseFunding:Wyeth ResearchResearch Objective:To describe a nationwide system for postmarketing follow up of new antirheumatic drugs; to analyze safety and effectiveness in an ETA-treated cohortStudy Design:Case seriesOverall N:1,073Study Duration: >2 yrsInclusion Criteria:Previous use of DMARDs: previous treatment with > 1 DMARD in addition to MTXActive RA as evaluated by the attending physicianExclusion Criteria: NRInterventions:D1: ETAEtanercept: 25mg twice weeklyN:D1: 1073Mean age (yrs):D1: 52Sex, % female:D1: 76.6Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:D1: 56.3Corticosteroid use, %:D1: 95.2MTX naive, %:NRTreatment resistant %:NRPatients with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.9D1: MTX use: 40.1In 294 pts (27%) , at least 1 adverse drug reaction (ADR) was reported (421 reports; mean 1.5 report per patient; median 1; rand 1 to 6)80 ADR reports (19%) were serious and 331 (79%)were non-serious76 pts (7%) experienced at least one serious event and 114 (11%) had events exclusively classified as nonseriousIncidence of adverse events remained constant over timeOverall: D1: 27 (% of pts)Serious AEs:D1: 7 (% of pts) Infections:D1: 22 (% of all AE diagnoses) Serious Infections:D1: 5.4 (% of all AE diagnoses) Infusion or injection reaction:NRAbdominal Pain:NRCardiovascular Events:D1: 4.8 (% of all AE diagnoses) Dizziness:NRHeadache:NRHepatotoxicity:D1: liver/biliary 0.6% (of all AE diagnoses) Malignancies:NRNausea:NRURTI:NRUTI:NROverall Attrition Rate, %:NAITT Analysis:Not applicable (Why not?)Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableFernandez-Nebro et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE.DATA 54Country and settingSpain, tertiary care centerSource of fundingNRResearch objectiveEvaluate effectiveness and safety of anti-TNF therapies and to identify factors involved in this responseStudy designDynamic Prospective Cohort StudyOverall N161Duration of study6 years (secondary outcomes [DAS28, HAQ, EULAR response] measured at 6 mos)Quality rating FairInclusion CriteriaTreatment resistantNo response to at least 2 DMARDs, including MTXRequired biological therapy inopinion of a physician. No formal level of disease activity was required. No restriction ofuse of DMARD, steroids and NSAIDsExclusion CriteriaNRInterventions, doseD1: IFX: VariedD2: ETN: VariedD3: ADA: VariedNumber in groupD1: 60D2: 79D3: 22Overall: 161Mean age, years (SD)D1: 54.0 (11.6)D2: 54.0 (12.4)D3: 54.0 (11.2)Overall: 54.0 (12)Sex, % femaleD1: 88D2: 76D3: 82Overall: 81Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 9.6 (7.9)D2: 9.9 (7.9)D3: 9.5 (8.3)Overall: NRPatients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100D3: 100Overall: 100Tender Joint Count, mean (SD)D1: 16.6 (8.3)D2: 13.6 (7.9)D3: 13.3 (6.2)Overall: NRSwollen Joint Count, mean (SD)D1: 11.1 (7.3)D2: 9.7 (6.7)D3: 9.5 (7.8)Overall: NRCorticosteroid use, %D1: 65D2: 67D3: 48Overall: NRDMARD use, %D1: 92D2: 54D3: 73Overall: 70MTX na?ve, %NRBaseline DAS scoreD1: 6.2 (1.3)D2: 5.9 (1.4)D3: 6.2 (0.9)Overall: NRRequired treatment for latent TBNROther population characteristics, %MTX use:D1: 83D2: 52D3: 50LEF use:D1: 8D2: 3D3: 9SSZ:D1: 0D2: 0D3: 5Hydroxcholoquine (HCQ):D1: 0D2: 0D3: 5MTX + HCQD1: 0D2: 0D3: 5Overall: NRACR mean difference/ absolute differenceNRHAQ (SD)D1: -0.32 (0.37) (n:?60)D2: -0.46 (0.63) (n:?78)D3: NROverall: -0.35 (0.54), (P = ?0.0001)DAS D1: -1.3 (1.2)D2: -1.7 (1.5)D3: NROverall: -1.5 (1.4) (P = ?0.0001)SF-36 NRRadiographic measures NRQuality of life scales, mean difference/absolute differenceNREULAR at 6 mo (%)IFX:Good 11%Moderate 49%No response 40%ETNGood 25%Moderate 43%No response 32% Overall: (P = ?0.218)MCID HAQ at 6 mo: IFX:? 58% ETN:? 57%P = 0.951 6 yr results: Time to failure (patient-years)IFX: 105.7ETN: 145.5ADA: 23.1Failure-Rate per 100 Patient-years (95% CI): IFX:?40.7 (28.5-52.8)ETN:? 25.4 (17.2-33.6)ADA:? 39.0 (13.5-64.4)Time to treatment failure: Multivariate Hazard Ratio ETN (Ref:? IFX):? 0.34 (95% CI 0.18-0.61) Patients receiving ETN V IFX over first 24 mo remained for longer without treatment failure (P = ?0.032) and had a lower failure rate through follow-up (rate ratio:? 0.6 95% CI 0.4-0.9)Attrition/withdrawalWithdrawals due to adverse events, n:Overall: 8.1% (n:?13)Primary efficacy endpoint of this study was time to treatment failure defined as definitive withdrawal of anti-TNF for any reason, or substitution or addition of concomitant DMARD to maintainefficacy ofanti-TNF.Overall adverse events reported, n:D1: 112D2: 84D3: 19Overall: 215Serious adverse eventsDeath, n:D1: 1D2: 1D3: 0Overall: 2Cardiovascular events (specify), n:D1: 1D2: 4D3: 0Overall: Total cardiovascular problems: 9% (n:?15)Arterial hypertension/ decompensation: 10Cardiac rhythm disorder: 2 Acute myocardial infarction: 1 Deep vein thrombosis: 1 Cardiac insufficiency: 1Increased transaminases, n:D1: 9D2: 2D3: 0Overall: 11MalignanciesLymphoma or leukemia, n:D1: 0D2: 0D3: 0Overall: 0Skin?cancer (basal cell?or squamous cell), n:D1: 0D2: basocellular carcinoma ofnasal dorsum: 1D3: cutaneous basocellular carcinoma: 1Overall: 2Other cancer (specify), n:D1: pulmonary carcinoid tumor: 1D2: pancreatic carcinoma: 1 monoclonal lymphoproliferation of B cells: 2; IgG-kappa monoclonal gammopathy: 1 D3: 0Overall: 5Respiratory eventsTuberculosis: NRPneumonia, n:D1: 0D2: 0D3: 1Overall: 1Other infectionsUrological sepsis, n:D1: 1D2: 1D3: 0Overall: 1Other infections, n:Brucellosis: 1Septic arthritis: 1Soft tissue:D1: 3D2: 3D3: 1Herpes zoster: D1: 0D2: 2D3: 1Overall: 12GINROtherInfusion/injection site reactions, n:D1: 7D2: 2D3: 1Overall: 10Skin rash, n:D1: 7D2: 5D3: 1Overall: 13Demyelenation or multiple sclerosis, n:D1: 0D2: 0D3: 0Overall: 0Worsening of ocular and oral dryness, n:D1: 0D2: 7D3: 0Overall: 7Total infections, n:D1: 30D2: 24D3: 8Overall: 62Herpes zoster, n:D1: 0D2: 2D3: 1Overall: 3Dryness worsening, n:D1: 0D2: 7D3: 0Overall: 7Onset of worsening high blood pressure: D1: 6 D2: 3D3: 1Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableFinckh et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy
Mzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij41NTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjIyMzk8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjIyMzk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5GaW5ja2gs
IEEuPC9hdXRob3I+PGF1dGhvcj5DaXVyZWEsIEEuPC9hdXRob3I+PGF1dGhvcj5CcnVsaGFydCwg
TC48L2F1dGhvcj48YXV0aG9yPkt5YnVyeiwgRC48L2F1dGhvcj48YXV0aG9yPk1vbGxlciwgQi48
L2F1dGhvcj48YXV0aG9yPkRlaGxlciwgUy48L2F1dGhvcj48YXV0aG9yPlJldmF6LCBTLjwvYXV0
aG9yPjxhdXRob3I+RHVkbGVyLCBKLjwvYXV0aG9yPjxhdXRob3I+R2FiYXksIEMuPC9hdXRob3I+
PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0eSBIb3NwaXRh
bCBvZiBHZW5ldmEsIEdlbmV2YSwgU3dpdHplcmxhbmQuIGF4ZWwuZmluY2toQGhjdWdlLmNoPC9h
dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+QiBjZWxsIGRlcGxldGlvbiBtYXkgYmUgbW9yZSBl
ZmZlY3RpdmUgdGhhbiBzd2l0Y2hpbmcgdG8gYW4gYWx0ZXJuYXRpdmUgYW50aS10dW1vciBuZWNy
b3NpcyBmYWN0b3IgYWdlbnQgaW4gcmhldW1hdG9pZCBhcnRocml0aXMgcGF0aWVudHMgd2l0aCBp
bmFkZXF1YXRlIHJlc3BvbnNlIHRvIGFudGktdHVtb3IgbmVjcm9zaXMgZmFjdG9yIGFnZW50czwv
dGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgUmhldW08L3NlY29uZGFyeS10aXRsZT48
c2hvcnQtdGl0bGU+QiBjZWxsIGRlcGxldGlvbiBtYXkgYmUgbW9yZSBlZmZlY3RpdmUgdGhhbiBz
d2l0Y2hpbmcgdG8gYW4gYWx0ZXJuYXRpdmUgYW50aS10dW1vciBuZWNyb3NpcyBmYWN0b3IgYWdl
bnQgaW4gcmhldW1hdG9pZCBhcnRocml0aXMgcGF0aWVudHMgd2l0aCBpbmFkZXF1YXRlIHJlc3Bv
bnNlIHRvIGFudGktdHVtb3IgbmVjcm9zaXMgZmFjdG9yIGFnZW50czwvc2hvcnQtdGl0bGU+PC90
aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QXJ0aHJpdGlzIGFuZCBSaGV1bWF0aXNtPC9m
dWxsLXRpdGxlPjxhYmJyLTE+QXJ0aHJpdGlzIFJoZXVtLjwvYWJici0xPjxhYmJyLTI+QXJ0aHJp
dGlzIFJoZXVtPC9hYmJyLTI+PGFiYnItMz5BcnRocml0aXMgJmFtcDsgUmhldW1hdGlzbTwvYWJi
ci0zPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQxNy0yMzwvcGFnZXM+PHZvbHVtZT41Njwvdm9sdW1l
PjxudW1iZXI+NTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xv
bmFsLyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBBZ2Vu
dHMvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMsIFJoZXVtYXRv
aWQvIGRydWcgdGhlcmFweS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Qi1MeW1waG9jeXRl
cy8gcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxr
ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+
SW1tdW5vY29uanVnYXRlcy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v
Z2xvYnVsaW4gRy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TG9uZ2l0dWRpbmFs
IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZSBEZXBsZXRpb24vIG1ldGhvZHM8
L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5
d29yZD48a2V5d29yZD5NdWx0aXZhcmlhdGUgQW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UHJv
c3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIFR1bW9yIE5lY3Jv
c2lzIEZhY3Rvci90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2Yg
SWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29y
ZD48a2V5d29yZD5UdW1vciBOZWNyb3NpcyBGYWN0b3ItYWxwaGEvIGFudGFnb25pc3RzICZhbXA7
IGluaGliaXRvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48
cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDQt
MzU5MSAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3NDY5MDk4PC9hY2Nlc3Npb24tbnVt
Pjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+PGN1
c3RvbTM+TzwvY3VzdG9tMz48Y3VzdG9tND5LUSAxIC8gZmFpcjwvY3VzdG9tND48L3JlY29yZD48
L0NpdGU+PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 55 (SCQM cohort)Country and settingSwitzerland, university hospitalsSource of fundingGeneva UniversityResearch objectiveCompare effectiveness of RTX with alternative anti-TNF agents in managing pts who had inadequate response to anti-TNF therapyStudy designProspective CohortOverall N116Duration of studyJanuary 1998 to end of September 2006Quality rating FairInclusion CriteriaTreatment resistant at least one anti-TNF agentInitiation of second or third alternative anti-TNF agent or RTXBaseline assessment of DAS28 at time of treatment switchAt least 1 f/u assessment within first 12 mosDiagnosis of RA by rheumatologistInadequate response to at least 1 anti-TNF agentExclusion CriteriaA treatment switch because of personal preferences (i.e., in absence of an inadequate response to previous anti-TNF agent) and RTX therapy for lymphoma. Any observations after interruption of anti-TNF treatment or re-treatment with RTX were censored.Interventions, doseD1: RIT: 2 infusions of 1,000 mgD2: ETN: 50 mg subcutaneously weeklyIFX: 3mg/kg intravenously ADA: 40 mg every two weeksNumber in groupD1: 50D2: 66Overall: NRMean age, medianD1: 55 D2: 54 P = 0.78Sex, % femaleD1: 77D2: 76P = 0.87Race, % whiteNRRace, % blackNREthnicity, LatinoNRDisease duration mean, medianD1: 10D2: 9Disease duration mean, IQRD1: 6-18D2: 5-16P =39Patients with early RA, three years or less, %NR Treatment resistant, %At least 1 anti-TNF agent:D1: 100 D2: 100 Overall: NRTJC, meanD1: 11 D2: 10 P = 0.44SJC, mean D1: 10 D2: 8 P = 0.17Corticosteroid use, %D1: 58D2: 55P = 0.71DMARD use, %MTX:D1: 52D2: 39P = 0.18LEF: D1: 16D2: 14P =.72Other DMARD:D1: 10D2: 9P = 0.87NoneD1: 28D2: 39P = 0.20 MTX na?veNRBaseline DAS score mean (CI)D1: 5.43 (4.99-5.87)D2: 5.01 (4.70-5.32)P = 0.11No. of previous anti-TNF agents (SD)D1: 1.96 - 0.7 ()D2: 1.53 - 0.6P = 0.001ACR NRHAQ NRDAS At 6 mos:D1: -1.6 mean decrease(95% CI) -1.97, -1.25 D2: -0.98 mean, (95% CI) -1.33, -0.62 P = 0.01SF-36 NRRadiographic measures NRQuality of life scales NRAttrition/withdrawalThere were 209 patients in SCQM databank who received RTX or a 2nd or 3rd anti-TNF agent. Of these, 60 (29%) were excluded from this study b/c of missing follow up assessments, 22 (11%) were excluded b/c they switched to an alternative biologic therapy b/c of personal preferences and not as a result of inadequate response to anti-TNF therapy, 8 (4%) were excluded b/c of missing baseline assessment, and 3 (1%) b/c RTX was administered to treat concomitant lymphoma rather than RARespiratory eventsTuberculosis: NRUpper respiratory infection, n:NROther infectionsNRGINROtherInfusion/injection site reactions, n:D1: 1D2: 9P = 0.03Allergic complications, n:D1: 3D2: 0P = 0.04Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableFinckh et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE.DATA 56 (SCQM cohort)Country and settingSwitzerland, multicenterSource of fundingSanofi-Aventis, Geneva University, SCQM Foundation, Swiss National Science FoundationResearch objectiveCompare retention rates, effectiveness and safety ofrapeutic regimen associating anti- TNF agents and LEF, MTX or other conventional DMARDs in a large population based RA cohort.Study designPopulation-based CohortOverall N1218Duration of studyMarch 1996-December 2006, mean patient follow up 17 mosQuality rating FairInclusion CriteriaDiagnosis of RA by rheumatologist and treatment with INF, ETN, or ADAExclusion CriteriaAbsence of concomitant DMARDrapy, and simultaneous prescription of LEF and MTX in combination with anti-TNF agents.Interventions, DoseD1: MTX: 15mg/week (median dose at baseline)Other: this D was anti-TNF agents (all combined) + MTXD2: LEF: 20mg/day (median dose at baseline)Other: anti-TNF agents (combined) + LEFD3: Sulfasalazine, Hydroxychlorquine, Anti-TNF agents (combined) + any oral DMARD that was not MTX or LEF (minocycline, azathioprine, cyclosporine A, D-penicillamine, oral or intramuscular gold salts)Number in groupD1: 842D2: 260D3: 116Overall: 1218Mean age (years)D1: 53D2: 53D3: 55P = 0.23Sex, % femaleD1: 76D2: 79D3: 78P = 0.57Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, medianD1: 8.4D2: 8.9D3: 9.9Overall: Mean disease duration, IQRD1: 3.7-14.9D2: 3.3-14.2D3: 4.4-15.8P = 0.14Patients with early RA, three years or less, %NR Treatment resistant, %Anti-TNF failure:D1: 33D2: 41D3: 28P = 0.06TJC, mean NRSJC, mean NRCorticosteroid use, %Concomitant steroid use ever: D1: 48D2: 51D3: 67P =.001Previous DMARD use, median, nD1: 1D2: 2D3: 2Previous DMARD use, IQR D1: 0-2D2: 1-3D3: 1-3P = 0.001MTX na?ve, %NRBaseline DAS28 score, mean (SD)D1: 4.1 (1.5)D2: 4.5 (1.4)D3: 4.6 (1.4)P = 0.31Required treatment for latent TBNRHAQ, mean (SD)D1: 1.24 (0.71)D2: 1.34 (0.67)D3: 1.33 (0.72)ACR NRHAQ, mean improvement after 1 year (CI)D1: 0.12 (0.08-0.15)D2: 0.14 (0.07-0.20)D3: 0.13 (0.03-0.23)P?=?0.09DAS, mean improvement after 1 year (CI)D1: 0.74 (0.63-0.84)D2: 0.63 (0.45-0.82)D3: 0.86 (0.60-1.12P = 0.33SF-36, mean difference/absolute differenceNRRadiographic damage progression measures (CI)D1: 0.91% (0.54-1.27)D2: 0.74% (0.21-1.27)D3: 0.71% (-0.02-1.44)P = 0.77Quality of life scalesNROverall adverse events reported, n:178; P?=?0.13Serious adverse eventsNRMalignanciesNROther infectionsNRGIAllergic complications, n (CI):D1: 0.45 0.20-0.98)D2: NRD3: NRP = 0.04Any other AEs: A total of 178 combinationrapies were interrupted because of adverse events (28%). most common adverse events leading to treatment interruption were: allergic reactions (28%), infections (19%), skin reactions (19%), and gastrointestinal side effects (12%). Hepatotoxicity (2%) and malignancies (6%) were rare causes of treatment interruption in this cohort.Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Fleischmann et al., 2003;PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQw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ADDIN EN.CITE.DATA 57; Tesser et al., 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1478</RecNum><DisplayText><style face="superscript">58</style></DisplayText><record><rec-number>1478</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1478</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tesser, John</author><author>Fleischmann, Roy</author><author>Dore, Robin</author><author>Bennett, Ralph</author><author>Solinger, Alan</author><author>Joh, Tenshang</author><author>Modafferi, Dennis</author><author>Schechtman, Joy</author></authors></contributors><titles><title>Concomitant medication use in a large, international, multicenter, placebo controlled trial of anakinra, a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis</title><secondary-title>Journal of Rheumatology</secondary-title></titles><periodical><full-title>Journal of Rheumatology</full-title><abbr-1>J. Rheumatol.</abbr-1><abbr-2>J Rheumatol</abbr-2></periodical><pages>649-54</pages><volume>31</volume><number>4</number><keywords><keyword>CN-00469658</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>P</custom3><custom4>4</custom4><custom7>DONE PT-SW goes w/ #409, 1081, 2008</custom7></record></Cite></EndNote>58; Schiff et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEw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ADDIN EN.CITE.DATA 59; Fleischmann et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE.DATA 60Country, Setting:Multinational, multicenterFunding:AmgenResearch Objective:Long term safety of AKA in a large population of pts with RAStudy Design:RCTOverall N:1414 (1399) enrolled (open label 1103)Study Duration: 6 mos (up to 30 mos open label for a total of 3 yrs)Inclusion Criteria:Age: 18+Diagnosed according to ACR criteria; duration 3+ mosStable doses of NSAIDs and Cs for one mo; and stable doses of DMARDs for 2 mosNSAIDS, Cs, and DMARDs (except TNF inhibitors) Exclusion Criteria:Pregnant or lactatingUncontrolled medical conditionMalignancy other than basal cell carcinoma of skin or in situ carcinoma of cervixFelty’s syndromeHIVLeukopeniaNeutropeniaTthrombocy-topeniaAbnormal liver function test resultHepatitis B or CInterventions, dose:D1: AKA (100mg/d)D2: placeboN:D1: 1116D2: 283Mean age, yrs:D1: 54.6D2: 55.7Sex, % female:D1: 74.7D2: 74.6Race, % white:D1: 87.8D2: 90.1Mean disease duration, yrs:D1: 10.2 (9.6)D2: 10.7 (9.5)TJC, mean:D1: 22.6 (14.7)D2: 22.6 (14.5)SJC, mean:D1: 18.8 (11.9)D2: 18.3 (11.7)DMARD use excluding MTX, and TNF inhibitors %:D1: 47.7D2: 47.7Corticosteroid use, %:D1: 57D2: 60.8MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 51.9D2: 59.46 mos-injection site reactions, AKA vs. placebo. (72.6% v. 32.9%) P-value NR13.4% AKA withdrew due to AE vs, 9.2% placebo (P = 0.057); overall discontinuation rates (21.6% vs. 18.7%)Serious infections AKA vs. placebo (2.1% v. 0.4%), may be clinically significant. (P = 0.068) Comorbid conditions, serious infectious events (2.5% vs. 0.0%; P = NR). Trend towards increased risk of serious infectious events with AKA in pts with pulmonary comorbidities vs. placebo (3.4% v. 1.6%), P = NS From 0-3 yrs rates per 100 yrs of patient exposureISRs (122.26 events), Rheumatoid arthritis progression (67.80 events)URTIs(26.09 events) Concomitant use of corticosteroids vs. not serious infection (7.13 events/100 PY v 2.87 events/100 PY). pneumonia (1.5 events/100 PY v 0.96 events/100 PY ) Cellulitis (1.2 events/100 PY v 0.21 events/100 PY)Overall: D1: 92D2: 92.2D3: 96SAEs:D1: 7.7D2: 7.8D3: 27Infections:D1: 41.2D2: 43.5Serious Infections:D1: 2.1D2: 0.4D3: 8Infusion or injection reaction:D1: 72.6D2: 32.9URTI:D1: 13.3D2: 18.4UTI:D1: 4.6D2: 5.3Adherence:AKA vs. placebo: 100% adherent with use of study drug: 43.8% vs. 47.8; <70% adherent: 0.8% vs. 1.7%>40% missed no injections and >90% received at least 90% of intended dosesOverall Attrition Rate, %:21ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableFleischmann et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0
OTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij42MTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0OTU8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjI0OTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91
cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y
PkZsZWlzY2htYW5uLCBSLjwvYXV0aG9yPjxhdXRob3I+VmVuY292c2t5LCBKLjwvYXV0aG9yPjxh
dXRob3I+dmFuIFZvbGxlbmhvdmVuLCBSLiBGLjwvYXV0aG9yPjxhdXRob3I+Qm9yZW5zdGVpbiwg
RC48L2F1dGhvcj48YXV0aG9yPkJveCwgSi48L2F1dGhvcj48YXV0aG9yPkNvdGV1ciwgRy48L2F1
dGhvcj48YXV0aG9yPkdvZWwsIE4uPC9hdXRob3I+PGF1dGhvcj5CcmV6aW5zY2hlaywgSC4gUC48
L2F1dGhvcj48YXV0aG9yPklubmVzLCBBLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kLCBWLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlVuaXZlcnNpdHkgb2Yg
VGV4YXMgU291dGh3ZXN0ZXJuIE1lZGljYWwgQ2VudGVyLCBEYWxsYXMsIDc1MjM1LCBVU0EuIHJm
bGVpc2NobWFubkBhcnRoZG9jcy5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5FZmZp
Y2FjeSBhbmQgc2FmZXR5IG9mIGNlcnRvbGl6dW1hYiBwZWdvbCBtb25vdGhlcmFweSBldmVyeSA0
IHdlZWtzIGluIHBhdGllbnRzIHdpdGggcmhldW1hdG9pZCBhcnRocml0aXMgZmFpbGluZyBwcmV2
aW91cyBkaXNlYXNlLW1vZGlmeWluZyBhbnRpcmhldW1hdGljIHRoZXJhcHk6IHRoZSBGQVNUNFdB
UkQgc3R1ZHk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uIFJoZXVtIERpczwvc2Vjb25kYXJ5
LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFubmFscyBvZiB0aGUgUmhl
dW1hdGljIERpc2Vhc2VzPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5uLiBSaGV1bS4gRGlzLjwvYWJi
ci0xPjxhYmJyLTI+QW5uIFJoZXVtIERpczwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFnZXM+ODA1
LTExPC9wYWdlcz48dm9sdW1lPjY4PC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGtleXdvcmRz
PjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5c2lzIG9mIFZhcmlhbmNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwvYWRtaW5pc3RyYXRpb24gJmFt
cDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0
aGVyYXB5L2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwv
a2V5d29yZD48a2V5d29yZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+
SW1tdW5vZ2xvYnVsaW4gRmFiIEZyYWdtZW50cy8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl
L3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2l2ZSBBZ2Vu
dHMvIGFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+
PGtleXdvcmQ+SW5qZWN0aW9ucywgU3ViY3V0YW5lb3VzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8
L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UG9seWV0aHls
ZW5lIEdseWNvbHMvIGFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS90aGVyYXBldXRpYyB1c2U8
L2tleXdvcmQ+PGtleXdvcmQ+U2FtcGxlIFNpemU8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50
IE91dGNvbWU8L2tleXdvcmQ+PGtleXdvcmQ+VHVtb3IgTmVjcm9zaXMgRmFjdG9yLWFscGhhL2Fu
dGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll
YXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh
dGVzPjxpc2JuPjE0NjgtMjA2MCAoRWxlY3Ryb25pYyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTkw
MTUyMDY8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1
c3RvbTI+SSBNVEM8L2N1c3RvbTI+PGN1c3RvbTM+Q1Q8L2N1c3RvbTM+PGN1c3RvbTQ+S1EgMSwg
MiwgMyAvIGZhaXI8L2N1c3RvbTQ+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 61,FAST4WARDCountry and setting36 sites in Austria,Czech Republic andUSA between June 2003 and July 2004. Setting NRSource of fundingUCBResearch objectiveExamine efficacy and safety of CZP 400 mg monotherapy in pts who had failed at least one prior DMARDStudy designControlled TrialsOverall N220Duration of study24 weeksQuality rating Fair Inclusion CriteriaTreatment resistant Failed ≥ 1DMARDAged 18-75 yrsAdult onset RA (defined byACR criteria) for ≥ 6 mosFailed ≥ 1 previous DMARD due to lack of efficacy or intoleranceActive disease at screening and baseline (defined by ≥ 9 tender joints, ≥ 9 swollen joints, ≥ 1 offollowing: ≥ 45 min morning stiffness, ESR ≥ 28 mm/h, or CRP > 10mg/l)DMARDs discontinued ≥ 28-d or 5 half lives of drug prior to administration of first study dose (exception being LEF, which was eliminated using cholestyramine administration followed by a further 28-d washout)Exclusion CriteriaInflammatory arthritis other than RAA history of chronic, serious or life-threatening infectionAny current infectionHistory of or chest x ray suggesting TB or a positive (defined by local practice) purified protein derivative (PPD) skin test (Patients positive for PPD who had received Bacille Calmette-Gue & acuteRin (BCG) vaccination and had a negative chest x ray and no clinical symptoms of TB could be enrolled)Received biological therapies for RA within 6 mosPrior treatment with TNFα inhibitorsIntra-articular, periarticular, intramuscular and intravenous corticosteroids (PRED equivalent 10 mg/day, stable for >4 weeks prior to enrollment and during study, non-steroidal anti-inflammatory drugs and analgesics were allowed)Interventions, dose D1: Certolizumab: 400mg every 4 weeksD2: Placebo: Every 4 weeksNumber in groupD1: 111D2: 109Mean age, years (SD)D1: 52.7 ± 12.7D2: 54.9 ± 11.6Sex, % femaleD1: 78.4%D2: 89.0%Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 8.7 yrs ± 8.2D2: 10.4 ± 9.6Patients with early RA, three years or less, %NR Treatment resistant, %Failed ≥ 1 previous DMARD D1: 100D2: 100Tender Joint Count, meanD1: 29.6 ±13.7D2: 28.3 ± 12.5Swollen Joint Count, mean D1: 21.2 ± 10.1D2: 19.9 ± 9.3Corticosteroid use, %D1: 55.9D2: 58.7DMARD use, %# of prior DMARDS:D1: 2 ± 1.19D2: 2 ± 1.25MTX na?ve, %D1: 18.0D2: 18.3DAS28 (ESR) 3D1: 6.3 ± 1.1D2: 6.3 ± 0.9Required treatment for latent TBNRHAQ-DI (mean/SD)D1: 1.4 ± 0.63D2: 1.6 ± 0.65ACR mean difference/ absolute difference (%)ACR 20:D1: 45.5D2: 9.3P = 0.001ACR 50:D1: 22.7D2: 3.7P = 0.001ACR 70:D1: 5.5D2: 0P =:?0.05HAQ-DI, clinically meaningful improvement in physical function at week 24 (%)D1: 49D2: 12P = 0.001DAS28(ESR)3 (least square mean change at wk 24 from baseline)D1: -1.5D2: -0.6P = 0.001SF-36 D1: Data not shownD2: Data not shownP = 0.001Radiographic measures NRQuality of life scales D1: HRQoL Others, (please name) Swollen joint count (least square mean change at wk 24 from baseline) CZP:?-11.6, Placebo:? -6.3 (P = ?0.001) (reduced by approximately 38% for CZP compared with 16% for placebo)Tender joint count (least square mean change at wk 24 from baseline): CZP:?-16.0, placebo:? -7.3 (P = ?0.001) (reduced by approximately 40% for CZP compared with 14% for placebo)Patient's global assessment of arthritis (least square mean change at wk 24 from baseline): CZP:?-0.7, Placebo:? 0.0 (P = ?0.001)Patient's assessment of arthritis pain (clinically meaningful reductions in arthritis pain at wk 24): CZP:?47%, Placebo:? 17% (P <0.001)Experienced minimally clinically important differences in Physical Component Summary: CZP:?46%, Placebo:? 16% (P = ?0.001)Experienced minimally clinically important differences in Mental Component Summary: CZP:?34%, Placebo:? 7% (P = ?0.001)Experienced minimally clinically important improvemtns in fatigue: CZP:?46%, Placebo:? 17% (P = ?0.001)Attrition/withdrawal (%)Overall, n:D1: 35 (31.5)D2: 81 (74.3)Overall: 116 (52.7)Withdrawals due to adverse events, n:D1: 5 (4.5)D2: 2 (1.8)Overall: 7 (3.2)Withdrawals due to lack of efficacy, n:D1: 24 (21.6)D2: 75 (68.8)Overall: 99 (45.0)Overall adverse events reported, n (%):D1: 84/111 (75.7)D2: 63/109 (57.8)Serious adverse eventsDeath, n:D1: 0D2: 0MalignanciesLymphoma or leukemia, n:D1: 0D2: 0Skin?cancer (basal cell?or squamous cell), n:D1: 0D2: 0Other cancer (specify), n:D1: 0D2: 0Respiratory eventsTuberculosis: NRPneumonitis, n:D1: 0D2: 1Other infectionsSerious infections, n:D1: 2 (1.8%)D2: 0GINROtherInfusion/injection site reactions, n:D1: 4.5%D2: 13.8%OverallSerious AEs?1, n (%):D1: 8 (7.2)D2: 3 (2.8)Severe severity, n (%):D1: 8 (7.2)D2: 11 (10.1)Moderate severity, n (%):D1: 52 (46.8)D2: 40 (36.7)Mild severity, n (%):D1: 62 (55.9)D2: 43 (39.4)Any other AEs: SAE CZP: Aggravated RA n: 2Bacterial arthritis n: 1Mastits n: 1Benign parathyroid tumour n: 1Uterine fibroids n: 1Postural dizziness n: 1Ischaemic stroke n: 1SAE Placebo: Vomiting: 1Pneumonitis: 1Chronic renal failure: 1Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth Outcomes Adverse Events, %Author, yr:Flendrie et al., 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQx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ADDIN EN.CITE.DATA 62Country, Setting:Netherlands. University medical centre (Nijmegen)Funding:Not reportedResearch Objective:To determine the drug survival during treatment of RA pts with TNF blocking agentsStudy Design:Retrospective cohort studyOverall N:230Study Duration: About 6 yrs. (maximum follow up times for 3 groups were 69, 35, and 30 mos)Inclusion Criteria:Age: adultDiagnosed with RA according to ACR criteria1) started treatment with ADA, INF, or ETA prior to January 1 2003 at department of rheumatology of University Medical Centre Nijmegen. 2) pts receiving ADA had been treated in phase 1, 2, and 3 clinical trials. ADA was given in different dosages subcutaneously or intravenously. The pts then entered an open label extension study. 3) INF and ETA pts were treated in daily clinical practice and fulfilled the Dutch criteria for TNF blocking therapy; had moderate to high disease activity, and high dosage MTX and at least one other DMARD had failedExclusion Criteria:NRInterventions:D1: ADAD2: INFD3: ETAN:D1: 94D2: 120D3: 16Mean age (yrs):D1: 55.2D2: 56.4D3: 50.6: 55.5Sex, % female:D1: 63D2: 72D3: 63Race, % white: NR Mean disease duration, yrs:D1: 11.4D2: 11.9D3: 10.1TJC, mean: NRSJC, mean: NRDMARD use, %:D1: previous DMARD use, mean 4.5D2: 4.1D3: 3.3Corticosteroid use, %:D1: 51D2: 24D3: 19MTX naive, %:NRTreatment resistant %: NRPatients with Early RA (≤3 yrs): NRBaseline DAS, mean:D1: 6.4D2: 5.9D3: 5.8 RF positive: D1: 93%D2: 82%D3: 88% About 70% of pts were still receiving TNF blocking agents after the first yr. One yr. drug survival percentages (percentage of pts still taking the drug) were 73% for ADA, 66% for INF, and 74% for ETA group. No significant differences between groupsOverall: D1: 12D2: 30D3: 7Serious AEs:NRInfections:D1: 2D2: 6D3: 0Serious Infections:D1: 6.4D2: 7.2D3: 0Infusion or injection reaction:D1: 3D2: 14D3: 0Malignancies:D1: 2D2: 0D3: 0Overall Attrition Rate, %:17ITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Flendrie et al., 2005 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1921</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>1921</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1921</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flendrie, M.</author><author>Vissers, W. H.</author><author>Creemers, M. C.</author><author>de Jong, E. M.</author><author>van de Kerkhof, P. C.</author><author>van Riel, P. L.</author></authors></contributors><auth-address>Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. m.flendrie@reuma.umcn.nl</auth-address><titles><title>Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study</title><secondary-title>Arthritis Res Ther</secondary-title></titles><pages>R666-76</pages><volume>7</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antirheumatic Agents/ adverse effects/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/pathology</keyword><keyword>Cohort Studies</keyword><keyword>Comparative Study</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Prospective Studies</keyword><keyword>Skin Diseases/ chemically induced/pathology</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists & inhibitors</keyword></keywords><dates><year>2005</year></dates><accession-num>15899052</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>DJ 9-20 (SW)</custom7></record></Cite></EndNote>63Country, Setting:Netherlands, Hospital rheumatology clinic Funding:NRResearch Objective:Whether dermatological conditions after TNF-alpha-blocking therapy are a significant and clinically important problem in RA pts receiving TNF-alpha -blocking therapy. Study Design:Prospective cohort study with historic control Overall N:578 Study Duration: 911PYInclusion Criteria:Previous use of DMARDs: failure or intolerability of at least 2 DMARDS, including MTX, in adequate dosage regimensControl pts selected from Nijmegen inception cohortPts required to meet Dutch guidelines for biological therapies: a moderate to high DAS score (DAS28 > 3.2)Besides therapy with registrated TNF-alpha-blocking agents -INF, ETA, and ADA -some pts were treated in clinical trials with lenerceptExclusion Criteria:NRInterventions, dose:D1: TNF-apha blockersD2: ControlN:NRMean age at diagnosis, yrs:D1: 44.5D2: 54.6Sex, % female:D1: 69D2: 62Race, % white:NRMedian disease duration, yrs:D1: 9.2D2: 6.2TJC, mean:NRSJC, mean:NRDMARD use, %:NRPNL at baseline (%)D1: 39D2: 7MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.9D2: 3.6Dermatological events recorded in 72/289 (25%) of RA pts receiving TNF-alpha-blocking therapy and in 37 (13%) of control groupOR of TNF-alpha-blocking therapy for dermatological referral was 2.26 (95% CI,1.46 to 3.50, P < 0.0005)128 dermatological events were recorded during follow-up in RA pts on TNF-alpha-blocking therapy (0.14 event per PY)Overall: D1: 25D2: 13Infections (skin):D1: 9.3 Overall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableFuerst et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3207</RecNum><DisplayText><style face="superscript">64</style></DisplayText><record><rec-number>3207</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3207</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Fuerst, M.</author><author>Mohl, H.</author><author>Baumgartel, K.</author><author>Ruther, W.</author></authors></contributors><auth-address>Department of Orthopedics, Rheumaklinik Bad Bramstedt, Oskar-Alexander-Str. 26, 24576 Bad Bramstedt, Germany. fuerst-hamburg@t-online.de</auth-address><titles><title>Leflunomide increases the risk of early healing complications in patients with rheumatoid arthritis undergoing elective orthopedic surgery</title><secondary-title>Rheumatol Int</secondary-title></titles><periodical><full-title>Rheumatology International</full-title><abbr-1>Rheumatol. Int.</abbr-1><abbr-2>Rheumatol Int</abbr-2></periodical><pages>1138-42</pages><volume>26</volume><number>12</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Antirheumatic Agents/ adverse effects/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/drug therapy/ surgery</keyword><keyword>Combined Modality Therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Isoxazoles/ adverse effects/therapeutic use</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Orthopedics</keyword><keyword>Postoperative Complications/ epidemiology</keyword><keyword>Risk</keyword><keyword>Surgical Wound Infection/ epidemiology</keyword><keyword>Wound Healing/ drug effects</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0172-8172 (Print)</isbn><accession-num>16736164</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>64Country and settingGermany, hospitalSource of fundingNot reportedResearch objectiveAssess whether tx with MTX or LEF increases risk of wound healing after elective orthopedic surgeryStudy designProspective Cohort StudyOverall N201Duration of study6 weeks+Quality rating FairInclusion CriteriaRA or PsA, 3+ months of continuous therapy with one of study drugs (MTX, LEF, ETA, INF, ADA, or ANA)Undergoing elective orthopedic surgeryExclusion CriteriaNRInterventions, DoseD1: MTX: 5-25 mgOther: Corticosteroids: dose: 2-10 mgD2: LEF: 10-30 mgOther: Corticosteroids: 2.5-8 mgNumber in groupD1: 59D2: 32Overall: 201Mean age (years)D1: 62.9D2: 62.3Overall: 62Sex, % femaleD1: 72.9D2: 78.1Overall: 84.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 15.2 yrsD2: 14.3 yrsPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 100%D2: 12.5%DMARD use, %D1: 0D2: 0MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR ACR 20: No measures of efficacy or QOL were reported for this articleACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNAOverall adverse events reported, n: SEE ADDITIONAL COMMENTSSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherLEF(+Cs) significantly increased risk for wound healing complications compared to MTX+Cs (40.6% vs. 13.6%, P?=?0.01). ETA and INF did not appear to increase risk of complications but N's were small (ETA: N?=?16, 18.8% with complicationsINF: N?=?4, 1pt report complications-they were taking INF+LEF+Cs).Logistic regression (wound complications, OR compared to those not receiving drug) MTX 0.99 (0.36-2.70), Corticosteroid 1.15 (0.51-2.59), LEF 3.48 (1.31-9.24), ETA 1.45 (0.35-5.93), INF 1.42 (0.35-5.92)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Furst, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ0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ADDIN EN.CITE.DATA 65STAR TrialCountry, Setting:US and Canada,multicenter (69 sites)Funding:Abbott Laboratories, Abbott Park IIResearch Objective:To evaluate the safety and efficacy of ADA when given with standard anti-rheumatic therapy in pts with active RA not adequately responding to standard therapiesStudy Design:RCTOverall N:636Study Duration: 24 wksInclusion Criteria:Age: 18+Diagnosed with RA (ACR criteria) Continued txt with standard anti-rheumatic therapy which included traditional DMARD, Cs, NSAID, or analgesicsExclusion Criteria:Prior txt with Anti-CD4 therapy or biologic DMARDParticipated in other trials biolgic DMARD in RAHistory of active: inflammatory arthritide other than RA or active listeriosis or mycobacterial infectionMajor infection requiring hospitalizationTxt with IV antibiotics within 30 dsOral antibiotics within 14 dsAny uncontrolled medical conditionInterventions, dose:D1: ADA (40mg s.c. eavery other week)D2: placeboN:D1: 318D2: 318Mean age, yrs:D1: 55 D2: 55.8Sex, % female:D1: 79.6D2: 79.2Race, % white:D1: 89D2: 85.8Mean disease duration, yrs:D1: 9.3 D2: 11.5TJC, mean:D1: 27.3 D2: 27.6SJC, mean:D1: 20.9 D2: 21.3 DMARD use, %:NRCorticosteroid use, %:D1: 50.9D2: 54.4MTX naive, %:D1: 20.9 (11)D2: 21.3 (11.2)Txt resistant %:NRPts with Early RA (≤3 yrs):D1: 50.9D2: 54.4Baseline patient DAS (mean):D1: 53.9D2: 52.9Baseline physician DAS (mean):D1: 59.9D2: 59.6Health Outcome Measures:At endpoint, significantly more ADA (28.9%) pts achieved an ACR50 response than placebo pts (11.3%) (P < 0.001)At endpoint, significantly more ADA (14.8%) pts achieved an ACR70 response than placebo pts (3.5%) (P < 0.001)Intermediate Outcome Measures:At endpoint, significantly more ADA (52.8%) pts achieved an ACR20 response than placebo pts (34.9%) (P < 0.001)Overall: D1: 86.5D2: 82.7SAEs:D1: 5.3D2: 6.9Infections:D1: 52.2D2: 49.4Serious Infections:D1: 1.3D2: 1.9Rash:D1: 10.7D2: 6.0Infusion or injection reaction:D1: 19.5D2: 11.6URTI:D1: 19.8D2: 15.1UTI:D1: 9.1D2: 5.7Back pain:D1: 5.3D2: 1.6Overall Attrition Rate, %:9.1ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableGalloway JB et al., 2011 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5464</RecNum><DisplayText><style face="superscript">66</style></DisplayText><record><rec-number>5464</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5464</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Galloway, J. B.</author><author>Hyrich, K. L.</author><author>Mercer, L. K.</author><author>Dixon, W. G.</author><author>Fu, B.</author><author>Ustianowski, A. P.</author><author>Watson, K. D.</author><author>Lunt, M.</author><author>Symmons, D. P.</author></authors></contributors><auth-address>Arthritis Research UK Epidemiology Unit, The University of Manchester, Department of Infectious Diseases, North Manchester General Hospital, Stopford Building, Oxford Road, Manchester M13 9PT, UK.</auth-address><titles><title>Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly</title><secondary-title>Rheumatology (Oxford, England)</secondary-title></titles><pages>124-31</pages><volume>50</volume><number>1</number><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1462-0332 (Electronic)
1462-0324 (Linking)</isbn><accession-num>20675706</accession-num><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 3 / fair</custom4><language>eng</language></record></Cite></EndNote>66British Society for Rheumatogy Biologics Register (BSRBR)Country and settingUK, multicenterSource of fundingUniversity of ManchesterResearch objectiveTo evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages.Study designObservationalOverall N15,396 (11,798 in anti-TNF cohort and 3,596 in non-biologic DMARD cohort)Duration of studyMedian duration of folow-up anti-THF cohort: 3.9 yrs (IQR, 2.4-4.9)Non-biologic DMARD cohort: 2.6 yrs (IQR, 1.4-3.8)Inclusion CriteriaActive RAEnrolled in BSRBRHad to have at least 1 returned consultant follow up questionnaire before 31 December 2008Exclusion CriteriaNAComparisons (dosage and frequency)D1: Non-biologic DMARDs: Dosage and frequency NRD2: All anti-TNF: Dosage and frequency NRD3: ETN: Dosage and frequency NRD4: INF:Dosage and frequency NRD5: ADA: Dosage and frequency NRNumber in groupD1: 3598D2: 11798D3: 4129D4: 3467D5: 4202Mean age (years)D1: 60D2: 56D3: 56D4: 56D5: 57Sex, % femaleD1: 2982D2: 8777D3: 3182D4: 2620D5: 3149Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsMedian (IQR)D1: 6 (1-15)D2: 11 (6-19)D3: 12 (6-19)D4: 12 (6-19)D5: 10 (5-18)TJC, meanNRSJC, mean NRCorticosteroid use, %D1: 23D2: 44D3: 48D4: 46D5: 39DMARD use, %: D1: 100MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreD1: 5.1D2: 6.6D3: 6.6D4: 6.6D5: 6.5Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): Diabetes, nD1: 234D2: 675D3: 254D4: 165D5: 252COPD, nD1: 300D2: 565D3: 222D4: 165D5: 178ACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): OverallNRSerious adverse events:Death (n): D1: 47D2: 110Malignancies:NRRespiratory events:NROther infections:Other infections (specify) (n): D1: 296D2: 1512D3: 609D4: 441D5: 462GI:NROther:Patients experienced at least one serious infection (SI), Rate/1000 pyrs (95% CI)D1: 32 (28-36) D2: 42 (40-44) D3: 38 (35-42) D4: 46 (42-50) D5: 43 (39-47) Unadjusted HRD1: Ref D2: 15 (1.3-1.7)D3: 1.4 (1.2-1.6) D4: 1.6 (1.4-1.9)D5: 1.4 (1.2-1.7) AdjHR (95% CI) (adjusted for age, gender, COPD, DM, smoking, disease duration, DAS, HAQ, entry yr, steroid use and MTX use)D1: RefD2: 1.2 (1.1-1.5)D3: 1.2 (1.0-1.4)D4: 1.3 (1.1-1.6)D5: 1.3 (1.1-1.5)30-day mortality rate D1: 16% (n=47)D2: 7% (n=110)P<0.001; adjusted OR, 05 (95% CI, 0.3-0.8)Quality rating for efficacy/effectiveness? Quality rating for observational studies FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Geborek, 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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==
ADDIN EN.CITE.DATA 67Country, Setting:Sweden, primary care clinics, unversity clinicFunding:NRResearch Objective:To assess efficacy and safety of ETA, INF, and LEF in a population-based settingStudy Design:Nonrandomized open-label trialOverall N:369 (33 pts tried 2 different txts and 1 tried all 3; 404 txts)Study Duration: 12 mosInclusion Criteria:Age: 18+Previous use of DMARDs: required to have failed to respond to or not tolerated at least 2 DMARDs, including MTXDiagnosis of RA according to clinical judgment of treating doctorAll pts included were required to have failed to respond to or not tolerated at least 2 DMARDs, including MTXPts were selected on basis of current disease activity and/or unacceptable steroid requirement as judged by treating doctor, but had different backgrounds concerning previous txt, concomitant diseases, and functional impairment and disabilityOther meds allowedExclusion Criteria:NRInterventions, dose:D1: ETA (25 mg/twice wkly)D2: INF (3 mg/kg or higher)D3: LEF (20 mg/d)N:D1: 166D2: 135D3: 103Mean age, yrs:D1: 54D2: 55.4D3: 61.3Sex, % female:D1: 78D2: 79D3: 82Race, % white:NRMean disease duration, yrs:D1: 14.9 D2: 14.1D3: 14.9TJC, mean:NRSJC, mean:NRDMARD use, %:D1: 100D2: 100D3: 100Corticosteroid use, %D1: 83D2: 81D3: 73MTX naive, %:D1: 0D2: 0D3: 0Txt resistant, %:D1: 100D2: 100D3: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.8D2: 5.6D3: 5.4HAQ:D1: 1.55D2: 1.47D3: 1.46At 3 monthsACR20/50:INF significantly higher than LEF (data NR; P < 0.01)ETA higher ACR 20 response rate than INF (data NR; P < 0.02) ETA had a significantly higher ACR50 response rate than INF (data NR; P < 0.05)At 6 monthsACR 20/50: ETA better than LEF (data NR; P < 0.01)ETA higher ACR 20 response rate than INF (data NR; P < 0.02) At 12 monthsNo significant difference between ETA and INF ETA and INF led to significant reduction in prednisolone use starting at 2 wksNo reduction in prednisolone use for LEFInfusion reaction:3.7% of INF pts experienced an infusion reactionOverall Attrition Rate, %:N/AITT Analysis:NoQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Geborek et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE.DATA 68Country, Setting:Sweden, rheumatology centersFunding:?sterlund and Kock Foundations, King Gustav V, and Reumatiker-f?rbundetResearch Objective:To determine whether TNF blockers increase tumour risk in pts with RAStudy Design:Retrospective cohort studyOverall N:1557Study Duration: Median duration of anti-TNF txt was 1.7 yrs (5,571 PY)Inclusion Criteria:ACR criteria were fulfilled by 98% of cohort Pts with RA treated with ETA or INF from South Swedish Arthritis Txt Group (SSATG), which includes pts from 8 rheumatologic centersFor comparison group, pts with RA not treated with anti-TNF drugs from a community based cohort in Malmo, a city from the SSATG catchment area. Controls recruited from Malmo University outpatient rheumatology clinic and from 4 rheumatologists in private practiceExclusion Criteria:Tumor diagnosis prior to studyInterventions, dose:D1: Anti-TNF txtD2: ComparisonETA: variedINF: variedN:D1: 757D2: 800Median age, yrs:D1: 56D2: 64Sex, % female:D1: 76D2: 73Race, % white:NRMean disease duration, yrs:D1: 12D2: 11TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NR% with HAQ quartile >: 3: D1: 61D2: 41Median number of previous DMARDS: D1: 3D2: 1Anti-TNF vs. Control:All tumors: SIR 1.1 (95% CI, 0.6-1.8) vs. 1.4 (95% CI, 1.1-1.8)Lymphomas: SIR 11.5 (95% CI,3.7 to 26.9) vs. 1.3 (95% CI,0.2 to 4.5)All tumors excluding lymphomas: SIR 0.79 (95% CI, 0.4-1.42) vs. 1.39 (95% CI, 1.08-1.76)Hazard ratio indicates a higher risk of lymphoma for anti-TNF drugs than for controls (RR: 4.9; 95% CI, 0.9-26.1)NAOverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Genovese, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ1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ADDIN EN.CITE.DATA 69Country, Setting:US, multicenter, specialty clinicFunding:Amgen, Inc., Thousand Oaks, CAResearch Objective:To determine potential for additive or synergistic effects of combination therapy with selective anti-TNF-alpha agent ETA and anti-IL1 agent AKAStudy Design:RCTOverall N:242Study Duration: 24 wksInclusion Criteria:Age > 18RA according to ACR criteriaDuration of condition: > 6 mos6+ swollen joints9+ tender/painful jointsAt least 2 of: morning stiffness lasting 45 or more minutes, serum CRP of > 1.5 mg/dl, or ESR > 28 mm/hr; and, MTX > 16 wks, stable dose of 10-25 mg/wk > 8 wks; continued txt with stable doses of MTX and other stable medications, such as corticosteroidsExclusion Criteria:Any DMARD other than MTX within past 4 wksTxt with AKA or any protein-based TNF-alpha inhibitorReceived any intraarticular or systemic corticosteroid injections within past 4 wksRecent history of significant infection or other important concurrent illnessInterventions, dose:D1: ETA (25 mg twice wkly)D2: ETA (12.5 mg once wkly) + AKA (100 mg/d)D3: ETA (25 mg twice wkly) + AKA (100 mg/d)N:D1: 80D2: 81D3: 81Mean age, yrs:D1: 54.4D2: 53.8D3: 55.7Sex, % female:D1: 82.5D2: 71.6D3: 77.8Race, % white:D1: 86.3D2: 77.8D3: 75.3Mean disease duration, yrs:D1: 9.7D2: 9.5D3: 10.6TJC, mean:D1: 31D2: 31D3: 35.9SJC, mean:D1: 21.4D2: 19.8D3: 23.4DMARD use, %:NRCorticosteroid use, %D1: 48.8D2: 54.3D3: 44.4MTX naive, %:Overall: 0Txt resistant, %:Overall: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use, %:Overall: 100HAQ: D1: 1.5D2: 1.5D3: 1.6At week 24ACR20, %:D1: 68D2: 51 D3: 62 D1 vs. D2 (P = 0.037)All others NS ACR50, %:D1: 41D2: 39D3: 31(P = 0.914)OR (ETA + AKA vs. ETA alone) 0.64 (90% CI, 0.37-1.09); sensitivity analysis yielded similar resultsACR70, %:D1: 21D2: 24D3: 14 (P = NR)Sustained ACR20 response: Between 43% and 54% of subjects in each group (specifics NR)EULAR response, %: D1: 79D2: 66D3: 73 (P = NR)Mean % reduction in DAS: D1: 39D2: 41D3: 40 (P = NR)Overall: D1: 90D2: 95.1D3: 93.8SAEs:D1: 2.5D2: 4.9D3: 14.8Infections:D1: 40D2: 37D3: 46.9Serious Infections:D1: 0D2: 3.7D3: 7.4Infusion or injection reaction:D1: 40D2: 67.9D3: 70.4URTI:D1: 20D2: 11.1D3: 13.6Overall Attrition Rate, %:15.7ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableGenovese et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE.DATA 70, TOWARDCountry and settingInternational (18 countries, half ofstudy sites US-based), multi-centerSource of fundingF. Hoffmann-L RocheResearch objectiveExamine efficacy and safety of tocilizumab combined with conventional DMARDs in pts with active RAStudy designControlled TrialsOverall N1220Duration of study24 wksQuality rating Fair Inclusion Criteria18 years or olderModerate-to-severe RA of at least 6 mos' durationDiagnosed according toACR 1987 revised criteria for classification of RASJC of ≥ 6TJC of ≥ 8CRP level of ≥ 1 mg/dl or an ESR of ≥ 28 mm/hour received stable doses of permitted DMARDs (MTX, chloroquine, HCQ, parenteral gold, SSZ, azathioprine, and LEF) for at least 8 weeks prior to study entry.Exclusion CriteriaUnsuccessfully treated with an anti-TNF agent previously treated with any cell-depleting therapy were excludedInterventions, doseD1: Tocilizumab: 8 mg/kg, 60-min infusion every 4 wksBackground of stable DMARD therapyD2: Placebo: 60-min infusion every 4 wksBackground of stable DMARD therapyNumber in groupD1: 803D2: 413Overall: 1216Mean age, years (SD)D1: 53D2: 54Sex, % femaleD1: 81D2: 84Race, % whiteD1: 72D2: 72Race, % blackD1: 4D2: 7EthnicityAsianD1: 9D2: 10American IndianD1: 10D2: 8OtherD1: 3D2: 3Mean disease duration, yearsD1: 9.8 (8.8)D2: 9.8 (9.1)Patients with early RA, three years or less, %Disease Duration?=?2 yrs: D1: 19D2: 20Treatment resistant, %NRTender Joint Count, meanD1: 30.1 (16)D2: 29.1 (14.8)Swollen Joint Count, mean D1: 19.7 (11.6)D2: 18.7 (10.8)Corticosteroid use, %D1: 51.2D2: 54.6DMARD use, %D1: 100D2: 100Overall: 100MTX na?ve, %NRBaseline DAS scoreD1: 6.7D2: 6.6Required treatment for latent TBNRACR ACR 20:D1: 60.8D2: 24.5P = 0.0001ACR 50:D1: 37.6D2: 9.0P = 0.0001ACR 70:D1: 20.5D2: 2.9P = 0.0001HAQ, HAQ-DI D1: -0.5D2: -0.2P = 0.0001DAS28 D1: -3.17D2: -1.16Overall: , P?=?0.0001DAS28?=?2.6 (%)D1: 30D2: 3P = 0.0001SF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name) SJC, mean change from baseline: Tocilizumab?=?-10.3Placebo?=?-4.9P =?0.0001TJC, mean change from baseline: Tocilizumab?=?-15.7Placebo?=?-8.5P =?0.0001Good or Moderate Eular Response: Tocilizumab?=?80%P =?0.0001FACIT-F, mean change from baseline: Tocilizumab?=?8.0Placebo?=?3.6P =?0.0001OverallOverall attrition/withdrawal, n:D1: 53D2: 43Overall: 96Withdrawals due to adverse events, n:D1: 32D2: 8Overall: 40Adherent/compliant, n:D1: 751D2: 370Overall: 1121Overall adverse events reported, n:D1: 584D2: 253Overall: 837Serious adverse eventsDeath, n:D1: 2D2: 2Overall: 4MalignanciesNRRespiratory eventsTuberculosis: NRPneumonia, n:D1: 3D2: 2Overall: 5Upper respiratory infection, n:D1: 9%D2: 7%Overall: NROther infectionsNRGINausea or vomiting, n:D1: 4%D2: 3%Overall: NRAbdominal pain, n:D1: 3%D2: 1%Overall: NRMouth ulceration, n (%):D1: 2D2: 1Overall: NRStomatitis, %:D1: 1D2: 0Upper gastrointestinal tract events suggestive of gastric inflammation, gastritis, and ulcer, % D1: 3D2: 1OtherHeadache, n:D1: 6%D2: 4%Overall: NRHypertension, %:D1: 5D2: 3Overall: NRElevations in alanine amino-transferase level, from normal at baseline to > 3-foldupper limit of normal, %:D1: 4D2: 1Elevated total cholesterol levels, %:D1: 23D2: 6Overall: NRGrade 3 neutropenia, %:D1: 3.7D2: 0Overall: NRAny other AEs: Cellulitis: Tocilizumab : 5Placebo : 0, Overall : 5Herpes Zoster: Tocilizumab : 3Placebo : 0Overall : 3Adverse events occurring in ≥ 5% of patients, Tocilizumab, Placebo, Overall:Infections and infestations?=?300, 131, 431Gastrointestinal disorders?=?167, 61, 228;Musculoskeletal and connective tissue disorders?=?104, 74, 178Skin and subcutaneous tissue disorders?=?133, 29, 162Nervous system disorders?=?93, 36, 129Laboratory investigations?=?94, 11, 105General disorders and administration-site conditions?=?66, 30, 96Injury, poisoning, and procedural complications?=?63, 29, 92Respiratory, thoracic, and mediastinal disorders?=?69, 21,90Vascular disorders?=?54; 21; 75Serious adverse events occurring in ≥ 3 patients, Tocilizumab, Placebo, Overall: Infections and infestations?=?22, 8, 30;Musculoskeletal disorders?=?2, 3, 5Gastrointestinal disorders?=?9, 1, 10Nervous system disorders?=?6, 2, 8Cardiac disorders?=?3, 1, 4Injuries, poisoning?=?7, 0, 7Renal and urinary disorders?=?3, 0, 3;Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableGoekoop-Ruiterman, 2005PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2Vrb29wLVJ1aXRlcm1hbjwvQXV0aG9yPjxZZWFyPjIw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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2Vrb29wLVJ1aXRlcm1hbjwvQXV0aG9yPjxZZWFyPjIw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=
ADDIN EN.CITE.DATA 71; Allaart et al., 2006PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxhYXJ0PC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGxhYXJ0PC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48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==
ADDIN EN.CITE.DATA 72; Goekoop-Ruiterman, 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE.DATA 73; van der Kooij, 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0
Njg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij43NDwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0Njg8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjI0Njg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91
cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y
PnZhbiBkZXIgS29vaWosIFMuIE0uPC9hdXRob3I+PGF1dGhvcj5kZSBWcmllcy1Cb3V3c3RyYSwg
Si4gSy48L2F1dGhvcj48YXV0aG9yPkdvZWtvb3AtUnVpdGVybWFuLCBZLiBQLjwvYXV0aG9yPjxh
dXRob3I+RXdhbHMsIEouIEEuPC9hdXRob3I+PGF1dGhvcj5IYW4sIEsuIEguPC9hdXRob3I+PGF1
dGhvcj5IYXplcywgSi4gTS48L2F1dGhvcj48YXV0aG9yPktlcnN0ZW5zLCBQLiBKLjwvYXV0aG9y
PjxhdXRob3I+UGVldGVycywgQS4gSi48L2F1dGhvcj48YXV0aG9yPnZhbiBaZWJlbiwgRC48L2F1
dGhvcj48YXV0aG9yPkJyZWVkdmVsZCwgRi4gQy48L2F1dGhvcj48YXV0aG9yPkh1aXppbmdhLCBU
LiBXLjwvYXV0aG9yPjxhdXRob3I+RGlqa21hbnMsIEIuIEEuPC9hdXRob3I+PGF1dGhvcj5BbGxh
YXJ0LCBDLiBGLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNz
PkxlaWRlbiBVbml2ZXJzaXR5IE1lZGljYWwgQ2VudGVyLCBMZWlkZW4sIFRoZSBOZXRoZXJsYW5k
cy4gc212YW5kZXJrb29pakBsdW1jLm5sPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+UGF0
aWVudC1yZXBvcnRlZCBvdXRjb21lcyBpbiBhIHJhbmRvbWl6ZWQgdHJpYWwgY29tcGFyaW5nIGZv
dXIgZGlmZmVyZW50IHRyZWF0bWVudCBzdHJhdGVnaWVzIGluIHJlY2VudC1vbnNldCByaGV1bWF0
b2lkIGFydGhyaXRpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgUmhldW08L3Nl
Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BcnRocml0aXMg
YW5kIFJoZXVtYXRpc208L2Z1bGwtdGl0bGU+PGFiYnItMT5BcnRocml0aXMgUmhldW0uPC9hYmJy
LTE+PGFiYnItMj5BcnRocml0aXMgUmhldW08L2FiYnItMj48YWJici0zPkFydGhyaXRpcyAmYW1w
OyBSaGV1bWF0aXNtPC9hYmJyLTM+PC9wZXJpb2RpY2FsPjxwYWdlcz40LTEyPC9wYWdlcz48dm9s
dW1lPjYxPC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0
PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9u
b2Nsb25hbC90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBB
Z2VudHMvIHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMsIFJoZXVt
YXRvaWQvIGRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3kvcHN5Y2hvbG9neTwva2V5d29yZD48
a2V5d29yZD5EaXNhYmlsaXR5IEV2YWx1YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RG9zZS1SZXNw
b25zZSBSZWxhdGlvbnNoaXAsIERydWc8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBUaGVyYXB5LCBD
b21iaW5hdGlvbjwva2V5d29yZD48a2V5d29yZD5FbmRwb2ludCBEZXRlcm1pbmF0aW9uPC9rZXl3
b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtl
eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvdGhlcmFwZXV0aWMgdXNl
PC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBhaW4gTWVh
c3VyZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudHMvcHN5Y2hvbG9neTwva2V5d29yZD48
a2V5d29yZD5QcmVkbmlzb25lL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5RdWFs
aXR5IG9mIExpZmUvcHN5Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxu
ZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwv
a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW4gMTU8
L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDA0LTM1OTEgKFByaW50KTwvaXNibj48
YWNjZXNzaW9uLW51bT4xOTExNjk2NTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3Rv
bTE+STwvY3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b20zPkNUPC9jdXN0b20zPjxj
dXN0b200PktRIDEsIDIgLyBnb29kPC9jdXN0b200PjxjdXN0b203PkNvbXBhbmlvbnM6IDQ4NiBm
cm9tIG9sZCByZXBvcnQsIDMyNzQsIDIxOTksIDI1ODcgKEJlU1QpPC9jdXN0b203PjwvcmVjb3Jk
PjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 74; van der Kooij, 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 75BeST StudyCountry and settingThe Netherlands18 peripheral and 2 university hospitalsSource of fundingSchering-Plough and Centocor. Dutch College of Health InsurancesResearch objectiveEvaluate whether initial clinical and radiographic efficacy of combination therapies could be maintaned after 2PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE.DATA 73 and 4 yrsPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1
ODc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij43NTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI1ODc8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjI1ODc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj52YW4gZGVy
IEtvb2lqLCBTLiBNLjwvYXV0aG9yPjxhdXRob3I+R29la29vcC1SdWl0ZXJtYW4sIFkuIFAuPC9h
dXRob3I+PGF1dGhvcj5kZSBWcmllcy1Cb3V3c3RyYSwgSi4gSy48L2F1dGhvcj48YXV0aG9yPkd1
bGVyLVl1a3NlbCwgTS48L2F1dGhvcj48YXV0aG9yPlp3aW5kZXJtYW4sIEEuIEguPC9hdXRob3I+
PGF1dGhvcj5LZXJzdGVucywgUC4gSi48L2F1dGhvcj48YXV0aG9yPnZhbiBkZXIgTHViYmUsIFAu
IEEuPC9hdXRob3I+PGF1dGhvcj5kZSBCZXVzLCBXLiBNLjwvYXV0aG9yPjxhdXRob3I+R3JpbGxl
dCwgQi4gQS48L2F1dGhvcj48YXV0aG9yPlJvbmRheSwgSC4gSy48L2F1dGhvcj48YXV0aG9yPkh1
aXppbmdhLCBULiBXLjwvYXV0aG9yPjxhdXRob3I+QnJlZWR2ZWxkLCBGLiBDLjwvYXV0aG9yPjxh
dXRob3I+RGlqa21hbnMsIEIuIEEuPC9hdXRob3I+PGF1dGhvcj5BbGxhYXJ0LCBDLiBGLjwvYXV0
aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkxlaWRlbiBVbml2ZXJz
aXR5IE1lZGljYWwgQ2VudGVyLCBUaGUgTmV0aGVybGFuZHMuIHNtdmFuZGVya29vaWpAbHVtYy5u
bDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkRydWctZnJlZSByZW1pc3Npb24sIGZ1bmN0
aW9uaW5nIGFuZCByYWRpb2dyYXBoaWMgZGFtYWdlIGFmdGVyIDQgeWVhcnMgb2YgcmVzcG9uc2Ut
ZHJpdmVuIHRyZWF0bWVudCBpbiBwYXRpZW50cyB3aXRoIHJlY2VudC1vbnNldCByaGV1bWF0b2lk
IGFydGhyaXRpczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gUmhldW0gRGlzPC9zZWNvbmRh
cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW5uYWxzIG9mIHRoZSBS
aGV1bWF0aWMgRGlzZWFzZXM8L2Z1bGwtdGl0bGU+PGFiYnItMT5Bbm4uIFJoZXVtLiBEaXMuPC9h
YmJyLTE+PGFiYnItMj5Bbm4gUmhldW0gRGlzPC9hYmJyLTI+PC9wZXJpb2RpY2FsPjxwYWdlcz45
MTQtMjE8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48bnVtYmVyPjY8L251bWJlcj48a2V5d29y
ZHM+PGtleXdvcmQ+QWN1dGUgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3Jk
PjxrZXl3b3JkPkFuYWx5c2lzIG9mIFZhcmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2Rp
ZXMsIE1vbm9jbG9uYWwvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlL3RoZXJhcGV1dGljIHVz
ZTwva2V5d29yZD48a2V5d29yZD5BbnRpcmhldW1hdGljIEFnZW50cy8gYWRtaW5pc3RyYXRpb24g
JmFtcDsgZG9zYWdlL3RoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMs
IFJoZXVtYXRvaWQvIGRydWcgdGhlcmFweS9waHlzaW9wYXRob2xvZ3kvcmFkaW9ncmFwaHk8L2tl
eXdvcmQ+PGtleXdvcmQ+QXJ0aHJvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPkRpc2Vhc2UgUHJv
Z3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBBZG1pbmlzdHJhdGlvbiBTY2hlZHVsZTwv
a2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENvbWJpbmF0aW9uPC9rZXl3b3JkPjxrZXl3
b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48
a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+Sm9pbnRzL3BoeXNpb3BhdGhvbG9neTwv
a2V5d29yZD48a2V5d29yZD5MaW5lYXIgTW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tl
eXdvcmQ+PGtleXdvcmQ+TWV0aG90cmV4YXRlL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS90
aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl
eXdvcmQ+UHJlZG5pc29uZS9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvdGhlcmFwZXV0aWMg
dXNlPC9rZXl3b3JkPjxrZXl3b3JkPlJlbWlzc2lvbiBJbmR1Y3Rpb248L2tleXdvcmQ+PGtleXdv
cmQ+U3VsZmFzYWxhemluZS9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvdGhlcmFwZXV0aWMg
dXNlPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29y
ZHM+PGRhdGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdW48L2RhdGU+PC9w
dWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNDY4LTIwNjAgKEVsZWN0cm9uaWMpPC9pc2JuPjxhY2Nl
c3Npb24tbnVtPjE4NjYyOTMzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5J
PC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+PGN1c3RvbTM+Q1Q8L2N1c3RvbTM+PGN1c3Rv
bTQ+S1EgMSwgMiwgMyAvIGdvb2Q8L2N1c3RvbTQ+PGN1c3RvbTc+Q29tcGFuaW9uczogNDg2IGZy
b20gb2xkIHJlcG9ydCwgMzI3NCwgMjQ2OCwgMjE5OSAoQmVTVCk8L2N1c3RvbTc+PC9yZWNvcmQ+
PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 75Study designRCTOverall N508Duration of study2- and 4-year follow up dataQuality rating Good Inclusion Criteria:Age > 18 yrsRA according to ACR criteriaDuration of condition:?2 yrsActive disease with at least 6 of 66 swollen jointsAt least 6 of 68 tender jointsESR > 28 mm/hr OR global health score greater than or equal to 20mm on 0 to 100 VASConcomittant NSAIDS and intraarticular steroidsExclusion Criteria:PregnantPrior txt with: DMARDS other than antimalarialsImpaired renal or hepatic systemInterventions, doseD1: Sequential monotherapyD2: Step-up combination therapyD3: Initial combination therapy with PREDD4: Initial combination therapy with IFXNumber in groupD1: 126D2: 121D3: 133D4: 128Overall: 508Mean age, years (SD)D2: 54D3: 55D4: 54Overall: 54Sex, % femaleD1: 86D2: 86D3: 86D4: 85Overall: 86Race, %NRMean disease duration, yearsD1: 23 wksD2: 26 wksD3: 23 wksD4: 23 wksPatients with early RA, three years or lessOverall: 100%Treatment resistant, %NRTender Joint Count, meanNRSwollen Joint Count, mean NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %Overall: 100Baseline DAS score, meanD1: 4.5 +/- 0.9D2: 4.5 +/- 0.8D3: 4.4 +/- 0.9D4: 4.3 +/- 0.9Required treatment for latent TBNRACR mean difference/ absolute differenceNRHAQ (mean ±SD)At 3 months:D1: 0.4 ± 0.6D2: 0.3 ± 0.6D3: 0.8 ± 0.7D4: 0.7 ± 0.6P = ?0.050 for D1/D2 vs. D3/D4At 6 months:D1: 0.5 ± 0.7D2: 0.5 ± 0.7D3: 0.9 ± 0.7D4: 0.8 ± 0.6P = ?0.050 for D1/D2 vs. D3/D4At 9 months:D1: 0.6 ± 0.7D2: 0.6 ± 0.7D3: 0.8 ± 0.7D4: 0.8 ± 0.6P = ?0.050 for D1/D2 vs. D3/D4At 12 months:D1: 0.7 ± 0.7D2: 0.7 ± 0.7D3: 0.9 ± 0.7D4: 0.9 ± 0.7P = ?0.050 for D1 vs. D3/D4At 15 months:D1: 0.7 ± 0.7D2: 0.8 ± 0.7D3: 0.7 ± 0.8D4: 0.9 ± 0.7P = ?NSAt 18 months:D1: 0.7 ± 0.7D2: 0.8 ± 0.7D3: 0.8 ± 0.8D4: 0.9 ± 0.7P = ?NSAt 21 months:D1: 0.7 ± 0.7D2: 0.8 ± 0.7D3: 0.8 ± 0.7D4: 0.9 ± 0.7P = ?NSAt 24 months:D1: 0.7 ± 0.7D2: 0.8 ± 0.7D3: 0.9 ± 0.7D4: 0.9 ± 0.7At 36 months:D1: 0.8 ± 0.7D2: 0.7 ± 0.7D3: 0.8 ± 0.8D4: 0.9 ± 0.7P = ?0.66At 48 months:D1: 0.8 ± 0.6D2: 0.7 ± 0.8D3: 0.8 ± 0.8D4: 0.8 ± 0.8P = ?0.64DAS44 goal of 2.4 reached, %D1: 75D2: 81D3: 78D4: 82P = ?NSOverall: 79P = ?0.554 Sustain DAS44 of less than or:?2.4. After 1 yr:D1: 53%D2: 64%D3: 71%D4: 74% P = ?0.004 for 1 vs. 3 P = ?0.001 for 1 vs. 4P = ?NS and NR for othersSF-36 D1: SF-36 PCS (values are mean change from baseline, except baseline values): Baseline 32.9, 3 mos 5.8, 6 mos 8.0, 12 mos 8.9, 24 mos 11.9, SF-36 MCS at baseline, 3 months, 6 months, 12 months, and 24 mos (values are mean change from baseline, except baseline values): Baseline 47.5; 3 mos 2.1; 6 mos 3.1; 12 mos 4.3; 24 mos 4.3D2: Baseline 32.9, 3 mos 3.9, 6 mos 8.5; 12 mos 11.2; 24 mos 12.3; SF-36 MCS at baseline, 3 mos, 6 mos, 12 mos, and 24 mos (values are mean change from baseline, except baseline values): Baseline 46.3; 3 mos 2.5; 6 mos 3.5; 12 mos 4.4; 24 mos 4.6D3: Baseline 32.8, 3 mos 11.2, 6 mos 12.5; 12 mos 11.9; 24 mos 12.3; SF-36 MCS at baseline, 3 mos, 6 mos, 12 mos, and 24 mos (values are mean change from baseline, except baseline values): Baseline 47.6; 3 mos 0.4; 6 mos 1.2; 12 mos 3.2; 24 mos 4.6D4: Baseline 33.4, 3 mos 9.6, 6 mos 12.4; 12 mos 12.0; 24 mos 12.7; SF-36 MCS at baseline, 3 mos, 6 mos, 12 mos, and 24 mos (values are mean change from baseline, except baseline values): Baseline 47.6; 3 mos 3.1; 6 mos 4.1; 12 mos 4.3; 24 mos 4.0Overall: At 3 and 6 mos, P=0.05 for SF-36 PCS comparing groups 1 and 2 to groups 3 and 4. Others were NS (For PCS: P = ?0.93 at baseline, 0.10 at 12 months, 0.95 at 24 months; For MCS at each timepoint: 0.73, 0.22, 0.17, 0.83, 0.97)Radiographic measures, mean difference (SD)Progression of SHS at 12 mos:D1: 2.0D2: 2.5D3: 1.0D4: 0.5(P = ?0.003 for group 1 vs. group 3; P = ?0.001 for 1 vs. 4; P = ?0.007 for 2 vs. 3; P = ?0.001 for 2 vs. 4)Progression of SHS at 24 months, mean (SD):Total Sharp ScoreD1: 9.0 ± 17.9D2: 5.2 ± 8.1D3: 2.6 ± 4.5D4: 2.5 ± 4.6Sharp van der Heijde median Increase at 12 mos:D1: 2.0D2: 2.5D3: 1.0D4: 0.5P = ?0.001Total Sharp Score, median (IQR):D1: 2.0 (0.0 - 8.6)D2: 2.0 (0.3 - 7.0)D3: 1.0 (0.0 - 2.5)D4: 1.0 (0.0 - 3.0)Narrowing-score:D1: 4.3 ± 9.8D2: 2.1 ± 3.8D3: 1.5 ± 3.2D4: 1.2 ± 2.9P = ?0.072Relative risk for SHS-progression, at 24 months:D1: 1.0D2: 0.91 (0.73, 1.12) D3: .74 (0.61, 0.89)D4: .73 (0.61, 0.88)Progression of SHS at 48 months, mean (SD):D1: 11.7 ± 17.3D2: 9.7 (12.8)D3: 6.7 (9.6)D4: 5.4 (9.2)P = ?0.002 D1 vs. D4SHS median (IQR)D1: 50 (1.0 - 15.8)D2: 5.5 (1.0 - 13.8)D3: 3.0 (1.0 - 7.5)D4: 2.5 (0.5 - 6.5)Narrowing-score at 48 months, mean (SD):D1: 5.7 (10)D2: 4.0 (7.0)D3: 3.7 (6.7)D4: 2.4 (4.6)Narrowing-score median (IQR):D1: 1.8 (0.0 - 7.0)D2: 1.0 (0.0 - 4.5)D3: 1.0 (0.0 - 3.9)D4: 1.0 (0.0 - 2.5)P = ?0.17Quality of life scales NROthers (CI/SD/P Value)Baseline:D1: 47.5D2: 47.1D3: 47.3D4: 47.0At 3 months:D1: 10.6D2: 9.5D3: 16.7D4: 17.3At 6 months:D1: 12.6D2: 15.4D3: 16.4D4: 19.112 months:D1: 15.2D2: 16.3D3: 16.9D4: 19.3P = 0.001 for 3 for D1 and 2 compared to D3 and 4, P = ?0.001 for D1 and 2 compared to D4 and D1 vs. D3 Attrition/withdrawalWithdrawals through 4 years of followup, n:D1: 11D2: 20D3: 14D4: 9Overall: 54 (11%)Over time, 27 (5%) patients who were equally distributed across treatment groups (P = ?0.474) were lost to follow-up: 12 withdrew consent (7 declined follow-up, 4 discontinued all medications despite having no adverse events, and 1 moved from area), 7 had a revised diagnosis, 1 discontinued treatment because of an adverse event, 4 died, and 3 were lost to follow-up for other reasons (2 were admitted to a nursing home and 1 wanted to become pregnant) (Figure 1). Noncompliant but included in ITT, n (%):D1: 12 (10)D2: 11 (9)D3: 14 (11)D4: 6 (5)Deviated from study protocol, n:D1: 19D2: 15D3: 36D4: 11(P = ?0.343) Overall adverse events reported, n210 (41%) of patients had an adverse event in year 1193 (38%) of patients had an adverse event in year 2 Mean number of adverse events per patient was 1.9 (SD, 1.2) in first year and 1.8 (SD, 1.2) in the second year. 56 serious adverse events were reported in the second year (16 events [13 patients] in group 1, 10 events [10 patients] in group 2, 17 events [11 patients] in group 3, and 13 events [8 patients] in group 4)Serious adverse eventsD1: NRD2: Cerebrovascular event: 1D3: Malignant ovarian cancer: 1D4: Mycardial infarction: 1, disseminated TB: 1Cardiovascular events, n: D1: Atrial fibrillation: 1, myocardial infarction: 1, coronary artery bypass: 1D2: NRD3: NRD4: Myocardial infarction: 1, unstable angina pectoris: 1Hepatotoxicity/elevated liver enzymes, n: NRMalignanciesBasal cell?carcinoma, n: D1: 1D2: NRD3: NRD4: NROther cancer (specify), n: D1: Renal cell carcinoma: 1D2: Malignant prostate cancer: 1D3: Malignant ovarian cancer: 1D4: Basal cell carcinoma: 1Respiratory eventsTuberculosis: NRPneumonia, n: D1: 1,D2: 1 D3: NRD4: NRPleural effusion, n: D1: 1D2: NRD3: NRD4: NROther infectionsUrinary tract infection, n: D1: pyelonephritis, n:?1D2: NRD3: NRD4: NROther infections (specify), n: D1: viral infection, n:?1D2: NRD3: NRD4: septic arthritis, n:?1GIGI bleed or ulcer, n: D1: NRD2: NRD3: NRD4: GI bleed, n:?1 OtherPerforated gastric ulcer, n: D1: 1D2: NRD3: NRD4: NRComplicated calcaneous fractures, n: D1: NRD2: 1D3: NRD4: NRAny other AEs: D1: Syncope:?1Ovarian cyst::?1MTX intoxication:?1Malaise:?1Depressive symptoms:?1D2: Pacemaker implantation:?1Symptomatic gallstone disease:?1Surgery for carpal tunnel syndrome:?1Uterus extirpation:?1Placement of total hip prostheses:?2D3:Placement of total hip prostheses:?2implantation of intracardiac device:?1syncope due to aortic valve dysfunction:?1limb amputation due to occlusion of the femoral artery:?1retinal hemorrhage:?1scleroderma:?1active RA:?1 D4: Active RA:?1cholecystectomy:?1placement of total knee prostheses:?1placement of elbow protheses:?1one patient had 4 episodes of disseminated TBStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Gomez-Reino, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ5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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjQ5
MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjc2PC9zdHls
ZT48L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NDkxPC9yZWMtbnVtYmVyPjxmb3Jl
aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJmejlh
eDl0YWZ4cGQ1Ij40OTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h
bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdv
bWV6LVJlaW5vLCBKLiBKLjwvYXV0aG9yPjxhdXRob3I+Q2FybW9uYSwgTC48L2F1dGhvcj48YXV0
aG9yPlZhbHZlcmRlLCBWLiBSLjwvYXV0aG9yPjxhdXRob3I+TW9sYSwgRS4gTS48L2F1dGhvcj48
YXV0aG9yPk1vbnRlcm8sIE0uIEQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh
dXRoLWFkZHJlc3M+SG9zcGl0YWwgQ2xpbmljbyBVbml2ZXJzaXRhcmlvIGFuZCBVbml2ZXJzaWRh
ZCBkZSBTYW50aWFnbyBkZSBDb21wb3N0ZWxhLCBTYW50aWFnbywgU3BhaW4uIGpncmVpbm9AaDEy
by5lczwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlRyZWF0bWVudCBvZiByaGV1bWF0b2lk
IGFydGhyaXRpcyB3aXRoIHR1bW9yIG5lY3Jvc2lzIGZhY3RvciBpbmhpYml0b3JzIG1heSBwcmVk
aXNwb3NlIHRvIHNpZ25pZmljYW50IGluY3JlYXNlIGluIHR1YmVyY3Vsb3NpcyByaXNrOiBhIG11
bHRpY2VudGVyIGFjdGl2ZS1zdXJ2ZWlsbGFuY2UgcmVwb3J0PC90aXRsZT48c2Vjb25kYXJ5LXRp
dGxlPkFydGhyaXRpcyBSaGV1bTwvc2Vjb25kYXJ5LXRpdGxlPjxzaG9ydC10aXRsZT5UcmVhdG1l
bnQgb2YgcmhldW1hdG9pZCBhcnRocml0aXMgd2l0aCB0dW1vciBuZWNyb3NpcyBmYWN0b3IgaW5o
aWJpdG9ycyBtYXkgcHJlZGlzcG9zZSB0byBzaWduaWZpY2FudCBpbmNyZWFzZSBpbiB0dWJlcmN1
bG9zaXMgcmlzazogYSBtdWx0aWNlbnRlciBhY3RpdmUtc3VydmVpbGxhbmNlIHJlcG9ydDwvc2hv
cnQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QXJ0aHJpdGlzIGFuZCBS
aGV1bWF0aXNtPC9mdWxsLXRpdGxlPjxhYmJyLTE+QXJ0aHJpdGlzIFJoZXVtLjwvYWJici0xPjxh
YmJyLTI+QXJ0aHJpdGlzIFJoZXVtPC9hYmJyLTI+PGFiYnItMz5BcnRocml0aXMgJmFtcDsgUmhl
dW1hdGlzbTwvYWJici0zPjwvcGVyaW9kaWNhbD48cGFnZXM+MjEyMi03PC9wYWdlcz48dm9sdW1l
PjQ4PC92b2x1bWU+PG51bWJlcj44PC9udW1iZXI+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9r
ZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8
L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbC8gYWR2ZXJzZSBlZmZlY3Rz
PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlyaGV1bWF0aWMgQWdlbnRzLyBhZHZlcnNlIGVmZmVjdHM8
L2tleXdvcmQ+PGtleXdvcmQ+QXJ0aHJpdGlzLCBSaGV1bWF0b2lkLyBkcnVnIHRoZXJhcHkvZXBp
ZGVtaW9sb2d5L2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHL2FkdmVyc2Ug
ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2lvbjwva2V5d29yZD48a2V5
d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk
PlJlY2VwdG9ycywgVHVtb3IgTmVjcm9zaXMgRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJlZ2lz
dHJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydCwgTm9uLVUuUy4gR292JmFw
b3M7dDwva2V5d29yZD48a2V5d29yZD5SZXRyb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtl
eXdvcmQ+UmlzayBGYWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlR1YmVyY3Vsb3NpcywgUHVsbW9u
YXJ5L2VwaWRlbWlvbG9neS8gaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5UdW1vciBOZWNy
b3NpcyBGYWN0b3ItYWxwaGEvIGFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+
PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPkF1Zzwv
ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxhY2Nlc3Npb24tbnVtPjEyOTA1NDY0PC9hY2Nlc3Np
b24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3Rv
bTI+PGN1c3RvbTM+T0FFPC9jdXN0b20zPjxjdXN0b200PjM8L2N1c3RvbTQ+PGN1c3RvbTc+TE0g
OC0xNCAoU1cpPC9jdXN0b203PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA 76Country, Setting:Spain 71 CentersFunding:Agencia Espa?ola del Medicamento (Ministerio de Sanidad y Consumo)Research Objective:Long-term safety of INF and ETA, in rheumatic diseases based on a national active-surveillanceStudy Design:Retrospective cohort studyOverall N:1,540 (1578 txts)Study Duration: Mean 1.1 yrsInclusion Criteria:Pts with rheumatic diseases being treated with biologic response modifiers registered in BIOBADASERExclusion Criteria:NAInterventions, dose:D1: INF/ETAETA: variesINF: variesN:D1: 1540 (1578 txts)Mean age, yrs:D1: 51Sex, % female:D1: 72Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRPsA:D1: 5.8AS: D1: 4.9Background TB incidence in Spain in 2000 was 21/100,000 1,893 cases of TB per 100,000 pts in yr 2000 and 1,113 cases per 100,000 pts in yr 2001 in pts treated with TNFRR of TNF pts compared general population 90.1 (95% CI,58.8-146.0) in yr 2000 and 53.0 (95% CI,34.5-89.0) in yr 2001Estimated annual incidence of TB among RA pts not exposed to TNF inhibitors was 95/100,000RR in RA pts who did not receive TNF of TB (adjusted for age and sex) was 4.13 (95% CI,2.59-6.83) relative to background rate RR of TB in INF-treated RA pts vs. RA pts not exposed to this therapy was 19.9 (95% CI,16.2-24.8) in yr 2000 and 11.7 (95% CI,9.5-14.6) in yr 200115 pts with TB were diagnosed as having RA, and 2 additional pts with TB had PsA; all pts with active TB were being treated with INF; 59% were diagnosed with TB within 3 mos of txt initiationInfections:D1: 7.7Infusion or injection reaction:D1: 2 (INF)URTI:D1: 9UTI:D1: 11Overall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableGreenberg JD et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE.DATA 77 Consortium of Rheumatology Researchers of North American (CORRONA) registryCountry and settingUSSource of fundingNational Institute of Arthritis and Musculoskeletal and Skin Disease; Arthritis FoundationResearch objectiveTo examine the association of MTX (MTX) and tumour necrosis factor (TNF) antagonists with the risk of infectious outcomes including opportunistic infections inpatients with rheumatoid arthritis (RA).Study designObservationalOverall N7971Duration of studyOctober 1, 2001 to September 30, 2006Inclusion CriteriaPatients with RAParticipants in CORRONA rheumatology practices enrolled from Oct 1, 2001-Sept 2006At least 1 follow-up visitExclusion CriteriaNAComparisons (dosage and frequency)D1: MTX: dosage and frequency NRD2: Anti-TNF: dosage and frequency NRD3: MTX: dosage and frequency NRAnti-TNF: dosage and frequency NRD4: Other DMARDs: dosage and frequency NRNumber in groupD1: 4206D2: 1804D3: 2855D4: 1274Mean age (years)D1: 59.7D2: 56.8D3: 57.9D4: 60.1Sex, % femaleD1: 73.8D2: 76.0D3: 77.7D4: 74.1Race, % whiteD1: 86.8D2: 86.7D3: 86.2D4: 88.2Race, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 9.5 (9.8)D2: 11.4 (9.6)D3: 11.1 (9.6)D4: 10.1 (9.8)TJC, meanD1: 4.2 D2: 4.8D3: 4.7D4: 3.6SJC, mean D1: 5.4D2: 5.1D3: 5.9D4: 4.1Corticosteroid use, %D1: 39.3D2: 40.9D3: 38.3D4: 36.6DMARD use, %: D1: 100D2: 0D3: 100D4: 100MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallOverall adverse events reported (n): D1: 1714D2: 890D3: 1514D4: 447Serious adverse events:NRMalignancies:NRRespiratory events:Pneumonia (n): Non-pyogenicD1: 51D2: 40D3: 61D4: 16PyogenicD1: 49D2: 22D3: 46D4: 22Upper respiratory infection?(n): D1: 660D2: 303D3: 522D4: 148Other infections:Urinary tract infection?(n): D1: 157D2: 81D3: 111D4: 32Cellulitis: D1: 59D2: 49D3: 71D4: 18GI:NROther:BursitisD1: 9D2: 5D3: 7D4: 3SinusitisD1: 370D2: 166D3: 331D4: 71Infectious arthritisD1: 9D2: 5D3: 5D4: 2SepticaemiaD1: 8D2: 8D3: 10D4: 4Other Site of Infection D1: 342D2: 211D3: 350D4: 131All Types of Infections,Unadjusted rate/100 pys- D1: 33.3D2: 41.8D3: 37.6D4: 26.9Rate of Infection,Adjusted rate/100 pys (95% CI)D1: 30.9 (29.2-32.7)D2: 40.1 (37.0-43.4)D3: (34.9-39.3)D4: 24.5 (21.8-27.5)IRR (95% CI)D1: 1.30 (1.12-1.50); P<0.001D2: 1.52 (1.30-1.78); P<0.001 vs. D3 (ref group)PRED use>10 mg daily independently associated with risk of infection: IRR (95% CI), 1.30 (1.11-1.53); P<0.001Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableGrijalva et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI5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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI5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 EN.CITE.DATA 78Country and settingUS - Tennessee Medicaid dataSource of fundingAHRQResearch objectiveEvaluate adherence and persistence during new episodes of traditional and biologic DMARD useStudy designRetrospective Cohort StudyOverall N6018pts with 10,574 episodes of new DMARD use.Duration of studyCohort members were followed from date when selection criteria were met to end of study (December 31, 2004), date of death, date of diagnosis of a serious medical condition, or loss of enrollment from TennCare, whichever came earliest.Quality rating Fair: Not controls for Disease Activity or Severity (would assume patients with higher severity/activity would be more likely to adhere), limited to a poor population in which access is likely to be an issue. Predetermined inclusion criteria of having fiInclusion CriteriaTennCare enrollees with RA Filled 1 prescription during screening periodExclusion Criteria<365 days of continuous enrollment prior to study entranceEstablished serious medical conditionsInterventions, DoseD1: MTX: variedD2: Hydroxychlorquine: variedD3: SSZ: variedD4: LEF: variedD5: MethylPNL: variedHydroxychlorquine: varied7 other groups (all dose varied): INX, ETA, ADA, MTX+INX, MTX+ETA, MTX + ADA, AKA and AKA+MTXNumber in group*N of new tx episodes*:D1: 3859D2: 3174D3: 944D4: 558D5: 904D6: 75D7: 374D8: 120D9: 98D10: 262D11: 107D12: 72Mean age (years)D1: 54D2: 51D3: 51D4: 55D5: 52D6: 53D7: 51D8: 58D9: 56D10: 53D11: 58D12: 53Sex, % femaleD1: 78.1D2: 82.7D3: 71.2D4: 79.4D5: 84.2D6: 74.7D7: 77.5D8: 80.8D9: 76.5D10: 83.6D11: 79.4D12: 72.2Race, % whiteD1: 72.4D2: 71.2D3: 76.5D4: 72D5: 69.9D6: 66.7D7: 70.9D8: 64.2D9: 72.4D10: 64.9D11: 61.7D12: 63.9Race, % black1Ethnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)ACR ACR 20: No efficacyACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference NROverallMedian Persistence in days, Cox Regression Model Adjusted* HR (95%CI): MTX 150, 1.0 (ref); HCQ 121, 1.03 (0.98-1.08); SSZ 53, 1.59 (1.47-1.72); LEF 136, 1.02 (0.93-1.11); MTX + HCQ 125, 1.05 (0.97-1.14); INX 85, 1.37 (1.09-1.73); ETA 175, 0.82 (0.73-0.92); ADA 134, 0.85 (0.67-1.08); MTX+IFX 155, 0.91 (0.73-1.15); MTX+ETA 147, 1.01 (0.87-1.17);MTX+ADA 219, 0.63 (0.48-0.84); ANK OR ANK+MTX 156, 0.94 (0.75-1.18). Mean Medication Possession Ratio, linear regression Adjusted* coefficient (95%CI): 0.80, 1.0 (ref); HCQ 0.79, 0.00 (-0.01 to 0.001); SSZ 0.77, -0.02 (-0.04 to 0); LEF 0.85, 0.05 (0.04 to 0.07); MTX+HCQ 0.66, -0.11 (-0.13 to -0.09); IFX 0.90, 0.11 (0.06 to 0.16); ETN 0.83, 0.04 (0.02 to 0.06); ADA 0.85, 0.04 (0.001 to 0.08); MTX+IFX 0.66, -0.12 (-0.17 to-0.07); MTX+ETN 0.64, -0.11 (-0.14 to-0.08); MTX+ADA 0.72, -0.07 (-0.11 to -0.03); ANA or ANA+MTX 0.71, -0.08 (-0.13 to -0.02) *Adjusted for age, sex, race, calendar year, residential location, disability, residence in nursing home, and risk scoreOverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNR Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableGrijalva et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0
MjA8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij43OTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjU0MjA8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjU0MjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5HcmlqYWx2
YSwgQy4gRy48L2F1dGhvcj48YXV0aG9yPkthbHRlbmJhY2gsIEwuPC9hdXRob3I+PGF1dGhvcj5B
cmJvZ2FzdCwgUC4gRy48L2F1dGhvcj48YXV0aG9yPk1pdGNoZWwsIEUuIEYuPC9hdXRob3I+PGF1
dGhvcj5HcmlmZmluLCBNLiBSLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0
aC1hZGRyZXNzPlZhbmRlcmJpbHQgVW5pdiwgU2NoIE1lZCwgMTUwMCAyMXN0IEF2ZSwgU3VpdGUg
MjYwMCwgTmFzaHZpbGxlLCBUTiAzNzIzMiwgVVNBIGNhcmxvcy5ncmlqYWx2YUB2YW5kZXJiaWx0
LmVkdTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluaXRpYXRpb24gb2YgcmhldW1hdG9p
ZCBhcnRocml0aXMgdHJlYXRtZW50cyBhbmQgdGhlIHJpc2sgb2Ygc2VyaW91cyBpbmZlY3Rpb25z
PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJoZXVtYXRvbG9neSAoT3hmb3JkKTwvc2Vjb25kYXJ5
LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlJoZXVtYXRvbG9neTwvZnVs
bC10aXRsZT48YWJici0xPlJoZXVtYXRvbG9neSAoT3hmb3JkKS48L2FiYnItMT48YWJici0yPlJo
ZXVtYXRvbG9neSAoT3hmb3JkKTwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFnZXM+ODItOTA8L3Bh
Z2VzPjx2b2x1bWU+NDk8L3ZvbHVtZT48a2V5d29yZHM+PGtleXdvcmQ+TWV0aG90cmV4YXRlLS10
b3hpY2l0eS08L2tleXdvcmQ+PGtleXdvcmQ+RXRhbmVyY2VwdC0tdG94aWNpdHktPC9rZXl3b3Jk
PjxrZXl3b3JkPkluZmxpeGltYWItLXRveGljaXR5LTwva2V5d29yZD48a2V5d29yZD5BZGFsaW11
bWFiLS10b3hpY2l0eS08L2tleXdvcmQ+PGtleXdvcmQ+U3VsZmFzYWxhemluZS0tdG94aWNpdHkt
PC9rZXl3b3JkPjxrZXl3b3JkPlRveGljaXR5LS1tZXRob3RyZXhhdGU8L2tleXdvcmQ+PGtleXdv
cmQ+QW50aSBpbmZsYW1tYXRvcnkgYWdlbnRzLS1tZXRob3RyZXhhdGU8L2tleXdvcmQ+PGtleXdv
cmQ+SW5mZWN0aW9ucy0tbWV0aG90cmV4YXRlPC9rZXl3b3JkPjxrZXl3b3JkPlRveGljaXR5LS1l
dGFuZXJjZXB0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGkgaW5mbGFtbWF0b3J5IGFnZW50cy0tZXRh
bmVyY2VwdDwva2V5d29yZD48a2V5d29yZD5JbmZlY3Rpb25zLS1ldGFuZXJjZXB0PC9rZXl3b3Jk
PjxrZXl3b3JkPlRveGljaXR5LS1pbmZsaXhpbWFiPC9rZXl3b3JkPjxrZXl3b3JkPkFudGkgaW5m
bGFtbWF0b3J5IGFnZW50cy0taW5mbGl4aW1hYjwva2V5d29yZD48a2V5d29yZD5JbmZlY3Rpb25z
LS1pbmZsaXhpbWFiPC9rZXl3b3JkPjxrZXl3b3JkPlRveGljaXR5LS1hZGFsaW11bWFiPC9rZXl3
b3JkPjxrZXl3b3JkPkFudGkgaW5mbGFtbWF0b3J5IGFnZW50cy0tYWRhbGltdW1hYjwva2V5d29y
ZD48a2V5d29yZD5JbmZlY3Rpb25zLS1hZGFsaW11bWFiPC9rZXl3b3JkPjxrZXl3b3JkPlRveGlj
aXR5LS1zdWxmYXNhbGF6aW5lPC9rZXl3b3JkPjxrZXl3b3JkPkFudGkgaW5mbGFtbWF0b3J5IGFn
ZW50cy0tc3VsZmFzYWxhemluZTwva2V5d29yZD48a2V5d29yZD5JbmZlY3Rpb25zLS1zdWxmYXNh
bGF6aW5lPC9rZXl3b3JkPjxrZXl3b3JkPk91dGNvbWVzLS1jbGluaWNhbDwva2V5d29yZD48a2V5
d29yZD5BbnRpYm9kaWVzLS1tb25vY2xvbmFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjIwMTA8L3llYXI+PC9kYXRlcz48aXNibj4xNDYyMDMyNDwvaXNibj48dXJscz48cmVsYXRl
ZC11cmxzPjx1cmw+aHR0cHM6Ly9hdXRoLmxpYi51bmMuZWR1L2V6cHJveHlfYXV0aC5waHA/dXJs
PWh0dHA6Ly9zZWFyY2guZWJzY29ob3N0LmNvbS9sb2dpbi5hc3B4P2RpcmVjdD10cnVlJmFtcDtk
Yj1pcGEmYW1wO0FOPTQ3LTAzNDYxJmFtcDtzaXRlPWVob3N0LWxpdmUmYW1wO3Njb3BlPXNpdGU8
L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9tMj5J
PC9jdXN0b20yPjxjdXN0b200PktRMyAvIGdvb2Q8L2N1c3RvbTQ+PHJlbW90ZS1kYXRhYmFzZS1u
YW1lPmlwYTwvcmVtb3RlLWRhdGFiYXNlLW5hbWU+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5F
QlNDT2hvc3Q8L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48L3JlY29yZD48L0NpdGU+PC9FbmRO
b3RlPgB=
ADDIN EN.CITE.DATA 79Country and settingUSA; Tennessee Medicaid-enrolled patientsSource of fundingVanderbilt Multidisciplinary Clinical Research Center (NIH/NIAMS Grant P60 AR056116)Research objectiveTo compare serious infections following initiation of different RA regimensStudy designObservationalOverall N21981Duration of study180 days of exposure during 2002-2005Inclusion CriteriaRA patients with new episodes of DMARD useExclusion CriteriaNRComparisons (dosage and frequency)D1: TNF-α antagonistsD2: LEFD3: SSZD4: HCQD5: MTXD6: low glucocorticoid regimeD7: med glucocorticoid regimeD8: high glucocorticoid regimeNumber in groupD1: 2192D2: 1097D3: 1283D4: 3398D5: 4355D6: 2058D7: 11117D8: 3406Mean age (years)D1: Median 54D2: 56D3: 52D4: 52D5: 55D6: 57D7: 55D8: 55Sex, % femaleD1: 74.86D2: 77.03D3: 68.04D4: 81.11D5: 76.21D6: 77.75D7: 76.38D8: 75.60Race, % whiteD1: 83.90D2: 84.32D3: 84.88D4: 79.64D5: 80.60D6: 80.47D7: 84.72D8: 84.44Race, % blackD1: 12.73D2: 13.49D3: 12.70D4: 18.01D5: 16.67D6: 17.15D7: 13.28D8: 13.30Ethnicity, LatinoNRMean disease duration, yearsNRTJC, meanNRSJC, mean NRCorticosteroid use, %100DMARD use, %: 0MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallNRSerious adverse events:NRMalignancies:NRRespiratory events:Pneumonia (n): Crude HR (95% CI)D1: 1.17 (0.67, 2.05)D2: 1.64 (0.79, 3.39)D3: 0.47 (0.14, 1.53)D4: 1.11 (0.67, 1.85)D5: 1.00 (reference)D6: 2.00 (1.1, 3.64)D7: 2.08 (1.31, 3.3)D8: 3.91 (2.31, 6.62)Age/gender adjusted HR (aHR) (95% CI)D1: 1.28 (0.73, 2.24)D2: 1.64 (0.79, 3.39)D3: 0.51 (0.16, 1.68)D4: 1.20 (0.72, 2)D5: 1.00 (reference)D6: 1.71 (0.94, 3.1)D7: 1.92 (1.22, 3.01)D8: 3.67 (2.19, 6.15) Propensity Score-adjusted HR (95% CI)D1: 1.61 (0.85, 3.03)D2: 1.65 (0.77, 3.54)D3: 0.60 (0.19, 1.97)D4: 1.24 (0.73, 2.08)D5: 1.00 (reference)D6: 2.30 (1.2, 4.41)D7: 2.36 (1.44, 3.87)D8: 4.33 (2.49, 7.54)Other infections:Any infectionCrude HR (95% CI)D1: 1.04 (0.66, 1.64)D2: 1.39 (0.78, 2.48)D3: 0.82 (0.4, 1.66)D4: 1.06 (0.71, 1.56)D5: 1.00 (reference)D6: 1.46 (0.88, 2.43)D7: 2.12 (1.47, 3.05)D8: 3.37 (2.19, 5.19)Age/gender adjusted HR D1: 1.12 (0.71, 1.77)D2: 1.39 (0.78, 2.48)D3: 0.89 (0.44, 1.8)D4: 1.13 (0.76, 1.67)D5: 1.00 (reference)D6: 1.28 (0.77, 2.13)D7: 1.98 (1.38, 2.83)D8: 3.21 (2.1, 4.9)Propensity Score-adjusted HR (95% CI)D1: 1.31 (0.78, 2.19)D2: 1.48 (0.81, 2.69)D3: 1.03 (0.51, 2.1)D4: 1.20 (0.81, 1.79)D5: 1.00 (reference)D6: 1.62 (0.94, 2.78)D7: 2.39 (1.63, 3.51)D8: 3.72 (2.37, 5.84)GI:NROther:NR Quality rating for efficacy/effectiveness? NRQuality rating for observational studies GoodStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Haagsma, 1997 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1670</RecNum><DisplayText><style face="superscript">80</style></DisplayText><record><rec-number>1670</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1670</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Haagsma, C.J.</author><author>van Riel, P.L.</author><author>de Jong, A.J.</author><author>van de Putte, L.B.</author></authors></contributors><titles><title>Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial</title><secondary-title>British journal of rheumatology</secondary-title></titles><periodical><full-title>British Journal of Rheumatology</full-title><abbr-1>Br. J. Rheumatol.</abbr-1><abbr-2>Br J Rheumatol</abbr-2></periodical><pages>1082-8</pages><volume>36</volume><number>10</number><keywords><keyword>CN-00145448</keyword></keywords><dates><year>1997</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>LM 9-27 (KD 8-7)</custom7></record></Cite></EndNote>80Country, Setting:Netherlands, 1 academic and 6 peripheral clinicsFunding:Pharmachemie BV; Pharmacia ABResearch Objective:Compare efficacy and safety of SSZ, MTX, and combination of both in pts with early RAStudy Design:RCTOverall N:105Study Duration: 52 wksInclusion Criteria:Age: ≥ 18Diagnosed with RA according to ACR criteria: ACR criteriaRF positive and/or HLA-DR4 positive and/or HLA DR1 positiveFunctional class of: DAS ≥ 3.0Duration of condition: < 12 mosAnalgesica and NSAIDS allowedExclusion Criteria:Prior txt with: DMARDS other than analgesics and NSAIDSOther: contraindications to SSZ or MTXInterventions, dose:D1: SSZ (1 g/day; max 3 g/day)D2: MTX (7.5 mg/wk; max 15 mg/wk)D3: MTX (7.5 mg/wk; max 15 mg/wk) + SSZ (1 g/day; max 3 g/day)N:D1: 34D2: 35D3: 36Mean age, yrs:D1: 56.8D2: 54.9D3: 57.0Sex, % female:D1: 61.8D2: 65.7D3: 66.7Race, % white:NRMean disease duration, yrs:D1: 3.1 mosD2: 3.0 mosD3: 2.6 mosTJC, mean:D1: 20.8D2: 20.6D3: 24.8SJC, mean:D1: 17.0D2: 19.9D3: 20.8DMARD use, %:Overall: 0Corticosteroid use, %Overall: 0MTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):Overall: 100Baseline DAS, mean:D1: 4.6D2: 4.7D3: 5.0HAQ:D1: 0.97D2: 0.92D3: 1.20No significant differences in efficacy between combination (MTX, SSZ) and single therapy (MTX or SSZ), only a trend favoring combination therapy, MTX and SSZ were comparableAt 52 weeksDAS mean change: D1: -1.6 (95% CI, -2.0 to -1.2)D2: -1.7 (95% CI, -2.0 to -1.4)D3: -1.9 (95% CI, -2.2 to -2.3)Ritchie mean change:D1: -8.6 (95% CI, -10.7 to -6.5)D2: -8.2 (95% CI, -10.1 to -6.4)D3: -9.4 (95% CI, -11.1 to -7.7)Swollen joints mean change: D1: SSZ -7.9 (95% CI, -10.1 to -5.7)D2: -10.2 (95% CI, -12.5 to -8.0)D3: -11.3 (95% CI, -13.5 to -9.2)HAQ change from baseline: D1: -0.32 (95% CI, -0.53 to -0.10)D2: -0.46 (95% CI, -0.68 to -0.25)D3: -0.51 (95% CI, -0.76 to -0.26)Number of pts with a response according to ACR criteria at end of study:D1: 25D2: 25D3: 28Number of pts with good response according to EULAR definition:D1: 14 D2: 15 D3: 14Overall: D1: 88.2D2: 77.1D3: 88.9SAEs:D1: 8.8D2: 0D3: 0Abdominal Pain:D1: 26.5D2: 20D3: 36Cardiovascular Events (Dyspnea):D1: 5.9D2: 0D3: 5.6Dizziness:D1: 17.6D2: 8.6D3: 27.8Headache:D1: 17.6D2: 11.4D3: 11.1Nausea:D1: 29.4D2: 25.7D3: 63.9URTID1: 17.6D2: 20.0D3: 27.8Overall Attrition Rate, %:19ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Harley, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE.DATA 81Country, Setting:US, Health Plan DataFunding:Centocor Research Objective: To examine txt compliance and dosage administration with MTX, ETC and INF therapy for RAStudy Design:Observational-retrospective data analysisOverall N:2662Study Duration: 30 mosInclusion Criteria:Commercial or Medicare enrolleesExclusion Criteria:MTX, ETA or INF within 182 days of index dateInterventions:D1: INFD2: ETAD3: INFN:D1: 141D2: 853D3: 1668Mean age (yrs):D1: 56.3D2: 47.4D3: 53.3Sex, % female:D1: 27D2: 26.3D3: 26.9Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:D1: 34D2: 41D3: 37.9Corticosteroid use, %:NRMTX naive, %: NRTreatment resistant %: NRPatients with Early RA (≤3 yrs): NRBaseline DAS, mean: NRCompliance with at least 80% of expected dosages:ETA: 68.4; OR 0.462; 95 CI, 0.290-0736MTX: 63.7; OR 0.385; 95 CI, 0.245-0604INF: 80.9OR:ReferenceP < 0.05Dosage Increases:MTX: 61.6%INF: 37.4%ETA: 7.4%NROverall Attrition Rate, %: NAITT Analysis:Not applicable Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableHarrison, 2009 et al., British Society for Rheumatology Biologics Register (BSRBR)PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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==
ADDIN EN.CITE.DATA 82Country and settingUK, hospitals/general practiceSource of fundingFinancial support to BSRBR comes indirectly from following UK companies marketing biologic agents in UK: Schering Plough, Wyeth Laboratories, Abbott Laboratories, and Amgen. The resources used to fund BSRBR are received under contractResearch objectiveTo compare incidence rates of psoriasis in RA patients treated with anti-TNFa therapy and traditional DMARDsStudy designProspective Cohort StudyOverall N12,706Duration of studyApproximately 1 to 2 years (current analysis based on early BSRBR data - follow up will continue for at least 5 years)Quality rating FairInclusion CriteriaTreatment cohort (all anti-TNFa): first 4000 patients with RA starting each anti-TNFa therapy were required by National Institute for Health and Clinical Excellence to be registered with BSRBR and followed up for information on drug use, disease activity and adverse events. All patients with a doctor diagnosis of RA who were receiving ETN, IFX or ADA as their first anti-TNFα therapy comprise anti-TNFα cohort for this study. Comparison cohort: biological naive, doctor-diagnosed RA, active disease (guideline DAS28 > 4.2), current treatment with a DMARDExclusion CriteriaComparison cohort: No previous exposure to any anti-TNFa drugInterventions, DoseD1: Other: NR (traditional DMARDs)D2: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRNumber in groupD1: 2880D2: 9826Overall: 12,706Mean age (years)D1: 60D2: 56.2Sex, % femaleD1: 72D2: 76Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 7 yrs (IQR:?1 - 15)D2: 11 yrs (IQR:?6 - 19)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: 100D2: 100Overall: 100MTX na?ve, %NRBaseline DAS score, mean (SD)D1: 5.0D2: 6.6Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Current Smoker: 24%Former Smoker: 40%Never smoked: 36%HAQ, median: 1.6D2: Current Smoker: 22%Former Smoker: 38%Never smoked: 40%HAQ, median: 2.1ACR NR HAQ, NR DAS NR SF-36 NR Radiographic measures NR Quality of life scales NR Others, (please name); mean difference/absolute difference (CI/SD/P Value)NR OverallWithdrawals due to adverse events, n:D1: NAD2: 8Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherPsoriasis, n:D1: 0; Rate of psoriasis/1000 person years (95% CI): 0 (upper 97.5% CI O.71)D2: 25; Rate of psoriasis/1000 person years (95% CI): 1.04 (0.67 - 1.54)Overall: Psoriasis, n: 25Subanalysis: Patients treated with ADA had a significantly increased risk of psoriasis compared to thosetreated with ETN (IRR 4.6, 95% CI 1.7 to 12.1) and IFX (IRR 3.5, 95% CI 1.3 to 9.3) adjusted for age, sex, smoking status and calendar year of registrationStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableHetland et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUz
OTk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij44Mzwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjUzOTk8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjUzOTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91
cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y
PkhldGxhbmQsIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5DaHJpc3RlbnNlbiwgSS4gSi48L2F1dGhv
cj48YXV0aG9yPlRhcnAsIFUuPC9hdXRob3I+PGF1dGhvcj5EcmV5ZXIsIEwuPC9hdXRob3I+PGF1
dGhvcj5IYW5zZW4sIEEuPC9hdXRob3I+PGF1dGhvcj5IYW5zZW4sIEkuVC48L2F1dGhvcj48YXV0
aG9yPktvbGxlcnVwLCBHLjwvYXV0aG9yPjxhdXRob3I+TGluZGUsIEwuPC9hdXRob3I+PGF1dGhv
cj5MaW5kZWdhYXJkLCBILk0uPC9hdXRob3I+PGF1dGhvcj5Qb3Vsc2VuLCBVLkUuPC9hdXRob3I+
PGF1dGhvcj5TY2hsZW1tZXIsIEEuPC9hdXRob3I+PGF1dGhvcj5KZW5zZW4sIEQuVi48L2F1dGhv
cj48YXV0aG9yPkplbnNlbiwgUy48L2F1dGhvcj48YXV0aG9yPkhvc3RlbmthbXAsIEcuPC9hdXRo
b3I+PGF1dGhvcj7DmHN0ZXJnYWFyZCwgTS48L2F1dGhvcj48YXV0aG9yPkFsbCBEZXB0IFJoZXVt
YXRvbG9neSBEZW5tYXJrLDwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h
ZGRyZXNzPkNvcGVuaGFnZW4gVW5pdiBIb3NwLCBEZXB0IFJoZXVtYXRvbCAyMzIsIEtldHRlZ2Fy
ZCBBbGxlIDMwLCBESy0yNjUwIEh2aWRvdnJlLCBEZW5tYXJrIG1lcmV0ZS5oZXRsYW5kQGRhZGxu
ZXQuZGs8L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5EaXJlY3QgY29tcGFyaXNvbiBvZiB0
cmVhdG1lbnQgcmVzcG9uc2VzLCByZW1pc3Npb24gcmF0ZXMsIGFuZCBkcnVnIGFkaGVyZW5jZSBp
biBwYXRpZW50cyB3aXRoIHJoZXVtYXRvaWQgYXJ0aHJpdGlzIHRyZWF0ZWQgd2l0aCBhZGFsaW11
bWFiLCBldGFuZXJjZXB0LCBvciBpbmZsaXhpbWFiIHJlc3VsdHMgZnJvbSBlaWdodCB5ZWFycyBv
ZiBzdXJ2ZWlsbGFuY2Ugb2YgY2xpbmljYWwgcHJhY3RpY2UgaW4gdGhlIE5hdGlvbndpZGUgRGFu
aXNoIERBTkJJTyBSZWdpc3RyeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgYW5k
IFJoZXVtYXRpc208L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10
aXRsZT5BcnRocml0aXMgYW5kIFJoZXVtYXRpc208L2Z1bGwtdGl0bGU+PGFiYnItMT5BcnRocml0
aXMgUmhldW0uPC9hYmJyLTE+PGFiYnItMj5BcnRocml0aXMgUmhldW08L2FiYnItMj48YWJici0z
PkFydGhyaXRpcyAmYW1wOyBSaGV1bWF0aXNtPC9hYmJyLTM+PC9wZXJpb2RpY2FsPjxwYWdlcz4y
Mi0zMjwvcGFnZXM+PHZvbHVtZT42Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxrZXl3b3Jk
cz48a2V5d29yZD5BZGFsaW11bWFiLS1hcnRocml0aXMtPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxp
eGltYWItLWFydGhyaXRpcy08L2tleXdvcmQ+PGtleXdvcmQ+RXRhbmVyY2VwdC0tYXJ0aHJpdGlz
LTwva2V5d29yZD48a2V5d29yZD5QcmVkbmlzb2xvbmUtLWFydGhyaXRpcy08L2tleXdvcmQ+PGtl
eXdvcmQ+QW50aSBpbmZsYW1tYXRvcnkgYWdlbnRzLS1hZGFsaW11bWFiPC9rZXl3b3JkPjxrZXl3
b3JkPkFudGkgaW5mbGFtbWF0b3J5IGFnZW50cy0tZXRhbmVyY2VwdDwva2V5d29yZD48a2V5d29y
ZD5EcnVnIGNvbXBhcmlzb25zLS1hZGFsaW11bWFiIGFuZCBldGFuZXJjZXB0PC9rZXl3b3JkPjxr
ZXl3b3JkPkRydWcgY29tcGFyaXNvbnMtLWV0YW5lcmNlcHQgYW5kIGFkYWxpbXVtYWI8L2tleXdv
cmQ+PGtleXdvcmQ+QW50aSBpbmZsYW1tYXRvcnkgYWdlbnRzLS1pbmZsaXhpbWFiPC9rZXl3b3Jk
PjxrZXl3b3JkPkRydWcgY29tcGFyaXNvbnMtLWFkYWxpbXVtYWIgYW5kIGluZmxpeGltYWI8L2tl
eXdvcmQ+PGtleXdvcmQ+RHJ1ZyBjb21wYXJpc29ucy0taW5mbGl4aW1hYiBhbmQgYWRhbGltdW1h
Yjwva2V5d29yZD48a2V5d29yZD5EcnVnIGNvbXBhcmlzb25zLS1ldGFuZXJjZXB0IGFuZCBpbmZs
aXhpbWFiPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgY29tcGFyaXNvbnMtLWluZmxpeGltYWIgYW5k
IGV0YW5lcmNlcHQ8L2tleXdvcmQ+PGtleXdvcmQ+UmF0aW9uYWwgdGhlcmFweS0tYWRhbGltdW1h
Yjwva2V5d29yZD48a2V5d29yZD5SaGV1bWF0aWMgZGlzZWFzZXMtLWFkYWxpbXVtYWI8L2tleXdv
cmQ+PGtleXdvcmQ+QXJ0aHJpdGlzLS1hZGFsaW11bWFiPC9rZXl3b3JkPjxrZXl3b3JkPlJhdGlv
bmFsIHRoZXJhcHktLWluZmxpeGltYWI8L2tleXdvcmQ+PGtleXdvcmQ+UmhldW1hdGljIGRpc2Vh
c2VzLS1pbmZsaXhpbWFiPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcy0taW5mbGl4aW1hYjwv
a2V5d29yZD48a2V5d29yZD5SYXRpb25hbCB0aGVyYXB5LS1ldGFuZXJjZXB0PC9rZXl3b3JkPjxr
ZXl3b3JkPlJoZXVtYXRpYyBkaXNlYXNlcy0tZXRhbmVyY2VwdDwva2V5d29yZD48a2V5d29yZD5B
cnRocml0aXMtLWV0YW5lcmNlcHQ8L2tleXdvcmQ+PGtleXdvcmQ+UmF0aW9uYWwgdGhlcmFweS0t
cHJlZG5pc29sb25lPC9rZXl3b3JkPjxrZXl3b3JkPlJoZXVtYXRpYyBkaXNlYXNlcy0tcHJlZG5p
c29sb25lPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcy0tcHJlZG5pc29sb25lPC9rZXl3b3Jk
PjxrZXl3b3JkPkFudGkgaW5mbGFtbWF0b3J5IGFnZW50cy0tcHJlZG5pc29sb25lPC9rZXl3b3Jk
PjxrZXl3b3JkPk91dGNvbWVzLS10aGVyYXBldXRpYzwva2V5d29yZD48a2V5d29yZD5BbnRpYm9k
aWVzLS1tb25vY2xvbmFsPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3ll
YXI+PC9kYXRlcz48aXNibj4wMDA0MzU5MTwvaXNibj48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+
aHR0cHM6Ly9hdXRoLmxpYi51bmMuZWR1L2V6cHJveHlfYXV0aC5waHA/dXJsPWh0dHA6Ly9zZWFy
Y2guZWJzY29ob3N0LmNvbS9sb2dpbi5hc3B4P2RpcmVjdD10cnVlJmFtcDtkYj1pcGEmYW1wO0FO
PTQ3LTE0MzY1JmFtcDtzaXRlPWVob3N0LWxpdmUmYW1wO3Njb3BlPXNpdGU8L3VybD48L3JlbGF0
ZWQtdXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxj
dXN0b200PktRIDEsIDMgLyBmYWlyPC9jdXN0b200PjxyZW1vdGUtZGF0YWJhc2UtbmFtZT5pcGE8
L3JlbW90ZS1kYXRhYmFzZS1uYW1lPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+RUJTQ09ob3N0
PC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUz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 EN.CITE.DATA 83Country and settingDenmark; natioal registrySource of fundingUnrestricted grants to DANBIO from Abbott,Wyeth, and Schering-Plough (since 2004), Bristol-Myers Squibb, and Roche (since 2006), and UCB-Nordic (since 2007).The Danish Regions provided financial support for the activities related to quality improvement of biologic treatment.Research objectiveTo compare TNF inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with RA and to identify clinical prognostic factors for response.Study designObservationalOverall N2326Duration of study1 yearInclusion CriteriaRA, as diagnosed by the treating rheumatologistTreated with 1 or more oral DMARD, but treatment failed to such an extent that therapy with either ADA, ETN, or INFExclusion CriteriaNRComparisons (dosage and frequency)D1: MTX: 70%, mean of 20 mg/weekADA: 40 mg every 2 wksD2: MTX: 61%, mean of 15 mg/weekETN: 45 mg every weekD3: MTX: 87%, mean of 15 mg/weekINF: 25 mg every 7 wksNumber in groupD1: 544D2: 425D3: 908*Note that the #s here did not include the full 2326, it excludes those who withdrew (19%)Mean age (years)D1: 56D2: 58D3: 57Sex, % femaleD1: 75D2: 72D3: 73Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: mean (range) 9 (0-51)D2: 8 (0-47)D3: 9 (0-68)TJC, meanNRSJC, mean NRCorticosteroid use, %D1: PNL 40%D2: 43%D3: 50%DMARD use, %: D1: MTX 70%D2: 61%D3: 87%MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NRBaseline DAS scoreD1: 5.3D2: 5.4D3: 5.4Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: NRACR 50: 6 mosD1: 8.7D2: 10.4D3: 3.612 mosD1: 12.4D2: 12.4D3: 5.8ACR 70:6 mosD1: 4.6D2: 5.5D3: 1.612 mosD1: 7.0D2: 7.8D3: 2.6HAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): DAS28 remission/ Lundex corrected (n)6 mosD1: 32/26 (536)D2: 26/21 (414) D3: 21/17 (889) DAS28 remission/ Lundex corrected (n)12 mosD1: 39/27 (444)D2: 33/24 (377)D3: 27/16 (/690)SF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): Adjusted ORs for ACR70 responseADA vs INF: 2.05 (1.52 to 2.76)ETN vs. INF: 1.78 (1.28 to 2.5)ADA vs. ETN: 1.15 (0.82 OverallOverall attrition/withdrawal (n): ADA vs ETA 1.47 (1.20-1.80)INF vs. ETA 1.98 (1.63-2.40)INF vs ADA 1.35 (1.15-1.58)Withdrawals due to adverse events?(n): ADA vs ETA 1.50 (1.04-2.16)INF vs. ETA 2.65 (1.88-3.73)INF vs ADA 1.77 (1.34 - 2.34)Withdrawals due to lack of efficacy?(n): ADA vs ETA 1.47 (1.15-1.87)INF vs. ETA 1.70 (1.35- 2.15INF vs ADA 1.16 (0.95-1.41)Serious adverse events:NRMalignancies:NRRespiratory events:NROther infections:NRGI:NROther:NR Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableHjardem et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMw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ADDIN EN.CITE.DATA 84Country and settingDanish, multicenterSource of fundingAbbott, Wyeth, Schering-PloughResearch objectiveInvestigate efficacy of switching to a second biologic drug in RAStudy designPopulation – based Dynamic Cohort StudyOverall N235 (switchers only)Duration of studyVaried, NRQuality rating Fair: No controls for confounding, baseline difference in current mtx useInclusion CriteriaRA pt who had received 2+ biologics (IFX, ETN, or ADA only)Exclusion CriteriaIncomplete baseline data (DAS)Interventions, DoseD1: IFX: varied, dose NRD2: ETN: varied, dose NRD3: ADA: varied, dose NRNumber in groupD1: 178D2: 18D3: 39Mean age (years)D1: 55D2: 54D3: 52Sex, % femaleD1: 77D2: 61D3: 74Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: mean (range): 9 yrs (4-17)D2: 11 (3-23)D3: 7 (3-17)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: current MTX: 82D2: 42D3: 62MTX na?ve, %NRBaseline DAS score, mean (SD)D1: 5.8 (5.0-6.5)D2: 5.9 (5.4-6.5)D3: 5.6 (5.0-6.7)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)ACR NRHAQ NRDAS D1: Efficacy outcomes stratified by 1st & 2nd drug and cannot be combined. SF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference NROverallAll pts included in study withdrew from their tx, reasoning as follows (% withdrew for :Lack of Efficacy/Adverse Event/Other): IFX 45/34/21, ETN 44/22/34, ADA 54/21/26Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNR Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableHoff, M. et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2532</RecNum><DisplayText><style face="superscript">85</style></DisplayText><record><rec-number>2532</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2532</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Hoff, M.</author><author>Kvien, T. K.</author><author>Kalvesten, J.</author><author>Elden, A.</author><author>Haugeberg, G.</author></authors></contributors><auth-address>Department of Rheumatology, St Olav's Hospital, Trondheim, Norway. mari.hoff@ntnu.no</auth-address><titles><title>Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: explorative analyses from the PREMIER study</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>1171-6</pages><volume>68</volume><number>7</number><keywords><keyword>Absorptiometry, Photon</keyword><keyword>Antibodies, Monoclonal/ therapeutic use</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/physiopathology/radiography</keyword><keyword>Bone Density/physiology</keyword><keyword>Bone Diseases, Metabolic/physiopathology/ prevention & control/radiography</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>Hand Bones</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1468-2060 (Electronic)</isbn><accession-num>18801760</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>CT</custom3><custom4>KQ 1 / fair</custom4><custom7>Companion study: 141 from old report (PREMIER)</custom7></record></Cite></EndNote>85PREMIERCountry and settingNorway, multicenterSource of fundingAbbott LaboratoriesResearch objectiveExamine effect of ADA on hand osteoporosis and relation to radiographic joint damage in 3 tx arms: ADA + MTX, ADA, and MTX to identify predictors of hand bone lossStudy designControlled TrialsOverall N768Duration of study2 yrsQuality rating Fair Inclusion CriteriaMTX Na?veEarly RAAggressive RA: ≥ 8 swollen joints, ESR ≥ 28 or CRP ≥ 1.5 mg/dl, erosions or rheumatoid factor positive. No prior treatment with cyclophos-phamide, cyclosporine, azathioprine or more than 2 other DMARDs.Exclusion CriteriaNRInterventions, doseD1: MTX: weekly by mouth (rapidly increased to 20 mg/week)ADA: 40 mg subcutaneously every other weekD2: ADA: 40 mg subcutaneously every other weekPlaceboD3: MTX: weekly by mouthPlaceboNumber in groupD1: 261D2: 261D3: 246Overall: 768Mean age, years (SD)D1: 52.2 (13.8)D2: 51.9 (13.7)D3: 51.9 (13.3)Sex, % femaleD1: 71.6D2: 78.5D3: 73.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 0.7 (0.8)D2: 0.7 (0.8)D3: 0.8 (0.9)Patients with early RA, three years or less, %D1: 100D2: 100D3: 100 Treatment resistant, %NRTJC, mean (SD)D1: 31.1 (14.1)D2: 31.7 (13.5)D3: 32.2 (14.3)SJC, mean D1: 21.2 (42.4)D2: 21.7 (10.2)D3: 21.6 (11.3)Corticosteroid use, %D1: 35.2D2: 36D3: 34.6DMARD use, %D1: 32.2D2: 33.3D3: 31.7MTX na?ve, %D1: 100D2: 100D3: 100Baseline DAS score (SD)D1: 6.3 (0.9)D2: 6.4 (0.9)D3: 6.3 (0.9)Required treatment for latent TBNRMedian Modified TSS (SD)D1: 12.8 (60.24)D2: 13.5(5.1-25.5)D3: 15.5 (7.5-28.5)MeanD1: 18.1 (20.3)D2: 18.4 (18.2)D3: 21.5 (21.8)ACR NRHAQ?(SD)D1: 1.5 (0.6)D2: 1.6 (0.6)D3: 1.5 (0.7)DAS NRSF-36 NRRadiographic measures (SD)Modified TSS change from baseline:Median at 26 weeks, n:D1: 0 (0.5)D2: 1.0 (3.4)D3: 0.5 (2.2)Median at 52 weeks:D1: 0 (0.9)D2: 2.0 (5.1)D3: 0.5 (3.3)Median at 104 weeks:D1: 0 (1.0) D2: 2.0 (6.4)D3: 1.0 (4.8)Quality of life scales NRAttrition/withdrawalOverall, n:D1: 65D2: 104D3: 88Overall: 257Adherent/compliant, n:D1: 203D2: 167D3: 169Overall: 539Overall adverse events reported, n: NRSerious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NROther infectionsNRGINRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Hyrich et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1417</RecNum><DisplayText><style face="superscript">86</style></DisplayText><record><rec-number>1417</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1417</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hyrich, K. L.</author><author>Symmons, D. P.</author><author>Watson, K. D.</author><author>Silman, A. J.</author></authors></contributors><auth-address>University of Manchester, Manchester, UK.</auth-address><titles><title>Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1786-1794</pages><volume>54</volume><number>6</number><dates><year>2006</year><pub-dates><date>May 30</date></pub-dates></dates><accession-num>16736520</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>1,3</custom4><custom6>RA</custom6><custom7>KD 9-27 (SW)</custom7></record></Cite></EndNote>86Country, Setting:Great Britain, multiclinicFunding:Schering Plough, Wyeth, Abbott, A mgenBritish Society for Rheumatology Biologics RegisterResearch Objective:Compare outcome at 6 mos in unselected real-world RA pts treated with ETA or INF alone or with MTX or another DMARDStudy Design:Prospective cohort studyInclusion Criteria:Age > 16 yrsDiagnosed with RA according to 1987 ACR criteria; starting either ETA or INF as first biologic drugOther meds were allowedExclusion Criteria:NRInterventions, dose:D1: ETA (25 mg 2x wk)D2: ETA + DMARDD3: ETA + MTXD4: INF (3 mg/kg wks 0,2,6 then every 8wks)D5: INF + DMARDD6: INF + MTXSome doses NRN:D1: 763D2: 245D3: 250D4: 128D5: 121 D6: 1204Mean age, yrs:D1: 58D2: 55D3: 54D4: 59D5: 58 D6: 55Sex, % female:D1: 80D2: 79D3: 76D4: 79D5: 74 D6: 77Race, % white:NRMean disease duration, yrs:D1: 16D2: 15D3: 13D4: 16D5: 14 D6: 14TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %D1: 54D2: 51D3: 44D4: 69D5: 59 D6: 48MTX naive, %:NRTreatment resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 6.8D2: 6.6D3: 6.6D4: 6.8D5: 6.8 D6: 6.7At 6 monthsEULAR response:D3 vs. D1: (OR 1.98, 95% CI, 1.45-2.71) D2 vs. D1 (OR 1.20, 95% CI, 0.89-1.61)D3 vs D2 (OR 1.66, 95% CI, 1.14-2.42)A better EULAR response in both MTX (OR 1.35 [95% CI, 0.92-2.00]) and DMARD (OR 1.26 [95% CI, 0.75-2.13]) subgroups as compared with INF monotherapyDAS28: D1: 4.8 +/-.4D2: 4.6 +/- 1.5D3: 4.3 +/- 1.5D4: 5.0 +/- 1.6D5: 4.9 +/- 1.6D6: 4.6 +/- 1.6Adherence:Drug survival at 6 mos: ETA 20% INF 21% ETA subgroups (22% mono, 16% MTX co-therapy, 19% DMARD co-therapy)INF subgroups (30% vs. 21% MTX co-therapy , vs. 22% DMARD co-therapy)Overall Attrition Rate, %:21ITT Analysis:N/A Quality; Rating:GoodStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableHyrich et al., 2006,PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+SHlyaWNoPC9BdXRob3I+PFll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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+SHlyaWNoPC9BdXRob3I+PFll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ADDIN EN.CITE.DATA 87 BSRBRCountry and settingUK, hospitals/general practiceSource of fundingBSRBR receives financial support from following UK companies: Schering Plough, Wheth Laboratories, Abbott Laboratories and Amgen. Aforementioned resources are used by BSR to provide research grants to University of Manchester.Research objectiveIdentify clinical factors present at start of anti-TNF-alpha therapy associated with response at 6 mosStudy designObservationalOverall N2879Duration of study6 mosQuality rating FairInclusion CriteriaPatients registered with BSRBR who had fulfilled1987 ACR criteria for RAStarted therapy with either ETN or IFX within 6 mos of registrationOnly patients who had reached 6 mos of follow-up prior to 10/1/04 were considered for study.Exclusion CriteriaNRInterventions, doseD1: ETN: 25 mg, twice/wkBoth study arms included participants who were concurrently using NSAIDs, corticosteroids, other DMARDs, or MTX (see patient characteristics for specifics)D2: IFX: 3 mg/kg at weeks 0, 2, 6, and 8 weekly thereafterBoth study arms included participants who were concurrently using NSAIDs, corticosteroids, other DMARDs, or MTX (see patient characteristics for specifics)Number in groupD1: 1267D2: 1612Overall: 2879Mean age, years (SD)D1: 55D2: 55Overall: 55Sex, % femaleD1: 78D2: 76Overall: 77Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 14 D2: 14 Overall: 14Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)D1: 16 (7)D2: 16 (7)Overall: 16SJC, mean (SD)D1: 12 (6)D2: 12 (6)Corticosteroid use, %D1: 50D2: 49Overall: 49.3DMARD use, %D1: 100D2: 100Overall: 100MTX na?ve, %D1: NRD2: NROverall: 2%Baseline DAS scoreD1: 6.7D2: 6.7Overall: 6.7Required treatment for latent TBNROther population characteristics, %Concurrent NSAIDs:D1: 65D2: 67Concurrent corticosteroids:D1: 50D2: 49Concurrent DMARDs:D1: 48D2: 94Concurrent MTX:D1: 28D2: 86 Overall: NRACR mean difference/ absolute difference (CI/SD/P Value)ACR 20: NRACR 50: NRACR 70: NRHAQ, mean difference/ absolute difference NRDAS, mean difference/absolute difference (CI/SD/P Value)D1: NRD2: NROverall: -2.1SF-36, mean difference/absolute difference NRRadiographic measures, mean difference/absolute difference NRQuality of life scales, mean difference/absolute difference NROthers, (please name), mean difference/absolute difference (CI/SD/P Value)Good EULAR response, n (%): ETN: 245 (17.3)IFX: 339 (18.70, Overall: 584 (18.1)Concurrent MTX + ETN: 101 (41)Concurrent steroids + ETN: 113 (46)Concurrent NSAIDs + ETN: 117 (72)Concurrent MTX + IFX: 300 (89)Concurrent steroids + IFX: 155 (46)Concurrent NSAIDs + IFX: 255 (75)Moderate EULAR response, n (%): ETN: 727 (51.5)IFX: 875 (48.3), Overall: 1602 (49.7)Concurrent MTX + ETN: 200 (27)Concurrent steroids + ETN: 352 (48)Concurrent NSAIDs + ETN: 472 (65)Concurrent MTX + IFX: 756 (86)Concurrent steroids + IFX: 442 (51)Concurrent NSAIDs + IFX: 575 (66)No EULAR response, n (%): ETN: 441 (31.2)IFX: 596 (32.9), Overall: 1037 (32.2)Concurrent MTX + ETN: 55 (18)Concurrent steroids + ETN: 163 (55)Concurrent NSAIDs + ETN: 176 (59)Concurrent MTX + IFX: 326 (82)Concurrent steroids + IFX: 195 (49)Concurrent NSAIDs + IFX: 248 (62)Remission, n (%): ETN: 120 (8.0)IFX: 172 (9.0), Overall: 292 (8.6)Predictors of remission at 6 mos, OR (95% CI): Concurrent MTX + ETN: 1.80 (1.14 - 2.85)Concurrent steroid + ETN: 0.81 (0.52 - 1.25)Concurrent NSAIDs + ETN: 1.79 (1.07 - 2.99)Concurrent MTX + IFX: 1.24 (0.68 - 2.27)Concurrent steroids + IFX: 1.10 (0.76 - 1.59)Concurrent NSAIDs + IFX: 1.93 (1.23 - 3.03)Attrition/withdrawalOverall, n:D1: 146D2: 198Withdrawals due to adverse events, n:D1: 129D2: 166Adherent/compliant, n:D1: 1149D2: 1460Overall adverse events reported, n:D1: 129D2: 166Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableHyrich et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE.DATA 88Country and settingUK, hospitals/general practiceSource of fundingSchering Plough, Wyeth, Abbott, Amgen, British Society for Rheumatology RegisterResearch objectiveCompare drug continuation rates between 1st and 2nd course of anti-TNF therapyStudy designProspective Cohort StudyOverall N6739Duration of studyMean length of followup per patient was 15 months (maximum 61 months). Due to difference in availability of 3 agents, mean followup of patients starting IFX (18 months) was longer than that of patients starting either ADA (11 months) or ETQuality rating FairInclusion CriteriaPatients registered with BSRBR with a diagnosis of RA (as determined by treating rheumatologist) who had reached a minimum of 6 months of followup by end of April 2005.Exclusion CriteriaNRInterventions, DoseD1: ADA: 40 mg, every two wksD2: ETN: 25 mg, twice/wkD3: IFX: 3 mg/kg, administered at weeks 0, 2, 6, and 8 and every 8 weeks thereafterNumber in groupD1: 876D2: 2826D3: 3037Mean age (years)55Sex, % female77Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)Overall: 14 yrs (9)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %49DMARD use, %100MTX na?ve, %0Baseline DAS score, mean (SD)6.6Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Overall: HAQ: 2.1Receiving concomittant DMARDS, All: 69%ETN group: 48, IFX group: 92ADA group: 58Receiving concomitant MTXAll: 56%ETN group: 30%IFX group: 85%ADA group: 40%ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallOverall attrition/withdrawal, n: D1: 265D2: 822D3: 1273Overall: 2360Withdrawals due to adverse events, n:D1: 98D2: 405D3: 520Overall: 1023Withdrawals due to lack of efficacy, n:D1: 109D2: 277D3: 455Overall: 841Adherent/compliant, n:D1: 611D2: 2004D3: 1764Overall: 4379Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNR Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Jacobsson et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjYw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjYw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ADDIN EN.CITE.DATA 89Country, Setting:Sweden, population-based (2 Swedish registers)Funding:NRResearch Objective:Risk of cardiovascular disease (CVD) in pts with RA treated with TNF inhibitors, compared to a standard RA populationStudy Design:Retrospective cohort studyOverall N:983 (combined cohort)Study Duration: NRInclusion Criteria:Age-: 20 -79 yrsDiagnosed according to 1987 ACR criteriaCase cohortSouth Swedish Arthritis Txt Group (SSATG): pts with RA treated with anti-TNF agents and included in SSATG register between 2/1/99 and 12/31/01Exclusion Criteria:Previous hospital discharge due to CVDInterventions, dose:D1: Anti-TNF exposedD2: Not Anti-TNF exposedN:D1: 531D2: 452Median age, yrs:D1: 55D2: 61Sex, % female:D1: 78D2: 75Race, % white:NRMedian disease duration, yrs:D1: 12D2: 11TJC, mean:NRSJC, mean:NRMedian # of previous DMARDs used (IQR):D1: 4 (2-5)D2: 2 (1-4)PNL use, %:D1: 75D2: 22MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMedian HAQ:D1: 1.50D2: 1.13VAS patient global assessment median: D1: 69D2: 48Decreased incidence and RR for the development of first-time CVD event when controlling for disease severity in pts with RA treated with TNF blocking therapyControlling for disability (HAQ), age-sex adjusted rate ratio was 0.46 (95% CI,0.25 -0.85; P = 0.013) in anti-TNF treated vs. not treatedAnti-TNF group, 13 CVD events (in 656 PY at risk); age-adjusted incidence rate: 14 events/1000 PYUnexposed comparison group, 85 CVD events (in 2056 PY at risk); age-adjusted incidence rate: 35.4 events/1000 PYRelative risk: 0.62 (95% CI, 0.34 to 1.12; P = 0.111)SMR revealed increased risk of new onset CVD in those not treated with TNF blockers in relation to background population of Malmo (SMR: 228, 95% CI,179 to 277) TNF blockers, risk of new onset CVD was lower, with CIs enclosing unity with background population (SMR: 157, 95% CI,72 -242)Cardiovascular Events:D1: n:13 (6 MI, 4 cerebrovascular disease, and 3 other)D2: n:85 (33 MIs, 15 cerebrovascular disease, 12 CHF, 2 ruptured aortic aneurysm, and 23 other)Overall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKaranikolas et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2
MTQ8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij45MDwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI2MTQ8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjI2MTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LYXJhbmlr
b2xhcywgRy48L2F1dGhvcj48YXV0aG9yPkNoYXJhbGFtYm9wb3Vsb3MsIEQuPC9hdXRob3I+PGF1
dGhvcj5WYWlvcG91bG9zLCBHLjwvYXV0aG9yPjxhdXRob3I+QW5kcmlhbmFrb3MsIEEuPC9hdXRo
b3I+PGF1dGhvcj5SYXB0aSwgQS48L2F1dGhvcj48YXV0aG9yPkthcnJhcywgRC48L2F1dGhvcj48
YXV0aG9yPkthc2thbmksIEUuPC9hdXRob3I+PGF1dGhvcj5TZmlrYWtpcywgUC4gUC48L2F1dGhv
cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5GaXJzdCBEZXBhcnRtZW50
IG9mIFByb3BlZGV1dGljIGFuZCBJbnRlcm5hbCBNZWRpY2luZSwgTGFpa28gSG9zcGl0YWwsIEF0
aGVucywgR3JlZWNlLiBna2FyYW5pa2dyQHlhaG9vLmdyPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48
dGl0bGU+QWRqdW5jdGl2ZSBhbmFraW5yYSBpbiBwYXRpZW50cyB3aXRoIGFjdGl2ZSByaGV1bWF0
b2lkIGFydGhyaXRpcyBkZXNwaXRlIG1ldGhvdHJleGF0ZSwgb3IgbGVmbHVub21pZGUsIG9yIGN5
Y2xvc3BvcmluLUEgbW9ub3RoZXJhcHk6IGEgNDgtd2VlaywgY29tcGFyYXRpdmUsIHByb3NwZWN0
aXZlIHN0dWR5PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJoZXVtYXRvbG9neSAoT3hmb3JkKTwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlJoZXVtYXRv
bG9neTwvZnVsbC10aXRsZT48YWJici0xPlJoZXVtYXRvbG9neSAoT3hmb3JkKS48L2FiYnItMT48
YWJici0yPlJoZXVtYXRvbG9neSAoT3hmb3JkKTwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFnZXM+
MTM4NC04PC9wYWdlcz48dm9sdW1lPjQ3PC92b2x1bWU+PG51bWJlcj45PC9udW1iZXI+PGtleXdv
cmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGlyaGV1bWF0aWMgQWdlbnRz
L2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhy
aXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkN5Y2xvc3Bv
cmluZS9hZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkRy
dWcgVGhlcmFweSwgQ29tYmluYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2l2ZSBBZ2Vu
dHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2luIDEgUmVjZXB0
b3IgQW50YWdvbmlzdCBQcm90ZWluL2FkdmVyc2UgZWZmZWN0cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPklzb3hhem9sZXMvYWR2ZXJzZSBlZmZlY3RzL3RoZXJhcGV1dGljIHVz
ZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvdHJleGF0ZS9h
ZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBB
Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPlByb3NwZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdv
cmQ+U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQg
T3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWIt
ZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2Mi0wMzMy
IChFbGVjdHJvbmljKTwvaXNibj48YWNjZXNzaW9uLW51bT4xODYwMzY2MDwvYWNjZXNzaW9uLW51
bT48dXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxj
dXN0b20zPk88L2N1c3RvbTM+PGN1c3RvbTQ+S1EgMSwgMyAvIGZhaXI8L2N1c3RvbTQ+PC9yZWNv
cmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA 90Country and settingGreece, multicenterSource of fundingNRResearch objectiveUnderstand if adding ANK totx regime will improve response of pts with suboptimal response to LEF, MTX, or CSA monotherapyStudy designOpen-label comparisonOverall N128Duration of study48wksQuality rating FairInclusion CriteriaTreatment resistant defined as an inadequate response to non-biologic DMARD18 years or olderActive RA (defined as 9+ TJC, 6 SJC, and one offollowing: ESR ≤?28mm/1st hr, ≥ 20mg/l and morning stiffness ≥?45minutes), stable dose of non-biologic DMARD (LEF MTX or CSA), NSAIDS, & oral corticosteroidsExclusion CriteriaTreatment with TNF-antagonist or intra-articular or systemic corticosteroids within 8 wksInterventions, doseD1: MTX: Continued at 25mg/wk or maximum tolerated doseANK: 100mg/dailyD2: LEF: Continued at 20mg/wk or maximum tolerated doseANK: 100mg/dailyD3: ANK: 100mg/dailyCSA: 3.5mg or maximum tolerated doseNumber in groupD1: 48D2: 42D3: 38Mean age, years (SD)D1: 48.1D2: 47.2D3: 47.6Sex, % femaleD1: 68D2: 69D3: 70Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 6.9 (5.1)D2: 6.8 (4.3)D3: 7.1 (4.7)Patients with early RA,:?2 years or less, %D1: 27D2: 25D3: 23 Treatment resistant, %D1: 100D2: 100D3: 100Overall: 100Tender Joint Count, meanNRSwollen Joint Count, mean NRCorticosteroid use, %D1: 60D2: 62D3: 63DMARD use, %D1: 100D2: 100D3: 100MTX na?ve, %D1: 0D2: NRD3: NRBaseline DAS scoreD1: 6.55D2: 6.93D3: 6.97Required treatment for latent TBNRACR ACR 20:D1: 65D2: 81D3: 74 (Comparison: P = ?0.218)ACR 50:D1: 38D2: 64D3: 47 (Comparison: P = ?0.039)ACR 70:D1: 15D2: 36D3: 21 (Comparison: P = ?0.057)HAQ NR for groupsDAS NR, Reported in graph onlySF-36 NRRadiographic measures Comparisons: SJC P = ?NSTJC P = ?NS HAQ P = ?NSQuality of life scales NRAttrition/withdrawalOverall, n:D1: 9D2: 3D3: 5Withdrawals due to adverse events, n:D1: 3* D2: 2*D3: 2(*includes 1 death)Withdrawals due to lack of efficacy, n:D1: 2D2: 1D3: 3Adherent/compliant, n: NROverall adverse events reported, n:D1: 34D2: 30D3: 20Serious adverse eventsDeath, n:D1: 1D2: 1Arterial hypertension, n:D1: 0D2: 4D3: 2Thrombocytopenia, n:D1: 1D2: 0D3: 0Hepatotoxicity/elevated liver enzymes, n:D1: 0D2: 0D3: 0MalignanciesOvarian cancer, n:D1: 1D2: 0D3: 0Respiratory eventsTuberculosis: NRUpper respiratory infection, n:D1: 4D2: 4D3: 0Other infectionsUrinary tract infection, n:D1: 1D2: 2D3: 0Ocular infection, n:D1: 0D2: 1D3: 0GIGI bleed or ulcer, n:D1: 0D2: 0D3: 1OtherInfusion/injection site reactions, n:D1: 20D2: 10D3: 7Skin rash, n:D1: 0D2: 0D3: 0Headache, n:D1: 0D2: 4D3: 1 Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKavanaugh et al., 2008,PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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==
ADDIN EN.CITE.DATA 91 TEMPO Country and settingMultinational, multicenterSource of fundingImmunex Corporation & Wyeth PharmaceuticalsResearch objectiveEvaluate clinical response between 12 and 24 wks in subjects with RA from TEMPO trialStudy designControlled TrialsOverall N682 Duration of study52 weeks (TEMPO trial), 12 & 24 weeks outcomes reported hereQuality rating Fair Inclusion Criteria:Age > 18Diagnosed according to ACR criteriaFunctional class I-IIILess than satisfactory response to at least 1 DMARD other than MTXDuration 6 mos to 20 yrsRA defined as > 10 swollen and > 12 painful joints and at least one of: ESR > 28 mm/h, CRP > 20 mg/L, or morning stiffness for > 45 minutesFolic acid 5 mg twice per wkNSAIDsExclusion Criteria:TNF antagonist, any immuno-suppressive drugs w/in 6 mosAny investigational drug or biologic agent within 3 mos DMARD or corticosteroid injection within 4 mosRelevant comorbidity, Previous txt with MTX if pt experienced clinically toxic side effects or had no responseInterventions, doseD1: MTX: 7.5mg/wk escalated to 20mg/wk over 8wksETN: 25mg, 2/wkD2: ETN: 25mg, 2/wkD3: MTX 7.5mg/wk escalated to 20mg/wk over 8 wksNumber in groupD1: 231D2: 223D3: 228Overall: 682Mean age, years (SD)D1: see TEMPOPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY3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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY3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==
ADDIN EN.CITE.DATA 92 for baseline characteristics by armOverall: 52.5Sex, % femaleNRRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: NRD2: NROverall: 6.8 yrsPatients with early RA, three years or less, %NRTreatment resistant, %NRTJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)NRACR At week 12ACR 20:D1: 75.8D2: 66.4D3: 61.0ACR 50:D1: 41.6D2: 32.7D3: 25.9ACR 70:D1: 22.1D2: 9.4D3: 5.7At week 24ACR 20:D1: 84.8D2: 77.1D3: 77.2ACR 50:D1: 57.6D2: 44.4D3: 41.7ACR 70:D1: 32.0D2: 14.8D3: 14.0HAQNRDAS D1: NR (different stratification for analysis)D2: NRD3: NROverall: NRSF-36 NRRadiographic measures D1: NR (different stratification for analysis)D2: NRD3: NROverall: NRQuality of life scales NROverallNRSerious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NR Other infectionsNRGINROtherNRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKay et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE.DATA 93Country and settingMultlinational, multienterSource of fundingCentocorResearch objectiveAsssess efficacy, safety and pharmacology of subcutaneous GOL in pts with active RA despite tx with MTXStudy designControlled TrialsOverall N172Duration of study16 wks (efficacy), 20 wks (AEs) after week 20- drug and dosing schedules were adjusted and patients were followed for efficacy & AEs -AE data reported (thru week 52) were not included inabstraction to prevent confusion.Quality rating Fair Inclusion CriteriaActive RA for 3+ mos (TJC and SJC ≥ 6 and 2 of following 3: CRP ≥ 1.5mg/dl, ESR ≥ 28mm, morning stiffness ≥ 30 minutes), Age ≥ 18Exclusion CriteriaAbnormal lab resultsLatent or active TBPlanning pregnancy or inadequate birth controlOther inflammatory diseaseDMARD use w/in 4wks of study startFailed 3+ DMARDSPrevious treatment with TNF-alpha antagonist (more reported online in journal suppl materials)Interventions, doseD1: MTX: continued 10mg/wk PlaceboALL ARMS: continued (stable dose for > 4wks) corticosteroids (max 10mg PRED/day) and NSAIDsD2: MTX: continued 10mg/wk GOL: 50mg/4wksD3: MTX: continued 10mg/wk GOL: 50mg/2wksD4: MTX: continued 10mg/wk GOL: 100mg/4wksD5: MTX: continued 10mg/wkGOL: 100mg/2wksNumber in groupD1: 35D2: 35D3: 34D4: 34D5: 34Overall: 172Mean age, medianD1: 52.0D2: 57.0D3: 48.0D4: 57.5D5: 53.5Overall: 53.5Sex, % femaleD1: 74.3D2: 85.7D3: 67.6D4: 76.5D5: 79.4Overall: 76.7Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, median (IQR)D1: 5.6 (1.4, 10.9)D2: 8.2 (4.1, 14.3)D3: 8.2 (2.9, 12.8)D4: 6.3 (3.4, 14.1)D5: 9.0 (4.1, 14.1)Overall: 7.8 (3.0, 13.3)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, medianD1: 22D2: 28D3: 28D4: 32D5: 22Overall: 26Swollen Joint Count, median D1: 13D2: 14D3: 14D4: 20D5: 14Overall: 15Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %D1: 0D2: 0D3: 0D4: 0D5: 0Overall: 0Baseline DAS28/CRP scoreD1: 5.3 D2: 5.3 D3: 4.8 D4: 5.4 D5: 5.1 Overall: 5.2 DAS28/ESR - medianD1: 6.3D2: 6.4D3: 6.4D4: 6.7D5: 6.2Overall: 6.4Required treatment for latent TBD1: 0 (exluded) HAQ disability index - medianD1: 1.3D2: 1.7D3: 1.6D4: 1.8D5: 1.3Overall: 1.6ACR ACR 20:D1: 37.1D2: 60.0D3: 50.0D4: 55.9D5: 79.4*Overall: ALL - compared to Placebo 61.3 *P = ?0.010ACR 50:D1: 5.7D2: 37.1*D3: 23.5*D4: 29.4*D5: 32.4*Overall: 30.7 *P = ?0.003ACR 70:D1: 0D2: 8.6D3: 14.7*D4: 17.6*D5: 8.8Overall: 12.4 *P = ?0.028HAQ NRDAS28-CRP mean (SD)D1: -0.9 (1.0)D2: -1.9 (1.3)D3: -1.4 (1.3)D4: -1.9 (1.5)D5: -1.9(1.1)Overall: -1.8 (1.3)DAS28-ESR mean (SD)D1: -1.0 (1.1)D2: -2.1 (1.4) D3: -1.9 (1.5)D4: -2.1(1.7)D5: -2.3(1.2) Overall: -2.1 (1.4)SF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name) mean difference/absolute difference (CI/SD/P Value)ACR-N mean (SD): D1: -2.4 (50)D2: 22.7 (46.8)D3: 16.2 (57.4)D4: 24.8 (41.7)D4: 30.4 (42.3) D2 vs. D1:P = ?0.006, D3 vs. D1 P = ?0.095, D4 vs. D1: P = ?0.01, D5 vs. D1: P?<?0.01Attrition/withdrawalOverall, n:D1: 6D2: 4D3: 6D4: 5D5: 2Overall: 23Withdrawals due to adverse events, n:D1: 3D2: 2D3: 3D4: 2D5: 1Overall: 11Withdrawals due to lack of efficacy, n:D1: 3D2: 2D3: 1D4: 3D5: 1Overall: 10Overall adverse events reported, n: Pts reporting 1+ AE:D1: 29D2: 34D3: 24D4: 29D5: 31Serious adverse eventsCongestive cardiac failure, n:D1: 0D2: 1D3: 0D4: 0D5: 0Cardia tamponade, n:D1: 0D2: 0D3: 0D4: 0D5: 1MalignanciesLung adenocarcinoma, n:D1: 0D2: 0D3: 1D4: 0D5: 0Respiratory eventsTuberculosis: NRPneumonia, n:D1: 0D2: 1D3: 1D4: 1D5: 0Other infections1+ infection, n:D1: 13D2: 12D3: 6D4: 9D5: 9GINausea, n:D1: 1D2: 2D3: 7D4: 6D5: 8Other1+ injection site disorder thru 20wk, n: D1: 4D2: 5D3: 2D4: 5D5: 13Headache, n:D1: 7D2: 6D3: 5D4: 7D5: 3Any other AEs: All AEs reported thru 20 weeks. Only those in ≥ 10% of all GOL groups combined or SAEs. Additional surveillance for AEs continued thru wk 52, however, treatment and dosing schedule was adjusted for 3/5 arms.Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Keane, 2001PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY1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ADDIN EN.CITE.DATA 94Country, Setting:Multinational, NANAFunding:National Heart, Lung and Blood Institute; Massachusetts Thoracic Society; American Lung Association of MassachusettsResearch Objective:To explore relationship between INF and tuberculosis based on data from MedWatchStudy Design:Database analysis; AERSOverall N:70 cases47 Crohn's: 18Other: 5Study Duration: 1-52 wksInclusion Criteria:If during or after txt with INF, patient received diagnosis of TB on basis of clinical, radiologic, and laboratory findingsExclusion Criteria:NRInterventions, dose:D1: TB ptsINF: variesN:D1: 57Median age, yrs:D1: 57Sex, % female:D1: 64Race, % white:D1: NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:D1: 20MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NREstimated incidence for pts with RA who have been treated with INF during previous is 24.4 cases per 100.000 per yr (95% CI,0.6 to 34.0); background incidence in US for pts with RA not exposed to TIM therapy: 6.2 cases per 100,000 per yr Median interval from start of INF txt until development of TB: 12 wks; 68.6% developed TB after 3 or fewer INF infusions; reported frequency of TB in association with INF was much higher than reported frequency of other opportunistic infections associated with this drugNROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKeystone, E. et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1
MDY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij45NTwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI1MDY8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjI1MDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LZXlzdG9u
ZSwgRS48L2F1dGhvcj48YXV0aG9yPkhlaWpkZSwgRC48L2F1dGhvcj48YXV0aG9yPk1hc29uLCBE
LiwgSnIuPC9hdXRob3I+PGF1dGhvcj5MYW5kZXdlLCBSLjwvYXV0aG9yPjxhdXRob3I+Vm9sbGVu
aG92ZW4sIFIuIFYuPC9hdXRob3I+PGF1dGhvcj5Db21iZSwgQi48L2F1dGhvcj48YXV0aG9yPkVt
ZXJ5LCBQLjwvYXV0aG9yPjxhdXRob3I+U3RyYW5kLCBWLjwvYXV0aG9yPjxhdXRob3I+TWVhc2Us
IFAuPC9hdXRob3I+PGF1dGhvcj5EZXNhaSwgQy48L2F1dGhvcj48YXV0aG9yPlBhdmVsa2EsIEsu
PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0
eSBvZiBUb3JvbnRvLCBUb3JvbnRvLCBPbnRhcmlvLCBDYW5hZGEuIGVka2V5c3RvbmVAbXRzaW5h
aS5vbi5jYTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNlcnRvbGl6dW1hYiBwZWdvbCBw
bHVzIG1ldGhvdHJleGF0ZSBpcyBzaWduaWZpY2FudGx5IG1vcmUgZWZmZWN0aXZlIHRoYW4gcGxh
Y2VibyBwbHVzIG1ldGhvdHJleGF0ZSBpbiBhY3RpdmUgcmhldW1hdG9pZCBhcnRocml0aXM6IGZp
bmRpbmdzIG9mIGEgZmlmdHktdHdvLXdlZWssIHBoYXNlIElJSSwgbXVsdGljZW50ZXIsIHJhbmRv
bWl6ZWQsIGRvdWJsZS1ibGluZCwgcGxhY2Viby1jb250cm9sbGVkLCBwYXJhbGxlbC1ncm91cCBz
dHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgUmhldW08L3NlY29uZGFyeS10
aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BcnRocml0aXMgYW5kIFJoZXVt
YXRpc208L2Z1bGwtdGl0bGU+PGFiYnItMT5BcnRocml0aXMgUmhldW0uPC9hYmJyLTE+PGFiYnIt
Mj5BcnRocml0aXMgUmhldW08L2FiYnItMj48YWJici0zPkFydGhyaXRpcyAmYW1wOyBSaGV1bWF0
aXNtPC9hYmJyLTM+PC9wZXJpb2RpY2FsPjxwYWdlcz4zMzE5LTI5PC9wYWdlcz48dm9sdW1lPjU4
PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbnRpcmhldW1h
dGljIEFnZW50cy8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3Jk
PkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5L3BoeXNpb3BhdGhvbG9neS9yYWRp
b2dyYXBoeTwva2V5d29yZD48a2V5d29yZD5EaXNlYXNlIFByb2dyZXNzaW9uPC9rZXl3b3JkPjxr
ZXl3b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBUaGVyYXB5
LCBDb21iaW5hdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEZhYiBGcmFnbWVudHMvIGFk
bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3Jk
PjxrZXl3b3JkPk1ldGhvdHJleGF0ZS8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3
b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHlldGh5bGVuZSBH
bHljb2xzLyBhZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48
ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1k
YXRlcz48L2RhdGVzPjxpc2JuPjAwMDQtMzU5MSAoUHJpbnQpPC9pc2JuPjxhY2Nlc3Npb24tbnVt
PjE4OTc1MzQ2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0b20x
PjxjdXN0b20yPkkgTVRDPC9jdXN0b20yPjxjdXN0b20zPkNUPC9jdXN0b20zPjxjdXN0b200PktR
IDEsIDIsIDMgLyBmYWlyPC9jdXN0b200PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA 95RAPID 1 trialCountry and settingMultinational, multicenterSource of fundingUCB Inc.Research objectiveEvaluate efficacy and safety of 2 dosage regimens of CZP as adjunctive therapy to MTX in RA pts with an inadequate response to MTXStudy designControlled TrialsOverall N982Duration of study52 weeksQuality rating Fair Inclusion Criteria≥ 18 years of ageDiagnosis of RA as defined byACR 1987 criteria for ≥ 6 mos prior to screening but for <?15 yearsActive disease was defined as ≥ 9 tender and 9 swollen joints at screening and at baseline, with either an ESR ≥ 30 mm//hr or a CRP level > 15 mg/liter. Pts were required to have received MTX for ≥ 6 onths prior to baseline.Exclusion CriteriaDiagnoses of any other inflammatory arthritis or secondary noninflammatory arthritis that could have interfered with their evaluation ofeffects of certolizumab pegol on RAHistory of TB or chest radiograph showing active or latent TBHigh risk of infectionHistory of malignancy, demyelinating disease, blood dyscrasias, or severe, progressive, and/or uncontrolled renal, hepatic, hematologic, GI, endocrine, pulmonary, cardiac, neurologic, or cerebral diseaseThose having received any biologic therapy within 6 mos (OR, had received ETN and/or ANK within 3 mos) of baseline and/or any privous biologic therapy resulted in a severe hypersensitivity or anaphylactic reactionThose who had previously failed to respond to treatment with an anti-TNF agent.Interventions, doseD1: MTXPlaceboD2: MTXCertolizumab: 400 mg at weeks 0, 2, and 4 followed by 200 mg every 2 weeksD3: MTXCertolizumab: 400 mg at weeks 0, 2, and 4 followed by 400 mg every 2 weeksNumber in groupD1: 199D2: 393D3: 390Overall: 982Mean age, years (SD)D1: 52.2 (11.2)D2: 51.4 (11.6)D3: 52.4 (11.7)Sex, % femaleD1: 83.9D2: 82.4D3: 83.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 6.2 (4.4)D2: 6.1 (4.2)D3: 6.2 (4.4)Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, meanD1: 29.8 (13.0)D2: 30.8 (12.4)D3: 31.1 (13.3)SJC, mean D1: 21.2 (9.7)D2: 21.7 (9.9)D3: 21.5 (9.8)Corticosteroid use, %NRPrevious DMARD use (except MTX), n (SD) D1: 1.4 (1.4)D2: 1.3 (1.3)D3: 1.3 (1.3)MTX na?ve, %NRBaseline DAS score, median (range)D1: 7.0 (4.9-8.7)D2: 6.9 (4.3-8.9)D3: 6.9 (4.8-9.1)Required treatment for latent TBNAOther population characteristics, %,?(CI/SD/P value)HAQ DI:D1: 1.7 (0.6D2: 1.7 (0.6 D3: 1.7 (0.6ACR ACR 20:Week 1:D1: 5.6D2: 22.9D3: 22.3Overall:: D1 vs. D2 P?<?0.001, D1 vs. D3 P < 0.001Week 24:D1: 13.6D2: 58.8D3: 60.8Overall:D1 vs. D2 P < 0.001, D1 vs. D3 P < 0. ACR 50:D1: In Figure, NRD2: In Figure, NRD3: In Figure, NROverall: by week 2, ACR50 responses in certolizumab Dwere significanlty higher thanplacebo D(P ≤ 0.01 for each comparison); difference remained (P ≤ 0.001 for weeks 4-52)ACR 70:D1: In Figure, NRD2: In Figure, NRD3: In Figure, NROverall: by week 4, ACR70 responses in certolizumab 200 Dwas significanlty higher thanplacebo D(P ≤ 0.05); and by week 6, forcertolizumab 400 D(P ≤ 0.05); differences remained (P ≤ 0.001 for weeks 10-52)% ChangeBaseline to week 1:D1: -2.4D2: -13.5D3: -10.9Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4:D1: -5.4D2: -21.5D3: -21.9Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 12:D1: -8.2D2: -30.4D3: -27.6Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Mean change, baseline to week 52 (SD)D1: -2.4 (1.3)D2: -3.3 (1.3)D3: -3.4 (1.4)Overall: Baseline to week 52: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001SF-36 NRRadiographic measures Sharp Baseline to week 52:D1: 2.8D2: 0.4D3: 0.2Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Quality of life scales NR% ChangeSJC?Baseline to week 1:D1: 4.5D2: -18.2D3: -18.8Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4: D1: -10.3D2: -37.3D3: -40.4Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to Week 12: D1: -10.7D2: -56.7D3: -61.5Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001TJC: Baseline to week1: D1: -6.7D2: -18.9D3: -19.1Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4: D1: -11.4D2: -36.2D3: -37.0D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to Week 12: D1: -10.8D2: -52.6D3: -56.8D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Patient's global assessment: Baseline to week1: D1: -2.9D2: -12.9D3: -16.1Overall: D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4: D1: -6.5D2: -10.4D3: -27.9D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to Week 12: D1: -4.9D2: -38.3D3: -39.2D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Patient's assessment of arthritis pain: Baseline to week1:D1: -1.0,D2: -20.6,D3: -19.0D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4:D1: -5.0,D2: -26.6,D3: -28.8 D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to Week 12:D1: -4.8,D2: -38.2,D3: -39.6 D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001ESR (ratio): Baseline to week1:D1: 0.96,D2: 0.73,D3: 0.70 D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to week 4:D1: 0.90,D2: 0.59,D3: 0.54 D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Baseline to Week 12:D1: 0.84,D2: 0.53,D3: 0.52 D1 vs. D2 P < 0.001, D1 vs. D3 P < 0.001Attrition/withdrawalWithdrawals due to adverse events, n:D1: 3D2: 17D3: 2212 patients discontinued due to infection (6 from each CZP arm).Overall adverse events reported, n:D1: 125.9D2: 96.6D3: 94.5Serious adverse eventsDeath, n:D1: 1 (myocardial infarction)D2: 2 (hepatic neoplasm, cardiac arrest)D3: 4 (stroke, myocardial necrosis, cardiac arrest, atrial fibrillation)MalignanciesMalignancy, incidence rate per 100 person years:D1: 1.1D2: 2.3D3: 1.3Respiratory eventsUpper respiratory infection, incidence rate per 100 person years:D1: 5.5D2: 7.9D3: 6.7Other infectionsUrinary tract infection, incidence rate per 100 person years:D1: 14.2D2: 7.6D3: 10.5Other infections (specify), incidence rate per 100 person years:Nasopharyngitis:D1: 3.3D2: 6.9D3: 9.5Lung/lower respiratory tract, incidence rate per 100 person years: D1: 0D2: 1.0D3: 1.3Herpes viral, incidence rate per 100 person years:D1: 0D2: 0.3D3: 0.3Bacterial peritonitis, incidence rate per 100 person years:D1: 0D2: 0.3D3: 0Opportunistic infection, incidence rate per 100 person years:D1: 0D2: 0D3: 0GIGastroenteritis, incidence rate per 100 person years:D1: 1.1D2: 0.0D3: 0.0Any other AEs: Headache, incidence rate per 100 person years:D1: 12.0D2: 7.3D3: 5.7Hypertension, incidence rate per 100 person years:D1: 2.2D2: 8.2D3: 10.2Back pain, incidence rate per 100 person years:D1: 2.2D2: 5.6D3: 6.4Injection site pain andinjection site reaction 200mg(2% and 2.3%) or 400mg(1.3% and 0.8%), none inplacebo group.Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKeystone, E. et al.; 2009; ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2436</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>2436</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2436</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Keystone, E.</author><author>Freundlich, B.</author><author>Schiff, M.</author><author>Li, J.</author><author>Hooper, M.</author></authors></contributors><auth-address>Mount Sinai Hospital, The Rebecca MacDonald Centre for Arthritis and Autoimmunity, Toronto, ON M5G 1X5, Canada. edkeystone@mtsinai.on.ca</auth-address><titles><title>Patients with moderate rheumatoid arthritis (RA) achieve better disease activity states with etanercept treatment than patients with severe RA</title><secondary-title>J Rheumatol</secondary-title></titles><periodical><full-title>Journal of Rheumatology</full-title><abbr-1>J. Rheumatol.</abbr-1><abbr-2>J Rheumatol</abbr-2></periodical><pages>522-31</pages><volume>36</volume><number>3</number><keywords><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/ therapeutic use</keyword><keyword>Male</keyword><keyword>Methotrexate/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Receptors, Tumor Necrosis Factor/ therapeutic use</keyword><keyword>Remission Induction</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0315-162X (Print)</isbn><accession-num>19228659</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 4 / fair</custom4><custom7>posthoc analysis of TEMPO and ERA data</custom7></record></Cite></EndNote>96 TEMPO and ERACountry and settingSee original abstractions for TEMPO and ERASource of fundingImmunex Corporation, a wholly owned subsidiary of Amgen Inc., and by Wyeth ResearchResearch objectiveExamine clinical and radiographic responses to MTX, ETA, and ETA + MTX in pts with moderate vs. severe RA in early and late diseaseStudy designPooled data – post hoc analysisOverall N1091Duration of study12 mosQuality rating FairInclusion CriteriaMTX NaiveERA sample only: early RA, pts who had had RA for no more than 3 years and had not been previously been treated with MTX.TEMPO sample only: active RA not adequately responding to DMARD other than MTX; Moderate RA was defined post hoc as DAS28 > 3.2 and ≤5.1; severe was > 5.1. See original abstractions of TEMPO and ERA studies for further detailsExclusion CriteriaSee original abstractions for TEMPO and ERAInterventions, DoseD1: MTX: TEMPO: twice weekly for 12 mosERA: 10 mg for 12 mosD2: ETN: TEMPO & ERA: 25 mg twice weekly for 12 mosD3: MTX: TEMPO: twice weekly for 12 mosETN:TEMPO: 25 mg twice weekly for 12 mosNumber in groupD1: TEMPO: Moderate 16Severe 211ERA: Moderate 33Severe 178D2: TEMPO: Moderate 8Severe 214ERA: Moderate 32Severe 171D3: TEMPO: Moderate 17Severe 211Overall: TEMPO: 677ERA: 414COMBO: 1091Mean age (years)TEMPO: 53;ERA: 50Sex, % femaleNRRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (years)TEMPOModerate:D1: 3.2D2: 5.1D3: 6.1Severe:D1: 7.1D2: 6.4D3: 6.8Overall: 6.6ERAModerate:D1: NRD2: NRD3:NRSevere:1Patients with early RA, three years or less, %TEMPONRERAD1: 100D2: 100D3: NR Overall: 100 Treatment resistant, %NRTJC, mean (SD)NRSJC, mean (SD) NRCorticosteroid use, %NRDMARD use, %MTX: TEMPO: 43ERA: 0MTX na?ve, %TEMPONRERAD1: 100D2: 100Overall: 100Baseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: HAQ: TEMPO: Moderate 0.92, SD 0.67Severe 1.77, SD 0.66D2: NRD3: NRACR mean difference/ absolute difference (%)TEMPOACR 20:ModerateD1: 75D2: 75D3: 82Severe:D1: 75D2: 76D3: 85ERAModerateD1: 55D2: 66Severe:D1: 65D2: 70Overall: P NSACR 50:TEMPOModerateD1: 31D2: 25D3: 71Severe:D1: 43D2: 50D3: 69Overall: P NSERAModerateD1: 39D2: 53Severe:D1: 40D2: 47ACR 70:TEMPOModerateD1: 13D2: 13D3: 65Severe:D1: 19D2: 25D3: 40Overall: TEMPO D3 P <0.05ERAModerateD1: 18D2: 22D3:Severe:D1: 21D2: 24HAQ score, HAQ scoreTEMPO (SD)Moderate:D1: 0.6 (0.1)D2: 0.6 (0.2)D3: 0.4 (0.2)Severe:D1: 1.1 (0.1)D2: 1.0 (0.1)D3: 0.8 (0.0)ERAModerate:D1: 0.6 (0.1)D2: 0.4 (0.1)Severe:D1: 0.8 (0.0)D2: 0.8 (0.1)HAQ less than or equal to 0.5 (%): TEMPOModerate:D1: 50D2: 50D3: 82Severe:D1: 33D2: 34D3: 41ERAModerate:D1: 58D2: 75Severe:D1: 44D2: 42HAQ mean change from baseline to 12 mos (SD):TEMPOModerate:D1: 0.29 (0.12)D2: 0.42 0.21)D3: 0.74 (0.18)Severe:D1: 0.68 (0.05)D2: 0.74 (0.05)D3: 1.00 (0.05)ERAModerate:D1: 0.44 (0.09)D2: 0.45 (0.09)Severe:D1: 0.77 (0.05)D2: 0.75 (0.05)Overall: HAQ score: TEMPO D1 P <0.05ERA D2 P <0.05TEMPO D3 P <0.05HAQ less than or equal to 0.5: ERA D2 P <0.001TEMPO D3 P <0.001HAQ change in mean scores: TEMPO D1 P <0.05ERA D1 P <0.05ERA D2 P <0.05DAS (%)DAS28 remission (%):TEMPOModerate:D1: 44D2: 38D3: 77Severe:D1: 15D2: 17D3: 35ERA:Moderate:D1: 33D2: 47D3:Severe:D1: 15D2: 14D3:DS28 low disease activity (%):TEMPOModerate:D1: 56D2: 63D3: 82Severe:D1: 28D2: 31D3: 50ERAModerate:D1: 55D2: 56Severe:D1: 28D2: 26DAS28 mean change from baseline to 12 mos (SD):TEMPOModerate:D1: 1.6 (0.3)D2: 1.5 (0.4)D3: 2.5 (0.3)Severe:D1: 2.6 (0.1)D2: 2.7 (0.1)D3: 3.5 (0.1)ERAModerateD1: 1.2 (0.2)D2: 1.7 (0.2)D3:SevereD1: 2.4 (0.1)D2: 2.4 (0.1)D3:Overall: DAS28 remission: TEMPO D1 P <0.05ERA D1 P <0.05ERA D2 P <0.001TEMPO D3 P <0.001DAS28 low disease activity: TEMPO D1 P <0.05ERA D1 P <0.05ERA D2 P <0.001TEMPO D3 P <0.05DAS28 change in mean scores: TEMPO D1 P <0.05ERA D1 P <0.001TEMPO D2 P <0.05ERA D2 P <0.05TEMPO D3 P <0.05SF-36 NRRadiographic measures (SD)TSS Progression: Moderate:D1: 0.62 (1.94)D2: -0.51 (1.04)D3:Severe:D1: 2.95 (13.08)D2: 0.55 (4.70)D3: -0.53 (3.64)ERA:Moderate:D1: 2.15 (6.27)D2: -0.04 (1.36)Severe:D1: 1.71 (3.99)D2: 0.89 (2.70)No radiographic progression (%): TEMPOModerateD1: 44D2: 75D3: NRSevereD1: 51D2: 59D3: NRERA:ModerateD1: 47D2: 69D382Severe:D1: 49D2: 65D3: 71Overall: NRQuality of life scales NROverallAdherent/compliant, n:D1: TEMPO: 227; ERA: 211D2: TEMPO: 222; ERA: 203D3: TEMPO: 228Overall: TEMPO: 677; ERA: 414; COMBO: 1091see original abstractions for TEMPO and ERA for attrition and withdrawal informationOverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKeystone et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE.DATA 97Country and settingMultinationalSource of fundingCentocor Research and developmentResearch objectiveEvaluate efficacy and safety of GOL intx of patients with active RA despite MTX therapyStudy designControlled TrialsOverall N444Duration of study24 weeksQuality rating Good Inclusion Criteria18 years of age or olderDiagnosis of RA for at least 3 mos before screeningOn a stable MTX dose of 15 mg/week or greater but 25 mg/week or less during4-week period immediately preceding screeningPatients were to have tolerated 15 mg/ week or greater of MTX for at least 3 mos before screening and to have active RA.Patients who were using NSAIDs or other analgesics for RA had to be taking stable dose for at least 2 wks before first dose of study agent.Patients who were taking oral corticosteroids had to have been receiving a stable dose equivalent to 10 mg/day or less of PRED for at least 2 wks before first dose of study agent.Exclusion CriteriaKnown hypersensitivity to human immunoglobulin proteins or other components of GOLAny previous use of any anti-TNF agent, RIT, RIT or cytotoxic agentsPts should not have received ANKDMARDs other than MTX or intravenous, intramuscular, or intra-articular corticosteroids within 4 weeks beforefirst dose of study agent or alefacept or efalizumab within 3 mos beforefirst dose ofstudy agent.Interventions, doseD1: MTX: dosage NR but stable throughout 24 week study period. Patients with less than 20% improvement in SJC and TJC by week 16 began receiving 50mg GOL/4wks forremainder ofstudyPlaceboD2: GOL: 100mg every 4 weeksPlacebo: Patients with?=?20% improvement in SJC and TJC and TJC at week 16 began receiving active MTX forremainder ofstudyD3: MTX: stable dose, NR (looks likely to be 15mg/wk not explicit in methods)GOL: 50mg every 4 weeks. Patients with <20% improvement in SJC and TJC at week 16 began receiving 100mg of GOL/4 wks forremainder ofstudyD4: MTX: Stable dose and frequency NRGOL: 100mg/4wksNumber in groupD1: 133D2: 133D3: 89D4: 89Mean age, years (SD)D1: 52 (42-58)D2: 51 (42-59)D3: 52 (43-57)D4: 50 (45-56)Sex, % femaleD1: 82D2: 105D3: 72D4: 72Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, median (IQR)D1: 6.5 (3.1-11.9)D2: 5.9 (2.4-12.2)D3: 4.5 (2.1-9.7)D4: 6.7 (2.4-14.3)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, median (IQR)D1: 21.0 (14.0-34.0)D2: 22.0 (14.0-32.0)D3: 26.0 (16.0-39.0)D4: 23.0 (15.0-33.0)Swollen Joint Count, median (OQR)D1: 12.0 (8.0-19.0)D2: 11.0 (8.0-17.0)D3: 13.0 (8.0-22.0)D4: 12.0 (8.0-18.0)Corticosteroid use, %D1: 65.4D2: 67.7D3: 75.3D4: 69.7DMARD use, other than MTX %D1: 70.7D2: 75.9D3: 78.7D4: 75.3MTX na?ve, %NRBaseline DAS score, n (CI)D1: DAS28 using CRP: 4.860 (4.194-5.480); DAS28 using ESR: 6.111 (5.260-6.574)D2: DAS28 using CRP: 4.803 (4.151-5.558); DAS28 using ESR: 6.013 (5.198-6.800)D3: DAS28 using CRP: 5.100 (4.060-5.651); DAS28 using ESR: 6.105 (5.366-6.940)D4: DAS28 using CRP: 4.902 (4.320-5.521); DAS28 using ESR: 5.905 (5.292-6.805)Required treatment for latent TB (%)D1: 23.3D2: 19.5D3: 20.2D4: 19.1ACR ACR 20:At 14 weeks:D1: 33.1D2: 44.4%, P?=?0.059D3: 55.1, P?=?0.001D4: 56.2, P?=?0.001At 24 weeks:D1: 27.8D2: 35.3, P?=?0.187D3: 59.6, P?=?0.001D4: 59.6%, P?=?0.001ACR 50:At 14 weeks:D1: 9.8D2: 20.3, P?=?0.016D3: 34.8, P?=?0.001D4: 29.2, P?=?0.001At 24 weeks:D1: 13.5D2: 19.5, P?=?0.187D3:, 37.1, P?=?0.001D4: 32.6, P?=?0.001ACR 70:At 14 weeks:D1: 3.8D2: 7.5, P?=?0.184D3: 13.5, P?=?0.008D4: 9.0, P?=?0.104At 24 weeks:D1: 5.3D2: 11.3, P?=?0.075D3: 20.2, P?=?0.001D4: 14.6, P?=?0.017Improvement from baseline in HAQ-DI at 24 weeks: (CI/SD/P Value)D1: -0.13 (-0.38-0.13)D2: -0.13 (-0.63-0.25), P?=?0.240 D3: -0.38 (-0.75--0.13), P?=?0.001D4: -0.50 (-0.75--0.13), P?=?0.001DAS D1: DAS28 (ESR) remission: 14 weeks: 1.5%, 24 weeks: 6.0%, DAS28 (ESR) sustained remission: 24 weeks: 0.8%, EULAR responders (DAS28 calculated using ESR): 14 weeks: 44.4%, 24 weeks: 42.1%D2: DAS28 (ESR) remission: 14 weeks: 8.3%, P?=?0.010, 24 weeks: 12.0%, P= 0.087; DAS28 (ESR) sustained remission: 24 weeks: 6.3%, P= 0.018; EULAR responders (DAS28 calculated using ESR): 14 weeks: 59.4%, P= 0.014; 24 weeks: 51.9%, P= 0.110D3: DAS28 (ESR) remission: 14 weeks: 15.7%, P<0.001; 24 weeks: 20.2%, P= 0.001; DAS28 (ESR) sustained remission: 24 weeks: 10.2%, P= 0.001; EULAR responders (DAS28 calculated using ESR): 14 weeks: 70.8%, P<0.001; 24 weeks: 71.9%, P<0.001D4: DAS28 (ESR) remission: 14 weeks: 18.0%, P<0.001; 24 weeks: 22.5%, P<0.001; DAS28 (ESR) sustained remission: 24 weeks: 11.9%, P<0.001; EULAR responders (DAS28 calculated using ESR): 14 weeks: 75.3%, P<0.001; 76.4%, P<0.001SF-36 NRRadiographic measures NRQuality of life scales NROthers, mean difference/absolute differenceACR90 (14 weeks):D1: 0.8D2: 0.8, P?=?1.000D3: 2.2, P?=?0.344D4: 0.0, P?=?0.412ACRIO (24 weeks):D1: 0.8D2: 2.3, P?=?0.314D3: 5.6, P?=?0.028D4: 2.2, P?=?0.344ACR-N (14 weeks):D1: 0.00 (-28-25.50)D2: 10.50 (-11.80-42.60), P?=?0.042D3: 28.20 (0.00-60.00), P?=?0.001D4: 25.00 (0.00-54.50), P?=?0.001ACR-N (24 weeks):D1: 0.00 (-25.00-22.20)D2: 0.00 (-25.40-37.10), P?=?0.151D3: 36.60 (0.00-60.40), P?=?0.001D4: 28.60 (0.00-55.30), P?=?0.001Attrition/withdrawalOverall, n: D1: 10D2: 9D3: 2D4: 7Overall: 28Withdrawals due to adverse events, n: D1: 6D2: 6D3: 2D4: 5Overall: 19Withdrawals due to lack of efficacy, n: D1: 2D2: 1D3: NRD4: NROverall: 3Adherent/compliant, n: D1: 123D2: 125D3: 87D4: 82Overall: 417D1: 1 lost to follow-up, 1 "other"D2: 1 discontinued oral study agentD3: NRD4: 1 lost to follow-up, 1 discontinued oral study agentOverall adverse events reported, n: D1: 89D2: 98D3: 87D4: 78Overall: 352Serious adverse eventsDeath, n: D1: NRD2: 1D3: NRD4: NROverall: 1MalignanciesLymphoma or leukemia, n: NRSkin?cancer (basal cell?or squamous cell), n: D1: 1D2: 2D3: NRD4: NROverall: 3Other cancer (specify), n: D1: NRD2: NRD3: NRD4: Breast: 1Overall: 1Respiratory eventsTuberculosis: NR Pneumonia, n: NRUpper respiratory infection, n: NROther infectionsUrinary tract infection, n: D1: 1D2: NRD3: NRD4: 2Overall: 3Other infections (specify), n: D1: NRD2: Sepsis: 2D3: Cellulitis: 1D4: Cellulitis: 1, Sepsis: 2, lower RTI: 1, Overall: 7Other GI symptoms, n: D1: 0D2: Colitis: 1, Diarrhoea: 1D3: 0D4: 0Overall: 2OtherInfusion/injection site reactions, n: D1: 4D2: 10D3: 5D4: 5Overall: 24Infective arthritis, n: D1: 0D2: 1D3: 0D4: 0Overall: 1Bacterial arthritis, n: D1: 0D2: 0D3: 0D4: 1Overall: 1Subcutaneous abscess, n: D1: 0D2: 0D3: 1D4: 0Overall: 1Skin laceration, n: D1: 0D2: 1D3: 0D4: 0Overall: 1Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKeystone et al., 2009 and 2010, Go-ForwardPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0
NzU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij45Nyw5ODwv
c3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjI0NzU8L3JlYy1udW1iZXI+
PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4
d2Z3ZjBmc2Z6Mjk1djkiPjI0NzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i
R2VuZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LZXlz
dG9uZSwgRS4gQy48L2F1dGhvcj48YXV0aG9yPkdlbm92ZXNlLCBNLiBDLjwvYXV0aG9yPjxhdXRo
b3I+S2xhcmVza29nLCBMLjwvYXV0aG9yPjxhdXRob3I+SHNpYSwgRS4gQy48L2F1dGhvcj48YXV0
aG9yPkhhbGwsIFMuIFQuPC9hdXRob3I+PGF1dGhvcj5NaXJhbmRhLCBQLiBDLjwvYXV0aG9yPjxh
dXRob3I+UGF6ZHVyLCBKLjwvYXV0aG9yPjxhdXRob3I+QmFlLCBTLiBDLjwvYXV0aG9yPjxhdXRo
b3I+UGFsbWVyLCBXLjwvYXV0aG9yPjxhdXRob3I+WnJ1YmVrLCBKLjwvYXV0aG9yPjxhdXRob3I+
V2lla293c2tpLCBNLjwvYXV0aG9yPjxhdXRob3I+VmlzdmFuYXRoYW4sIFMuPC9hdXRob3I+PGF1
dGhvcj5XdSwgWi48L2F1dGhvcj48YXV0aG9yPlJhaG1hbiwgTS4gVS48L2F1dGhvcj48L2F1dGhv
cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIFRvcm9udG8gYW5k
IE1vdW50IFNpbmFpIEhvc3BpdGFsLCBPbnRhcmlvLCBDYW5hZGEuIGVka2V5c3RvbmVAbXRzaW5h
aS5vbi5jYTwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdvbGltdW1hYiwgYSBodW1hbiBh
bnRpYm9keSB0byB0dW1vdXIgbmVjcm9zaXMgZmFjdG9yIHthbHBoYX0gZ2l2ZW4gYnkgbW9udGhs
eSBzdWJjdXRhbmVvdXMgaW5qZWN0aW9ucywgaW4gYWN0aXZlIHJoZXVtYXRvaWQgYXJ0aHJpdGlz
IGRlc3BpdGUgbWV0aG90cmV4YXRlIHRoZXJhcHk6IHRoZSBHTy1GT1JXQVJEIFN0dWR5PC90aXRs
ZT48c2Vjb25kYXJ5LXRpdGxlPkFubiBSaGV1bSBEaXM8L3NlY29uZGFyeS10aXRsZT48L3RpdGxl
cz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm5hbHMgb2YgdGhlIFJoZXVtYXRpYyBEaXNlYXNl
czwvZnVsbC10aXRsZT48YWJici0xPkFubi4gUmhldW0uIERpcy48L2FiYnItMT48YWJici0yPkFu
biBSaGV1bSBEaXM8L2FiYnItMj48L3BlcmlvZGljYWw+PHBhZ2VzPjc4OS05NjwvcGFnZXM+PHZv
bHVtZT42ODwvdm9sdW1lPjxudW1iZXI+NjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BY3V0
ZSBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5
c2lzIG9mIFZhcmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwv
IGFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMg
dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5
L2ltbXVub2xvZ3kvbWljcm9iaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkJhY3RlcmlhbCBJbmZl
Y3Rpb25zL2NvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpLVNxdWFyZSBEaXN0cmli
dXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5
d29yZD5EcnVnIEFkbWluaXN0cmF0aW9uIFNjaGVkdWxlPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcg
VGhlcmFweSwgQ29tYmluYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxr
ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2l2ZSBBZ2VudHMv
IGFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWMg
dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkluamVjdGlvbnMsIFN1YmN1dGFuZW91czwva2V5d29yZD48
a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvdHJleGF0ZS90aGVyYXBldXRpYyB1
c2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+VGltZSBG
YWN0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxrZXl3
b3JkPlR1bW9yIE5lY3Jvc2lzIEZhY3Rvci1hbHBoYS8gYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJp
dG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWItZGF0
ZXM+PGRhdGU+SnVuPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTQ2OC0yMDYwIChF
bGVjdHJvbmljKTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTA2NjE3NjwvYWNjZXNzaW9uLW51bT48
dXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9tMj5JIE1UQzwvY3VzdG9tMj48
Y3VzdG9tMz5DVDwvY3VzdG9tMz48Y3VzdG9tND5LUSAxLCAyLCAzIC8gZ29vZDwvY3VzdG9tND48
L3JlY29yZD48L0NpdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVj
TnVtPjUyOTY8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjUyOTY8L3JlYy1udW1iZXI+PGZv
cmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSI1OWFzeHN4dnlmeHh4dmVlMDJwcGF4d2Z3
ZjBmc2Z6Mjk1djkiPjUyOTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iR2Vu
ZXJpYyI+MTM8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5LZXlzdG9u
ZSwgRS48L2F1dGhvcj48YXV0aG9yPkdlbm92ZXNlLCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+S2xh
cmVza29nLCBMLjwvYXV0aG9yPjxhdXRob3I+SHNpYSwgRS4gQy48L2F1dGhvcj48YXV0aG9yPkhh
bGwsIFMuPC9hdXRob3I+PGF1dGhvcj5NaXJhbmRhLCBQLiBDLjwvYXV0aG9yPjxhdXRob3I+UGF6
ZHVyLCBKLjwvYXV0aG9yPjxhdXRob3I+QmFlLCBTLiBDLjwvYXV0aG9yPjxhdXRob3I+UGFsbWVy
LCBXLjwvYXV0aG9yPjxhdXRob3I+WHUsIFMuPC9hdXRob3I+PGF1dGhvcj5SYWhtYW4sIE0uIFUu
PC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+VW5pdmVyc2l0
eSBvZiBUb3JvbnRvIGFuZCBNb3VudCBTaW5haSBIb3NwaXRhbCwgNjAgTXVycmF5IFN0cmVldCwg
Mm5kIEZsb29yLCBSb29tIDItMDA2LCBUb3JvbnRvLCBPbnRhcmlvIE01RyAxWDUsIENhbmFkYS4g
ZWRrZXlzdG9uZUBtdHNpbmFpLm9uLmNhPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+R29s
aW11bWFiIGluIHBhdGllbnRzIHdpdGggYWN0aXZlIHJoZXVtYXRvaWQgYXJ0aHJpdGlzIGRlc3Bp
dGUgbWV0aG90cmV4YXRlIHRoZXJhcHk6IDUyLXdlZWsgcmVzdWx0cyBvZiB0aGUgR08tRk9SV0FS
RCBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Bbm5hbHMgb2YgdGhlIHJoZXVtYXRpYyBk
aXNlYXNlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl
PkFubmFscyBvZiB0aGUgUmhldW1hdGljIERpc2Vhc2VzPC9mdWxsLXRpdGxlPjxhYmJyLTE+QW5u
LiBSaGV1bS4gRGlzLjwvYWJici0xPjxhYmJyLTI+QW5uIFJoZXVtIERpczwvYWJici0yPjwvcGVy
aW9kaWNhbD48cGFnZXM+MTEyOS0zNTwvcGFnZXM+PG51bWJlcj42PC9udW1iZXI+PGtleXdvcmRz
PjxrZXl3b3JkPkFudGlib2RpZXMsIE1vbm9jbG9uYWwgW2FkdmVyc2UgZWZmZWN0c10gW3RoZXJh
cGV1dGljIHVzZV08L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBBZ2VudHMgW2FkdmVy
c2UgZWZmZWN0c10gW3RoZXJhcGV1dGljIHVzZV08L2tleXdvcmQ+PGtleXdvcmQ+QXJ0aHJpdGlz
LCBSaGV1bWF0b2lkIFtkcnVnIHRoZXJhcHldPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJsZS1CbGlu
ZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBUaGVyYXB5LCBDb21iaW5hdGlvbjwva2V5
d29yZD48a2V5d29yZD5JbW11bm9zdXBwcmVzc2l2ZSBBZ2VudHMgW2FkdmVyc2UgZWZmZWN0c10g
W3RoZXJhcGV1dGljIHVzZV08L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG90cmV4YXRlIFthZHZlcnNl
IGVmZmVjdHNdIFt0aGVyYXBldXRpYyB1c2VdPC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9m
IElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdv
cmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPlNyLW11c2tlbDwva2V5d29yZD48
L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjwvZGF0ZXM+PGFjY2Vzc2lvbi1udW0+
Q04tMDA3NDg2MTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6
Ly93d3cubXJ3LmludGVyc2NpZW5jZS53aWxleS5jb20vY29jaHJhbmUvY2xjZW50cmFsL2FydGlj
bGVzLzYxMi9DTi0wMDc0ODYxMi9mcmFtZS5odG1sPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz
PjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9tND5LUTEgLyBn
b29kPC9jdXN0b200PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE.DATA 97,98Country and settingMultinationalSource of fundingCentocor Research and developmentResearch objectiveEvaluate efficacy and safety of GOL intx of patients with active RA despite MTX therapyStudy designControlled TrialsOverall N444Duration of study24 weeks with open label extension up to 52 weeksQuality rating Good Inclusion Criteria18 years of age or olderDiagnosis of RA for at least 3 mos before screeningStable MTX dose of 15 mg/week or greater but 25 mg/week or less during 4-week period immediately preceding screeningTolerated 15 mg/ week or greater of MTX for at least 3 mos before screening and have active RA.Patients taking NSAIDs or other analgesics for RA had to be taking stable dose for at least 2 wks before first dose of study agent.Patientstaking oral corticosteroids had to have been receiving a stable dose equivalent to 10 mg/day or less of PRED for at least 2 wks before first dose of study agent.Exclusion CriteriaKnown hypersensitivity to human immunoglobulin proteins or other components of GOLPrior use of any anti-TNF agent, RIT or cytotoxic agentsPrior use of ANKDMARDs other than MTX or intravenous, intramuscular, or intra-articular corticosteroids within 4 weeks before first dose of study agent or alefacept or efalizumab within 3 mos beforefirst dose of study agent.Interventions, doseD1: MTX: dosage NR but stable throughout 24 week study period. Patients with less than 20% improvement in SJC and TJC by week 16 began receiving 50mg GOL/4wks for remainder ofstudyPlaceboD2: GOL: 100mg every 4 weeksPlacebo: Patients with?=?20% improvement in SJC and TJC and TJC at week 16 began receiving active MTX forremainder ofstudyD3: MTX: stable dose, NR (looks likely to be 15mg/wk not explicit in methods)GOL: 50mg every 4 weeks. Patients with <20% improvement in SJC and TJC at week 16 began receiving 100mg of GOL/4 wks forremainder ofstudyD4: MTX: Stable dose and frequency NRGOL: 100mg/4wksNumber in groupD1: 133D2: 133D3: 89D4: 89Mean age, years (SD)D1: 52 (42-58)D2: 51 (42-59)D3: 52 (43-57)D4: 50 (45-56)Sex, % femaleD1: 82D2: 105D3: 72D4: 72Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, median (IQR)D1: 6.5 (3.1-11.9)D2: 5.9 (2.4-12.2)D3: 4.5 (2.1-9.7)D4: 6.7 (2.4-14.3)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, median (IQR)D1: 21.0 (14.0-34.0)D2: 22.0 (14.0-32.0)D3: 26.0 (16.0-39.0)D4: 23.0 (15.0-33.0)Swollen Joint Count, median (OQR)D1: 12.0 (8.0-19.0)D2: 11.0 (8.0-17.0)D3: 13.0 (8.0-22.0)D4: 12.0 (8.0-18.0)Corticosteroid use, %D1: 65.4D2: 67.7D3: 75.3D4: 69.7DMARD use, other than MTX %D1: 70.7D2: 75.9D3: 78.7D4: 75.3MTX na?ve, %NRBaseline DAS score, n (CI)D1: DAS28 using CRP: 4.860 (4.194-5.480); DAS28 using ESR: 6.111 (5.260-6.574)D2: DAS28 using CRP: 4.803 (4.151-5.558); DAS28 using ESR: 6.013 (5.198-6.800)D3: DAS28 using CRP: 5.100 (4.060-5.651); DAS28 using ESR: 6.105 (5.366-6.940)D4: DAS28 using CRP: 4.902 (4.320-5.521); DAS28 using ESR: 5.905 (5.292-6.805)Required treatment for latent TB (%)D1: 23.3D2: 19.5D3: 20.2D4: 19.1ACR ACR 20:At 14 weeks:D1: 33.1D2: 44.4%, P?=?0.059D3: 55.1, P?=?0.001D4: 56.2, P?=?0.001ACR 50:At 14 weeks:D1: 9.8D2: 20.3, P?=?0.016D3: 34.8, P?=?0.001D4: 29.2, P?=?0.001ACR 70:At 14 weeks:D1: 3.8D2: 7.5, P?=?0.184D3: 13.5, P?=?0.008D4: 9.0, P?=?0.104DAS D1: DAS28 (ESR) remission: 14 weeks: 1.5%, 24 weeks: 6.0%, EULAR responders (DAS28 calculated using ESR): 14 weeks: 44.4%, 24 weeks: 42.1%D2: DAS28 (ESR) remission: 14 weeks: 8.3%, P?=?0.010, EULAR responders (DAS28 calculated using ESR): 14 weeks: 59.4%, P= 0.014; D3: DAS28 (ESR) remission: 14 weeks: 15.7%, P<0.001; EULAR responders (DAS28 calculated using ESR): 14 weeks: 70.8%, P<0.001; D4: DAS28 (ESR) remission: 14 weeks: 18.0%, P<0.001; EULAR responders (DAS28 calculated using ESR): 14 weeks: 75.3%, P<0.001; SF-36 NRRadiographic measures NRQuality of life scales NROthers, mean difference/absolute differenceACR90 (14 weeks):D1: 0.8D2: 0.8, P?=?1.000D3: 2.2, P?=?0.344D4: 0.0, P?=?0.412ACR-N (14 weeks):D1: 0.00 (-28-25.50)D2: 10.50 (-11.80-42.60), P?=?0.042D3: 28.20 (0.00-60.00), P?=?0.001D4: 25.00 (0.00-54.50), P?=?0.001Attrition/withdrawalOverall, n: D1: 10D2: 9D3: 2D4: 7Overall: 28Withdrawals due to adverse events, n: D1: 6D2: 6D3: 2D4: 5Overall: 19Withdrawals due to lack of efficacy, n: D1: 2D2: 1D3: NRD4: NROverall: 3Adherent/compliant, n: D1: 123D2: 125D3: 87D4: 82Overall: 417D1: 1 lost to follow-up, 1 "other"D2: 1 discontinued oral study agentD3: NRD4: 1 lost to follow-up, 1 discontinued oral study agentOverall adverse events reported, n: D1: 89D2: 98D3: 87D4: 78Overall: 352Serious adverse eventsDeath, n: D1: NRD2: 1D3: NRD4: NROverall: 1MalignanciesLymphoma or leukemia, n: NRSkin?cancer (basal cell?or squamous cell), n: D1: 1D2: 2D3: NRD4: NROverall: 3Other cancer (specify), n: D1: NRD2: NRD3: NRD4: Breast: 1Overall: 1Respiratory eventsTuberculosis: NR Pneumonia, n: NRUpper respiratory infection, n: NROther infectionsUrinary tract infection, n: D1: 1D2: NRD3: NRD4: 2Overall: 3Other infections (specify), n: D1: NRD2: Sepsis: 2D3: Cellulitis: 1D4: Cellulitis: 1, Sepsis: 2, lower RTI: 1, Overall: 7Other GI symptoms, n: D1: 0D2: Colitis: 1, Diarrhoea: 1D3: 0D4: 0Overall: 2OtherInfusion/injection site reactions, n: D1: 4 D2: 10D3: 5 D4: 5Overall: 24Infective arthritis, n: D1: 0 D2: 1D3: 0 D4: 0Overall: 1Bacterial arthritis, n: D1: 0 D2: 0D3: 0 D4: 1Overall: 1Subcutaneous abscess, n: D1: 0 D2: 0D3: 1 D4: 0Overall: 1Skin laceration, n: D1: 0 D2: 1D3: 0 D4: 0Overall: 1Adverse events at 52 weeks- N (%) and Events per 100 patient yrsAny adverse event D1:98 (73.7) 546 (486 to 612) D2: 108 (81.2) 514 (471 to 560) D3: 167 (78.8) 459 (425 to 495) D4:122 (85.9) 595 (552 to 641) Serious adverse events D1: 6 (4.5) 15 (6 to 29) D2: 16 (12.0) 28 (19 to 40) D3: 17 (8.0) 14 (9 to 22) D4: 26 (18.3) 34 (24 to 46) Any infection D1:42 (31.6) 132 (104 to 167) D2: 69 (51.9) 133 (112 to 158) D3:98 (46.2) 114 (98 to 133) D4:75 (52.8) 156 (135 to 181) Serious infections D1:1 (0.8) 2 (0 to 10) D2:5 (3.8) 8 (3 to 15) D3:4 (1.9) 3 (1 to 8) D410 (7.0) 10 (5 to 18) ? Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKievit et al., 2008,PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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ADDIN EN.CITE.DATA 99 DREAM Country and settingThe NetherlandsSource of fundingDutch affiliations of Wyeth Pharmaceuticals, Abbott Pharmaceuticals and Roche Pharmaceuticals enabled data collection for DREAM cohort. Sponsors had no influence on content of this manuscript. Funding from Dutch National Health Insurance BoardResearch objectiveEvaluate effects of ADA, ETN and IFX on disease activity, functional ability, QOL and medication costsStudy designProspective cohort comparisonOverall NN:?707Between February 2003 and August 2007, 916 patients were included. In total, 707 patients had at least 1-year follow-up and fully accessible data at time of analysis (August 2007).Duration of studyOne yearQuality rating FairInclusion CriteriaAll RA patients seen in 11 rheumatology centers who started for first time on 1 of anti-TNFa agents. In Netherlands, patients can start with an anti-TNFa treatment when they have at least moderate disease activity (Disease Activity Score (DAS28) > 3.2 and failed on at least 2 DMARDs including MTX (MTX) at an optimal dose of 25 mg/week.Exclusion CriteriaNRInterventions, doseD1: ADA Patients starting with ADA and ETN did so at registered dose in 97% and 98% of cases, respectively. Within 12 mos, 7.1% and 4.8% of ADA and ETN patients had a dose increase. Median of12-month averaged dose was 40 mg per 2 weeks for ADA.D2: ETN Patients starting with ADA and ETN did so at registered dose in 97% and 98% of cases, respectively. Within 12 mos, 7.1% and 4.8% of ADA and ETN patients had a dose increase. Median of12- month averaged dose was 50 mg per week for ETN.D3: IFX patients started in 80% of cases with an average dose of 3 mg/kg per 8 weeks, in 18% of cases with an average dose of 4 mg/kg per 8 weeks and 2% started with higher dosages. All patients who started with average dose of 4 mg/kg dose didNumber in groupD1: 267D2: 289D3: 151Mean age, years (SD)D1: 55.1D2: 54.6D3: 57.8Sex, % femaleD1: 70.0D2: 68.9D3: 70.2Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 7.7D2: 6D3: 7.7Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS scoreD1: 5.3D2: 5.5D3: 5.2Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Number of previous DMARDsD1: 3D2: 3D3: 3HAQD1: 1.3D2: 1.4D3: 1.4With one or more erosions (%)D1: 71.7D2: 65.3D3: 72.7ACR NRHAQ, mean (SD)Absolute difference in HAQ from baseline at 3, 6, 9, and 12 mos:At 3 mos, decrease:D1: -0.35 (0.5)D2: -0.33 (0.5)D3: -0.19 (0.5)At 6 mos, decrease:D1: -0.42 (0.5)D2: -0.35 (0.5)D3: -0.23 (0.5)At 9 mos, decrease:D1: -0.4 (0.5)D2: -0.36 (0.6)D3: -0.26 (0.5)At 12 mos, decrease:D1: -0.42 (0.6)D2: -0.35 (0.6)D3: -0.26 (0.5)D1: Missing HAQ values, all groups combined(%): baseline 9.9 3 mos 9.26 mos 12.29 mos 15.612 mos 16.3.P value for ADA compared to IFX: P = 0.05 for all time pointsP value for ETN compared to IFX: P = 0.05 only at 3 mosDAS D1: Absolute difference in DAS28 from baseline at 3, 6, 9, and 12 mos (values are means with SD): 3 mos, decrease -1.6 (1.3)EULAR response 76%*, 6 mos, decrease -1.8 (1.4)EULAR response 78%*, 9 mos, decrease -1.8 (1.4)EULAR response 79%*, 12 mos,SF-36 NRRadiographic measures NRQuality of life scales NROthers Mean score and 95% CI, at each follow up for DAS28, SF-36, and HAQ were presented in graphs, so numbers are NR. Repeated measures analyses (linear mixed model) showed significant differences in DAS28 course over 12 mos between IFX and both ADA and ETN patients (P = 0.001) and between ADA and ETN patients (P = 0.031).Figures for HAQ and EQ-5D show same trend: functionality and QoL was best for ADA patients. However,repeated measures analyses did not show any significant differences.OverallOverall attrition/withdrawal, n (%):D1: 22D2: 21D3: 31Overall: IFX compared to ADA, P = 0.049IFX compared to ETN, P = 0.024Overall: occurrence of adverse events was reason for discontinuation in 48% of patientsOverall: 33%reason was a lack of efficacyAdherent/compliant, n: After discontinuation ofinitial anti-TNFa treatment, 42% of ADA and ETN users switched to another anti-TNFa treatment, and 67% of IFX switched.same anti-TNFa treatment was rechallenged in 8%, 15% and in 2%, respectively. Another option was to start with one ofconventional DMARD therapies, which occurred in 27% ofADA patients, 25% of ETN patients and 20% of IFX patients. Remaining patients did not start with another consecutive treatment after stopping with initial anti-TNFa treatment, but they remained on their co-medication. Complete data of first 12 mos after treatment initiation with a TNF blocking agent were analysed on an ITT basis. This means that all patients were analysed ingroup of medication on which they initially started, regardless of whether they received or adhered that treatment for full 12 mos.Serious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableKim et al., 2007PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA 100Country and settingKorea; multicenterSource of fundingAbbott LaboratoriesResearch objectiveTo investigate the efficacy and safety of 40 mg ADA with MTX versus placebo with MTX in Korean RA patients with an insufficient responses to MTXStudy designControlled TrialsOverall N128Duration of study24 wksInclusion CriteriaTreatment resistant ≥18 yrs oldMet ACR criteria for diagnosis of active RA≥ 6 swollen joints and ≥ 9 tender joints at both screening and baseline visitsReceived at least 1 prior DMARD other than MTX but could have had efficacy failures to no more than 4 standard DMARDs other than MTXBeen treated with MTX for at least 6 mos Been receiving stable dosage for at least 4 wks prior to screeningExclusion CriteriaPatients with acute inflammatory joint diseases other than RAActive Listeria or tuberculosis infectionPositive serology for human immuno-deficiency virus antibody, hepatitis B surface antigen, or hepatitis C antibodyCalcified granuloma and/or pleuralComparisons (dosage and frequency)D1: MTX: dose NRADA: 40 mg, every other weekD2: MTX: NRPlaceboNumber in groupD1: 65D2: 63Overall: 128Mean age (years)D1: 48.5D2: 49.8Overall: NRSex, % femaleD1: 95.4D2: 85.7Overall: 90.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 6.8 (4.2)D2: 6.9 (4.5)Overall: NRTJC, meanD1: mean (SD): 19.2 (9.2)D2: mean (SD): 20.3 (8.6)Overall: NRSJC, mean D1: mean (SD): 12.2 (5.6)D2: mean (SD): 12.8 (5.8)Overall: NRCorticosteroid use, %NRDMARD use, %: D1: 100D2: 100Overall: 100MTX na?ve, %: D1: 0D2: 0Overall: 0Treatment resistant, %: D1: 100D2: 100Overall: 100Patients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: D1: 61.5 D2: 36.5Overall: P<0.01ACR 50: D1: 43.1D2: 14.3Overall: P<0.001ACR 70: D1: 21.5D2: 7.9Overall: P< 0.05HAQ, mean difference/ absolute difference?(CI/SD/P Value): Disability Index of the KHAQ, mean (SD)D1: -0.5 (0.55) D2: -0.2 (0.50)Overall: P=0.002DAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): Duration of morning stiffness, mean (SD)D1: -116.7 (165.3)D2: -16.7 (166.5)Overall: NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): TJC, mean (SD): D1: -9.5 (9.61)D2: -3.4 (11.50)Overall: P=0.002SJC mean (SD):D1: -7.9 (6.78)D2: -2.0 (7.17)Overall: P<0.001CRP, mg/L, mean (SD): D1: -1.4 (3.23)D2: -0.4 (1.94)Overall: P=0.001 Physician's Global Assessment of Disease Activity, mm VAS, mean (SD): D1: -29.2 (27.48)D2: -9.6 (26.47)Overall: P < 0.001 Patient's Global Assessment of Disease Activity, mm VAS, mean (SD):D1: -23.7 (26.54)D2: -10.7 (24.85)Overall: P = 0.004 Patient's Global Assessment of Pain, mm VAS, mean (SD): D1: -23.7 (22.86)D2: -7.3 (27.50)Overall: P < 0.001OverallOverall attrition/withdrawal (n): D1: 6D2: 4Overall: 10Withdrawals due to adverse events?(n): D1: 4D2: 4Overall: 8Adherent/compliant?(n): D1: 59D2: 59Overall: 118Overall adverse events reported (n): D1: 84.6%D2: 82.5%Overall: NRSerious adverse events:Death (n): D1: 1D2: NRMalignancies:Lymphoma or leukemia?(n): D1: 0D2: 0Overall: 0Skin?cancer (basal cell?or squamous cell)?(n): D1: 0D2: 0Overall: 0Other cancer (specify)?(n): D1: 0D2: 0Overall: 0Respiratory events:Pneumonia (n): D1: 2D2: NROverall: NRUpper respiratory infection?(n): D1: 18D2: 18Overall: 36Other infections:NRGI:NROther:Infusion/injection site reactions?(n): Injection site pain: D1: 2D2: 5Overall: 7Headache?(n): D1: 4D2: 3Overall: 7Vasovagal attack:D1: 1D2: NROverall: NRAcute respiratory distress syndrome: D1: 1 D2: NROverall: NRCough:D1: 7D2: 2Overall: 9Rhinorrhea: D1: 6D2: 1Overall: 7Fatigue (n):D1: 5D2: 3Pruritus (n):D1: 4D2: 1Alanine aminotransferase increased (n):D1: 4D2: 0Aspartate aminotransferase increased (n): D1: 4D2: 1Hypercholesterolemia (n): D1: 4D2: 0RA flare-up (n): D1: 0D2: 4Quality rating for efficacy/effectiveness? FairQuality rating for observational studies NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Kirwan et al., 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1470</RecNum><DisplayText><style face="superscript">101</style></DisplayText><record><rec-number>1470</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1470</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirwan, J R</author><author>Hallgren, R</author><author>Mielants, H</author><author>Wollheim, F</author><author>Bjorck, E</author><author>Persson, T</author><author>Book, C</author><author>Bowman, S</author><author>Byron, M</author><author>Cox, N</author><author>Field, M</author><author>Kanerud, L</author><author>Leirisalo-Repo, M</author><author>Malaise, M</author><author>Mohammad, A</author><author>Palmer, R</author><author>Petersson, I F</author><author>Ringertz, B</author><author>Sheldon, P</author><author>Simonsson, M</author><author>Snowden, N</author><author>Van den Bosch, F</author></authors></contributors><titles><title>A randomised placebo controlled 12 week trial of budesonide and prednisolone in rheumatoid arthritis</title><secondary-title>Annals of the rheumatic diseases</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>688-95</pages><volume>63</volume><number>6</number><keywords><keyword>CN-00468319</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1, 2, 3</custom4><custom7>DJ 10-9 (LL 8-2)</custom7></record></Cite></EndNote>101Country, Setting:Belgium, Sweden, and United Kingdom,multicenter (16)Funding:Astra-ZenecaResearch Objective:To compare BUD, a locally acting glucocorticoid with minimal systemic exposure, with conventional glucocorticoid txt and placebo in RAStudy Design:RCTOverall N:143Study Duration: 12 wksInclusion Criteria:Age 18 to 80 yrsDiagnosed according to ACR criteriaFunctional class I-IIIStable doses of NSAIDs (30 ds) and/or DMARDs (90 ds)Exclusion Criteria:Pregnant or lactatingGlucocorticoids by any route for at least 30 dsSystemic lupus erythematosusPolymyalgia rheumaticaPsoriatic arthropathySpondylo-arthropathySmyloidosisActive peptic ulcer diseaseUncontrolled DMOther significant diseaseLocal or systemic infectionAllergy to BUD or other glucocorticoids; txt w/ live viruses (i.e., polio) or live bacteria (i.e., tubercle bacilli) during previous 90 daysUndergone resection of stomach or more than 100 cm of small bowelInterventions, dose:D1: BUD (3 mg/d)D2: BUD (9 mg/d)D3: PNL (7.5 mg/d)D4: PlaceboN:D1: 37D2: 36D3: 39D4: 31Mean age, yrs:D1: 54.2D2: 57.8D3: 53.4D4: 54.7Sex, % female:D1: 70D2: 77D3: 62D4: 77Race, % white:NRMean disease duration, yrs:D1: 13.1D2: 8.5D3: 7.0D4: 7.2TJC, mean:D1: 14.2 D2: 11.8D3: 12.3 D4: 12.6SJC, mean:D1: 12.9 D2: 9.8D3: 11.6 D4: 11.8DMARD use, %:D1: 76 D2: 69D3: 67 D4: 65Corticosteroid use, %NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRHAQ:D1: 1.61D2: 1.57D3: 1.51D4: 1.52Functional capacity and health related quality of life are secondary outcomes for this studyACR20, %: D1: 22 D2: 42D3: 56D4: 25D2 vs D3, P = 0.11TJC: D1: 2.23 (-0.63 to 5.1)D2: 3.65 (0.75 to 6.54) (P < 0.05)D3: 4.83 (2.01 to 7.65) (P < 0.001)SJC: D1: 1.53 (0.92 to 3.98) D2: 3.81 (1.3 to 6.52) (P < 0.01)D3: 3.67 (1.25 to 6.09) (P < 0.01)Pain: D1: 6.6 (-5.8 to 18.9) D2: 11.4 (-1.3 to 24) D3: 22.3 (10 to 34.6) (P < 0.001)DAS, patient: D1: 7.9 (-4.7 to 20.5) D2: 16.4 (3.6 to 29.3) (P < 0.05)D3: 24.5 (12.1 to 37) (P < 0.001)DAS, physician: D1: 0.25 (-0.12 to 0.62) D2: 0.45* (0.07 to 0.82) (P < 0.05)D3: 0.66 (0.3 to 1.03) (P < 0.001)HAQ: D1: 0.009 (-0.19 to 0.21) D2: 0.107 (-0.31 to 0.09) D3: 0.383 (0.188 to 0.578) (P < 0.001)Difference:D3 vs. D1: 0.393; P < 0.001D3 vs. D2: 0.276; P < 0.01SF-36: D1: 2 (-2 to 6) D2: 3.7 (-0.4 to 7.8) D3: 7.4 (3.5 to 11.4) (P < 0.001) SF-36 Mental Subscale D1: 4.8 (-0.8 to 10.4) D2: 6.0 (0.4 to 11.7) ( D3 vs D1; P < 0.05)D3: 7.2 (1.7 to 12.8) (D3 vs D2; P < 0.001)Overall: D1: 89D2: 94D3: 85D4: 90SAEs:D1: 5D2: 0D3: 5D4: 6Abdominal Pain:D1: 11D2: 8D3: 10D4: 6Headache:D1: 11D2: 14D3: 15D4: 3URTI:D1: 19D2: 11D3: 15D4: 3Overall Attrition Rate, %:16ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Klareskog, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY3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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjY3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==
ADDIN EN.CITE.DATA 92; van der Heijde, 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEy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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEy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=
ADDIN EN.CITE.DATA 102, van der Heijde, 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEy
NTc8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xMDM8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjU3PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJm
ejlheDl0YWZ4cGQ1Ij4xMjU3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj52YW4gZGVyIEhlaWpkZSwgRC48L2F1dGhvcj48YXV0aG9yPktsYXJlc2tvZywgTC48L2F1dGhv
cj48YXV0aG9yPlNpbmdoLCBBLjwvYXV0aG9yPjxhdXRob3I+VG9ybmVybywgSi48L2F1dGhvcj48
YXV0aG9yPk1lbG8tR29tZXMsIEouPC9hdXRob3I+PGF1dGhvcj5Db2RyZWFudSwgQy48L2F1dGhv
cj48YXV0aG9yPlBlZGVyc2VuLCBSLjwvYXV0aG9yPjxhdXRob3I+RnJldW5kbGljaCwgQi48L2F1
dGhvcj48YXV0aG9yPkZhdGVuZWphZCwgUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRv
cnM+PGF1dGgtYWRkcmVzcz5SaGV1bWF0b2xvZ3ksIFVuaXZlcnNpdHkgSG9zcGl0YWwgTWFhc3Ry
aWNodCwgTWFhc3RyaWNodCwgVGhlIE5ldGhlcmxhbmRzLiBkaGVAc2ludC5hem0ubmw8L2F1dGgt
YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5QYXRpZW50IHJlcG9ydGVkIG91dGNvbWVzIGluIGEgdHJp
YWwgb2YgY29tYmluYXRpb24gdGhlcmFweSB3aXRoIGV0YW5lcmNlcHQgYW5kIG1ldGhvdHJleGF0
ZSBmb3IgcmhldW1hdG9pZCBhcnRocml0aXM6IHRoZSBURU1QTyB0cmlhbDwvdGl0bGU+PHNlY29u
ZGFyeS10aXRsZT5Bbm4gUmhldW0gRGlzPC9zZWNvbmRhcnktdGl0bGU+PHNob3J0LXRpdGxlPlBh
dGllbnQgcmVwb3J0ZWQgb3V0Y29tZXMgaW4gYSB0cmlhbCBvZiBjb21iaW5hdGlvbiB0aGVyYXB5
IHdpdGggZXRhbmVyY2VwdCBhbmQgbWV0aG90cmV4YXRlIGZvciByaGV1bWF0b2lkIGFydGhyaXRp
czogdGhlIFRFTVBPIHRyaWFsPC9zaG9ydC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5Bbm5hbHMgb2YgdGhlIFJoZXVtYXRpYyBEaXNlYXNlczwvZnVsbC10aXRsZT48YWJi
ci0xPkFubi4gUmhldW0uIERpcy48L2FiYnItMT48YWJici0yPkFubiBSaGV1bSBEaXM8L2FiYnIt
Mj48L3BlcmlvZGljYWw+PHBhZ2VzPjMyOC0zNDwvcGFnZXM+PHZvbHVtZT42NTwvdm9sdW1lPjxu
dW1iZXI+MzwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29y
ZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlyaGV1bWF0aWMgQWdlbnRzLyB0aGVyYXBldXRp
YyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QXJ0aHJpdGlzLCBSaGV1bWF0b2lkLyBkcnVnIHRoZXJh
cHk8L2tleXdvcmQ+PGtleXdvcmQ+RGlzYWJpbGl0eSBFdmFsdWF0aW9uPC9rZXl3b3JkPjxrZXl3
b3JkPkRvdWJsZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBUaGVyYXB5LCBD
b21iaW5hdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SGVh
bHRoIFN0YXR1cyBJbmRpY2F0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48
a2V5d29yZD5JbW11bm9nbG9idWxpbiBHLyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv
cmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvIHRoZXJhcGV1dGljIHVzZTwv
a2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QYXRpZW50IFNh
dGlzZmFjdGlvbjwva2V5d29yZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+PGtl
eXdvcmQ+UmVjZXB0b3JzLCBUdW1vciBOZWNyb3NpcyBGYWN0b3IvIHRoZXJhcGV1dGljIHVzZTwv
a2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0LCBOb24tVS5TLiBHb3YmYXBvczt0PC9r
ZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh
dGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXI8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48YWNjZXNzaW9uLW51bT4xNjA3OTE3MjwvYWNjZXNzaW9uLW51bT48dXJscz48
L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b20zPkhS
Q1Q8L2N1c3RvbTM+PGN1c3RvbTQ+MSwyLDM8L2N1c3RvbTQ+PGN1c3RvbTc+RE9ORSBQVC1TVyBn
b2VzIHdpdGggMTI1NiwgNjc3LCAxOTk4JiN4RDs8L2N1c3RvbTc+PC9yZWNvcmQ+PC9DaXRlPjwv
RW5kTm90ZT5=
ADDIN EN.CITE.DATA 103, van der Heijde, 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE.DATA 104TEMPO studyCountry, Setting:Multinational (Europe),multicenterFunding:Wyeth ResearchResearch Objective:To compare safety and efficacy of combination of ETA and MTX with monotherapies in pts with RA who had failed previous DMARD txtStudy Design:RCTOverall N:686 (2 yr results: 503)Study Duration: 52 wks (2 yrs, 100 wks)Inclusion Criteria:Age ≥ 18Diagnosed according to ACR criteriaFunctional class I-IIILess than satisfactory response to at least 1 DMARD other than MTXDuration 6 mos to 20 yrsRA defined as > 10 swollen and > 12 painful joints and at least one of: ESR > 28 mm/h, CRP > 20 mg/L, or morning stiffness for > 45 minutesFolic acid 5 mg twice per wkNSAIDsExclusion Criteria:TNF antagonist, any immuno-suppressive drugs w/in 6 mosAny investigational drug or biologic agent w/in 3 mos DMARD or css injection w/in 4 mosPrevious txt with MTX if pt experienced clinically toxic side effects or had no responseInterventions, dose:D1: MTX (20 mg/wk)D2: ETA (25 mg 2x wkly)D3: ETA (25 mg 2x wkly) + MTX (7.5 titrated to 20 mg/wk)N:D1: 228 (152)D2: 223 (163)D3: 231 (188)Overall (at 2yrs): 503Mean age, yrs:D1: 53D2: 53.2D3: 52.5Overall (at 2yrs): 52.1Sex, % female:D1: 79D2: 77D3: 74Overall (at 2yrs): 76Race, % white:D1: 98D2: 99D3: 98Overall (at 2yrs): 99Mean disease duration, yrs:D1: 6.8 D2: 6.3D3: 6.8TJC, mean:D1: 33.1 D2: 35D3: 34.2SJC, mean:D1: 22.6 D2: 23D3: 22.1DMARD use, %:NRCorticosteroid use, %D1: 64 D2: 57D3: 62MTX naive, %:D1: 58 D2: 58D3: 56Txt resistant, %:Overall: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.5 D2: 5.7D3: 5.5Sharp:D1: 26.8 D2: 21.8D3: 21.8JSN: D1: 13.3D2: 11.5D3: 10.3At 24 weeksAUC of ACR-N, %-yrs:D1: 12.2D2: 14.7 D3: 18.3 (P < 0.0001)ACR20, %: D1: 75D2: 76D3: 85 (P = 0.0151) ACR50, %: D1: 43D2: 48D3: 69 (P < 0.0001)ACR70, %: D1: 19D2: 24D3: 43 (P < 0.0001)At 52 weeksDAS < 1.6 remission, %: D1: 13D2: 16D3: 35 (D3 vs. D2: P < 0.0001; D2 vs. D1: P = 0.5031)HAQ, decline: D1: 0.65D2: 0.7D3: 1.0 (P < 0.05)D3 therapy significantly more likely to attain HAQ DI similar to population norms (< 0.5) than monotherapy Radiograhic outcomes Total Sharp Score change: D1: 0.28D2: 0.52D3: -0.54; D3 vs D2; P = 0.0006D2 vs D1; P = 0.047Erosion score change: D1: 1.68D2: 0.21D3: -0.30; D3 vs D2; P = 0.0001D2 vs D1; P = 0.008JSN score change: D2: 0.32D3: -0.23; P = 0.0007At 2 yearsTotal Sharp score change: D1: 1.12D2: 1.10D3: -0.56; P = 0.05D3 vs D2; P = 0.05D2 vs D1; P = NRErosion score changeD2: 0.36D3: -0.76P < 0.05JSN score changeD2: 0.74D3: 0.20; P = NS, NROverall: D1: 81 (87)D2: 86 (92)D3: 81 (86)Infections:D1: 64 (75)D2: 59 (71)D3: 67 (76)Serious Infections:D1: 4 (7)D2: 4 (6)D3: 4 (6)Infusion or injection reaction:D1: 2 (2)D2: 21 (21)D3: 10 (11)Abdominal Pain:D1: 18D2: 12D3: 18Hypertension:D1: 5D2: 13D3: 9Headache:D1: 14D2: 15D3: 15Nausea:D1: 32 (39)D2: 10 (13)D3: 24 (29)Overall Attrition Rate, %:52 wks: 23.5 2 Yrs: 38.4ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Kremer, 2002 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1535</RecNum><DisplayText><style face="superscript">105</style></DisplayText><record><rec-number>1535</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1535</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kremer, Joel M</author><author>Genovese, Mark C</author><author>Cannon, Grant W</author><author>Caldwell, Jacques R</author><author>Cush, John J</author><author>Furst, Daniel E</author><author>Luggen, Michael E</author><author>Keystone, Ed</author><author>Weisman, Michael H</author><author>Bensen, William M</author><author>Kaine, Jeffrey L</author><author>Ruderman, Eric M</author><author>Coleman, Patricia</author><author>Curtis, David L</author><author>Kopp, Elliot J</author><author>Kantor, Seth M</author><author>Waltuck, Jonathan</author><author>Lindsley, Herbert B</author><author>Markenson, Joseph A</author><author>Strand, Vibeke</author><author>Crawford, Bruce</author><author>Fernando, Indra</author><author>Simpson, Karen</author><author>Bathon, Joan M</author></authors></contributors><titles><title>Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomized, double-blind, placebo-controlled trial</title><secondary-title>Annals of internal medicine</secondary-title></titles><periodical><full-title>Annals of Internal Medicine</full-title><abbr-1>Ann. Intern. Med.</abbr-1><abbr-2>Ann Intern Med</abbr-2></periodical><pages>726-33</pages><volume>137</volume><number>9</number><keywords><keyword>CN-00411129</keyword></keywords><dates><year>2002</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>P</custom3><custom4>3</custom4><custom7>GG 10-2 (LL 8-16)</custom7></record></Cite></EndNote>105Country, Setting:US and Canada, multicenter (20 outpatient practice centers)Funding:Aventis PharmaceuticalsResearch Objective:To evaluate efficacy and safety of LEF vs. Placebo when added to ongoing stable dose MTX therapy in pts with persistently active RAStudy Design:RCTOverall N:263Study Duration: 24 wksInclusion Criteria:Age: 18 or 75Diagnosed with RA according to ACR criteria: Active:>9 tender joints, >6 sollen joints, >45 mornign stiffnessPrevious use of DMARDs: Failed in 11 ptsOther (Please include concomitant drugs that are allowed)? MTX (15-20mg/wk or 10-15mg/wk if max tolerated dose) for at least 6 mos, AND stable dosing for at least 8 wksExclusion Criteria:Pregnant or lactatingPrior txt with: prohibited DMARDs in past 30 dsImpaired renal or hepatic system: Hep B or C, 3 or more elevations of AST or ALT, elevated SrCRPsoriatic Arthritis or other acute inflammatory joint disease not RAInterventions, dose:D1: MTX + LEFD2: MTX + PlaceboMethotrexate: 15 -20 mg/wk or 10 -15 mg/wk if toleration problemsLeflunomide: 100 mg 2 ds then 10mg/d or 10mg/every other d if adverse effectsPlacebo: Folate 1 mg/d for ALLN:D1: 130D2: 133Mean age, yrs:D1: 55.6D2: 56.6Sex, % female:D1: 76.2D2: 80.5Race, % white:D1: 90.8D2: 87.2Mean disease duration, yrs:D1: 10.5D2: 12.7TJC, mean:D1: 26.9D2: 26.4SJC, mean:D1: 17.3D2: 18.7DMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPatients with Early RA (≤3 yrs):NRBaseline DAS, mean:NRHAQDI:D1: 1.6D2: 1.5ACR20: LEF 46.2%; Placebo 19.5% P <0.001HAQ:LEF -0.42Placebo -0.09 P < 0.001SF-36: LEf + 6.8Placebo + 0.3 P < 0.001Overall: D1: 89.2D2: 89.5Infections:D1: 40.8D2: 51.9Dizziness:D1: 7.7D2: 5.3Headache:D1: 10D2: 8.3Nausea:D1: 16.2D2: 11.3URTI:D1: 22.3D2: 24.1Adherence:Overall, 98% adherentMean adherenceAdherence: Rates 80 120% Lef 87.7% Placebo 90.2%Overall Attrition Rate, %:Discontinuation Rates: LEF 23.1 Placebo 24.8%ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableKremer et al., 2010 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5478</RecNum><DisplayText><style face="superscript">106</style></DisplayText><record><rec-number>5478</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5478</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Kremer, J. L.</author><author>Blanco, R.</author><author>Brzosko, M.</author><author>Burgos-Vargas, R.</author><author>Halland, A. M.</author><author>Vernon, E.</author><author>Ambs, P.</author><author>Fleischmann, R.</author></authors></contributors><auth-address>Albany Medical College and The Center for Rheumatology, Albany, NY, USA.</auth-address><titles><title>Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate at 1 year: The LITHE study</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><dates><year>2010</year><pub-dates><date>Nov 19</date></pub-dates></dates><isbn>1529-0131 (Electronic)
0004-3591 (Linking)</isbn><accession-num>21104724</accession-num><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I MTC</custom2><custom4>KQ 1, 2, 3 / fair</custom4><language>Eng</language></record></Cite></EndNote>106LITHE Study; Venkiteshwaran et al., 2009 CDER Statistical Review Application Number 125276Country and settingMultinational and multicenterSource of fundingRocheResearch objectiveEfficacy and safety of TCZ plus MTX vs. MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate to severe RA and inadequate responses to MTX.Study designRCTOverall N1196Duration of studyOne year RCT (with 16 week escape) then open labelInclusion CriteriaTreatment resistantInadequate response to MTXRA diagnosis according to ACR criteriaModerate to severe in the investigator's opinion and lasted for ≥ 6 mos≥1 radiographic-ally confirmed joint erosion despite having received MTX for at least 12 wks before baseline (stable at 10-25 mg/wk for ≥ 8 wks)Exclusion CriteriaSerious concomitant diseasesSignificant systemic involvement of RAFunctional class IV RAOther inflammatory joint diseasesCurrent/ recurrent infectionsAbnormal ALT or AST (>1.5X ULN), total bilirubin (>ULN), hemoglobin (<8.5 g/dL), or triglyceridComparisons (dosage and frequency)D1: TCZ: 8 mg/kg every 4 wksD2: TCZ: 4 mg/kg every 4 wksD3: Placebo: NA (Rescue at 16 wks)D4: D5: Number in groupD1: 398D2: 399D3: 393Mean age (years)D1: 53.4D2: 51.4D3: 51.3Sex, % femaleD1: 82D2: 84D3: 83Race, % whiteD1: NRD2: NRD3: NRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 9.3 (0.6-48.8)D2: 9.4 (0.5-43.2)D3: 9.0 (0.5- 44.3)TJC, meanD1: 29.3D2: 27.9D3: 27.9SJC, mean D1: 17.3D2: 17.0D3: 16.6Corticosteroid use, %D1: 62D2: 69D3: 70DMARD use, %: D1: Past use 75.4D2: 78..4D3: 71.2MTX na?ve, %: D1: 0D2: 0D3: 0Treatment resistant, %: D1: 100D2: 100D3: 100Patients with early RA, three years or less, %: NR Baseline DAS scoreD1: 6.6D2: 6.5D3: 6.5Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: Week 24D1: 56%D2: 51% D3: 27%Week 52NRACR 50: Week 24 D1: 32% D2: 25%D3: 10% Week 52NRACR 70: Week 24D1: 13%D2: 11% D3: 2% Week 52 NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): AUC HAQ-DI change from baseline to week 52 (LOCF)D1: -144.1 units, P<0.0001 vs. placeboD2: -128.4 units, P<0.0001 vs. placeboD3: -58.1HAD-DI change to week 24D1:-0.4 (0.6)D2: -0.4 (0.5)D3: -0.1 (0.5)DAS, mean difference/absolute difference?(CI/SD/P Value): Mean improvements at 52 wksD1: -3.8, vs. placebo P<0.0001D2: -3.0, vs. placebo P<0.0001D3: -2.0 DAS28 clinical remission (<2.6) D1: 47.2% (127/269), vs. placebo P<0.0001D2: 30.2% (70/232), vs. placebo P<0.0001D3: -2.0; 7.9% (12/151)SF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): Reduction in structural damage at 52 wks (extrapolated)D1: 74%, P<0.0001 compared with placeboD2: 70%, P<0.0001 compared with placeboQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): Change in total Genant modified Sharp score ≤0 from baseline to week 52 D1: 84%D2: 81%D3: 67%P≤0.0001, linear extrapolation, exploratory analysisOverallOverall attrition/withdrawal (n): NROverall: 167Withdrawals due to adverse events?(n): D1: 33 (8%)D2: 28 (7%)D3: 11 (3%)Withdrawals due to lack of efficacy?(n): D1: 2D2: 4D3: 12Overall adverse events reported (n): Per 100 PYD1: 325.4D2: 324.0D3: 279.6Serious adverse events:Death (n): D1: 4D2: 0D3: 2Malignancies:Skin?cancer (basal cell or squamous cell)?(n): NROverall: 5 nonmelanoma skin cancers and 1 unclassified skin cancerOther cancer (specify)?(n): D1: 1 (uterine)D2: 5 (lung, cervical, breast, 2 prostate)D3: 1 (breast)Respiratory events:Pneumonia (n): Pnuemonia/bronchitis, n (%)D1: 2 (0.5)D2: 3 (0.8)D3: 2 (0.5)Other infections:Serious infections per 100 PYD1: 4.0D2: 3.7D3: 2.3GI:NROther:Infusion/injection site reactions?(n): D1/D2: 6 (4 were serious anaphylactic reaction/shock events)D3: NR Quality rating for efficacy/effectiveness? FairQuality rating for observational studies NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Kristensen et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcw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ADDIN EN.CITE.DATA 107Country, Setting:Sweden, multicenterFunding:Osterlund and Kock Founda-tions, 80-yr Fund of King Gustav V, and Reumat-ikerfor-bundetResearch Objective:LUNDEX index to compare long-term efficacy and tolerability of biologic therapies in RA pts treated in clinical practiceStudy Design:Prospective cohort studyOverall N:949Study Duration: Varied (results reported for 3 yrs)Inclusion Criteria:Unsuccessful txt with 2 DMARDS including MTXPts diagnosed with RA according to clinical judgment of treating physicianTreated at 8 centers in Southern Sweden during March 1999 through January 2004Meds allowed, NRExclusion Criteria:Prior txt with biologic therapyInterventions, dose:D1: ETA (25 mg s.c. twice wkly)D2: INF (≥3 mg/kg at 0, 2, 6, and 12 wks and then every 8 wks)N:D1: 309D2: 640Mean age, yrs:D1: 55.1D2: 56.2Sex, % female:D1: 82D2: 75Race, % white:NRMean disease duration, yrs:D1: 14.7D2: 12.7TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %NRMTX naive, %:NRTxt resistant, %:Overall: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.9D2: 5.6MTX use, %:D1: 31D2: 73HAQ: D1: 1.6D2: 1.4At 3 monthsD1: 63D2: 45 (P < 0.001)At 6 monthsD1: 61 D2: 47 (P = NS) At 12 monthsLUNDEX values (index of drug efficacy in clinical practice):D1: ~ 55% (~ 4 0% at 3 yrs)D2: ~ 45% (~ 30% at 3 yrs)ACR20, %:D1: 69 D2: 53 (P = 0.001) At 24 monthsACR20, %:D1: 65 D2: 56 (P = NS)At 36 monthsACR20, %: D1: 63 D2: 61 (P = NS)ACR50, %: D1: 39 D2: 39 (P = NS)ACR 70, %: D1: 16D2: 18 (P = NS)EULAR (moderate), %: D1: 46 D2: 29 (P = NS)EULAR (good), %:D1: 36 D2: 45 (P = NS)Intermediate Outcome Measures:INF had significantly lower adherence compared to ETA (P < 0.001)NROverall Attrition Rate, %:NRITT Analysis:N/A Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableKristensen et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+S3Jpc3RlbnNlbjwvQXV0aG9y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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZVllYXI9IjEiPjxBdXRob3I+S3Jpc3RlbnNlbjwvQXV0aG9y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ADDIN EN.CITE.DATA 108Country and settingSouthern Sweden, 8 hospital centersSource of fundingOsterlund and Kock Foundations, King Gustav V 80-year fund, ReumatikerforbundetResearch objectiveCompare therapy aderence of ETN and IFX during first TNF-blocking treatment course and to identify potential predictors for tx termination andimpact of concomitant MTX on other DMARDsStudy designObservationalOverall N1,161Duration of studyMarch 1999 to December 2004 clinical data collected at 0, 3, 6, and 12 mos and subsequently every 3 to 6 mos.Quality rating FairInclusion CriteriaDiagnonsis of RA according to clinical judgment of treating physician (98% fullfilled ACR classification)Biologic na?ve, no formal level of disease activityPts should have received at least 2 DMARDs, including MTX prior to inclusion without satisfactory responseExclusion CriteriaHaving received biologic therapy prior to inclusion in study.Interventions, doseD1: LEFETN: 25 mg subcutaneously 2 times/weekAzathioprineD2: IFX3 mg/kg at 0, 2, and 6 weeks and then every 8th week depending on primary or secondary failure IFX could be increased in increments of 100 mg to max of 500 mg administered at 4 to 8 week intervalsAzathioprineD3: MTX: 16.1 mg/wkETN: 25 mg subcutaneously 2x per weekD4: MTX: 14.3 mg/wkIFX: 3 mg/kg at 0, 2, and 6 weeks and then every 8th week depending on primary or secondary failure IFX could be increased in increments of 100 mg to max of 500 mg administered at 4 to 8 week intervalsD5: LEF: NRSSZ: NRHydroxychlorquine: NRAzathioprineETN: 25 mg subcutaneously 2x per weekD6: LEF: NRSSZ: NRHydroxychlorquine: NRAzathioprine: NRIFX: 3 mg/kg at 0, 2, and 6 weeks and then every 8th week depending on primary or secondary failureNumber in groupD1: 193D2: 104D3: 179D4: 501D5: 68D6: 116Mean age, years (SD)D1: 57.7D2: 61.0D3: 53.4D4: 55.0D5: 54.0D6: 57.4Sex, % femaleD1: 84D2: 78D3: 78D4: 74D5: 84D6: 75Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, mosD1: 185.3 (121.4)D2: 192.9 (132.4)D3: 132.8 (107.3)D4: 133.5 (113.8)D5: 180.1 (115.1)D6: 165.4 (118.5)Patients with early RA, three years or less, %NR Treatment resistant, %Inadequate response to previous DMARD including MTX (%)D1: 100 D2: 100 D3: 100D4: 100 D5: 100 D6: 100TJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %D1: 0D2: 0D3: 100D4: 100D5: 100D6: 100MTX na?ve, %D1: 0D2: 0D3: 0D4: 0D5: 0D6: 0Baseline DAS score (SD)D1: 5.9 (1.1)D2: 5.7 (1.2)D3: 5.5 (1.0)D4: 5.5 (1.2)D5: 5.8 (1.2)D6: 5.8 (1.1)Required treatment for latent TBNROther population characteristics, %,?(SD)HAQ:D1: 1.60 (0.65) D2: 1.69 (0.58)D3: 1.30 (0.61)D4: 1.34 (0.62)D5: 1.61 (0.58)D6: 1.57 (0.58)VAS global (mm): D1: ): 66 (21)D2: 67 ( 22)D3: 60 (22)D4: 60 (22)D5: 71 (17)D6: 70 (18)VAS pain (mm): D1: 65 (22)D2: 64 (24)D3: 60 (22)D4: 60 (23)D5: 66 (19)D6: 70 (17) EVAL global (mm): D1: 60 (24)D2: 58 (23)D3: 56 (24)D4: 57 (23)D5: 56 (21)D6: 57 (22)ACR mean difference/ absolute difference (CI/SD/P Value)ACR 20: NRACR 50: NRACR 70: NRHAQ, mean difference/ absolute difference NRDAS, mean difference/absolute difference NRSF-36, mean difference/absolute difference NRRadiographic measures, mean difference/absolute difference NRQuality of life scales, mean difference/absolute difference NROthers, (please name) mean difference/absolute difference (CI/SD/P Value)There were no differences in DAS28 at treatment termination between patients terminating because of failure in IFX D(DAS28= 5.1 95% CI, 4.9-5.4) compared with ETN D (DAS28= 5.1 95% CI, 4.8-5.4)Attrition/withdrawalAdherent/compliant, %:At 1 year:D1: 74D2: 47D3: 89D4: 69D5: 85D6: UnadjustedAt 4 years:D1: 53D2: 18D3: 75D4: 38D5: 71D6:NRAt 5 yearsD1: NRD2: NRD3: 65D4: 36 D5: NR D6: NRFor treatment failure withdrawal, IFX had sig more withdrawals than ETN only for subarm of patients receiving MTX (P?= 0.026) and Monotherapy (P = 0.002)Patients receiving concomitant MTX compared to monotherapy had fewer dropouts due to AE (P < 0.001)Adjusted HR for terminating treatment: IFX V ETN: 2.92 (95% CI, 2.32-3.69)Monotherapy V MTX: 1.82 (95% CI, 1.45-2.29)Other DMARDs V MTX: 1.45 (9% CI 1.12-1.87)Monotherapy V other DMARDS: 1.22 (95% CI, 1.22 (95% CI, 0.94-1.61)Adjusted HR for terminating treatment (all reasons, time-dependent cox regression analysis):IFX V ETN: 2.83 (95% CI, 2.27-3.54)Monotherapy V MTX: 1.48 (95% CI, 1.19-1.85)Other DMARDs V MTX: 1.33 (95% CI, 1.08-1.55)Monotherapy V other DMARD: 1.10 (95%CI 0.86-1.40)Adjusted HR for terminating treatment (AE): Monotherapy V MTX: 2.14 (95% CI, 1.61-2.84)Other DMARD V MTX: 1.75 (95% CI, 1.28-2.04)Monotherapy V other DMARD: 1.23 (95% CI, 0.88-1.71)Adjusted HR for terminating treatment (Treatment Failure):Monotherapy V MTX: 1.31 (95% CI, 0.86-1.99)Other DMARD V MTX: 1.07 (95% CI, 0.66-1.73)Monotherapy V other DMARD: 1.22 (95% CI, 0.72-2.06)Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Kristensen et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>4706</RecNum><DisplayText><style face="superscript">109</style></DisplayText><record><rec-number>4706</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">4706</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Kristensen, L. E.</author><author>Christensen, R.</author><author>Bliddal, H.</author><author>Geborek, P.</author><author>Danneskiold-Sams??e, B.</author><author>Saxne, T.</author></authors></contributors><auth-address>Department of Rheumatology, Lund University Hospital, Lund, Sweden
Parker Institute, Musculoskeletal Statistics Unit, Frederiksberg Hospital, Frederiksberg, Denmark
Department of Rheumatology, Lund University Hospital, SE-221 85 Lund, Sweden</auth-address><titles><title>The number needed to treat for adalimumab, etanercept, and infliximab based on ACR50 response in three randomized controlled trials on established rheumatoid arthritis: A systematic literature review</title><secondary-title>Scandinavian Journal of Rheumatology</secondary-title></titles><periodical><full-title>Scandinavian Journal of Rheumatology</full-title><abbr-1>Scand. J. Rheumatol.</abbr-1><abbr-2>Scand J Rheumatol</abbr-2></periodical><pages>411-417</pages><volume>36</volume><number>6</number><dates><year>2007</year></dates><urls><related-urls><url> and setting:NRFunding:The OakFoundation, Osterlund and Kock Foundations, Reumatikerforbundet, and the King Gustav V 80-year fund.Aims of Review:To compare NNTs based on the 3 different types of NNT calculations for ADA, ETN, and INF combined with MTX, from the publisheddouble-blind, 12-month RCTs in established RA.Quality Rating:FairStudy design:Systematic ReviewNumber of Patients:1,126Studies Included:N?=?3Characteristics of Included Studies:Double-blind RCTs with a minimum of 2 arms comparing ADA, ETN, or INF and concomitant use of MTX compared to MTX alone; explicit data on the ACR50 response after at least 12 months of follow-up was collected in all included studies.Characteristics of Included PopulationsRA patients with an average disease duration of at least 5 yearsCharacteristics of Interventions:1 INF trial (doses: 3 mg/8 wks, 3 mg/4 wks, or placebo)1 ETN trial (doses: 2 x 25 mg/wk or placebo)1 ADA trial (doses: 40 mg/2 wks or placebo)Study Results:NNT (control event-adjusted; among randomized)INF 3mg/8 wks: 8 (4-66)INF 3mg/4 wks: 4 (3-11)ETN 2 x 25 mg/wk: 4 (3-6)ADA 40 mg/2 wks: 4 (3-6)NNT (unadjusted; among randomized)INF 3mg/8 wks: 8 (5-38) INF 3mg/4 wks: 4 (3-7)ETN 2 x 25 mg/wk: 4 (3-6) ADA 40 mg/2 wks: 4 (3-5)NNT (unadjusted; 1-year completers)INF 3mg/8 wks: 8 (4-35) INF 3mg/4 wks: 4 (3-9)ETN 2 x 25 mg/wk: 5 (4-9) ADA 40 mg/2 wks: 3 (2-4)Adverse Events:NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Kristensen et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcw
NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjEwNzwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjcwNzwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjVmeHR3MmV0NnR2cmZ3ZTB6cHM1MnByZno5
YXg5dGFmeHBkNSI+NzA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5L
cmlzdGVuc2VuLCBMLiBFLjwvYXV0aG9yPjxhdXRob3I+U2F4bmUsIFQuPC9hdXRob3I+PGF1dGhv
cj5HZWJvcmVrLCBQLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRy
ZXNzPkRlcGFydG1lbnQgb2YgUmhldW1hdG9sb2d5LCBMdW5kIFVuaXZlcnNpdHkgSG9zcGl0YWws
IEx1bmQsIFN3ZWRlbi4gTGFyc0VyaWsuS3Jpc3RlbnNlbkBza2FuZS5zZTwvYXV0aC1hZGRyZXNz
Pjx0aXRsZXM+PHRpdGxlPlRoZSBMVU5ERVgsIGEgbmV3IGluZGV4IG9mIGRydWcgZWZmaWNhY3kg
aW4gY2xpbmljYWwgcHJhY3RpY2U6IHJlc3VsdHMgb2YgYSBmaXZlLXllYXIgb2JzZXJ2YXRpb25h
bCBzdHVkeSBvZiB0cmVhdG1lbnQgd2l0aCBpbmZsaXhpbWFiIGFuZCBldGFuZXJjZXB0IGFtb25n
IHJoZXVtYXRvaWQgYXJ0aHJpdGlzIHBhdGllbnRzIGluIHNvdXRoZXJuIFN3ZWRlbjwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5BcnRocml0aXMgUmhldW08L3NlY29uZGFyeS10aXRsZT48c2hvcnQt
dGl0bGU+VGhlIExVTkRFWCwgYSBuZXcgaW5kZXggb2YgZHJ1ZyBlZmZpY2FjeSBpbiBjbGluaWNh
bCBwcmFjdGljZTogcmVzdWx0cyBvZiBhIGZpdmUteWVhciBvYnNlcnZhdGlvbmFsIHN0dWR5IG9m
IHRyZWF0bWVudCB3aXRoIGluZmxpeGltYWIgYW5kIGV0YW5lcmNlcHQgYW1vbmcgcmhldW1hdG9p
ZCBhcnRocml0aXMgcGF0aWVudHMgaW4gc291dGhlcm4gU3dlZGVuPC9zaG9ydC10aXRsZT48L3Rp
dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BcnRocml0aXMgYW5kIFJoZXVtYXRpc208L2Z1
bGwtdGl0bGU+PGFiYnItMT5BcnRocml0aXMgUmhldW0uPC9hYmJyLTE+PGFiYnItMj5BcnRocml0
aXMgUmhldW08L2FiYnItMj48YWJici0zPkFydGhyaXRpcyAmYW1wOyBSaGV1bWF0aXNtPC9hYmJy
LTM+PC9wZXJpb2RpY2FsPjxwYWdlcz42MDAtNjwvcGFnZXM+PHZvbHVtZT41NDwvdm9sdW1lPjxu
dW1iZXI+MjwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFs
LyB0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBBZ2VudHMv
IHRoZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMsIFJoZXVtYXRvaWQv
ZGlhZ25vc2lzLyBkcnVnIHRoZXJhcHkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk
PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5
d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVsaW4gRy8gdGhlcmFwZXV0
aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFn
ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzLCBUdW1vciBOZWNyb3NpcyBGYWN0b3IvIHRo
ZXJhcGV1dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0LCBOb24tVS5T
LiBHb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlJoZXVtYXRvbG9neS8gbWV0aG9kczwva2V5
d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3Jk
PlN3ZWRlbjwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tl
eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRl
PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGFjY2Vzc2lvbi1udW0+MTY0NDcyMzc8L2FjY2Vzc2lvbi1u
dW0+PHVybHM+PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1c3RvbTI+STwvY3VzdG9tMj48
Y3VzdG9tMz5ITzwvY3VzdG9tMz48Y3VzdG9tND4xLDM8L2N1c3RvbTQ+PGN1c3RvbTc+TE0gOC0x
NCAoU1cpPC9jdXN0b203PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjcw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ADDIN EN.CITE.DATA 107Country, Setting:Sweden, multicenterFunding:Osterlund and Kock Founda-tions, 80-yr Fund of King Gustav V, and Reumat-ikerfor-bundetResearch Objective:LUNDEX index to compare long-term efficacy and tolerability of biologic therapies in RA pts treated in clinical practiceStudy Design:Prospective cohort studyOverall N:949Study Duration: Varied (results reported for 3 yrs)Inclusion Criteria:Unsuccessful txt with 2 DMARDS including MTXPts diagnosed with RA according to clinical judgment of treating physicianTreated at 8 centers in Southern Sweden during March 1999 through January 2004Meds allowed, NRExclusion Criteria:Prior txt with biologic therapyInterventions, dose:D1: ETA (25 mg s.c. twice wkly)D2: INF (≥3 mg/kg at 0, 2, 6, and 12 wks and then every 8 wks)N:D1: 309D2: 640Mean age, yrs:D1: 55.1D2: 56.2Sex, % female:D1: 82D2: 75Race, % white:NRMean disease duration, yrs:D1: 14.7D2: 12.7TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %NRMTX naive, %:NRTxt resistant, %:Overall: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 5.9D2: 5.6MTX use, %:D1: 31D2: 73HAQ: D1: 1.6D2: 1.4At 3 monthsD1: 63D2: 45 (P < 0.001)At 6 monthsD1: 61 D2: 47 (P = NS) At 12 monthsLUNDEX values (index of drug efficacy in clinical practice):D1: ~ 55% (~ 4 0% at 3 yrs)D2: ~ 45% (~ 30% at 3 yrs)ACR20, %:D1: 69 D2: 53 (P = 0.001) At 24 monthsACR20, %:D1: 65 D2: 56 (P = NS)At 36 monthsACR20, %: D1: 63 D2: 61 (P = NS)ACR50, %: D1: 39 D2: 39 (P = NS)ACR 70, %: D1: 16D2: 18 (P = NS)EULAR (moderate), %: D1: 46 D2: 29 (P = NS)EULAR (good), %:D1: 36 D2: 45 (P = NS)Intermediate Outcome Measures:INF had significantly lower adherence compared to ETA (P < 0.001)NROverall Attrition Rate, %:NRITT Analysis:N/A Quality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableLacaille, 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 110Country and settingProvince of BC, Canada, administrative dataSource of fundingBristol-Myers Squibb, Canadian Arthritis Network, Arthritis Society of CandaResearch objectiveDetermine effect of nonbiologic DMARDs on infection risk in RAStudy designRetrospective longitudinal cohort studyOverall N27,710Duration of study7 years (162,720 person years of follow-up)Quality rating Fair: analysis did not adjust for all confounders, such as baseline disease activity or severity (however it did adjust for RA duration); Use of administrative billing data.Inclusion CriteriaRA diagnosisAt least 2 physician visits more than 2 months apart with an RA ICD-9 RA diagnostic codeExclusion CriteriaAt least 2 visits subsequent to second RA visit with diagnoses of other inflammatory arthritides (systemic lupus erythematosus, other connective tissue diseases, PsA, ankylosing spondylitis, and other spondylarthri-tides)Those with a diagnosis of RA not confirmed by a rheumatologistInterventions, DoseD1: MTX: dosage NRD2: LEF: dosage NRD3: DMARD and corticosteroid (CS): dosage NRD4: DMARD aloneD5: Corticosteroid alone: 10.4 mg PRED other CS NRNumber in groupD1: NRD2: NRD3: NRD4: NRD5: NROverall: 27,710Mean age (years)D1: NRD2: NRD3: NRD4: NRD5: NROverall: 57 ±17Sex, % femaleD1: NRD2: NRD3: NRD4: NRD5: NROverall: 67Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: NRD2: NRD3: NRD4: NRD5: NROverall: 5 years or less: 36%; more than 5 years: 17%Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: NRD2: NRD3: NRD4: NRD5: NROverall: 44DMARD use, %D1: NRD2: NRD3: NRD4: NRD5: NROverall: 45MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR NAHAQ, NADAS NASF-36 NARadiographic measures NAQuality of life scales NAOthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallOverall attrition/withdrawal, n: NAOverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsUnadjusted rate of infection per person yr of follow-up, n:D1: 1.28 (95% CI 1.25-1.32)D2: 1.67 (95% CI 1.41-1.97)D3: 1.12 (95% CI 1.08-1.16) P = ?0.0001; Serious infections:? 1.63 (95% CI 1.5-1.77) P = ?0.0001D4: 0.9 (95% CI 0.88-0.93) P = ?0.0001; Serious infections:? 0.92 (95% CI 0.85-1.0) P = ?0.0502D5: 1.15 (95% CI 1.11-1.19) P = ?0.0001; Serious infections:? 1.9 (95% CI 1.75-2.05) P = ?0.0001Overall: NRGINROtherNR Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Langer, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0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ADDIN EN.CITE.DATA 111Country, Setting:Germany, multiple sites, daily clinical practiceFunding:AmgenResearch Objective:To assess the response rate, time to response, efficacy and safety of anakinra during 52 wks of therapy after launch in daily clinical practice in Germany and to gain knowledge of the routine application of anakinra in RA pts under special conditions (RA pts who failed TNF-blocking drugs)Study Design:Case series; postmarketing surveillanceOverall N:454Study Duration: 52 wksInclusion Criteria:Age: adultPatients who fell within approved indication for anakinraPts with RA who had been ineffectively treated with at least 2 DMARDs including MTXExclusion Criteria:NRInterventions:D1: AKA, all ptsD2: AKA, TNF-blocker naiveD3: AKA, TNF-blocker pretreatedAnakinraN:D1: 166D2: 105D3: 61Mean age (yrs):D1: 53.7D2: 54.7D3: 51.9Sex, % female:D1: 78.9D2: 78.1D3: 80.3Race, % white:NR Mean disease duration, yrs:D1: 12.3D2: 12.0D3: 12.8TJC, mean:D1: 12.8D2: 12.4D3: 13.4SJC, mean:D1: 10.5D2: 10.4D3: 10.8DMARD use, %:D1: on MTX: 66.3D2: 72.4 D3: 55.7Corticosteroid use, %:D1: 84.9D2: 81.9D3: 90.1MTX naive, %: NRTreatment resistant %:NRPatients with Early RA (≤3 yrs): NRBaseline DAS, mean:D1: 5.8D2: 5.6D3: 6.1D1: morning stiffness (minutes) 112.5D2: 104.1 D3: 126.6D1: # of previous DMARDs: 3.6D2: 3.0D3: 4.4Pts responded well to AKA therapy; 67.5% had good (21.0%) or moderate (46.5%) EULAR response after 6 mos. of therapyDAS decreased by 44% for all ptsTender joint count decreased by 53%, swollen joint count by 49%, pain by 31%, and global health by 28%Response to AKA was rapid, within 1 mo; shown in figures Data suggest AKA is effective in pts who have failed anti-TNF therapy with comparable results to anti-TNF naive pts69.4% of TNF-blocker pretreated pts had a good or moderate EULAR response at 6 mos. compared to 66.3% of TNF-blocker naive ptsDisease activity decreased by 39% and 47% respectivelyPain decreased by 35% and 29% respectivelyTender joint count by 49% vs. 55%Swollen joint count 44% vs. 52%Global health by 33% vs. 26%See adverse eventsOverall: D1: 41.2Serious AEs:D1: 4.2Infections:D1: 6.6Serious Infections:D1: 1.5Infusion or injection reaction:D1: 20.7Abdominal Pain:NRCardiovascular Events:NRDizziness:NRHeadache:D1: 2Hepatotoxicity:NRMalignancies:NRNausea:NRURTI:NROverall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Lebwohl, 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0
NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjExMjwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjc0NDwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjVmeHR3MmV0NnR2cmZ3ZTB6cHM1MnByZno5
YXg5dGFmeHBkNSI+NzQ0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5M
ZWJ3b2hsLCBNLjwvYXV0aG9yPjxhdXRob3I+Qmx1bSwgUi48L2F1dGhvcj48YXV0aG9yPkJlcmtv
d2l0eiwgRS48L2F1dGhvcj48YXV0aG9yPktpbSwgRC48L2F1dGhvcj48YXV0aG9yPlppdG5paywg
Ui48L2F1dGhvcj48YXV0aG9yPk9zdGVlbiwgQy48L2F1dGhvcj48YXV0aG9yPldhbGxpcywgVy4g
Si48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRt
ZW50IG9mIERlcm1hdG9sb2d5LCBNb3VudCBTaW5haSBTY2hvb2wgb2YgTWVkaWNpbmUsIE5ldyBZ
b3JrLCBOWSwgVVNBLiBMZWJ3b2hsQGFvbC5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRs
ZT5ObyBldmlkZW5jZSBmb3IgaW5jcmVhc2VkIHJpc2sgb2YgY3V0YW5lb3VzIHNxdWFtb3VzIGNl
bGwgY2FyY2lub21hIGluIHBhdGllbnRzIHdpdGggcmhldW1hdG9pZCBhcnRocml0aXMgcmVjZWl2
aW5nIGV0YW5lcmNlcHQgZm9yIHVwIHRvIDUgeWVhcnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+
QXJjaCBEZXJtYXRvbDwvc2Vjb25kYXJ5LXRpdGxlPjxzaG9ydC10aXRsZT5ObyBldmlkZW5jZSBm
b3IgaW5jcmVhc2VkIHJpc2sgb2YgY3V0YW5lb3VzIHNxdWFtb3VzIGNlbGwgY2FyY2lub21hIGlu
IHBhdGllbnRzIHdpdGggcmhldW1hdG9pZCBhcnRocml0aXMgcmVjZWl2aW5nIGV0YW5lcmNlcHQg
Zm9yIHVwIHRvIDUgeWVhcnM8L3Nob3J0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs
LXRpdGxlPkFyY2hpdmVzIG9mIERlcm1hdG9sb2d5PC9mdWxsLXRpdGxlPjxhYmJyLTE+QXJjaC4g
RGVybWF0b2wuPC9hYmJyLTE+PGFiYnItMj5BcmNoIERlcm1hdG9sPC9hYmJyLTI+PC9wZXJpb2Rp
Y2FsPjxwYWdlcz44NjEtNDwvcGFnZXM+PHZvbHVtZT4xNDE8L3ZvbHVtZT48bnVtYmVyPjc8L251
bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QXJ0aHJpdGlz
LCBSaGV1bWF0b2lkL2RpYWdub3Npcy8gZHJ1ZyB0aGVyYXB5LyBlcGlkZW1pb2xvZ3k8L2tleXdv
cmQ+PGtleXdvcmQ+Q2FyY2lub21hLCBTcXVhbW91cyBDZWxsL2NoZW1pY2FsbHkgaW5kdWNlZC8g
ZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxr
ZXl3b3JkPkNvbW9yYmlkaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkNvbXBhcmF0aXZlIFN0dWR5PC9r
ZXl3b3JkPjxrZXl3b3JkPkRvc2UtUmVzcG9uc2UgUmVsYXRpb25zaGlwLCBEcnVnPC9rZXl3b3Jk
PjxrZXl3b3JkPkRydWcgQWRtaW5pc3RyYXRpb24gU2NoZWR1bGU8L2tleXdvcmQ+PGtleXdvcmQ+
RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3
b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbW11bm9nbG9idWxpbiBHL2FkbWluaXN0cmF0
aW9uICZhbXA7IGRvc2FnZS8gYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkluY2lk
ZW5jZTwva2V5d29yZD48a2V5d29yZD5Mb25nLVRlcm0gQ2FyZTwva2V5d29yZD48a2V5d29yZD5N
YWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw
dG9ycywgVHVtb3IgTmVjcm9zaXMgRmFjdG9yL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwv
a2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0LCBOb24tVS5TLiBHb3YmYXBvczt0PC9r
ZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5S
aXNrIEFzc2Vzc21lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+U2tpbiBOZW9wbGFzbXMvY2hlbWljYWxs
eSBpbmR1Y2VkLyBlcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+
MjAwNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz
PjxhY2Nlc3Npb24tbnVtPjE2MDI3MzAxPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3Vz
dG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+PGN1c3RvbTM+T0FFPC9jdXN0b20z
PjxjdXN0b200PjM8L2N1c3RvbTQ+PGN1c3RvbTc+TE0gOC0xNCAoU1cpPC9jdXN0b203PjwvcmVj
b3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 112Country, Setting:US, clinical trial participants receiving ETA from private and institutional practicesFunding:Amgen Inc. Research Objective:Incidence of cutaneous SCC in pts with rheumatoid arthritis receiving ETA for up to 5 yrsStudy Design:Postmarketing database reviewOverall N:1,442 (4257 PY) Study Duration: Mean 3.7 yrsInclusion Criteria:Participant in 1 of various studies* of ETA in pts with rheumatoid arthritisPts had active RA; and, received 10 to 50 mg ETA subcutaneously twice weekly for majority of time they received study drug. Specific inclusion criteria varied by included studyExclusion Criteria:NRInterventions, dose:D1: ETAN:D1: 1442Mean age, yrs:D1: 49.9Sex, % female:D1: 76.5Race, % white:D1: 87.4Mean disease duration, yrs:D1: 7.1TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRHealth Outcome Measures:Total # of cases of SCC reported from post-marketing database population: 4 casesAge and sex-matched expected incident cases based on:From Arizona general population-based incidence study: 13.1 casesFrom Minnesota general population-based incidence study: 5.9 casesNumber of cases of SCC per PY of exposure to ETAIn clinical trial population: 0.9/1000 PYFrom post-marketing surveillance data: .01/1000 PYSummary Statement: The incidence of SCC among pts taking ETA is likely no different from that of the general population.NROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:Fair: Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Lee, 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc0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ADDIN EN.CITE.DATA 113Country, Setting:US, clinicsFunding:NRResearch Objective:To identify post-licensure cases of opportunistic histoplasmosis in pts treated with INF and ETAStudy Design:Database analysis; AERSOverall N:10 cases (from FDA passive surveillance database for monitoring postlicensure AEs)Study Duration: variedInclusion Criteria:Any report of histoplasmosis in a patient receiving ETA or INF had been received by AERS by July 2001Exclusion Criteria:NRInterventions, dose:D1: ETAD2: INFD3: OverallETA: variedINF: variedN:D1: 9D2: 1D3: 10Mean age, yrs:D1: 11-78 (range)D3: median: 43.5Sex, % female:D1: 4/9 (44.4%)D2: 0/1 (0% )D3: 40Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRConcomitant immunosuppressive:D1: 100D2: 100Cases of histoplasmosis reported to the AERS by July 20019 cases among pts receiving INF1 case among pts receiving ETAThrough August 2001, number of pts treatedWith INF: ~150,000With ETA: ~96,500Histoplasmosis case rates per 100,000 pts receiving drugINF: ~6/100,000ETA: ~1/100,000Deaths due to histoplasmosisINF: 1/10ETA 0/1Summary: More cases of histoplasmosis were reported to AERS by July 2001 among pts receiving INF than those receiving ETA. When accounting for actual number of pts taking each of drug, histoplasmosis case rate was ~6 times higher among pts receiving INF than among those receiving ETANROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Lee et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>4710</RecNum><DisplayText><style face="superscript">114</style></DisplayText><record><rec-number>4710</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">4710</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Lee, Y. H.</author><author>Woo, J. H.</author><author>Rho, Y. H.</author><author>Choi, S. J.</author><author>Ji, J. D.</author><author>Song, G. G.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine, Korea University Medical Center, 126-1 Ka, Anam-Dong, Seongbuk-Ku, Seoul 136-705, South Korea</auth-address><titles><title>Meta-analysis of the combination of TNF inhibitors plus MTX compared to MTX monotherapy, and the adjusted indirect comparison of TNF inhibitors in patients suffering from active rheumatoid arthritis</title><secondary-title>Rheumatology international</secondary-title></titles><periodical><full-title>Rheumatology International</full-title><abbr-1>Rheumatol. Int.</abbr-1><abbr-2>Rheumatol Int</abbr-2></periodical><pages>553-559</pages><volume>28</volume><number>6</number><keywords><keyword>Adjusted indirect comparison</keyword><keyword>Meta-analysis</keyword><keyword>Rheumatoid arthritis</keyword><keyword>TNF inhibitors</keyword></keywords><dates><year>2008</year></dates><urls><related-urls><url> 1, 3 / poor</custom4></record></Cite></EndNote>114Country and setting:NRFunding:NRAims of Review:To examine whether combination therapy with the TNF blockersand MTX is effective compared to MTX mono-therapy and if ADA, ETN, and INF have the same effect in patients suffering from active RAQuality Rating:fairStudy design:Systematic Review and Meta-analysisNumber of Patients:1, 040Studies Included:N?=?3Characteristics of Included Studies:A study was included in the analysis if: (1) it was published before February 2006; (2) it was original data; (3) it was a double blind, RCT that completed 50-55 weeks of trials and (4) it compared TNF inhibitors plus MTX withMTX alone in patients with aCharacteristics of Included PopulationsPatients with active RA despite treatment with DMARDsCharacteristics of Interventions:1 ETN trial: 25 mg twice weekly1 INF trial: 3 mg/kg intravenously every 8 wks1 ADA trial: 40 mg subcutaneously every 2 wksStudy Results:Meta-analysis results:TNF blockers + MTX vs. MTX monotherapyACR20: RR, 1.89 (95% CI, 0.89- 4.00)ACR50: RR, 2.61 (95% CI, 1.20- 5.66)ACR70: RR, 3.43 (95% CI, 1.74- 6.75)Adjusted indirect comparisons of the anti-TNF inhibitors:ETN vs. INFACR20: RR, 0.45 (95% CI, 0.27-0.73); P?=?0.001ACR50: RR, 0.59 (95% CI, 0.27-1.29); P?=?0.19ACR70: RR, 0.44 (95% 0.10-2.03); P?=?0.29ETN vs. ADAACR20: RR, 0.46 (95% 0.34-0.61); P < 0.0001ACR50: RR, 0.37 (95% 0.22-0.60); P < 0.0001ACR70: RR, 0.44 (95% 0.21-0.93); P?=?0.03INF vs. ADAACR20: RR, 1.03 (95% 0.59-1.78); P?=?0.92ACR50: RR, 0.62 (95% 0.25-1.49); P?=?0.28ACR70: RR, 0.99 (95% 0.19-5.13); P?=?0.99Adverse Events:Meta-analysis results:TNF blockers + MTX vs. MTX monotherapyWithdrawals due to lack of efficacy: RR, 0.38 (95% CO 0.22-0.64)Withdrawals due to adverse events: RR, 1.05 (95% CI, 0.52-2.09)Adjusted indirect comparisons of the anti-TNF inhibitors:ETN vs. INFWithdrawals due to lack of efficacy: RR, 0.52 (95% 0.19-1.42); P?=?0.20Withdrawals due to adverse events: RR, (95% 1.01 0.30-3.42); P?=?0.98ETN vs. ADAWithdrawals due to lack of efficacy: RR, 1.12 (95% 0.32-3.94); P?=?0.86Withdrawals due to adverse events: RR, 0.38 (95% 0.17-0.86); P?=?0.02INF vs. ADAWithdrawals due to lack of efficacy: RR, 2.16 (95% 0.77-6.07); P?=?0.14Withdrawals due to adverse events: RR, 0.37 (95% 0.11-1.36); P?=?0.14Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableLi et al., 2008, AIM TrialPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE.DATA 115,116Country and settingmultinational, multicenterSource of fundingNRResearch objectiveExamine relationship between external help home use and clinical/ patient-reported outcomes and whether ABA + MTX tx reduces need for external home helpStudy designControlled TrialsOverall N0Duration of study12 mosQuality rating Fair Inclusion CriteriaNR, see #3475Exclusion CriteriaNR, see #3475Interventions, DoseD1: MTX: dosage and frequency NR, see #3475PlaceboD2: MTX: dosage and frequency NR, see #3475Abatacept patients 60 kg or less: 500 mgPatients 60-100 kg: 750 mgPatients greater than 100 kg: 1000 mgDosing schedule: 30 minute IV infusion given at baseline, days 15 and 30, and monthly thereafterNumber in groupD1: 219D2: 433Overall: 590Mean age (years)D1: NR, see #3475D2: NROverall: 51.0Sex, % femaleOverall: 80Race, % whiteOverall: 87Race, % blackOverall: 2.4Ethnicity, LatinoNRMean disease duration, years (SD)NR Overall: 8.7 yrs (7.3)Patients with early RA, three years or less, %NR Treatment resistant, %NRTJC, mean (SD)Overall: 31.8 (13.3)SJC, mean (SD) Overall: 21.8 (8.8)Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NR Overall: 6.8 (0.9)Required treatment for latent TBNROther population characteristics, n (%)EHH use:D1: 75 (38)D2: 157 (40)Mean number of days of EHH:D1: 16D2: 15Overall: 15.6 (11.3)ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name) FOR PLACEBO GROUP: EHH use at 12 mos (among those who reported no EHH use at baseline): 21 (17%)No EHH use at 12 mos: 42.5%Needing full help at 12 mos: 12.3%. FOR ABA group: 22 (9%), 53.2% 9.0% Mean improvements from baseline in EHH at 12 mos were greater in ABA Gthan placebo G (AUC 361.8 (P?=?0.001). After 12 mos, proportions of patients who were shifted to lesser help categories were similar between 2 groups, with fewer patients requiring full help of?>?2 weeks of help.OverallOverall attrition/withdrawal, n:D1: 43D2: 19Withdrawals due to adverse events, n:D1: 4D2: 18Withdrawals due to lack of efficacy, n:D1: 40D2: 13Adherent/compliant, n:D1: 3D2: 1Overall adverse events reported, n:NRSerious adverse eventsNR MalignanciesNR Respiratory eventsNR Other infectionsNRGINR OtherNR Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableLi et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUy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ADDIN EN.CITE.DATA 117Country and settingUnited States; Medicaid patientsSource of fundingAbbott LabsResearch objectiveTo examine adherence, discontinuation, and switching of RA biologics over a 1-year period after initiation of the biologic treatment in Medicaid patients with RAStudy designObservationalOverall N2638Duration of study12 mosInclusion CriteriaTreatment resistantContinuous eligibility under fee-for-service Medicaid in the 12-month pre-index and 12-month post-index datesAt least 1 inpatient or 2 outpatient diagnoses of RA across Medicaid or Medicare claims in the 12-month pre-index dateExclusion CriteriaPrevious use of any RA biologic in the 12-month pre-index dateComparisons (dosage and frequency)D1: ETN: 25 mg twice a weekD2: ANK: 100 mg dailyD3: INF: NRNumber in groupD1: 1359D2: 267D3: 1012Mean age (years)D1: 54.9D2: 55.9D3: 63.3Sex, % femaleD1: 88.4D2: 91.8D3: 87.6Race, % whiteD1: 45.8D2: 47.9D3: 49.6Race, % blackD1: 12.6D2: 14.6D3: 13.0Ethnicity, LatinoD1: 18.3D2: 20.2D3: 13.9Mean disease duration, yearsNRTJC, meanNRSJC, mean NRCorticosteroid use, %D1: 76.5D2: 77.9D3: 71.2DMARD use, %: D1: 83.4D2: 82.0D3: 85.5MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): Mean PDC over 12 mosD1: (ref group): 0.57 D2: 0.36 (P<0.05)D3: 0.64 (P<0.05)Discontinuation with continuous gap of 120 days or more D1: 34.5%D2: 70.0% (P<0.05)D3: 33.6%Continuous gap of 90 days or moreD1: 40.7%D2: 76.0% (p<0.05) D3: 40.OverallAdherent/compliant?(n): D1: 435 (32%)D2: 28 (10.5%)D3: 435 (43%)P<0.05 for ANK compared to the other armsAdherence defined as PDC of 0.80 or greater.Serious adverse events:NRMalignancies:NRRespiratory events:NROther infections:NRGI:NROther:NRQuality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Listing et al., 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc3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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc3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 EN.CITE.DATA 118Country, Setting:Germany, population-basedFunding:Joint grant from Essex, Wyeth, Amgen, and AbbottResearch Objective:Incidence rates of serious and non-serious infections in pts with RA who start txt with a biologic agent, and to compare these rates with those in pts with RA who receive conventional txtStudy Design:Prospective cohort studyOverall N:1529Study Duration: Up to 12 mosInclusion Criteria:Age: 18 to 75Diagnosed according to ACR criteria new txt with ETA, INF, or AKAControls: pts started on DMARD therapy after failure of > 1 other DMARD, or with additional DMARD added to existing DMARDExclusion Criteria:NRInterventions, dose:D1: ETAD2: INFD3: AKAD4: DMARDS (control)N:D1: 512D2: 346D3: 70D4: 601Mean age, yrs:D1: 53.7D2: 53.6D3: 54.3D4: 56.5Sex, % female:D1: 78.1D2: 70.8D3: 77.1D4: 82.7Race, % white:NRMean disease duration, yrs:D1: 9D2: 8D3: 13D4: 6TJC, mean:D1: 13.3D2: 12.7D3: 12.6D4: 10SJC, mean:D1: 10.5D2: 10.8D3: 10.2D4: 7.7DMARD use, %:D1: 51.6D2: 89.6D3: 71.4D4: 0Glucocorticoids use, %:D1: 87.4D2: 85.2D3: 87D4: 77.2MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 6.1D2: 6.0D3: 6.1D4: 5.4MTX use:D1: 33D2: 64.5D3: 61.4D4: 20.1See AEsOverall: D1: 22.6 per 100 PYD2: 28.3 per 100 PY D3: 17.5 per 100 PY (95% CI,8.8-31.2)D4: 6.8 per 100 PYSAEs:D1: 6.4 per 100 PYD2: 6.2 per 100 PYD3: 3.2 per 100 PY (95% CI,0.4-11.5)D4: 2.3 per 100 PYInfections:D1: 15D2: 21D4: 6Serious Infections:D1: 6.4 per 100 PYD2: 6.2 per 100 PYDrug 3D4: 2.3 per 100 PYURTI:D1: 7.0D2: 11.4D3: 1.8Overall Attrition Rate, %:11.1ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Listing et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1952</RecNum><DisplayText><style face="superscript">119</style></DisplayText><record><rec-number>1952</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1952</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Listing, J.</author><author>Strangfeld, A.</author><author>Rau, R.</author><author>Kekow, J.</author><author>Gromnica-Ihle, E.</author><author>Klopsch, T.</author><author>Demary, W.</author><author>Burmester, G. R.</author><author>Zink, A.</author></authors></contributors><auth-address>German Rheumatism Research Centre, Berlin, Germany. Listing@drfz.de</auth-address><titles><title>Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low--results from RABBIT, the German biologics register</title><secondary-title>Arthritis Res Ther</secondary-title></titles><pages>R66</pages><volume>8</volume><number>3</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Arthritis, Rheumatoid/ epidemiology/ therapy</keyword><keyword>Biological Products/ therapeutic use</keyword><keyword>Cohort Studies</keyword><keyword>Comparative Study</keyword><keyword>Germany/epidemiology</keyword><keyword>Humans</keyword><keyword>Middle Aged</keyword><keyword>Registries</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Time Factors</keyword><keyword>Treatment Failure</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2006</year></dates><accession-num>16600016</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HO</custom3><custom4>1,2</custom4><custom6>RA</custom6><custom7>PT 10-2 (LL 8-23)</custom7></record></Cite></EndNote>119Country, Setting:GermanyRegistry DataFunding:Pharmas: Essex, Wyeth, A mgen, AbbottResearch Objective:To investigate frequency of remission and improved functional status in pts with 2 or more DMARD failures who have received new txt with biologicsStudy Design:Prospective cohort studyOverall N:1,083Study Duration: 1 yrInclusion Criteria:Age: 18 to 75Diagnosed with RA according to ACR criteriaFailed at least 2 prior treatments with DMARDsExclusion Criteria:Only 1 DMARD failureNo failure of MTXRec'd new txt ≥ 1 days before study entryDAS < 3.2 at baselineInterventions, dose:D1: Biologics (ADA, ANA, ETN, INF) (dose NR)D2: DMARDs as a class (dose NR)N:D1: 818D2: 265Mean age, yrs:D1: 53.7D2: 57.4Sex, % female:D1: 76.6D2: 83.8Race, % white:NRMean disease duration, yrs:D1: 10D2: 9TJC, mean:D1: 12.9D2: 10.5SJC, mean:D1: 10.5D2: 8.2DMARD use, %:100Corticosteroid use, %NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 6.1D2: 5.5# previous DMARDs:D1: 4.0D2: 2.8Biologics had double chance of remission compared to conventional DMARD therapies, via multivariate regression (OR: 1.95; 95% CI, 1.20-3.19)Severely disabled pts (≤ 50% of full function) in D1 (biologics) significantly more likely to achieve physical independence (≥ 67% of full function) than D2 (DMARDs/controls) (OR 3.88, 95% CI, 1.7-8.8)Functional remission (≥ 83% of full function) more often achieved in D1 (biologics)than in D2 (DMARDs/controls) (OR 2.18 95% CI, 1.04-4.6)At 12 monthsDAS28 remission, %: D1: 24.9D2: 12.4 (P < 0.004)ARA remission, %:D1: 16.1 D2: 8.3 (P < 0.036)Pts in remission by DAS Criteria, %: D1: 16.3D2: 15.3Pts in ARA Remission, %: D1: 13.2D2: 10.2Approximately half of pts in remission at 6 mos relapsed until 12 mos, %: D1: 55D2: 58Patients with moderate disease acitvity (DAS28, 3.2-5.1) at start of treatment, had high remission rates in biologics group: DAS 30.6ARA 16.9%Sustained remission at 6 and 12 months achieved in <10 % of patientsNROverall Attrition Rate, %:14%ITT Analysis:NoQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableListing et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE.DATA 120Country and settingGermanySource of fundingUnconditional, joint grants from Essex and Wyeth since 2001, from Essex, Wyeth, and Amgen since January 2003, and from Essex, Wyeth, Amgen, and Abbott since September 2003Research objectiveDetermine hazard risk of developing or worsening heart failure in RA pts treated with tumor necrosis factor inhibitors.Study designCross Sectional Cohort StudyOverall N4,248Duration of study5 yearsQuality rating GoodInclusion CriteriaTreated with ADA, ETN, IFX, or conventional DMARDExclusion CriteriaTreated with ANKInterventions, DoseD1: ETN: dose NRIFX: dose NRADA: dose NRD2: Conventional DMARDs: dose NRNumber in groupD1: 2,757D2: 1,491Mean age (years)D1: 53.7D2: 56.1 P = 0.00001Sex, % femaleD1: 78.1D2: 78.9Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: median duration 9 yearsD2: median duration 6 yearsP = 0.00001Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) D1: mean 9.3D2: mean 6.8P = 0.00001Corticosteroid use, %D1: 83.9D2: 76.1D 3P = 0.00001DMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)D1: mean 5.8D2: mean 5.1D 3P = 0.00001Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Comorbidiities: Heart failure 75 (2.7%); Coronary heart disease 149 (5.4%); cardiovascular disease total 1,026 (37.3%); Diabetes 226 (8.2%); Chronic lung disease 201 (7.3%); Rhuematoid factor positive 2,219 (80.5%). D2: Comorbidiities: Heart failure 23 (1.5%), P = ?0.014; Coronary heart disease 105 (7.0%), P = ?0.033; cardiovascular disease total 569 (38.2%), P = ?0.566; Diabetes 128 (8.6%), P = ?0.673; Chronic lung disease 95 (6.4%), P = ?0.256; Rhuematoid factor positive 1,069 (71.7%), P = ?0.00001.ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallAt followup, 101 pts (2.4%) had died, 14 due to heart failure. Four hundred twelve patients (9.7%) dropped out, and 168 (4.0%) had not attended last 2 or 3 followup visits. annual loss-to-followup rate (with loss-to-followup defined as dropping out or failure to attend last 2 or 3 visits) was 5.1%. annual dropout rate was 3.9% on average, and total dropout rate at 48 months was 15.5% (Kaplan-Meier estimate). Patients who dropped out did not differ significantly from those who completed study with regard to age, sex, treatment with TNFα inhibitors, or cardiovascular disease status, but they did have slightly more active disease at start of treatment (mean ± SD DAS28 score 5.7 ± 1.3 versus 5.5 ± 1.3).Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherAdjusted hazard ratios (HR) for developing heart failure de novo: Anti-TNF vs. conventional DMARDs (multivariate analysis final model): adjusted HR:?1.66, 95% CI:?0.67, 4.10; P = ?0.28Adjusted HR for heart failure: Anti-TNF vs. conventional DMARDs (multivariate analysis final model): adjusted HR:?1.49, 95% CI 0.70, 3.18; P = ?0.31Adjusted HR for heart failure in 98 patients with prevalent heart failure Anti-TNF vs. conventionals 1.18 95% CI 0.30-4.733.90 P = ?0.81. Patients with heart failure prior to study entry compared to patients without CVD at study entry had an adjusted HR of 23.88 (95% CI 8.04, 70.90) P = ?0.0001. In a multivariate analysis adjusted HR was 15.99 (95% Ci 5.40, 47.36), P = ?0.0001. And in a simplified model to offset efficacy of anti-TNF treatment, adjusted HR was 18.06 (95% Ci 6.10, 53.49) P = ?0.0001. When incident heart failure cases were compared to matched controls, controls had a significantly lower mean DAS28 score at follow up compared to cases (4.4 vs. 5.1, P = ?0.03). Adverse events were not systematically reported; there were 101 deaths, 14 of which were result of heart failure. Twenty five patients experienced heart failure for first time during study period. A worsening of severity of prevalent heart failure was observed in 12 of 98 patients.Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Maini et al. 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc5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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjc5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==
ADDIN EN.CITE.DATA 18Country, Setting: Multinational MulticenterFunding: CentocorResearch Objective: Efficacy and safety of repeated administration of infliximab plus MTX over a 2-yr period in pts with RAStudy Design:RCT plus extensionOverall N: 428 (259 in extension)Study Duration: 54 wks plus additional yr of follow-up Inclusion Criteria:Age 18-75Active RA despite MTXExclusion Criteria:NRInterventions, dose:D1: INFD2: PlaceboMean age, yrs:Overall: 54Sex, % female:Overall: 78Race, % white:NRMean disease duration, yrs:D1: TJC, mean:Overall: 31SJC, mean:Overall: 20DMARD use, %: NRCorticosteroid use, %: NR MTX na?ve, %:NRDMARD Txt resistant, %:NR Patients with Early RA (≤ 3 yrs):NRThe incidence of serious adverse events remained constant over timeSerious adverse events were reported by similar proportions of pts who received MTX only (33%) and infliximab plus MTX (29%)Number of observed cancer cases vs. number expected Placebo 0 vs. 1.02 INF 5 vs. 5.15Overall Attrition Rate, %:At 52 wks 27% At 2 yrs 17% of those that continued into extensionITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMaini et al., 2006,PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMx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ADDIN EN.CITE.DATA 121 CHARISMACountry and settingRheumatology Centers, EuropeSource of fundingChugai Pharmaceuticals (a member ofRoche Group)Research objectiveEstablish safety and efficacy of repeat infusions of tocilizumab alone and in combination with MTXStudy designControlled TrialsOverall N359Duration of study16 wks (20 wks for Safety)Quality rating Fair Inclusion CriteriaTreatment resistantPatients must have shown an inadequate response to MTX or a disease flare while receiving MTX (at a dosage of 10-25 mg weekly) during a minimum of 6 mos of therapy. Inadequate response was defined as presence of active disease, as described above, despite MTX therapyDagnosis of RA according to ACR revised criteriaDisease duration of at least 6 mosActive disease (defined as ≥ 6 tender joints and 6 swollen joints, based on a 28-joint count)ESR of ≥ 28 mm/hour, and/or a CRP level ≥ 1.0 mg/dl. If patients required concomitant treatment with nonsteroidal antiinflammatory drugs and/or oral steroids, dose must have been stable for at least 4 weeks prior to study entry and during course ofstudy (for steroids, ≥ 10 mg PNL or equivalent).Exclusion CriteriaLeukopenia and/or thrombocytopenia, any hepatic dysfunction as shown by aspartate transaminase and alanine transaminase levels > 1.5-fold upper limit of normal or significant renal impairment (serum creatinine level > 1.5-fold upper limit of normal)Patients who received DMARDs (excluding MTX) within 4 weeks prior tostart ofstudyPatients who received anti-TNF agents within 12 weeks or LEF within 6 mos of infusion of study medication.Interventions, doseD1: Tocilizumab: 2 mg/kg every 4 weeksPlacebo MTX placebo: once/weekD2: Tocilizumab: 4 mg/kg every 4 weeksPlacebo MTX placebo: once/weekD3: Tocilizumab: 8 mg/kg every 4 wksPlacebo MTX placebo: once/weekD4: MTX: once/weekTocilizumab: 2 mg/kg every 4 weeksD5: MTX: once/weekTocilizumab: 4 mg/kg every 4 wksD6: Tocilizumab: 8 mg/kg every 4 wks + MTX once/weekD7: MTX: once/wk + placebo infusions every 4 wksNumber in groupD1: 53D2: 54D3: 52D4: 52D5: 49 D6: 50 D7: 49Overall: 359Mean age, yearsD1: 52.2D2: 49.3D3: 50.1D4: 49.2D5: 50.2 D6: 50.1 D7: 50.9 Overall: 50.3Sex, % femaleD1: 83D2: 76D3: 73D4: 87D5: 76 D6: 78 D7: 78Overall: 79Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, mosD1: 9.19D2: 9.79D3: 9.21D4: 9.33D5: 7.82 D6: 10.62 D7: 11.24Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100D3: 100D4: 100D5: 100 D6: 100 D7: 100Overall: 100TJC, meanD1: 15D2: 15D3: 15D4: 15D5: 13D6: 15 D7: 16Overall: 15SJC, mean D1: 11D2: 11D3: 12D4: 11D5: 11 D6: 11D7: 12 Overall: 11Corticosteroid use, %NRDMARD use, %D1: 100D2: 100D3: 100D4: 100D5: 100 D6: 100D7: 100Overall: 100MTX na?ve, %D1: 0D2: 0D3: 0D4: 0D5: 0 D6: 0 D7: 0Overall: 0Baseline DAS scoreD1: 6.48D2: 6.55D3: 6.43D4: 6.58D5: 6.34 D6: 6.47D7: 6.75Required treatment for latent TBNRACR ACR 20:D1: 31D2: 61D3: 63D4: 64D5: 63 D6: 74D7: 414 mg/kg and 8 mg/kg of tocilizumab vs. placebo plus MTX (P < 0.05)2 mg/kg of tocilizumab vs. placebo plus MTX (NS)Tocilizumab (2 mg/kg, 4 mg/kg, and 8 mg/kg) plus MTX vs.ACR 50:D1: 6D2: 28D3: 41D4: 32D5: 37 D6: 53 D7: 298 mg/kg of tocilizumab plus MTX vs. placebo plus MTX (P < 0.05). All others NS.ACR 70:D1: 2D2: 6D3: 16D4: 14D5: 12D6: 37D7: 168 mg/kg of tocilizumab plus MTX vs. placebo plus MTX (P < 0.05). All others NS.HAQ NRDAS D1: NR (in figure only)D2: NR (in figure only)D3: NR (in figure only)D4: NR (in figure only)D5: NR (in figure only) D6: -3.57 D7: NR (in figure only)monotherapy with 2 mg/kg of tocilizumab vs. placebo + MTX (P = NS)SF-36 NRRadiographic measures NRQuality of life scales NRMean difference/absolute difference (CI/SD/P Value): Rate of Remission According toDAS: 8 mg/kg of tocilizumab + MTX: 34%, Monotherapy with 8 mg/kg tocilizumab: 17%, Placebo + MTX: 8%, other arms and overall: NRMean Reduction in SJCs Monotherapy with 8 mg/kg of tocilizumab vs. placebo + MTX (P < 0.01), 8 mg/kg of tocilizumab + MTX vs. placebo + MTX (P?<?0.001), other drugs: NRMean Reduction inTJC: 8 mg/kg of tocilizumab plus MTX vs. placebo + MTX (P < 0.009), other drugs: NRCRP/ESR: NR for all drugs (in figure only)Attrition/withdrawalOverall, n:D1: 12D2: 11D3: 8D4: 6D5: 7D6: 7D7: 9Withdrawals due to adverse events, n:AE and Possible Drug-Related Toxicity:D1: 4D2: 6D3: 5D4: 3D5: 6 D6: 6 D7: 4Withdrawals due to lack of efficacy, n:D1: 6D2: 5D3: 2D4: 1D5: 1 D6: 1 D7: 6Adherent/compliant, n:D1: 41D2: 43D3: 44D4: 46D5: 42 D6: 43D7: 40Overall adverse events reported, n:Patients with 1 or more treatment-emergent AE:D1: 30D2: 27D3: 31Treatment-related AE: D1: 13D2: 14D3: 15Serious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NROther infectionsLimb abscessD1: 1All else NROsteomyelitis:D1: 1All else NRRespiratory infection:D1: 2All else NRInfective arthritis:D3: 1All else NRSepsisD3: 1All else NRAnaphylactic shock/reaction and hypersensitivity:D1: 3D2: 1D3: 0D4: 0D5: 0D6: 0D7: 0Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMalysheva et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE.DATA 122Country and settingGermanySource of fundingNot reportedResearch objectiveAssess incidence and severity of DMARD-induced AEs in pts taking/not taking glucocorticoids and whether glucocorticoids can prolong survival time of DMARD in pts receiving combination therapyStudy designRetrospective Cohort StudyOverall N154Duration of study2-62 monthsQuality rating FairInclusion CriteriaACR criteria for RAExclusion CriteriaPrevious history of active gastrointestinal problemsSerious complicating diseases such as arterial hypertension, psychiatric, or mental problemsDiabetes mellitusPatients with steroid pulse therapyInterventions, DoseD1: MTX: 7.5-20 mg/weekD2: MTX: 7.5-20 mg/weekOther: 7.5 mg/day or less glucocorticoidsD3: Hydroxychlorquine: 200-400 mg/dayD4: Hydroxychlorquine: 200-400 mg/dayOther: 7.5 mg/day or less glucocorticoidsD5: SSZ: 1-2 g/dayOther: with and without 7.5mg/day glucocorticoidNumber in groupD1: 74D2: 51D3: 69D4: 22D5: 28 // 19Overall: 154Mean age (years)NR Overall: 47.2Sex, % femaleNR Overall: 84Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)Overall: 17.8 yrs (3.9)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NR ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)Time in months until withdrawal of DMARD due to AD (mean + SD)- MTX: 21.8 (2.9)MTX + GC: 43.3 (2.7)SSZ: 10.4 (2.3)SSZ + GC: 22.5 (1.9)Time in months until occurence of AE: MTX: 3.0 (0.6)MTX + GC: 18.8 (1.3)HCQ: 34.5 (4.6)HCQ + GC: 54.4 (5.1)Time to cessation due to loss of efficacy: SSZ: 16.8 (1.2); SSZ + GC: 31.3 (2.9)OverallUse of GC significantly increased time until withdrawal of DMARD therapy due to AE (18.6 ± 2.3 vs. 12.5 ± 1.4 mo; P = ?0.05). However, timing of withdrawal of DMARD due to loss of efficacy was not different between RA patients taking GC and GC-na?ve patients, probably due to higher level of disease activity in RA patients with GC comedication. Stratifying for DMARD revealed that comedication with GC significantly increased duration of therapy with SSZ from 10.4 ± 2.3 to 22.5 ± 1.9 months (SSZ + GC; P = ?0.05) and for MTX from 21.8 ± 2.9 to 43.3 ± 2.7 months (MTX + GC; P = ?0.01). GC comedication significantly increased time until occurrence of AE for MTX (3.0 ± 0.6 vs. 18.8 ± 1.3 mo; P = ?0.05), HCQ (34.5 ± 4.6 vs. 54.4 ± 5.1 mo; P = ?0.05). Patients taking SSZ, time to cessation due to loss of efficacy increased significantly under GC comedication, from 16.8 ± 1.2 to 31.3 ± 2.9 months (P = ?0.05).Overall adverse events reported, n:D1: 9D2: 17D3: 19D4: 12D5: 4//5Overall: 64Serious adverse eventsNRMalignanciesOther cancer (specify), n: NR Overall: unspecified: 5Respiratory eventsNROther infectionsNRGINROtherGrade 1 AE (mild, not requiring treatment), n:D1: 3D2: 7D3: 1D4: 1D5: 2//1Grade 2 AE (moderate, resolved with treatment), n:D1: 4D2: 5D3: 17D4: 9D5: 1//2Grade 3 AE (severe, result in inability to carry on normal activities and requiring professional medical attention), n:D1: 2D2: 4D3: 4D4: 1D5: 4//1Overall: nephrectomy: 1Osteoporosis (DMARD monotherapy versus DMARD + GC): 16 vs. 22Diabetes mellitus: 4 vs. 10Malignancy: 6 vs. 3Thyroid dysfunction: 5 vs. 5Infections: 2 vs. 3Gastrointestinal Complications: 11 vs. 6Mucocutaneous complications: 5 vs. 7Intolerance: 6 vs. 5Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableMarchesoni et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE.DATA 123 LOHREN registryCountry and settingItaly, LombarySource of fundingNRResearch objectiveTo evaluate survival of INF, ETN, and ADA in a RA patient cohortStudy designObservationalOverall N1064Duration of study36 mosInclusion CriteriaPatients with RA according to ACR with at least one dose of anti-TNF treatmentExclusion CriteriaActive infectionHistory of malignancyPre-malignant conditionClass 3/4 congestive heart failureDemyelinating disordersComparisons (dosage and frequency)D1: INF: dose NRD2: ADA: dose NRD3: ETN: dose NRNumber in groupD1: 519D2: 303D3: 242Overall: 1064Mean age (years)D1: 55.72D2: 56.07D3: 55.81Overall: 55.84Sex, % femaleD1: 81.5D2: 85.1D3: 84.3Overall: 83.2Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 9.28 (7)D2: 9.56 (7.9)D3: 9.63 (7.11)Overall: 9.44 (7.29)TJC, meanNRSJC, mean NRCorticosteroid use, %D1: 80.7D2: 76.9D3: 84.3Overall: 84.2DMARD use, %: NRMTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreD1: 6.01 (0.94)D2: 5.68 (0.96)D3: 5.93 (1.02)Overall: 5.90 (0.97)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): ACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallOverall attrition/withdrawal (n): D1: 226D2: 111D3: 68Overall: 405Withdrawals due to adverse events?(n): D1: 106D2: 60D3: 28Overall: 194Withdrawals due to lack of efficacy?(n): D1: 104D2: 45D3: 31Overall: 180Long-term survival rate at 36 mos (INF vs. ADA vs. ETN): 49.1% vs. 53.6% vs. 62.5% RR of discontinuation due to all causes compared to ETN ADA: 1.45 (1.05 to 2.00, P=0.024)INF: 1.50 (1.10 to 2.05; P=0.011)RR of discontinuation due to loss of efficaSerious adverse events:Death (n): D1: 3D2: 5D3: 5Overall: 13Malignancies:Malignancies: D1: 6D2: 8D3: 4Overall: 18Respiratory events:NROther infections:Serious infections (specify) (n): D1: 42D2: 20D3: 11Overall: 73GI:NROther:Infusion/injection site reactions?(n): D1: 48D2: 8D3: 2Overall: 58 Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMcDonald, J.R. et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2414</RecNum><DisplayText><style face="superscript">124</style></DisplayText><record><rec-number>2414</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2414</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>McDonald, J. R.</author><author>Zeringue, A. L.</author><author>Caplan, L.</author><author>Ranganathan, P.</author><author>Xian, H.</author><author>Burroughs, T. E.</author><author>Fraser, V. J.</author><author>Cunningham, F.</author><author>Eisen, S. A.</author></authors></contributors><auth-address>St. Louis Veterans Affairs Medical Center, St. Louis, Missouri 63106, USA. Jay.McDonald1@</auth-address><titles><title>Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis</title><secondary-title>Clin Infect Dis</secondary-title></titles><periodical><full-title>Clinical Infectious Diseases</full-title><abbr-1>Clin. Infect. Dis.</abbr-1><abbr-2>Clin Infect Dis</abbr-2></periodical><pages>1364-71</pages><volume>48</volume><number>10</number><keywords><keyword>Age Factors</keyword><keyword>Aged</keyword><keyword>Arthritis, Rheumatoid/ complications</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Herpes Zoster/ epidemiology</keyword><keyword>Humans</keyword><keyword>Immunosuppressive Agents/adverse effects/therapeutic use</keyword><keyword>Incidence</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Retrospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Veterans</keyword></keywords><dates><year>2009</year><pub-dates><date>May 15</date></pub-dates></dates><isbn>1537-6591 (Electronic)</isbn><accession-num>19368499</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>124Country and settingUnited States; Veterans hospitalSource of fundingUS Department of Veterans Affairs, Veterans Health Administration, and National Institutes of HealthResearch objectiveExamine HZ risk, risk factors, treatments and outcomes with a focus on contribution of different classes of immunosuppressive medications to risk of HZStudy designRetrospective Cohort StudyOverall N20,357Duration of studyOctober 1998 to June 2005Quality rating FairInclusion CriteriaAd Veterans who had an ICD-9-CM code diagnosis of RA during study period and who, after a ≥ 4 month history of receiving medications from VA during study period, subsequently received a first prescription for a DMARD.Exclusion CriteriaDiagnosis of HZ at any time prior to receiving a DMARD or who did not have ≥ 2 separate outpatient or inpatient clinical encounters during study period.Interventions, DoseD1: SSZ: dose NRHCQ: dose NRAuronofin, injectable gold, penicillamine: NRD2: MTX: dose NRLEF: dose NRANK: dose NRAzathioprine, cyclophosphamid, cyclosporine: dose NRD3: ETN: dose NRIFX: dose NRADA: dose NRNumber in groupD1: 9673D2: 12888D3: 3661Overall: 20357Mean age (years)D1: 61.9, SD 12.8D2: 63.7, SD 12.0D3: 59.3, SD 11.6Sex, % femaleD1: 10.9D2: 8.7D3: 9.0Race, % whiteD1: 65.2D2: 67.5D3: 70.1Race, % blackD1: 13.6D2: 10.1D3: 8.9Ethnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: PRED: 34.5D2: PRED: 62.7D3: PRED: 55.0DMARD use, %D1: HCQ: 72.8; SSZ: 39.7; MTX: 0; LEF: 0; CSA: 0; CYC: 0; ANK: 0; ETN: 0; IFX: 0; ADA: 0D2: HCQ: 28.7; SSZ: 17.3; MTX: 83.7; LEF: 19.8; CSA: 2.7; CYC: 2.7; ANK: 0.5; ETN: 0; IFX: 0; ADA: 0D3: HCQ: 22.0; SSZ: 17.0; MTX: 51.5; LEF: 19.8; CSA: 1.3; CYC: 0.6; ANK: 1.5; ETN: 68.9; IFX: 22.0; ADA: 32.4MTX na?ve, %D1: 100D2: NRD3: NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Episodes of HZ (%): 2.2; Episodes of HZ per 1000 patient-years: 8.00D2: Episodes of HZ (%): 3.2; Episodes of HZ per 1000 patient-years: 11.18D3: Episodes of HZ (%): 2.6; Episodes of HZ per 1000 patient-years: 10.60Overall: Episodes of HZ per 1000 patient-years: D2 vs. D1 P = ?0.001; D3 vs. D1 P = ?0.001ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)Antiviral Treatment: Oral: D1 65.4, D2 65.5, D3 69.8, D2 vs. D1: P > 0.5, D3 vs. D1: P > 0.1; Intravenous: D1 1.0, D2 6.8, D3 3.1, D2 vs. D1: P = ?0.001, D3 vs. D1: P > 0.1; HZ complication: HZ Meningitis: D1 0.5, D2 0.5, D3 0, D2 vs. D1: P > 0.1, D3 vs. D1: P > 0.5; Other HZ nervous system complication: D1 20.7, D2 18.6, D3 17.7, D2 vs. D1: P > 0.5, D3 vs. D1: P > 0.5; Ophthalmic HZ: D1 7.2, D2 6.8, D3 5.2, D2 vs. D1: P > 0.5, D3 vs. D1: P > 0.1; Other HZ complication: D1 6.3, D2 6.8, D3 4.2, D2 vs. D1: P > 0.5, D3 vs. D1: P > 0.1; Hospitalization for HZ: D1 2.9, D2 6.1, D3 4.2, D2 vs. D1: P > 0.5, D3 vs. D1: P > 0.1;OverallNAOverall adverse events reported, n: NASerious adverse eventsNAMalignanciesNARespiratory eventsNAOther infectionsNAGINAOtherNAStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMease et al., 2008, DANCER trialPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE.DATA 46,125Country and settingUnited StatesmulticenterSource of fundingGenentech, Inc.Research objectiveEvaluate effect of RIT treatment on HRQOLStudy designControlled TrialsOverall N367Duration of study24 weeksQuality rating Fair Inclusion CriteriaTreatment resistant failed to respond to treatment with at least 1 but not more than 5 DMARD or biologic agentsSJC of 8 or moreTJC of 8 or moreCRP serum levels of 1.5 mg/dl or more or erythrocyte sedimentation rate of 28 mm/h or more despite ongoing MTX treatment of more than 12 weeksSeePEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE.DATA 46 for more detailsExclusion CriteriaSeePEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM1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=
ADDIN EN.CITE.DATA 46Interventions, DoseD1: MTX: 10-25 mg/weekPlaceboIV infusion on days 1 and 15D2: MTX: 10-25 mg/weekRIT: 500 mg IV infusion on days 1 and 15D3: MTX: 10-25 mg/weekRIT: 1000 mg IV infusion on days 1 and 15 Number in groupD1: 122D2: 123D3: 122Overall: 367Mean age (years)D1: 50.8D2: 51.4D3: 52.1Overall: 51.0Sex, % femaleD1: 79.5D2: 83.7D3: 76.2Overall: 80.0Race, % whiteD1: 77.9D2: 76.4D3: 82.8Overall: 79.0Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 9.6 yrs (7.7)D2: 11.2 (8.5)D3: 11.3 (8.5)Overall: 11.0 (NR)Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100D3: 100Overall: 100TJC, mean (SD)D1: 35D2: 33D3: 32SJC, mean (SD) D1: 21D2: 22D3: 22Corticosteroid use, %NRDMARD use, %D1: 27D2: 39D3: 31.1Overall: 32.4MTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS score, mean (SD)D1: 6.85 (0.74)D2: 6.84 (0.79)D3: 6.67 (0.82)Overall: 6.79 (NR)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)NAACR NRHAQ, D1: NR, in figure onlyD2: NR, in figure onlyD3: NR, in figureOverall: Significant differences were seen for 1000mg Gps. placebo after 8 weeks (P?=?0.05) and were maintained over 24 weeks. For 500mg group, significant differences vs. placebo were seen by 12 weeks (P NR). At week 24, 34.4% vs. 62.6% vs. 67.2% achieved prespecified MCID of 0.22 points (P?=?0.05 for both groups vs. placebo)DAS NRSF-36 (SD)Mean changes from baseline to 24 weeks: physical component summary (PCS):D1: 2.36 (0.78)D2: 7.08 (0.77)D3: 7.40 (0.78)Mental component summary:D1: 1.88 (1.00)D2: 4.49 (1.22)D3: 3.03 (1.11)Physical function:D1: 2.18 (0.83)D2: 6.44 (0.90)D3: 5.79 (0.88)Role-physical: D1: 0.64 (1.25)D2: 7.19 (0.98)D3: 5.51 (1.22)Bodily pain:D1: 4.16 (0.89)D2: 8.96 (0.97)D3: 8.51 (0.85)General health:D1: 2.15 (0.89)D2: 3.94 (0.80)D3: 4.52 (0.87)Vitality:D1: 2.69 (0.95)D2: 6.71 (0.96)D3: 6.02 (0.98)Social function:D1: 2.68 (1.11)D2: 6.97 (1.22)D3: 5.93 (0.98)Role-emotional:D1: 0.95 (1.39)D2: 5.54 (1.57)D3: 3.27 (1.57)Mental health:D1: 2.34 (1.03)D2: 3.96 (1.04)D3: 2.83 (1.01)Overall: For 500 mg vs. placebo and 1000 mg vs. placebo, respectively: PCS, P?=?0.001 for both comparisonsMCS, P?=?0.087, P?=?0.167Proportion of patients achieving an MCID (minimal clinically important difference) of 5 points on PCS: 23.8% vs. 55.3% vs. 52.5%, significantly higher (P?=?0.05) for both groups vs. placeboMCS scores were not significantly different (data NR)Radiographic measures NRQuality of life scales D1: FACIT-Fatigue, change from baseline: 3.91D2: 7.63 D3: 8.20 P = 0.009 placebo vs. 500 mg groupP?=?0.001 for 1000 mg vs. placeboOverallOverall attrition/withdrawal, n:D1: see belowD2: see belowD3: see belowOverall: 33-53Withdrawals due to adverse events, n: NRWithdrawals due to lack of efficacy, n: NRAdherent/compliant, n: NRMissing outcome data (%?without baseline and endpoint scores): For SF-36, 26% vs. 9% vs. 4%For HAQ, 27% (placebo) vs. 2% (combined RIT groups)For FACIT-Fatigue, 27% vs. 1%.Overall adverse events reported, n: NRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMichaud, K. et al.; 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2332</RecNum><DisplayText><style face="superscript">126</style></DisplayText><record><rec-number>2332</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2332</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Michaud, K.</author><author>Wolfe, F.</author></authors></contributors><auth-address>National Data Bank for Rheumatic Diseases, University of Kansas School of Medicine, Wichita, Kansas 67214, USA.</auth-address><titles><title>The association of rheumatoid arthritis and its treatment with sinus disease</title><secondary-title>J Rheumatol</secondary-title><short-title>The association of rheumatoid arthritis and its treatment with sinus disease</short-title></titles><periodical><full-title>Journal of Rheumatology</full-title><abbr-1>J. Rheumatol.</abbr-1><abbr-2>J Rheumatol</abbr-2></periodical><pages>2412-5</pages><volume>33</volume><number>12</number><keywords><keyword>Antirheumatic Agents/adverse effects</keyword><keyword>Arthritis, Rheumatoid/drug therapy/ epidemiology/physiopathology</keyword><keyword>Chronic Disease</keyword><keyword>Comorbidity</keyword><keyword>Female</keyword><keyword>Fibromyalgia/epidemiology/physiopathology</keyword><keyword>Health Status</keyword><keyword>Hospitalization</keyword><keyword>Humans</keyword><keyword>Longitudinal Studies</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Osteoarthritis/epidemiology/physiopathology</keyword><keyword>Prevalence</keyword><keyword>Questionnaires</keyword><keyword>Severity of Illness Index</keyword><keyword>Sinusitis/ epidemiology/etiology/physiopathology</keyword><keyword>United States/epidemiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0315-162X (Print)</isbn><accession-num>17143978</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>126Country and settingUnited States; doctors officesSource of fundingNational Database for Rheumatic DiseasesResearch objectiveDetermine sinus disease rates are increased in pts with RA and whether tx alters risk of sinus disease.Study designCohort StudyOverall N7,243 patients with RADuration of studylongitudinal (length not specified); questionnaire completion December 2003Quality rating FairInclusion CriteriaNDB participants who completed a questionnaire in December 2003 that included questions related to sinus problems.Exclusion CriteriaNRInterventions, DoseD1: PRED: NRMTX: NRLEF: NRSSZ: NRHydroxychlorquine: NRETN: NRIFX: NRADA: NRNumber in groupD1: 7243Mean age (years)D1: 62.2, SD 12.4Sex, % femaleD1: 78.5Race, % whiteD1: 92.7Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: PRED: 34.1DMARD use, %D1: HCQ: 19.0; MTX: 57.5; IFX: 31.9; LEF: 14.6; ETN: 14.5; ADA: 3.0; SSZ: 5.8MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR NRHAQ, D1: 1.03, CI 1.07 - 1.25, SD 0.72, P?=?0.05DAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)Association of sinus problems: OR (95% CI); Fatigue (0-10 scale, unnamed): 4.2, CI 1.05 - 1.09, SD 2.87, P?=?0.05; Pain (0-10 scale, unnamed): 3.5, CI 1.03 - 1.07, SD 2.68, P?=?0.05OverallNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherOR (95% CI) for visits to physician for sinus problems:MTX: 1.06 (0.93, 1.20) 0.371PRED: 0.98 (0.86, 1.11) 0.776IFX: 1.00 (0.88, 1.15) 0.973HCQ: 1.08 (0.93, 1.25) 0.313LEF: 0.84 (0.70, 0.99) 0.041ETN: 1.21 (1.02, 1.42) 0.025ADA: 1.09 (0.79, 1.51) 0.600SSZ: 0.68 (0.51, 0.90) 0.007Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableMigliore et al. 2009PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWdsaW9yZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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 EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWdsaW9yZTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+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 EN.CITE.DATA 127Country and settingItaly, MulticenterSource of fundingNRResearch objectiveTo determine the safety profiles for ETN, INF and ADA in patients of 65+ yrs, undergoing anti-TNF treatment for an active inflammatory disease such as rheumatoid arthritisStudy designObservationalOverall N138Duration of studyDuration of treatment with anti-TNF: 39 mos (SD 14)Inclusion CriteriaAge 65 or more with RAExclusion CriteriaTreated for other conditions, or with other anti-TNFs or different dosesComparisons (dosage and frequency)D1: ETN:50 mg/weekD2: ADA: 40 mg every 2 wksD3: INF: 3-5 mg/kg every 6 to 8 wksNumber in groupD1: 54D2: 39D3: 45Overall: 138Mean age (years)Ages 65-70D1: 41 (76%)D2: 17(44%)D3: 13(29%)Overall: 71 (51%)Ages 71-75D1: 4 (7%)D2: 5 (38%)D3: 23 (51%)Overall: 42 (30%)Age 76 or olderD1: 9 (17%)D2: 7 (18%)D3: 9 (20%)Overall: 25 (18%)Overall, across all groups: 71.2Sex, % femaleD1: NRD2: NRD3: NROverall: 79%Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsNROverall: 11.6 (7.8)TJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %: 100MTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreNRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallNRSerious adverse events:NRMalignancies:NRRespiratory events:Tuberculosis?(n): NRPneumonia (n): NRUpper respiratory infection?(n): NROther infections:Urinary tract infection?(n): NROther infections (specify) (n): Infections (total, not stratified by age)TotalD1: 10 D2: 10 D3: 10MildD1: 2 D2: 8 D3: 5ModerateD1: 2 D2: 0 D3: 1SevereD1: 0 D2: 0 D3: 1Infections, age 65-70TotalD1: 4D2: 4 D3: 3 MildD1: 4D2: 4 D3: 3 ModerateD1: 0D2: 0 D3: 0 SevereD1: 0D2: 0 D3: 0 Infections, age 71-75TotalD1: 1 D2: 1 MildD1: 0 D2: 0 ModerateD1: 0 D2: 0 SevereD1: 0 D2: 0 Infections, age 76+TotalD1: 5D2: 3D3: 3MildD1: 4D2: 3D3: 3ModerateD1: 1D2: 3D3: 1SevereD1: 0,D2: 0D3: 1GI:NROther:Allergic reactions (total, not stratified by age)TotalD1: 4D2: 2D3: 5 MildD1: 2D2: 1D3: 2 ModerateD1: 2D2: 1D3: 2 SevereD1: 0D2: 0D3: 1 Allergic reactions, age 65-70TotalD1: 2D2: 4D3: 1MildD1: 1D2: 2D3: 1ModerateD1: 1D2: 2D3: 0SevereD1: 0 D2: 0, D3: 0Allergic reactions, age 71-75TotalD1: 1D2: 1 D3: NR MildD1: 1D2: 0D3: NRModerateD1: 0D2: 1 D3: 0SevereD1: 0D2: 0D3: 1 Allergic reactions, age 76+TotalD1: 1D2: 0 D3: 0MildD1: 0D2: 0 D3: 0ModerateD1: 1D2: 0 D3: 0SevereD1: 0D2: 0 D3: 0Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableMiyasaka, 2008,CHANGE study ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2747</RecNum><DisplayText><style face="superscript">128</style></DisplayText><record><rec-number>2747</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2747</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Miyasaka, N.</author></authors></contributors><auth-address>Department of Medicine and Rheumatology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan miya.rheu@tmd.ac.jp</auth-address><titles><title>Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study</title><secondary-title>Mod Rheumatol</secondary-title></titles><pages>252-62</pages><volume>18</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antibodies, Monoclonal/ administration & dosage/adverse effects/pharmacokinetics</keyword><keyword>Antirheumatic Agents/ administration & dosage/adverse effects/pharmacokinetics</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Japan</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Placebos</keyword><keyword>Rheumatoid Factor/blood</keyword><keyword>Treatment Outcome</keyword><keyword>Tumor Necrosis Factor-alpha/antagonists & inhibitors</keyword></keywords><dates><year>2008</year></dates><isbn>1439-7595 (Print)</isbn><accession-num>18330677</accession-num><urls></urls><custom1>I</custom1><custom2>I MTC</custom2><custom3>CT</custom3><custom4>KQ 1, 2, 3 / fair</custom4></record></Cite></EndNote>128Country and settingJapan, MulticenterSource of fundingAbbott Japan Co., Ltd. and Eisai Co.Research objectiveCompare effects of 3 doses of ADA vs. placebo in Japanese RA ptsStudy designControlled TrialsOverall N352Duration of study24 weeksQuality rating Fair Inclusion Criteria20 years or olderMet ACR criteria for active RAFailed 1 DMARD10 or more swollen joints and 12 or more tender joints (excluding distal interphalangeal joints) and a CRP concentration 2 mg/dL or moreExclusion CriteriaAcute inflammatory joint diseases other than RAActive Listeria or TB, lymphoma, or leukemia, or any malignancy except for successfully treated nonmetastatic basal-cell carcinoma ofskin, HIV, hepatitis B virus surface antigen, or anti-hepatitis C virus antibodyOngoing or active infectionAdvanced or poorly controlled diabetesCNS demyelinating disordersPregnancyInterventions, doseD1: ADA: 20 mg every other weekD2: ADA: 40 mg every other weekD3: ADA: 80 mg every other weekD4: PlaceboNumber in groupD1: 87D2: 91D3: 87D4: 87Overall: 352Mean age, years (SD)D1: 54.8D2: 56.9D3: 54.3D4: 53.4Overall: 54.9Sex, % femaleD1: 79.3D2: 79.1D3: 82.8D4: 77Overall: 79.5Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, mean years (SD)D1: 10 (7.7) D2: 9.9 (7.9) D3: 9.5 (8.3) D4: 8.4 (8.2) Overall: 9.5Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanD1: 24.6D2: 24.4D3: 24.9D4: 23.7Overall: 24.4Swollen Joint Count, mean D1: 19.2D2: 19.1D3: 20.8D4: 19.3Overall: 19.6Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS scoreNRRequired treatment for latent TBNRMean Subject's global assessment of disease activity VAS (mm): D1: 73.1 D2: 71.2 D3: 75.7 D4: 64.6 Overall: NRMean Subject's assessment of pain VAS (mm): D1: 69 D2: 68.1 D3: 70.4 D4: 62.7 Overall: NRMean HAQ DI score: D1: 1.57D2: 1.64D3: 1.77D4: 1.39Overall: NRMean Duration of morning stiffness (min): D1: 216.7 D2: 193.3 D3: 202.3 D4: 195.5 Overall: NRAny morning stiffness (%): D1: 81.4D2: 76.9D3: 88.4D4: 86.2Overall: NRACR mean difference/ absolute difference (%)ACR 20:Week 12, n:D1: 39 (44.8)D2: 39 (49.2)D3: 47 (54)D4: 11 (12.6)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P < 0.05, P < 0.05, P < 0.05 Week 24, n:D1: 25 (28.7)D2: 40 (44)D3: 44 (50.6)D4: 12 (13.8)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P < 0.05, P < 0.0001, P < 0.0001ACR 50:Week 12, nD1: 16 (18.4)D2: 19 (20.9)D3: 23 (26.4)D4: 3 (3.3)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P = ?0.05, P = ?0.05, P = ?0.05Week 24, n:D1: 14 (16.1)D2: 22 (24.2)D3: 28(32.2)D4: 5 (5.7)Overall :Placebo vs. ADA 20, ADA 40, ADA 80: P = ?NS, P = ?0.05, P = ?0.05ACR 70:Week 12, n:D1: 6 (6.9)D2: 15 (16.5)D3: 10 (11.5)D4: 1 (1.1)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P = ?NS, P = ?0.05, P = ?0.05Week 24, n (%)D1: 9 (10.3)D2: 11 (12.1)D3: 13 (14.9)D4: 1 (1.1Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P = ?0.05, P = ?0.05, P = ?0.05HAQ, 12 week, mean difference (SD):D1: 0.2 (0.5)D2: -0.3 (0.6)D3: -0.4 (0.5)D4: -0.1 (0.6)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P = ?0.05, P = ?NS, P = ?0.0524 week, mean difference (SD):D1: -0.2 (0.5)D2: -0.2 (0.6)D3: -0.4 (0.6)D4: -0.1 (0.6)Overall: Placebo vs. ADA 20, ADA 40, ADA 80: P = ?NS, P = ?NS, P = ?NSDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers TJC week 12:D1: -8.3D2: -11.2D3: -10.1D4: -0.6Overall: Placebo vs. 20, 40, 80: P = ?0.05, P = ?0.05, P = ?0.05TJC week 24: D1: -6.6D2: -10.7D3: -10.0D4: -0.5Overall: Placebo vs. 20, 40, 80: P = ?NS, P = ?0.05, P = ?0.05SJC week 12: D1: -6.8D2: -8.1D3: -8.7D4: -1.6Overall: Placebo vs. 20, 40, 80: P = ?0.05, P = ?0.05, P = ?0.05SJC week 24: D1: -5.9D2: -8.2D3: -8.7D4: -1.8Overall: Placebo vs. 20, 40, 80: P = ?0.05, P = ?0.05, P = ?0.05Patient's global assessment of disease activity week 12: D1: -19.9D2: -19.1D3: -25.9D4: -2.1Overall: Patient's global assessment of disease activity week 12 vs. 20, 40, 80: P = ?0.05, P = ?0.05, P = ?0.05Patient's global assessment of disease activity week 24: D1: -16.6D2: -19.9D3: -25.8D4: -2.6Overall: Placebo vs. 20, 40, 80: P = ?NS, P = ?0.05, P = ?0.05Patient's assessment of pain 12 week: D1: -17.3D2: -17.2D3: -20.5D4: -2.3Overall: Placebo vs. 20, 40, 80: P = ?NS, P = ?0.05, P = ?0.05Patient's assessment of pain 24 week: D1: -12.8D2: -17.4D3: -20.3D4: -3.5Overall: Placebo vs. 20, 40, 80: P = ?NS, P = ?0.05, P = ?NSAttrition/withdrawalOverall, n:D1: 7D2: 16D3: 4D4: 7Overall: 34Withdrawals due to adverse events, n:D1: 5D2: 12D3: 3D4: 4Overall: 24Other reasons for discontinuation included withdrawal of consent, protocol violations, and administrative reasons. 107 patients received rescue medication after 8+ weeks of double-blind study treatment (45, 26, 17, and 19 in placebo and ADA 20, 40, and 80 mg groups, respectively)3 discontinuations that occurred during rescue period occurred in one patient each from placebo, ADA 40 mg, and ADA 80 mg groups.Overall adverse events reported, n:D1: 80D2: 90D3: 81D4: 71Overall: 322Serious adverse eventsDeath, n:D1: 0D2: 1D3: 1D4: 0MalignanciesNR Respiratory eventsTuberculosis, n: 2,747Upper respiratory infection, n: Overall: ADA 4.5% vs. Placebo 2.3%Other infectionsNRGINROtherFractures, n: Infusion/injection site reactions, n:D1: 27D2: 28D3: 29D4: 2Serious AE, n:D1: 10D2: 17D3: 8D4: 8Overall: 43Severe AE, n:D1: 3D2: 4D3: 5D4: 5Overall: 17Infectious AE, n:D1: 30D2: 41D3: 37D4: 32Overall: 140Serious Infectious AE, n:D1: 4D2: 6D3: 3D4: 1Overall: 14Immunologic reaction: ADA 20: 4ADA 40: 2ADA 80: 0Placebo: 0Overall: 6Malignancies: ADA 20: 0ADA 40: 0ADA 80: 0Placebo: 2Overall: 2Opportunistic infection including TB: ADA 20: 0ADA 40: 0ADA 80: 0Placebo: 0Overall: 0Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Mohan et al, 2001PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg2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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg2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=
ADDIN EN.CITE.DATA 129Country, Setting:US, NA Medwatch, AERSFunding:NRResearch Objective:To review occurrence of neurologic events suggestive of demylenation during anti TNF alpha therapy for inflammatory arthritidesStudy Design:Database analysis; AERSOverall N:20 casesStudy Duration: 4 mosInclusion Criteria:Pts with refractory RA who developed confusion and difficulty walkingOther meds allowed: MTX, prednisone, amlodipine, estradiol, zolpidem, dexamethasone, a;prasolam, hydrocodone, naproxen sodium, acyclovir, metronidazole, ceftriaxone, ranitidine, atenolol, fluoxetine, piroxicamExclusion Criteria:NAInterventions, dose:NRN:NRMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRNRIn addition to 1 case reported of suspected demyelination, 17 cases of demyelination after ETA and 2 cases after INF txt were detected in MedWatchNROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Mohan et al., 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjg2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ADDIN EN.CITE.DATA 130Country, Setting:Multinational, population-basedFunding:NRResearch Objective:To summarize all cases of TB following use of ETA reported to AERS from November 1998 through March 2002Study Design:Database analysis; AERSOverall N:25 cases Study Duration: NAInclusion Criteria:All pts receiving ETA and reported to have active TBExclusion Criteria:NRInterventions, dose:D1: ETAN:D1: 25 casesMean age at diagnosis, yrs:D1: 59Sex, % female:D1: 72Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRAs of April 2002, a total of 25 reports of TB associated with ETA therapy reported to FDA from 11/1998 through 3/200217 cases (68%) were reported from US, 7 (28%) from Europe, and 1 (4%) from India46% of 24 pts with a reported clinical manifestation had pulmonary TB 2 deaths occurred among 25 pts17 US cases of TB have been reported to the FDAAccording to ETA manufacturer, 113,238 pts treated with ETA in US between 11/1998 and 5/2002, with estimated 172,212 PY of exposure; thus reporting rate of TB among pts in US receiving ETA is ~10 cases / 100,000 PY of exposureNROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Mottonen, 1999 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1620</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>1620</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1620</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mottonen, T</author><author>Hannonen, P</author><author>Leirisalo-Repo, M</author><author>Nissila, M</author><author>Kautiainen, H</author><author>Korpela, M</author><author>Laasonen, L</author><author>Julkunen, H</author><author>Luukkainen, R</author><author>Vuori, K</author><author>Paimela, L</author><author>Blafield, H</author><author>Hakala, M</author><author>Ilva, K</author><author>Yli-Kerttula, U</author><author>Puolakka, K</author><author>Jarvinen, P</author><author>Hakola, M</author><author>Piirainen, H</author><author>Ahonen, J</author><author>Palvimaki, I</author><author>Forsberg, S</author><author>Koota, K</author><author>Friman, C</author></authors></contributors><titles><title>Comparison of Combination Therapy With Single-Drug Therapy in Early Rheumatoid Arthritis: a Randomised Trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>1568-73</pages><volume>353</volume><number>9164</number><keywords><keyword>CN-00413880</keyword><keyword>RCT</keyword></keywords><dates><year>1999</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2</custom4><custom7>Goes w/ #1536</custom7></record></Cite></EndNote>131; Korpela, 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1491</RecNum><DisplayText><style face="superscript">132</style></DisplayText><record><rec-number>1491</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1491</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Korpela, Markku</author><author>Laasonen, Leena</author><author>Hannonen, Pekka</author><author>Kautiainen, Hannu</author><author>Leirisalo-Repo, Marjatta</author><author>Hakala, Markku</author><author>Paimela, Leena</author><author>Blafield, Harri</author><author>Puolakka, Kari</author><author>Mottonen, Timo</author></authors></contributors><titles><title>Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the Fin-Raco Study</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2072-81</pages><volume>50</volume><number>7</number><keywords><keyword>CN-00482280</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>PT 10-2 (LL 8-16) GOES W #1536 & #1487, #1620</custom7></record></Cite></EndNote>132; Puolakka, 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1487</RecNum><DisplayText><style face="superscript">133</style></DisplayText><record><rec-number>1487</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1487</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puolakka, K</author><author>Kautiainen, H</author><author>Mottonen, T</author><author>Hannonen, P</author><author>Korpela, M</author><author>Julkunen, H</author><author>Luukkainen, R</author><author>Vuori, K</author><author>Paimela, L</author><author>Blafield, H</author><author>Hakala, M</author><author>Leirisalo Repo, M</author></authors></contributors><titles><title>Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>55-62</pages><volume>50</volume><number>1</number><keywords><keyword>CN-00460092</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>2</custom4><custom7>PT 10-2 (LL 8-16) GOES W/ #1536 & #1491, #1620</custom7></record></Cite></EndNote>133FIN-RACo StudyCountry, Setting:Finland, NR Funding:Finnish Society for Rheumatology and Medical Research Foundation of Turku University Central HospitalResearch Objective:Efficacy and tolerability of combo of DMARDs vs. a single DMARD Study Design:RCTOverall N:199 randomized, 187 completed 2 yrs, 160 at 5 yrsStudy Duration: 24 mos (5 yr followup)Inclusion Criteria:Age: 18 to 65Diagnosed with RA according to ACR criteria: active disease, 1987 criteriaDuration of condition: < 2 yrsExclusion Criteria:Previous use of DMARDsUnderwent glucocorticoid glucocorticoid therapy within the previous2 weeksserious comorbiditysuspected inabilty tocomply with the protocolhypersensitivity to any study medicationhistory of cancerpregnant women women of childbearing age who were not using reliable methods of contraceptionInterventions, dose:D1: Combo: MTX + HCQ + SSZ + PNLD2: Single DMARD (SSZ could be changed to MTX or 3rd DMARD) + PNLPNL: 5 to 10 mg/dayMTX: 7.5 to 10 mg/wkSSZ: 2 g/dayCombo: 500 mg/2xdSingle: 1000 mg 2xd w/ or w/out PNLHCQ: 300 mg/dCombo: if patient reaches remission in first year, patietn could be tapered and PNL could be discontinued at 9 and 18 monthsN:D1: 97D2: 98Mean age, yrs:D1: 45D2: 46Sex, % female:D1: 58D2: 66Race, % white:NRMean disease duration, yrs:D1: 7.3 mosD2: 8.6 mosTJC, mean:D1: 18D2: 20SJC, mean:D1: 14D2: 14DMARD use, %:NRCorticosteroid use, %NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRLarsen Score:D1: 0D2: 2At 2 yearsEroded joints, number: D1: 2D2: 3 (P = 0.006) btw groupsProgression of radiological joint damage lower in combination versus monotherapy Larsen Erosion Score improvement: D1: 2D2: 10 (P = 0.002)Median increase in Larsen Score: D1: 1.5D2: 2.0 (P < 0.001) Clinical remission, %:D1: 37.9D2: 18.4 (P = 0.011)ACR50, %:D1: 71D2: 58 (P = 0.058)Median work disability per pt-observation yr, days: D1: 12.4 D2: 32.2 (P = 0.008)At 5 yearsEroded joints, number: D1: 3D2: 6 Larsen Erosion Score: D1: 11D2: 24 (P = 0.001)Median increase in Larsen Score: D1: 1.5D2: 2.0 (P < 0.001) 5 year RemiissionD1: 28D2: 22(P = NS)Increase in Larsenscore D1: lower than (P = 0.004)Overall: D1: 70D2: 71SAEs:D1: 3D2: 5Cardiovascular Events:D1: 1 MID2: 2 MIsMalignancies:1 prostate cancer; 1 multiple myelomaURTI:1 pneumoniaOverall Attrition Rate, %:195 started txt (97/98) 178 completed 2 yrs (87/91); 160 at 5 yrs (78/82)ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Mottonen, 1999 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1620</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>1620</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1620</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mottonen, T</author><author>Hannonen, P</author><author>Leirisalo-Repo, M</author><author>Nissila, M</author><author>Kautiainen, H</author><author>Korpela, M</author><author>Laasonen, L</author><author>Julkunen, H</author><author>Luukkainen, R</author><author>Vuori, K</author><author>Paimela, L</author><author>Blafield, H</author><author>Hakala, M</author><author>Ilva, K</author><author>Yli-Kerttula, U</author><author>Puolakka, K</author><author>Jarvinen, P</author><author>Hakola, M</author><author>Piirainen, H</author><author>Ahonen, J</author><author>Palvimaki, I</author><author>Forsberg, S</author><author>Koota, K</author><author>Friman, C</author></authors></contributors><titles><title>Comparison of Combination Therapy With Single-Drug Therapy in Early Rheumatoid Arthritis: a Randomised Trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>1568-73</pages><volume>353</volume><number>9164</number><keywords><keyword>CN-00413880</keyword><keyword>RCT</keyword></keywords><dates><year>1999</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2</custom4><custom7>Goes w/ #1536</custom7></record></Cite></EndNote>131; Mottonen, 2002 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1536</RecNum><DisplayText><style face="superscript">134</style></DisplayText><record><rec-number>1536</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1536</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mottonen, Timo</author><author>Hannonen, Pekka</author><author>Korpela, Markku</author><author>Nissila, Martti</author><author>Kautiainen, Hannu</author><author>Ilonen, Jorma</author><author>Laasonen, Leena</author><author>Kaipiainen-Seppanen, Oili</author><author>Franzen, Per</author><author>Helve, Tapani</author><author>Koski, Juhani</author><author>Gripenberg-Gahmberg, Marianne</author><author>Myllykangas-Luosujarvi, Riitta</author><author>Leirisalo-Repo, Marjatta</author></authors></contributors><titles><title>Delay to Institution of Therapy and Induction of Remission Using Single-Drug or Combination-Disease-Modifying Antirheumatic Drug Therapy in Early Rheumatoid Arthritis</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>894-8</pages><volume>46</volume><number>4</number><keywords><keyword>CN-00379522</keyword></keywords><dates><year>2002</year></dates><urls></urls><custom1>I</custom1><custom2>B</custom2><custom3>HRCT</custom3><custom7>PT 10-2 (LL 8-16) GOES W/ #1487 & #1491, #1620
Main study is #1620</custom7></record></Cite></EndNote>134; Korpela, 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1491</RecNum><DisplayText><style face="superscript">132</style></DisplayText><record><rec-number>1491</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1491</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Korpela, Markku</author><author>Laasonen, Leena</author><author>Hannonen, Pekka</author><author>Kautiainen, Hannu</author><author>Leirisalo-Repo, Marjatta</author><author>Hakala, Markku</author><author>Paimela, Leena</author><author>Blafield, Harri</author><author>Puolakka, Kari</author><author>Mottonen, Timo</author></authors></contributors><titles><title>Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the Fin-Raco Study</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2072-81</pages><volume>50</volume><number>7</number><keywords><keyword>CN-00482280</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>PT 10-2 (LL 8-16) GOES W #1536 & #1487, #1620</custom7></record></Cite></EndNote>132; Puolakka, 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1487</RecNum><DisplayText><style face="superscript">133</style></DisplayText><record><rec-number>1487</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1487</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Puolakka, K</author><author>Kautiainen, H</author><author>Mottonen, T</author><author>Hannonen, P</author><author>Korpela, M</author><author>Julkunen, H</author><author>Luukkainen, R</author><author>Vuori, K</author><author>Paimela, L</author><author>Blafield, H</author><author>Hakala, M</author><author>Leirisalo Repo, M</author></authors></contributors><titles><title>Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>55-62</pages><volume>50</volume><number>1</number><keywords><keyword>CN-00460092</keyword></keywords><dates><year>2004</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>2</custom4><custom7>PT 10-2 (LL 8-16) GOES W/ #1536 & #1491, #1620</custom7></record></Cite></EndNote>133FIN-RACo StudyCountry, Setting:Finland, NR Funding:Finnish Society for Rheumatology and Medical Research Foundation of Turku University Central HospitalResearch Objective:Efficacy and tolerability of combo of DMARDs vs. a single DMARD Study Design:RCTOverall N:199 randomized, 187 completed 2 yrs, 160 at 5 yrsStudy Duration: 24 mos (5 yr followup)Inclusion Criteria:Age: 18 to 65Diagnosed with RA according to ACR criteria: active disease, 1987 criteriaDuration of condition: < 2 yrsExclusion Criteria:Previous use of DMARDsUnderwent glucocorticoid therapy within the previous2 weeksserious comorbiditysuspected inability tocomply with the protocolhypersensitivity to any study medicationhistory of cancerpregnant women women of childbearing age who were not using reliable methods of contraceptionInterventions, dose:D1: Combo: MTX + HCQ + SSZ + PNLD2: Single DMARD (SSZ could be changed to MTX or 3rd DMARD) + PNLPNL: 5 to 10 mg/dayMTX: 7.5 to 10 mg/wkSSZ: 2 g/dayCombo: 500 mg/2xdSingle: 1000 mg 2xd w/ or w/out PNLHCQ: 300 mg/dCombo: if patient reaches remission in first year, patietn could be tapered and PNL could be discontinued at 9 and 18 mosN:D1: 97D2: 98Mean age, yrs:D1: 45D2: 46Sex, % female:D1: 58D2: 66Race, % white:NRMean disease duration, yrs:D1: 7.3 mosD2: 8.6 mosTJC, mean:D1: 18D2: 20SJC, mean:D1: 14D2: 14DMARD use, %:NRCorticosteroid use, %NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRLarsen Score:D1: 0D2: 2At 2 yearsEroded joints, number: D1: 2D2: 3 (P = 0.006) btw groupsProgression of radiological joint damage lower in combination versus monotherapy Larsen Erosion Score improvement: D1: 2D2: 10 (P = 0.002)Median increase in Larsen Score: D1: 1.5D2: 2.0 (P < 0.001) Clinical remission, %:D1: 37.9D2: 18.4 (P = 0.011)ACR50, %:D1: 71D2: 58 (P = 0.058)Median work disability per pt-observation yr, days: D1: 12.4 D2: 32.2 (P = 0.008)At 5 yearsEroded joints, number: D1: 3D2: 6 Overall: D1: 70D2: 71SAEs:D1: 3D2: 5Cardiovascular Events:D1: 1 MID2: 2 MIsMalignancies:1 prostate cancer; 1 multiple myelomaURTI:1 pneumoniaOverall Attrition Rate, %:195 started txt (97/98) 178 completed 2 yrs (87/91); 160 at 5 yrs (78/82)ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableNadareishvili et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 135Country and settingUS, multicenterSource of fundingCentocor, Sanofi-Aventis, Bristol Myers Squibb, Abbott, Amgen, Wyeth-Australia, Merck, PfizerResearch objectiveTo determine risk of stroke in patients with RA and risk factors associated with strokeStudy designNested Case / Control, Prospective Cohort StudyOverall N269Duration of studyvaried (prospective cohort)Quality rating Fair: Possibility that databank has a higher proportion of moderate-serverly ill RA pts decreases generalizability. Use of covariates in statistical analyses decreases potential for bias. Recall bias avoided by a review of medical records of pts reporting strokes.Inclusion CriteriaRA, Ischemic strokeExclusion Criteriaintracerebral, subarachnoid, subdural, and epidural hemorrhages, as well as transient ischemic attacksInterventions, DoseD1: Other: Patients grouped by Case vs. Control; included txts relevant to this review: PRED, LEF, SSZ, HCQ, MTX, and anti-TNF (combined ETA, INF, and ADA) dosing not reportedNumber in groupD1: 41D2: 791Overall: 269Mean age (years)D1: at stoke: 69.8D2: 69.9Overall: mean time of databank follow-up: 4.0 yearsSex, % femaleD1: 73.2D2: 74.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR ACR 20: No measures of efficacy or QOL were reported for this article, go to AEsACR 50: NRACR 70: NRHAQ, NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherResults of multivariate analysis of association of RA therapy (within a 6mo window prior to event) and ischemic stroke in RA: PRED OR:?1.75, P = ?0.114 [95%CI 0.87-3.53]; MTX OR:?0.63 P = ?0.191 [CI: 0.32-1.26]; Anti-TNF OR: 0.79, P = ?0.584 [CI: 0.34-1.82]. A significant increased risk was found for Rofecoxib (not included in this review). An analysis assessing length of treatment exposure was associated with stroke; a univariate but not multivariate effect was seen for PRED OR: 1.19, P = ?0.039 [CI: 1.00-1.40]; no other drug effects seen. Further analysis suggested a possible dose effect for PRED. NOTE: A second set of analyses were conducted using only drug pts were on at baseline. I did not think this was as comprehensive as this analysis so I did not include it - SWLStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableNaranjo et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE.DATA 136Country and settingMultinational, multicenterSource of fundingAbbott LaboratoriesResearch objectiveAssess prevalence of CV morbidity in RA patients and its association with traditional risk factors, clinical features, and DMARD useStudy designCross – Sectional Cohort StudyOverall N4363Duration of studyvaried (prospective cohort)Quality rating FairInclusion CriteriaRA diagnosisExclusion CriteriaNRInterventions, DoseD1: MTXD2: GlucocorticoidsD3: AntimalarialsD4: SSZD5: GoldD6: LEFD7: TNF-alpha blockersDosing not reportedNumber in groupOverall: 4364Mean age (years)Overall: 57Sex, % femaleOverall: 78Race, % whiteOverall: 90Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)Overall: 11 yrs (9)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference NROverallNR Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherAll results adjusted for age, gender, disease activity/severity, rheumatoid arthritic characteristics (e.g. RF+), and traditional cardiovascular risk factors (e.g. hypertension). CV All/MI/Stroke: MTX 0.85(0.81-0.89)/0.82 (0.74-0.91)/0.89 (0.82-0.98), Glucocorticoids: 0.95 (0.92-0.98)/ 0.96(0.91-1.0)/0.98(0.93-1.03), SSZ 0.92 (0.87-0.98)/ 0.82 (0.69-0.98)/ 0.90 (0.79-1.03)LEF 0.59 (0.43-0.79)/0.52(0.26-1.06)/0.91 (0.65-1.28)TNF-alpha 0.64 (0.49-0.83)/0.42 (0.21-0.81)/ 0.64 (0.39-105)Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableNishimoto et al, 2009, SATORIPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE.DATA 137Country and setting25 sites in Japan, setting NRSource of fundingChugai PharmaceuticalResearch objectiveInvestigate efficacy and safety of tocilizumab monotherapy in pts with inadequate response to MTXStudy designControlled TrialsOverall N127Duration of study24 wksQuality rating Fair Inclusion CriteriaAges 20 to 75 years oldActive RA as define byACRRA > 6 mosMTX 8 mg/week for at least 8 weeks prior to enrollmentAt least 6 tender joints (of 49 evaluated)At least 6 swollen joints (of 46 evaluated)ESR of at least 30 mm/h or CRP of at least 10 mg/l at enrollmentInadequate response to MTX defined aspresence of active diseaseWhite blood cell counts at least 3.5 x 109/lLymphocyte counts at least 0.5 x 109/l Platelet count of at least lower limit of normal as defined by respective local laboratory usedSexually active premenopausal women were required to have a negative urine pregnancy test at entry to study and to use effective contraception during study period.Exclusion CriteriaTreatment with anti-TNF agents or LEF (within 12 weeks prior tofirst dose)Plasma exchange therapy or surgical treatments (within 4 weeks prior to first dose)DMARDs other than MTX or immuno-suppressants (within 2 weeks prior to first dose)Functional class IV using Steinbrocker's criteriaAspartate transaminase (AST), Alanine transaminase (ALT) and serum creatinine at least 1.5-fold upper limit of normal, were HBs antigen and/ or HCV antibody positive, had pulmonary fibrosis or active pulmonary diseaseHistory of serious adverse drug reaction to MTX, concomitant pleural effusion, ascites, varicella infectionExcessive users of alcohol on a regular basis. Patients were also excluded if they had significant cardiac, blood, respiratory system, neurologic, endocrine, renal, hepatic, or gastrointestinal disease, or had an active infection requiring medication within 4 weeks before first dose or medical history of a serious allergic reaction. Sexually active premenopausal women were required to have negative urine pregnancy test at entry to study and to use effective contraception during study period. Oral corticosteroids (PNL, less than or equal to 10 mg/day) were allowed ifdosage had not been changed within 2 weeks.Interventions, doseD1: MTX: 8 mg/wk (control)Placebo toculizumab placeboD2: Tocilizumab: 8 mg/kg every 4 wksPlacebo MTX placeboNumber in groupD1: 66D2: 61Overall: 127Mean age, years (SD)D1: 50.8 ± 12.2D2: 52.6 ± 10.6Sex, % femaleD1: 75.0D2: 90.2Overall: 81.1Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 8.7 yrs ± 7.1D2: 8.5 ± 8.4Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanD1: 14.2 ± 8.6D2: 13.8 ±7.5Swollen Joint Count, mean D1: 12.7 ± 7.5D2: 12.4 ± 5.9Corticosteroid use, %NR# failed DMARD use, (mean/range)D1: 3.6 (1-8)D2: 3.3 (1-8)MTX na?ve, %D1: 0D2: 0Overall: 0Baseline DAS28 scoreD1: 6.2 ± 0.9D2: 6.1 ± 0.9Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Functional class I/II/III/IV:? 7:50:7:0RA stage I/II/III/IV:? 3:18:17:26D2: Functional class I/II/III/IV:? 2:49:10:0RA stage I/II/III/IV:? 1:20:22:18ACR ACR 20 (% at week 24):D1: 25D2: 80.3P = 0.001ACR 50 (% at last observation):D1: 10.9 D2: 49.2ACR 70 (% at last observation):D1: 6.3D2: 29.5HAQ (%)Decrease of at least 0.22 units in HAQ at last OBS D1: 34D2: 67P = 0.001DAS28 at last OBS (%)GoodD1: 3.2D2: 65.5Good or ModerateD1: 39.7D2: 96.6P = 0.001SF-36 NRRadiographic measures NRQuality of life scales NROthers Remission at last OBS (defined as DAS28:?2.6): MTX arm:? 1.6TOC arm:? 43.1%P = ?0.001Attrition/withdrawalOverall, n (%):D1: 33 (50)D2: 7 (11)Overall: 40 (31.5)Withdrawals due to adverse events, n (%):D1: 3 (4.6)D2: 2 (3.28)Overall: 5 (3.94)Withdrawals due to lack of efficacy, n (%):D1: 20 (30.3)D2: 1 (1.64)Overall: 21 (16.6)Note: In control (MTX) group, 2 patients withdrew before treatment but after randomization, these are included in attrition countOverall adverse events reported, n (%):D1: 104 AE in 46/64 patients (71.9)D2: 211 AE in 56/61 patients (91.8)Overall: 315 AE in 102/125 patients (81.6)Serious adverse eventsNRHepatotoxicity/elevated liver enzymes, n:D1: 0D2: 0Overall: 0MalignanciesNRRespiratory eventsTuberculosis: NRPneumonia, n (%):D1: 1 (1.56)D2: 1 (1.64)Overall: 2 (1.6)Upper respiratory infection, n (%):D1: "upper respiratory tract Inflammation" 4 (6.3)D2: Inflammation 3 (4.9)Overall: 7 (5.6%)Other infectionsStomatitis, n (%):D1: 0D2: 7 (11.5)Overall: 7 (5.6)GINRDiarrhea (%)D1: 1 (1.6)D2: 4 (6.6)Overall: 5 (4)OtherFractures, n:D1: 2 (3.13%) (spinal compression fracture and femoral neck fracture)D2: NROverall: 2 (1.6%)Infusion/injection site reactions, n (%):D1: NRD2: 7 (8 events 7 patients) (11.5)Overall: 7 (5.6)Skin rash, n (%):D1: 2 (3.1)D2: 4 (6.6)Overall: 6 (4.8)Headache, n (%):D1: 2 (3.1)D2: 4 (6.6)Overall: 6 (4.8)Nasopharyngitis, n (%):D1: 7 (10.9)D2: 11 (18.0)Overall: 18 (14.4)Serious AE (pneumonia, spinal compression fracture, femoral neck fracture), n (%):D1: 3/64 (4.7)D2: 4/61 (6.6)Hyperlipidemia, n (%):D1: 1 (1.6)D2: 4 (6.6)Overall: 5 (4)Lab test abnormalities, n (%):D1: 15 (23)D2: 34 (56)Overall: 49 (39.2)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Nuki et al. 2002PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjky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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjky
MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQiPjEzODwvc3R5
bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjkyMzwvcmVjLW51bWJlcj48Zm9y
ZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9IjVmeHR3MmV0NnR2cmZ3ZTB6cHM1MnByZno5
YXg5dGFmeHBkNSI+OTIzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu
YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5O
dWtpLCBHLjwvYXV0aG9yPjxhdXRob3I+QnJlc25paGFuLCBCLjwvYXV0aG9yPjxhdXRob3I+QmVh
ciwgTS4gQi48L2F1dGhvcj48YXV0aG9yPk1jQ2FiZSwgRC48L2F1dGhvcj48L2F1dGhvcnM+PC9j
b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IG9mIEVkaW5idXJnaCwgRWRpbmJ1
cmdoLCBTY290bGFuZCwgVUsuIGcubnVraUBlZC5hYy51azwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+
PHRpdGxlPkxvbmctdGVybSBzYWZldHkgYW5kIG1haW50ZW5hbmNlIG9mIGNsaW5pY2FsIGltcHJv
dmVtZW50IGZvbGxvd2luZyB0cmVhdG1lbnQgd2l0aCBhbmFraW5yYSAocmVjb21iaW5hbnQgaHVt
YW4gaW50ZXJsZXVraW4tMSByZWNlcHRvciBhbnRhZ29uaXN0KSBpbiBwYXRpZW50cyB3aXRoIHJo
ZXVtYXRvaWQgYXJ0aHJpdGlzOiBleHRlbnNpb24gcGhhc2Ugb2YgYSByYW5kb21pemVkLCBkb3Vi
bGUtYmxpbmQsIHBsYWNlYm8tY29udHJvbGxlZCB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRs
ZT5BcnRocml0aXMgUmhldW08L3NlY29uZGFyeS10aXRsZT48c2hvcnQtdGl0bGU+TG9uZy10ZXJt
IHNhZmV0eSBhbmQgbWFpbnRlbmFuY2Ugb2YgY2xpbmljYWwgaW1wcm92ZW1lbnQgZm9sbG93aW5n
IHRyZWF0bWVudCB3aXRoIGFuYWtpbnJhIChyZWNvbWJpbmFudCBodW1hbiBpbnRlcmxldWtpbi0x
IHJlY2VwdG9yIGFudGFnb25pc3QpIGluIHBhdGllbnRzIHdpdGggcmhldW1hdG9pZCBhcnRocml0
aXM6IGV4dGVuc2lvbiBwaGFzZSBvZiBhIHJhbmRvbWl6ZWQsIGRvdWJsZS1ibGluZCwgcGxhY2Vi
by1jb250cm9sbGVkIHRyaWFsPC9zaG9ydC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs
bC10aXRsZT5BcnRocml0aXMgYW5kIFJoZXVtYXRpc208L2Z1bGwtdGl0bGU+PGFiYnItMT5BcnRo
cml0aXMgUmhldW0uPC9hYmJyLTE+PGFiYnItMj5BcnRocml0aXMgUmhldW08L2FiYnItMj48YWJi
ci0zPkFydGhyaXRpcyAmYW1wOyBSaGV1bWF0aXNtPC9hYmJyLTM+PC9wZXJpb2RpY2FsPjxwYWdl
cz4yODM4LTQ2PC9wYWdlcz48dm9sdW1lPjQ2PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxr
ZXl3b3Jkcz48a2V5d29yZD5BbnRpcmhldW1hdGljIEFnZW50cy8gdGhlcmFwZXV0aWMgdXNlPC9r
ZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gdGhlcmFweTwva2V5d29yZD48
a2V5d29yZD5Eb3VibGUtQmxpbmQgTWV0aG9kPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5
d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TG9uZy1UZXJtIENhcmU8L2tl
eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y
ZD48a2V5d29yZD5SZWNvbWJpbmFudCBQcm90ZWlucy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+
PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydCwgTm9uLVUuUy4gR292JmFwb3M7dDwva2V5d29yZD48
a2V5d29yZD5TYWZldHk8L2tleXdvcmQ+PGtleXdvcmQ+U2lhbG9nbHljb3Byb3RlaW5zLyB0aGVy
YXBldXRpYyB1c2U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48
cHViLWRhdGVzPjxkYXRlPk5vdjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxhY2Nlc3Npb24t
bnVtPjEyNDI4MjIzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMT5JPC9jdXN0
b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+PGN1c3RvbTM+TzwvY3VzdG9tMz48Y3VzdG9tND4zPC9j
dXN0b200PjxjdXN0b203PktEIDktMjcgKFBUKSBjb250aW51YXRpb24gcGhhc2UgYSAxNDUsIGdv
ZXMgd2l0aCA2MDk8L2N1c3RvbTc+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA 138Country, Setting: Multinational multicenterFunding: AmgenResearch Objective: Long-term efficacy of anakinra, in pts with RAStudy Design:RCT plus extensionOverall N: 472 (309 enrolled in 54 wk extension)Study Duration: 76 wksInclusion Criteria:ACR criteriaDisease duration of > 12 mos < 8.5 yrsExclusion Criteria:NR is this articleInterventions, dose:D1: AnakinraD2: PlaceboN:D1: 351D2: 121Mean age, yrs:D1: 53.4D2: 52.2Sex, % female:D1: 76.6D2: 70.2Race, % white:NRMean disease duration, yrs:D1: 4.1D2: 3.7TJC, mean:D1: 34.8D2: 32.8SJC, mean:D1: 26.3D2: 25.6DMARD use, %:D1: 73.5D2: 80.0Corticosteroid use, %D1: 43.6D2: 39.7MTX na?ve, %:NRDMARD Txt resistant, %:NRPatients with Early RA (≤ 3 yrs):NRSee AEsNumber of occurrences per subject-yr of exposure n for safety:D1: 427D2: 121ISRs:D1: 2.00D2: 0.82Frequency of injection site reactions (ISRs) was 0.82 per patient-yr of exposure in placebo group (first 24 wks) and 1.01, 2.43, and 3.73 for 30-mg, 75-mg, and 150-mg doses over 72 wksOverall Attrition Rate, %:At 24 wks 27% At 76 wks 32% of those that continued into extensionITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, year:O'Dell et al., 1996PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE.DATA 139Country, Setting:US, multicenter (Rheumatology clinics)Funding:Lederle, Sanofi, Winthrop, and Pharmacia provided study drugsResearch Objective:To determine whether DMARDs were effective as combination therapy for RA and whether combinations studied had better efficacy than MTX alone Study Design:RCTOverall N102Study Duration: 2 yrsInclusion Criteria:Age 19-70Diagnosed w/ ACR criteria > 6 mosPoor response to at least 1 DMARDAt least 3 of: ESR > 28 mm/hr, morning stiffness > 45 mins, > 8 tender joints, > 3 swollen joints; stable therapy w/ Css < 10 mg/day;NSAIDs allowed Exclusion Criteria:Pregnant or lactatingPrior combo treatment with any 2: gold, HCQ, penicil-lamine, SSZ, MTXImpaired renal or hepatic systemStage IV diseaseAllergy to study drugsPulmonary or CVDVisual difficulties Retinal diseaseMacular degenerationActive peptic ulcer diseaseInterventions:D1: MTX (7.5 to 17.5 mg/week)D2: SSZ (1 g/day) + HCQ (400 mg/day)D3: MTX + SSZ+HCQN D1: 36 D2: 35D3: 31Mean age, yrs:D1: 50D2: 49D3: 50Sex, % female:D1: 69D2: 74D3: 65Race, % white:NRMean disease duration, yrs:D1: 10 D2: 6 D3: 10TJC, mean:D1: 31 D2: 32 D3: 29 SJC, mean:D1: 31 D2: 31D3: 27DMARD use, %:All groups: 100Current Corticosteroid use, %)D1: 53%D2: 46%D3: 52%MTX naive, %:D1: 92 D2: 89D3: 87Treatment resistant, %: All 100Pts with Early RA (≤3 yrs):All groups: 0Baseline DAS, mean: NRDuration of morning stiffness (minutes):D1: 190 D2: 156 D3: 135 RF: D1: 89%D2: 85%D3: 84%Outcome improved by at least 50%, as determined by whether 3 following requirements had been fulfilled (modified Paulus composite criteria): morning stiffness of less than 30 minutes' duration, decreased by 50%; joint tenderness decreased by 50%; joint swelling decreased by 50%; ESR < 30 mm per hour in women and < 20 mm per hour in men Comparison between MTX + SSZ+HCQ and each of other groups with respect to good responses was statistically significant (P = 0.003 by log-rank test)At 2 yearsMaintenance of at least 50% improvement at 9 mos to end of 2-year treatment period (total n=50): D1: 33%, 12/36 ptsD2: 40%, 14/35 pts D3: 77%, 24/31 pts (D3 vs D2, P = 0.003 and D3 vs. D1, P < 0.001 for respective comparisons between D3 (3-drug group) and D2; D3 vs D1)Similar withdrawal rates due to Adverse Events across groupsTreatment with all 3 drugs did not produce more toxic effects than did MTX alone D1: discontinued treatment because of toxic effects: 2 w/ pneumonia; 1 each had stomatitis, diarrhea, nausea, and vertigo; 1 pt had sepsis and died. D2: 3 discontinued due to pneumonia, diarrhea, and Crohn's disease; D3: 3 in 3-drug group discontinued due to nausea, cervical cancer, and weight gain. No pt had serum aspartate aminotransferase values more than twice upper limit of normalD3: higher serum creatinine values than D2 or D1 at nine mos (P = 0.03)Overall Attrition Rate, %:51%ITT Analysis:YesQuality Rating:Fair for KQ1Good for KQ3Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:O'Dell et al., 2002 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1551</RecNum><DisplayText><style face="superscript">140</style></DisplayText><record><rec-number>1551</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1551</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>O'Dell, James R</author><author>Leff, Robert</author><author>Paulsen, Gail</author><author>Haire, Claire</author><author>Mallek, Jack</author><author>Eckhoff, P James</author><author>Fernandez, Ana</author><author>Blakely, Kent</author><author>Wees, Steven</author><author>Stoner, Julie</author><author>Hadley, Stephen</author><author>Felt, Jeffrey</author><author>Palmer, William</author><author>Waytz, Paul</author><author>Churchill, Melvin</author><author>Klassen, Lynell</author><author>Moore, Gerald</author></authors></contributors><titles><title>Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1164-70</pages><volume>46</volume><number>5</number><keywords><keyword>CN-00390202</keyword></keywords><dates><year>2002</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,3</custom4><custom7>PT 9-26 (DJ 8-7)</custom7></record></Cite></EndNote>140Country, Setting:US, multicenter (7)Funding:Pharmacia & Upjohn, Mylan,Sanofi-Winthrop- meds. Albert G. and Bernice F. Hansen FoundationResearch Objective:Efficacy of combination therapy with MTX, HCQ, and SSZ to MTX + HCQ and to MTX + SSZ in txt of RAStudy Design:RCTOverall N:171Study Duration: 2 yrsInclusion Criteria:Age: 19-80 yrsDiagnosed with RA according to ACR criteriaDuration of condition: > 6 mosActive disease with at least 3 of 4 following features: ESR > 28 mm/hour, duration of morning stiffness ≥ 45 minutes, ≥ 8 tender joints, and ≥ 3 swollen jointsExclusion Criteria:Previous combination therapy with any medications studiedSignificant liver or renal diseaseStage IV diseaseAllergy to any study drugswomen of childbearing age not using adequate contraceptionSignificant hematologic, pulmonary, or CVDInterventions, dose:D1: MTX and HCQD2: MTX and SSZD3: MTX, HCQ, and SSZ: All ptsMTX: accelerated from 7.5 mg/wk to 17.5 mg/wk in all pts not in remissionSSZ: escalated from 500 mg twice daily to 1gram twice daily in pts not in remissionHCQ: 200 mg twice dailyN:D1: 58D2: 55D3: 58Overall: 171Mean age, yrs:D1: 50.9D2: 52.5D3: 48.9Overall: 50.9Sex, % female:D1: 78D2: 84D3: 76Overall: 79Race, % white:NRMean disease duration, yrs:D1: 7.9 +/- 10D2: 5.8 +/- 5.9D3: 6.9 +/- 8.4TJC (mean +/- SD):D1: 15.7 +/- 8.2 D2: 15.6 +/- 7.4D3: 19.7 +/- 9.2SJC, mean:D1: 21.1 +/- 8.3D2: 19.1 +/- 7.9D3: 24.0 +/- 8.8DMARD use, %:NRCorticosteroid use, %D1: 71 D2: 56D3: 50MTX naive, %:D1: 43.1 D2: 54.5D3: 41.4Txt resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NR% RF positive:D1: 88 D2: 88D3: 89ESR: D1: 28.5 +/- 20.3D2: 34.1 +/- 26.5D3: 30.1 +/- 21.0At 2 yearsACR 20, %:D1: 60, 35/58 pts D2: 49 27/55 pts D3: 78, 45/58 pts (D3 vs D2; P = 0.002)(D3 vs. D1; (P = 0.05) ACR 50, %: D1: 40D2: 29D3: 55 (D3 vs D2; P = 0.005) (D3 vs. D1, P = 0.10)ACR 70, %: D1: 26D2: 18D3: 16 (P = NS) Changes in values for ACR core set, improvement in triple therapy group was greater than either of other 2 txt groups. TJC differences were statistically significant, D3 vs D1 (P ≤ 0.005) Reduced morning stiffness, minutes:D1: -59.2 +/- 103.3 D2: -53.2 +/- 89.5 D3: -109.3 +/- 86.4 minutes (D3 vs. D1; P = 0.01) (D3 vs. D2; P = 0.006)Overall: D1: 8.6D2: 9.1D3: 6.9Infections:D2: 1.8Serious Infections:D1: 1.7Cardiovascular Events:D1: 1.7 (1 MI)Headache:D2: 1.8Hepatotoxicity:D3: 1.7Malignancies:D3: 1.7 (1 non-Hodgkins lymphoma)Overall Attrition Rate, %:14.6% (25/171 subjects)ITT Analysis:YesQuality Rating:GoodStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:O'Dell et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjky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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjky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ADDIN EN.CITE.DATA 141Country, Setting:US, multicenterFunding:NRResearch Objective:Determine safety and efficacy of ETA in combination with SSZ, hydroxychloro-quine, IM Gold over 48 wksStudy Design:ObservationalOverall N:119Study Duration: 48 wksInclusion Criteria:Age: 19-75Diagnosed according to ACR criteria; stable SSZ or HCQ doses; 10mg or less/d steroids > 4wksActive disease with 6 or more swollen and tender jointsExclusion Criteria:Pregnant or lactatingETABiologics in past 4 wksImpaired renal or hepatic systemAntibody to TNFalphaAnti CD4 antibodyDiphterial interleukin 2 fusion proteinActive or chronic infectionsInterventions, dose:D1: ETA (25mg sc twice weekly) + SSZD2: ETA (25mg sc twice weekly ) + HCQD3: (Gold + ETA)N:D1: 50D2: 50D3: 19Mean age, yrs:D1: 47D2: 49.7Sex, % female:D1: 78D2: 76Race, % white:D1: 88D2: 92Mean disease duration, yrs:D1: 8.1D2: 8.7TJC, mean:D1: 16.5D2: 16.4SJC, mean:D1: 17.7D2: 17.1DMARD use, %:NRCorticosteroid use, %:D1: 58D2: 68MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRHAQ:D1: 1.32D2: 1.33Pts in each ETA combination showed significant improvement at 24 and 48 wksNo significant differences for ACR20/50 BETWEEN combination groups at 24 or 48 wks (NR). At 24 and 48 wks, ETA/SSZ combo showed highest ACR70 response (NR)At 24 wks change in HAQ SSZ -0.56+/-0.77 HCQ -0.71+/-0.65 P = NRNROverall Attrition Rate, %:30%ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicablePallavicini et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0
Njg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xNDM8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj41NDY4PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNTlhc3hzeHZ5Znh4eHZlZTAycHBheHdm
d2YwZnNmejI5NXY5Ij41NDY4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikdl
bmVyaWMiPjEzPC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGFsbGF2
aWNpbmksIEYuIEIuPC9hdXRob3I+PGF1dGhvcj5DYXBvcmFsaSwgUi48L2F1dGhvcj48YXV0aG9y
PlNhcnppLVB1dHRpbmksIFAuPC9hdXRob3I+PGF1dGhvcj5BdHplbmksIEYuPC9hdXRob3I+PGF1
dGhvcj5CYXp6YW5pLCBDLjwvYXV0aG9yPjxhdXRob3I+R29ybGEsIFIuPC9hdXRob3I+PGF1dGhv
cj5NYXJjaGVzb25pLCBBLjwvYXV0aG9yPjxhdXRob3I+RmF2YWxsaSwgRS4gRy48L2F1dGhvcj48
YXV0aG9yPk1vbnRlY3VjY28sIEMuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh
dXRoLWFkZHJlc3M+UmhldW1hdG9sb2d5IERlcGFydG1lbnQsIElSQ0NTIFBvbGljbGluaWNvIFMu
IE1hdHRlbywgVW5pdmVyc2l0eSBvZiBQYXZpYSwgUGF2aWEsIEl0YWx5LjwvYXV0aC1hZGRyZXNz
Pjx0aXRsZXM+PHRpdGxlPlR1bW91ciBuZWNyb3NpcyBmYWN0b3IgYW50YWdvbmlzdCB0aGVyYXB5
IGFuZCBjYW5jZXIgZGV2ZWxvcG1lbnQ6IGFuYWx5c2lzIG9mIHRoZSBMT1JIRU4gcmVnaXN0cnk8
L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QXV0b2ltbXVuIFJldjwvc2Vjb25kYXJ5LXRpdGxlPjwv
dGl0bGVzPjxwYWdlcz4xNzUtODA8L3BhZ2VzPjx2b2x1bWU+OTwvdm9sdW1lPjxudW1iZXI+Mzwv
bnVtYmVyPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFk
dWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5k
IG92ZXI8L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBBZ2VudHMvYWRtaW5pc3RyYXRp
b24gJmFtcDsgZG9zYWdlLyphZHZlcnNlIGVmZmVjdHMvdGhlcmFwZXV0aWM8L2tleXdvcmQ+PGtl
eXdvcmQ+dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8qZHJ1ZyB0
aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkLCBQ
cmVzY2hvb2w8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdv
cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxr
ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZhbnQ8L2tleXdvcmQ+PGtleXdvcmQ+
SW5mYW50LCBOZXdib3JuPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+
TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TmVvcGxhc21zLypldGlvbG9neTwva2V5d29y
ZD48a2V5d29yZD5SaXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+VHVtb3IgTmVjcm9zaXMg
RmFjdG9yLWFscGhhLyphbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3
b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3ll
YXI+PHB1Yi1kYXRlcz48ZGF0ZT5KYW48L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4x
ODczLTAxODMgKEVsZWN0cm9uaWMpJiN4RDsxNTY4LTk5NzIgKExpbmtpbmcpPC9pc2JuPjxhY2Nl
c3Npb24tbnVtPjE5NjQ3MTAzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVy
bD5odHRwOi8vd3d3Lm5jYmkubmxtLm5paC5nb3YvZW50cmV6L3F1ZXJ5LmZjZ2k/Y21kPVJldHJp
ZXZlJmFtcDtkYj1QdWJNZWQmYW1wO2RvcHQ9Q2l0YXRpb24mYW1wO2xpc3RfdWlkcz0xOTY0NzEw
MyA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48Y3VzdG9t
Mj5JPC9jdXN0b20yPjxjdXN0b200PktRIDMgLyBmYWlyPC9jdXN0b200PjxsYW5ndWFnZT5lbmc8
L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 143Country and settingItaly, 4 tertiary centers and 2 general population cancer registriesSource of fundingNRResearch objectiveTo compare cancer risk in a RA cohort population treated with TNF antagonists,and identify the characteristics of the patients at higher riskStudy designObservationalOverall N1064Duration of studyaverage follow up 23.22 mosInclusion CriteriaRA patients treated with anti-TNF agentsExclusion CriteriaNAComparisons (dosage and frequency)D1: ETN: dosage and frequency NRINF: dosage and frequency NRADA: dosage and frequency NRD2: General populationNumber in groupD1: 1064Mean age (years)D1: 55.84Sex, % femaleD1: 83Race, % whiteD1: NRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1:<5 yrs=324; 5-10 yrs=338; >10 yrs=402TJC, meanD1: 11.35SJC, mean D1: 10.06Corticosteroid use, %D1: NRDMARD use, %: D1: 100MTX na?ve, %: D1: NRTreatment resistant, %: D1: 100Patients with early RA, three years or less, %: D1: NR Baseline DAS scoreD1: 5.90Required treatment for latent TBD1: NROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallNRSerious adverse events:NRMalignancies:Risk of cancer: ETN: reference groupADA: HR 1.66 (95% CI 0.50-5.52); P=0.407INF: HR 0.59 (95% CI 0.17-2.09); P=0.412Respiratory events:NROther infections:NRGI:NROther:NRQuality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicablePan, S.M. et al.; 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0
MDY8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xNDQ8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNDA2PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNTlhc3hzeHZ5Znh4eHZlZTAycHBheHdm
d2YwZnNmejI5NXY5Ij4yNDA2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikdl
bmVyaWMiPjEzPC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGFuLCBT
LiBNLjwvYXV0aG9yPjxhdXRob3I+RGVobGVyLCBTLjwvYXV0aG9yPjxhdXRob3I+Q2l1cmVhLCBB
LjwvYXV0aG9yPjxhdXRob3I+Wmlzd2lsZXIsIEguIFIuPC9hdXRob3I+PGF1dGhvcj5HYWJheSwg
Qy48L2F1dGhvcj48YXV0aG9yPkZpbmNraCwgQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli
dXRvcnM+PGF1dGgtYWRkcmVzcz5HZW5ldmEgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR2VuZXZhLCBT
d2l0emVybGFuZC4gc29waGllLm1hcnRpbi1kdS1wYW5AaGN1Z2UuY2g8L2F1dGgtYWRkcmVzcz48
dGl0bGVzPjx0aXRsZT5Db21wYXJpc29uIG9mIGRydWcgcmV0ZW50aW9uIHJhdGVzIGFuZCBjYXVz
ZXMgb2YgZHJ1ZyBkaXNjb250aW51YXRpb24gYmV0d2VlbiBhbnRpLXR1bW9yIG5lY3Jvc2lzIGZh
Y3RvciBhZ2VudHMgaW4gcmhldW1hdG9pZCBhcnRocml0aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0
bGU+QXJ0aHJpdGlzIFJoZXVtPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+
PGZ1bGwtdGl0bGU+QXJ0aHJpdGlzIGFuZCBSaGV1bWF0aXNtPC9mdWxsLXRpdGxlPjxhYmJyLTE+
QXJ0aHJpdGlzIFJoZXVtLjwvYWJici0xPjxhYmJyLTI+QXJ0aHJpdGlzIFJoZXVtPC9hYmJyLTI+
PGFiYnItMz5BcnRocml0aXMgJmFtcDsgUmhldW1hdGlzbTwvYWJici0zPjwvcGVyaW9kaWNhbD48
cGFnZXM+NTYwLTg8L3BhZ2VzPjx2b2x1bWU+NjE8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48
a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48
a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsLyBhZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3Nh
Z2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlyaGV1bWF0aWMgQWdlbnRz
LyBhZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr
ZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3
b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgSHlwZXJzZW5zaXRpdml0
eS9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVt
YW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcvIGFkbWluaXN0cmF0aW9uICZh
bXA7IGRvc2FnZS9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+S2FwbGFuLU1laWVy
cyBFc3RpbWF0ZTwva2V5d29yZD48a2V5d29yZD5Mb25naXR1ZGluYWwgU3R1ZGllczwva2V5d29y
ZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr
ZXl3b3JkPlJlY2VwdG9ycywgVHVtb3IgTmVjcm9zaXMgRmFjdG9yLyBhZG1pbmlzdHJhdGlvbiAm
YW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+VHVtb3IgTmVjcm9zaXMgRmFjdG9yLWFscGhh
LyBhbnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVz
Pjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5NYXkgMTU8L2RhdGU+PC9wdWItZGF0
ZXM+PC9kYXRlcz48aXNibj4wMDA0LTM1OTEgKFByaW50KTwvaXNibj48YWNjZXNzaW9uLW51bT4x
OTQwNTAwMDwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+STwvY3VzdG9tMT48
Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b20zPk88L2N1c3RvbTM+PGN1c3RvbTQ+S1EgMyAvIGZh
aXI8L2N1c3RvbTQ+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE.DATA 144Country and settingSwitzerland; doctors offices, non-academic hospitals, academic centersSource of fundingSwiss Clinical Quality Management was sponsored by Abbott, Essex, Roche, Bristol-Myers Squibb, Mepha, Novartis, and Sanofi-AventisResearch objectiveCompare tx retention rates between ETN, IFX, and ADA and compare causes of discontinuationStudy designPopulation Based Cohort StudyOverall N2364Duration of studyJanuary 1997 to December 2006Quality rating FairInclusion CriteriaExistence in Swiss Clinical Quality Management for Rheumatoid Arthritis (SCQM-RA) registry treated with an anti-TNF agent between January 1997 and December 2006.Exclusion CriteriaNRInterventions, DoseD1: IFX: dosage and frequency NRD2: ETN: dosage and frequency NRD3: ADA: dosage and frequency NRNumber in groupD1: 595D2: 887D3: 882Overall: 2364Mean age (years)D1: 53, SD 13D2: 54, SD 14D3: 55, SD 13P = 0.16Sex, % femaleD1: 76D2: 78D3: 79P = 0.42Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 10 yrs, SD 9D2: 10 yrs, SD 9D3: 10 yrs, SD 9P = 0.2Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 52D2: 52D3: 49DMARD use, %D1: MTX: 74; LEF: 17; Other: 17; No DMARD: 11D2: MTX: 55; LEF: 17; Other: 19; No DMARD: 29D3: MTX: 61; LEF: 18; Other: 20; No DMARD: 22Overall: MTX: P?=?0.001; LEF: P?=?0.765; Other: P?=?0.246; No DMARD: P?=?0.001MTX na?ve, %NRBaseline DAS score, mean (SD)D1: 4.27, SD 1.52D2: 4.23, SD 1.53D3: 4.14, SD 1.42P = 0.066Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Glucocorticoids: 52%; Failure of previous anti-TNF agent: 23%; RADAI: 4.29, SD 2.14D2: Glucocorticoids: 52%;; Failure of previous anti-TNF agent: 19%; RADAI: 4.31, SD 2.24D3: Glucocorticoids: 49%; Failure of previous anti-TNF agent: 27%; RADAI: 4.16, SD 2.15Overall: Glucocorticoids: P?=?0.409; Failure of previous anti-TNF agent: P?=?0.001; RADAI: P?=?0.37ACR NRHAQ, D1: Baseline: 1.32, SD 0.72D2: Baseline: 1.25, SD 0.76D3: Baseline: 1.17, SD 0.71Baseline: P?=?0.117DAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)Causes of treatment discontinuation (Hazard models with D1 as reference): All adverse events: D2 0.79 (0.55-1.13), D3 0.67 (0.45-0.97), P?=?0.02; Acute systemic reaction: : D2 0.40 (0.21-0.78), D3 0.56 (0.29-1.09), P?=?0.018; Dermatologic disease: D2 0.85 (0.43-1.70), D3 1.04 (0.54-2.02), P?=?0.81; Infection: D2 1.14 (0.68-1.92), D3 0.56 (0.30-1.04), P?=?0.18; Malignancy: D2 0.54 (0.16-1.85), D3 0.20 (0.37-1.06), P?=?0.12; Miscellaneous: D2 0.81 (0.55-1.19), D3 0.85 (0.58-1.25), P?=?0.55; All nontoxic causes: D2 0.90 (0.64-1.26), D3 0.82 (0.58-1.18), P?=?0.38; Ineffectiveness: D2 0.95 (0.71-1.26), D3 0.82 (0.61-1.11), P?=?0.42; Remission: D2 0.85 (0.22-3.3), D3 1.10 (0.36-3.44), P?=?0.91; Desire for Pregnancy: D2 0.75 (0.10-5.55), D3 1.89 (0.24-14.9), P?=?0.95; Preference: D2 0.68 (0.37-1.45), D3 0.85 (0.41-1.77), P?=?0.68OverallOverall attrition/withdrawal, n: D1: 209D2: 237D3: 213Overall: 659Withdrawals due to adverse events, n:D1: 154D2: 172D3: 149Overall: 318; P?=?0.093Withdrawals due to lack of efficacy, n:D1: 90D2: 125D3: 112Overall: 327; P?=?0.17Adherent/compliant, n:D1: 386D2: 650D3: 669Overall: 1705 Overall adverse events reported, n:D1: 108D2: 118D3: 92Overall: 318Serious adverse eventsDeath, n:D1: 2D2: 0D3: 2Overall: 4; P?=?0.33MalignanciesMalignancy), n:D1: 8D2: 5D3: 2Overall: 15; P?=?0.12Respiratory eventsNROther infectionsNRGINROtherInfusion/injection site reactions, n:D1: 50D2: 24D3: 31Overall: 105; P?=?0.001Infection, n:D1: 26D2: 41D3: 22Overall: 89; P?=?0.088Dermatologic disease, n:D1: 16D2: 20D3: 29Overall: 65; P?=?0.09General (inc fatigue, headache, weight changes), n:D1: 14D2: 13D3: 9Overall: 36; P?=?0.46Neuropsychiatric:, n:D1: 15D2: 13D3: 21Overall: 49; P?=?0.22Any other AEs: Opthamologic: D1: 3D2: 7D3: 2Overall: 12, P?=?0.29Ear nose throat: D1: 2D2: 3D3: 0Overall: 5, P?=?0.29Cardiovacular: D1: 7D2: 14D3: 6Overall: 27, P?=?0.23Pulmonary: D1: 3D2: 10D3: 5Overall: 18, P?=?0.22Gastroenterological: D1: 11D2: 17D3: 16Overall: 44, P?=?0.67Renal disease: D1: 4D2: 7D3: 0Overall: 11, P?=?0.03Hematologic: D1: 2D2: 4D3: 2Overall: 8, P?=?0.75Osteoarticular: D1: 6D2: 4D3: 4Overall: 14, P?=?0.63Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableRussell et al., 2006 and 2007, AIMPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 145; Kremer et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3475</RecNum><DisplayText><style face="superscript">116</style></DisplayText><record><rec-number>3475</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3475</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kremer, J. M.</author><author>Genant, H. K.</author><author>Moreland, L. W.</author><author>Russell, A. S.</author><author>Westhovens, R.</author><author>et al.,</author></authors></contributors><auth-address>Ctr Rheumatol, 1367 Washington Ave, Suite 1, Albany, NY 12206, USA jkremer@joint-</auth-address><titles><title>Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis - a randomized trial</title><secondary-title>Annals of Internal Medicine</secondary-title></titles><periodical><full-title>Annals of Internal Medicine</full-title><abbr-1>Ann. Intern. Med.</abbr-1><abbr-2>Ann Intern Med</abbr-2></periodical><pages>865-876</pages><volume>144</volume><keywords><keyword>Abatacept--arthritis-</keyword><keyword>Methotrexate--arthritis-</keyword><keyword>Immunomodulating agents--abatacept</keyword><keyword>Immunogenicity--abatacept</keyword><keyword>Arthritis--abatacept</keyword><keyword>Toxicity--abatacept</keyword><keyword>Resistance--methotrexate</keyword><keyword>Arthritis--methotrexate</keyword><keyword>Anti inflammatory agents--methotrexate</keyword><keyword>Outcomes--clinical</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I MTC</custom2><custom3>CT</custom3><custom4>KQ 1, 2, 3 / fair</custom4><custom7>Companion studies: 2204, 2669 (AIM)</custom7></record></Cite></EndNote>116, AIMCountry and settingNRSource of fundingBristol-Myers SquibbResearch objectiveExamine impact of ABA tx on HRQOL in patients with RAStudy designControlled TrialsOverall N0Duration of study12 mosQuality rating Fair Inclusion CriteriaDiagnosis of RA according to ARA and classification within functional status I, II, or III according to revised criteria of ACRRA disease duration of > 1 year from initial diagnosisTreatment with MTX for at least 3 months, and at a stable dose for 28 days before treatmentWashout of all DMARDs other than MTX at least 28 days before treatmentActive diseaseCharacterized by > 10 swollen joints, > 12 tender joints, and CRP > 10 mg/l.Exclusion CriteriaNRInterventions, DoseD1: MTX: 15 mg or more per weekAbatacept: fixed dose of 10 mg/kg at days 1, 15, 29, and every 28 days thereafter for up to 1 yearD2: MTX: 15 mg or more per weekPlacebo: dose NRNumber in groupD1: 433D2: 219Overall: 652Mean age (years)D1: 51.5D2: 50.4Overall: 51.5Sex, % femaleD1: 77.8D2: 81.7Overall: 79.2Race, % whiteD1: 87.5D2: 88.1Overall: 87.7Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 8.5 (7.3)D2: 8.9 (7.1)Overall: 8.6Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: 100D2: 100Overall: 100MTX na?ve, %D1: 0D2: 0Overall: 0Baseline DAS score, mean (SD)D1: 6.4D2: 6.4Overall: NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)MTX dose (mg/week): D1: 16.1D2: 15.7Pain (VAS 100 mm) :D1: 63.3D2: 65.9Patient global assessment of disease activity (VAS 100 mm): D1: 62.7D2: 62.8DAS28 (CRP):D1: 6.4D2: 6.4SF-36 Physical functioning (PF):D1: 28.7D2: 28.3SF-36 Mental health (MH): D1: 39.4D2: 39.7SF-36 Physical component summary (PCS): D1: 30.6D2: 30.7SF-36 Mental component summary (MCS):D1: 41.8D2: 40.8HAQ Disability Index (0-3): D1: 1.7D2: 1.7Fatigue (VAS 100 mm): D1: 63.2D2: 66.2ACR mean difference/ absolute difference (%)ACR 20:At 6 months:D1: 67.9 (N:?424)D2: 39.7 (N:?214)P = 0.001, difference 28 percentage points, 95% CI:?19.8 - 36.7 percentage pointsAt 1 year:D1: 73.1 (N:?424)D2: 39.7 (N:?214)Overall: difference:?33.4 percentage points, 95% CI:?25.1 - 41.7ACR 50:At 6 months:D1: 39.9 (N:?424)D2: 16.8 (N:?214)Overall: Difference at 6 mos:?23 percentage points, 95% CI:?15 - 31.1 percentage points (P = ?0.001)At 1 year:D1: 48.3 (N:?424)D2: 18.2 (N:?214)Overall:Difference at 1 year:?30.1 percentage points, 95% CI:?21.8, 38.5 percentage points (P = ?0.001)ACR 70:At 6 months:D1: 19.8 (N:?424)D2: 6.5 (N:?214)Overall: Difference at 6 mos:?13.3 percentage points, 95% CI:?7.0 - 19.5 percentage points (P = ?0.001)At 1 year:D1: 28.8 (N:?424)D2: 6.1 (N:?214)Overall: Difference at 1 year:?22.7 percentage points, 95% CI:?15.6 - 29.8 percentage points (P = ?0.001)HAQ-DI (%)Significantly ImprovedD1: 63.70D2: 39.30Modified worst-case sensitivity analysisD1: 64D2: 42Worst-case analysisD1: 64D2: 64Overall: [from #3475] P = ?0.001, difference 24.4 (CI 15.9-32.9)DAS NRSF-36D1: NR - reported in figure onlyD2: NR - reported in figure onlyOverall: PCS, abatacept vs. placebo, day 29: (P = ?0.01)MCS, abatacept vs. placebo, 6 months: (P = ?0.01)Fatigue, abatacept vs. placebo, day 29: (P = ?0.01)Physical function, abatacept vs. placebo, day 57: (P = ?0.05)Radiographic measures D1: (Note: for radiographic data, N:?391 for abatacept group) mean change from baseline for total score:?1.21D2: (Note: for radiographic data, N:?195 for placebo group) mean change from baseline for total score:?2.32Overall: NRQuality of life scales NROthers, (please name) Achieved normative PCS benchmark, 6 months: abatacept:?47.1%, Placebo: 30.7, overall, Number Needed to Treat:?6Achieved normative MCS benchmark, 6 months: abatacept:?60.4%, Placebo: 50.5%, overall, Number Needed to Treat:?10Percentage of patients who exhibited improved HRQOL scores by at least 0.5 SD over 12 month period of study: PCS (abatacept:?67.2%, Placebo: 51.1%, P = ?0.001), HAQ (abatacept:?72.4%, Placebo: 55.2%, P = ?0.001), Fatigue (abatacept:?64.9%, Placebo: 47.4%, P = ?0.001)Attrition/withdrawalOverall, n:D1: 48D2: 57Overall: 105Withdrawals due to adverse events, n:D1: 18D2: 4Overall: 22Withdrawals due to lack of efficacy, n:D1: 13D2: 40Overall: 53Adherent/compliant, n:D1: 385D2: 162Overall: 547Overall adverse events reported, n:D1: 378D2: 184Overall: NRSerious adverse eventsDeath, n:D1: 1D2: 1Overall: NRCardiac disorders, n:D1: 4D2: 2Hypertension:D1: 24D2: 3Overall: NRMalignanciesNRNeoplasms, n:D1: 4D2: 2Overall: NRRespiratory eventsNROther infections, nNasopharyngitis:D1: 66D2: 25Pharyngitis:D1: 26D2: 10Sinusitis: D1: 18D2: 15Bronchitis: D1: 18D2: 12Serious Infections (not prespecified):D1: 17D2: 5Bronchopneumonia: D1: 2D2: 5Cellulitis: D1: 1D2: 0Sepsis: D1: 1D2: 1Abscess: D1: 1D2: 0Bacterial arthritis: D1: 1D2: 0Bronchopulmonary aspergillosis: D1: 1D2: 0Acute pyelonephritis: D1: 1D2: 0Limb abscess: D1: 0D2: 1Overall: NRGINausea or vomiting, n:D1: 52D2: 24Overall: NRAbdominal pain, n:D1: 19D2: 13Overall: NRDiarrhea, n:D1: 47D2: 21Dyspepsia, n:D1: 27D2: 10OtherAcute infusional adverse events, n:D1:38D2: 9Per-Infusional adverse event, n:D1: 106D2: 37Overall: NRSkin rash, n:NRDemyelenation or multiple sclerosis, n:NRProgressive multifocal leukoencephalopathy, n:D1: NRD2: NROverall: NR Headache, n:D1: 76D2: 26Overall: NRDizziness, n:D1: 40D2: 16Overall: NRMusculoskeletal and connective tissue disorders, n:D1: 20D2: 10Cough, n: D1: 29D2: 13Influenza, n:D1: 31D2: 12Back pain, n: D1: 40D2: 12 Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Saag et al., 1994PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEw
NTU8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xNDY8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMDU1PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJm
ejlheDl0YWZ4cGQ1Ij4xMDU1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5TYWFnLCBLLiBHLjwvYXV0aG9yPjxhdXRob3I+S29laG5rZSwgUi48L2F1dGhvcj48YXV0aG9y
PkNhbGR3ZWxsLCBKLiBSLjwvYXV0aG9yPjxhdXRob3I+QnJhc2luZ3RvbiwgUi48L2F1dGhvcj48
YXV0aG9yPkJ1cm1laXN0ZXIsIEwuIEYuPC9hdXRob3I+PGF1dGhvcj5aaW1tZXJtYW4sIEIuPC9h
dXRob3I+PGF1dGhvcj5Lb2hsZXIsIEouIEEuPC9hdXRob3I+PGF1dGhvcj5GdXJzdCwgRC4gRS48
L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50
IG9mIEludGVybmFsIE1lZGljaW5lLCBVbml2ZXJzaXR5IG9mIElvd2EsIElvd2EgQ2l0eS48L2F1
dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Mb3cgZG9zZSBsb25nLXRlcm0gY29ydGljb3N0ZXJv
aWQgdGhlcmFweSBpbiByaGV1bWF0b2lkIGFydGhyaXRpczogYW4gYW5hbHlzaXMgb2Ygc2VyaW91
cyBhZHZlcnNlIGV2ZW50czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIE1lZDwvc2Vjb25k
YXJ5LXRpdGxlPjxzaG9ydC10aXRsZT5Mb3cgZG9zZSBsb25nLXRlcm0gY29ydGljb3N0ZXJvaWQg
dGhlcmFweSBpbiByaGV1bWF0b2lkIGFydGhyaXRpczogYW4gYW5hbHlzaXMgb2Ygc2VyaW91cyBh
ZHZlcnNlIGV2ZW50czwvc2hvcnQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0
bGU+QW1lcmljYW4gSm91cm5hbCBvZiBNZWRpY2luZTwvZnVsbC10aXRsZT48YWJici0xPkFtLiBK
LiBNZWQuPC9hYmJyLTE+PGFiYnItMj5BbSBKIE1lZDwvYWJici0yPjwvcGVyaW9kaWNhbD48cGFn
ZXM+MTE1LTIzPC9wYWdlcz48dm9sdW1lPjk2PC92b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGtl
eXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5
IEFnZW50cy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3
b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVyYXB5PC9rZXl3b3Jk
PjxrZXl3b3JkPkRydWcgQWRtaW5pc3RyYXRpb24gU2NoZWR1bGU8L2tleXdvcmQ+PGtleXdvcmQ+
RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3
b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5Mb2dpc3RpYyBNb2RlbHM8L2tleXdvcmQ+PGtl
eXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29y
ZD5QcmVkbmlzb25lL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8gYWR2ZXJzZSBlZmZlY3Rz
PC9rZXl3b3JkPjxrZXl3b3JkPlJlc2VhcmNoIFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8
L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydCwgVS5TLiBHb3YmYXBvczt0LCBQLkgu
Uy48L2tleXdvcmQ+PGtleXdvcmQ+UmV0cm9zcGVjdGl2ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3
b3JkPlRpbWUgRmFjdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk0PC95
ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGFjY2Vz
c2lvbi1udW0+ODEwOTU5NjwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTE+STwv
Y3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b20zPk88L2N1c3RvbTM+PGN1c3RvbTQ+
MzwvY3VzdG9tND48Y3VzdG9tNz5MTSA5LTI4IChESiA4LTcpPC9jdXN0b203PjwvcmVjb3JkPjwv
Q2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE.DATA 146Country, Setting:US, multicenter Funding:General Clinical Research Program, NIH and Halifax Clinical Research CenterResearch Objective:To determine whether low dose steroids in txt of RA independently cause an increased incidence of steroid-associated SAEsStudy Design:ObservationalOverall N:224Study Duration: At least one yr (4.9 +/-3.9 yrs of txt).Inclusion Criteria:Age > 16Diagnosed according to ACR criteriaOn low-dose steroids > 1 yr; matched for age, sex, race, and duration of disease prior to study inception; allowed occasional intraarticular or parenteral steroids or oral steroid pulses to certain defined limits. SAARDs were allowedExclusion Criteria:CXT, chlorambucil, nitrogen mustard, or experimental antirheumatic drugsImpaired renal or hepatic systemConcurrent or alternative rheumatic disorderBedridden statusReferral 2nd to a steroid complicationInterventions, dose:D1: Treated (with low dose long-term corticosteroids) D2: Untreated (with low dose long-term corticosteroids)Prednisone: corticosteroids, less than or equal to 15mg/d of PRE (or equivalent dose of an alternative steroid)N:D1: 112D2: 112Mean age, yrs:D1: 51.8D2: 51.7Sex, % female:D1: 75D2: 75Race, % white:D1: 98.2D2: 98.2Mean disease duration, yrs:D1: 4.9 +/-6.3D2: 4.9 +/-6.7TJC, mean:NRSJC, mean:NRAverage no of SAARDs:D1: 0.47 +/-0.82D2: 0.13 +/-0.37Corticosteroid use, %:D1: 100D2: NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRF:D1: 77.7D2: 58.0 ESR: D1: 50 +/-29.7D2: 36.4 +/-30.5Extra-articular disease D1: 16.1%D2: 6.3%n for Treated and Untreated groups respectively: Fracture 21 and 8; GI bleed or ulcer 11 and 4; cataracts 17 and 5; diabetic complications 8 and 3; herpes zoster 8 and 1; glaucoma 1 and 1; death 2 and 0.OR of 32.3 (95% CI,4.6, 220) (P = 0.0004) for pts treated with > 10 up to 15mg/d PRE equivalent; OR of 4.5 (95% CI,2.1, 9.6) (P = 0.0001) for pts treated with 5-10mg/d; Prednisone dose <5mg/d did not show a significant increase in risk of having an AE compared to the untreated group; *Although PRE average dose and cumulative dose had small but significant emsitmated relative risks (OR 1.21, 95%CI,1.0-1.5 for both), PRE use (yes/no) was most highly linked to infection (OR 8.0, 95% CI,1.0-64.0, P < 0.05)Fracture (OR 3.9, 95% CI,0.8-18.1, P < 0.09)First GI event: OR 3.3 (95% CI,0.9-12.1, P < 0.07) Overall: D1: n:92 AEsD2: n:31Serious Infections:D1: n:14D2: n:4Cardiovascular Events:D1: n:10 (4 myocardial infarctions, 6 strokes)D2: n:5 (4 myocardial infarction, 1 stroke)Overall Attrition Rate, %:NAITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Salliot et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1942</RecNum><DisplayText><style face="superscript">147</style></DisplayText><record><rec-number>1942</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1942</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salliot, C.</author><author>Gossec, L.</author><author>Ruyssen-Witrand, A.</author><author>Luc, M.</author><author>Duclos, M.</author><author>Guignard, S.</author><author>Dougados, M.</author></authors></contributors><titles><title>Infections during tumour necrosis factor-{alpha} blocker therapy for rheumatic diseases in daily practice: a systematic retrospective study of 709 patients</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology</full-title><abbr-1>Rheumatology (Oxford).</abbr-1><abbr-2>Rheumatology (Oxford)</abbr-2></periodical><pages>327-34</pages><volume>46</volume><number>2</number><dates><year>2007</year><pub-dates><date>July 31, 2006</date></pub-dates></dates><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>KD 9-6 (SW)</custom7><electronic-resource-num>10.1093/rheumatology/kel236</electronic-resource-num></record></Cite></EndNote>147Country, Setting:France, tertiary careFunding:NRResearch Objective:To evaluate rate of infections in rheumatic pts treated with TNF-alpha blockers in daily practice and to determine potential risk factors of infectionsStudy Design:Case seriesOverall N:709 w/ follow-up at least once and 623 w/ with a control periodStudy Duration: NRInclusion Criteria:Pts receiving a TNF-alpha blocker and with a follow-upThose with control period before txt initiationExclusion Criteria:NAInterventions, dose:D1: Follow upD2: Follow up and controlN:D1: 709D2: 623Mean age, yrs:D1: 45.9D2: 46.5Sex, % female:D1: 60.4D2: 60.4Race, % white:NRMean disease duration, yrs:D1: 11.8D2: 12.1TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:D1: 58.5D2: 58.3MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 43.7D2: 43.634.5% experienced infection during course of txt; Incidence rate: 48.2 per 100 PY 6.2 percent experienced a serious infection; incidence rate: 10.4 per 100 PY? Infections by txt:Any: INF 69.8ETA 44.1Adalimumab 37.3 per 100 PYSerious: INF 10.2ETA 12.3Adalimumab 5.3 per 100 PYInfections:D1: 50.5D2: 34.2D3: 15.3URTI:D1: 13.4D2: 9.4D3: 9.9UTI:D1: 5.1D2: 1.1D3: 1.6Overall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Schaible et al., 2000 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1926</RecNum><DisplayText><style face="superscript">148</style></DisplayText><record><rec-number>1926</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1926</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schaible, T. F.</author></authors></contributors><auth-address>Immunology Medical Affairs, Centocor Inc, Malvern, Pennsylvania 19355, USA. schaible@</auth-address><titles><title>Long term safety of infliximab</title><secondary-title>Can J Gastroenterol</secondary-title></titles><periodical><full-title>Canadian Journal of Gastroenterology</full-title><abbr-1>Can. J. Gastroenterol.</abbr-1><abbr-2>Can J Gastroenterol</abbr-2></periodical><pages>29C-32C</pages><volume>14</volume><number>Suppl C</number><keywords><keyword>Antibodies, Monoclonal/administration & dosage/ therapeutic use</keyword><keyword>Crohn Disease/ drug therapy</keyword><keyword>Gastrointestinal Agents/administration & dosage/ therapeutic use</keyword><keyword>Humans</keyword><keyword>Infusions, Intravenous/adverse effects</keyword></keywords><dates><year>2000</year><pub-dates><date>Sep</date></pub-dates></dates><accession-num>11023558</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>DJ 9-6 (SW)</custom7></record></Cite></EndNote>148Country, Setting:US; safety database of efficacy trialsFunding:CentocorResearch Objective: Long term safety of infliximabStudy Design:ObservationalOverall N:963Study Duration: Up to 3 yrsInclusion Criteria:12 clinical trialsExclusion Criteria:NRInterventions:InfliximabN:963Mean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTreatment resistant %:NRPatients with Early RA (≤3 yrs):NRBaseline DAS, mean:NRAcute infusion reactions (headache, fever, chills, urticaria, chest pain: infliximab 17% versus placebo 7%; P = NR 0.5% of infliximab pts had severe infusion reactionsLess than 2% discontinued treatment because of infusion reactionsInfections: Infliximab 26% over 27 wks of follow-up versus placebo 16% over 20 wks of follow-up)Incidence of serious infections per patient-yr infliximab 0.064 versus placebo 0.114See outcomesOverall Attrition Rate, %:ITT Analysis:Not applicable Quality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Schiff et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE.DATA 149Country, Setting:Mulitnational, multicenterFunding:Abbott LabsResearch Objective:To assess safety of adalimumab in global clinical trials and postmarketing surveillance among pts with rheumatoid arthritisStudy Design:Retrospective cohort study; postmarketing surveillanceOverall N:10,050 (12506 PY)Study Duration: VariedInclusion Criteria:Pts from RCTs, open label extensions, and two phase IIIb open label trials were and post-marketing spontaneous reports of adverse events in USExclusion Criteria:NAInterventions, dose:NRN:10,050Mean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRates per 100 PY:TB: 0.27 Histoplasmosis: 0.03 Demyelinating diseases: 0.08Lymphoma: 0.12 SLE/lupus-like syndrome: 0.10Congestive heart failure: 0.28NAOverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSchiff et al., 2008, ATTESTPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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 EN.CITE.DATA 150Country and settingInternational, Multi-centerSource of fundingBristol-Myers Squibb, Princeton, New Jersey, USAResearch objectiveEvaluate change from baseline in DAS for ABA vs. placebo and reduction in DAS28 for IFX vs. placebo and ABA vs. IFXStudy designControlled TrialsOverall N431Duration of studyABA vs. placebo and IFX vs. placebo: 197 daysABA vs. IFX: 365 daysQuality rating Fair Inclusion CriteriaTreatment resistantACR criteria for RA≥ 18 years oldRA ≥ 1 year, inadequate response to MTX, as demonstrated by ongoing active disease (at randomization SJC >10, TJC >12, and CRP >1 mg/dlAll patients had received MTX >15 mg/week for >3 mos prior to randomization (stable for at least 28 days) and washed out all DMARDs (>28 days prior) except for MTXAnti-TNF-therapy naiveExclusion CriteriaPositive screen for TB by purified protein derivative testing and chest x ray.Interventions, doseD1: MTX: dosage and frequency NRAbatacept: 500-1000 mg, days 1, 15, 29, and every 28 days thereafterD2: MTX: dosage and frequency NRPlaceboD3: MTX: dosage and frequency NRIFX: 3 mg/kg, days 1, 15, 43, 85, and every 56 days thereafterNumber in groupD1: 156D2: 110D3: 165Overall: 431Mean age, years (SD)D1: 49.0 (12.5)D2: 49.4 (11.5)D3: 49.1 (12.0)Sex, % femaleD1: 83.3D2: 87.3D3: 82.4Race, % whiteD1: 80.8D2: 76.4D3: 80.6Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 7.9 (8.5)D2: 8.4 (8.6)D3: 7.3 (6.2)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanD1: 31.3 (13.9)D2: 30.3 (11.7)D3: 31.7 (14.5)Swollen Joint Count, mean D1: 21.3 (8.6)D2: 20.1 (7.0)D3: 20.3 (8.0)Corticosteroid use, %D1: 75.6D2: 70D3: 71.5Overall: 72.6DMARD use, %D1: 100D2: 100Overall: 100MTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS scoreD1: 6.9D2: 6.8D3: 6.8Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Erythrocyte sedimentation rate, mm/h (SD): D1: 49.4 (31.2)D2: 47.0 (32.6)D3: 47.8 (30.4)Overall: NRHAQ-DI, 0-3 (SD): D1: 1.8 (0.6)D2: 1.8 (0.7)D3: 1.7 (0.7)Overall: NRTotal patients on concomitant medications, n (%): D1: 156 (100)D2: 110 (100)D3: 165 (100)Overall: 431 (100)MTX Dose, mg/week (SD): D1: 16.5 (3.7)D2: 16.6 (3.7)D3: 16.3 (3.6)Overall: NRMTX Duration, months (SD): D1: 18.3 (20.0)D2: 23.7 (25.6)D3: 23.6 (26.8)Overall: NRCorticosteroids, n (%): D1: 118 (75.6)D2: 77 (70.0)D3: 118 (71.5)Overall: 313 (72.6)NSAIDs, n (%): D1: 133 (85.3) D2: 93 (84.5) D3: 142 (86.1) Overall: 368 (85.4)ACR ACR 20:Day 197D1: 66.7D2: 41.8D3: 59.4Overall: ABA vs. Placebo: (P = ?0.001), IFX vs. Placebo: (P = ?0.006)Day 365:D1: 72.4D2: 41.8D3: 55.8Overall: ABA vs. IFX: estimate of difference of 16.7 (5.5, 27.8)ACR 50:Day 197:D1: 40.4D2: 20D3: 37Overall: ABA vs. Placebo: (P = ?0.001), IFX vs. Placebo: (P = ?0.004)Day 365:D1: 45.5D2: 20D3: 36.4Overall:Overall: ABA vs. IFX: estimate of difference (95% CI): 9.1 (-2.2, 20.5)ACR 70:Day 197D1: 20.5D2: 9.1D3: 24.2Overall: ABA vs. Placebo: (P = ?0.019), IFX vs. Placebo: (P = ?0.002)Day 365:D1: 26.3D2: 9.1D3: 20.6Overall: ABA vs. IFX): estimate of difference (95% CI): 5.7 (-4.2, 15.6)HAQ, mean difference/ absolute difference (CI/SD/P Value)Proportion demonstrating improvement in physical functionDay 197D1: 61.5D2: 40.9D3: 58.8Overall: Proportion demonstrating improvement in physical function, ABA vs. Placebo: (P = ?0.001), IFX vs. Placebo: (P = ?0.005)Day 365D1: 57.7D2: 40.9D3: 52.7Overall: ABA vs. IFX: estimate of difference (95% CI): 5.0 (-6.5, 16.5)DAS Day 197D1: 2.53D2: -1.48D3: 2.25 Overall: ABA vs. Placebo: (P = ?0.001), IFX vs. Placebo: (P = ?0.001)Day 365D1: -2.88D2: -1.48D3: -2.25 Overall: ABA vs. IFX: estimate of difference (95% CI): -0.62 (-0.96, -0.29)SF-36 NR Overall: Day 197, ABA vs. Placebo: PCS (P = ?0.001) and MCS (P = ?0.004) ofSF-36IFX vs. Placebo: PCS (P = ?0.002) and MCS (P = ?0.027) of SF-36ABA vs. IFX, PCS (difference of 1.93, 95% CI:?0.02, 3.84)MCS (difference of 1.92, 95% CI:?-0.30, 4.15)Radiographic measures NRQuality of life scales NROthers, (please name) Day 197: Proportion of patients achieving a good EULAR response, ABA: 20&, Placebo: 10.8%, IFX: 22.9%LDAS, ABA: 20.7%, Placebo: 10.8%, IFX: 25.6%DAS28 (ESR)-defined remission, ABA: 11.3%, Placebo: 2.9%, IFX: 12.8%Day 365:Proportion of patients achieving a good EULAR response (ABA 32.0 vs. INF 18.5%, estimate of difference (95% CI): 13.5% (3.6, 23.3))LDAS (ABA 35.3 vs. INF 22.4%, estimate of difference (95% CI): 12.9 (2.1, 23.7))DAS28 (ESR)-defined remission (ABA 18.7 vs. INF 12.2%, estimate of difference (95% CI): 18.7 (-2.2, 15.2))Attrition/withdrawalOverall, n:D1: 17D2: 6D3: 24Overall: 47Withdrawals due to adverse events, n:D1: 4D2: 1D3: 12Overall: 17Withdrawals due to lack of efficacy, n:D1: 4D2: 2D3: 6Overall: 12Adherent/compliant, n:D1: 139D2: 104D3: 141Overall: 384Overall adverse events reported, n:Day 197D1: 129D2: 92D3: 140Overall: 361Day 365D1: 139D2: 92D3: 154Overall: 293Serious adverse eventsDeath, n:Day 197D1: 1D2: 0D3: 1Overall: 2Day 365D1: 1D2: 0D3: 2Overall: 3MalignanciesMalignant neoplasms, n:Day 197:D1: 1D2: 1D3: 2Overall: 4Day 365:D1: 1D2: 1D3: 2Overall: 3Respiratory eventsTuberculosis, n: 2863Pneumonia, n:Day 197:D1:2D2:0D3:2Overall: 4Day 365:D1: 2D2: 0D3: 3Overall: 5Other infectionsInfections and Infestations, n:Day 197:D1: 2D2:3D3: 7Overall: 12Day 365:D1: 3D2: 0D3: 14Overall: 17GINausea or vomiting, n:Day 197:D1: 2D2: 1D3: 6Overall: 9Day 365:D1: 3D2: D3: 7Overall: 10OtherNR Headache, n:Day 197:D1: 2D2: 2D3: 7Overall: 11Day 365:D1: 2D2: D3: 7Overall: 9Dizziness, n:Day 197:D1: 0D2:D3: 2Overall: 2Day 365:D1: 1D2: 0D3: 4Overall: 5Autoimmune symptoms and disorders:Day 197: ABA: 1Placebo: 1IFX: 1Day 365: ABA: 2IFX: 1HypotensionDay 197: ABA: 0Placebo: 0IFX: 7Day 365:ABA: 0IFX: 8FlushingDay 197: ABA: 1Placebo: 0IFX: 4Day 365ABA: 1IFX 5DyspneaDay 197: ABA: 0Placebo: 0 IFX: 4,Day 365: ABA: 0IFX: 5; UrticariaDay 197: ABA: 0Placebeo: 1IFX: 4Day 365: ABA: 0IFX: 8;PruritusDay 197: ABA: 0Placebo: 0IFX: 2Day 365: ABA: 0IFX: 5SinusitisDay 197: ABA: 1Placebo: 0IFX: 0Day 365: ABA: 1IFX: 0Postoperative wound infectionDay 197: ABA: 0Placebo: 1IFX: 0Day 365: ABA: 0IFX: 1 Soft tissue abscessDay 197: ABA: 0Placebo: 1IFX: 0Day 365:ABA: 0IFX: 0Infective bursitisDay 197: ABA: 0Placebo: 1IFX: 0Day 365: ABA: 0IFX: 0BronchitisDay 197: ABA: 0Placebo: 0IFX: 1Day 365: ABA: 0IFX: 1CellulitisDay 197: ABA: 0Placebo: 0IFX: 1Day 365: ABA: 0IFX: 1GastroenteritisDay 197: ABA: 0Placebo: 0IFX: 1Day 365: ABA: 0IFX: 1Herpes zosterDay 197: ABA: 0Placebo: 0IFX: 1Day 365: ABA: 0IFX: 1Lung infection pseudomonalDay 197: ABA: 0Placebo: 0IFX: 1Day 365: ABA: 0IFX: 1Pneumocystis jiroveci pneumoniaDay 197: ABA: 0Placebo: 0IFX: 1Day 365:ABA: 0IFX: 1Infection skin ulcerDay 197: ABA: 0Placebo: 0IFX: 0Day 365: ABA: 1IFX: 0Encephalitis herpeticDay 197: ABA: 0Placebo: 0IFX: 0Day 365: ABA: 0IFX: 1Erysipelas, Day 197: ABA: 0Placebo: 0IFX: 0Day 365: ABA: 0IFX: 1Lobar pneumoniaDay 197: ABA: 0Placebo: 0IFX: 0Day 365: ABA: 0IFX: 1Septic shockDay 197: ABA: 0Placebo: 0IFX: 0Day 365: ABA: 0IFX: 1Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableSchipper et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3705</RecNum><DisplayText><style face="superscript">151</style></DisplayText><record><rec-number>3705</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3705</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Schipper, L. G.</author><author>Fransen, J.</author><author>Barrera, P.</author><author>den Broeder, A. A.</author><author>Van Riel, P. L.</author></authors></contributors><auth-address>Department of Rheumatology, Radboud University Nijmegen Medical Centre, PO Box 9101, NL-6500 HB, Nijmegen, The Netherlands. LSchipper@reuma.umcn.nl</auth-address><titles><title>Methotrexate therapy in rheumatoid arthritis after failure to sulphasalazine: to switch or to add?</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology</full-title><abbr-1>Rheumatology (Oxford).</abbr-1><abbr-2>Rheumatology (Oxford)</abbr-2></periodical><pages>1247-53</pages><volume>48</volume><number>10</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Epidemiologic Methods</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Methotrexate/ therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Patient Selection</keyword><keyword>Sulfasalazine/ therapeutic use</keyword><keyword>Treatment Failure</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1462-0332 (Electronic)
1462-0324 (Linking)</isbn><accession-num>19638454</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 1, 3 / fair</custom4></record></Cite></EndNote>151Nijmegen RA Inception CohortCountry and settingNetherlandsSource of fundingWyethResearch objectiveTo compare the efficacy of a swtich to MTX monotherapy with that of the addition of MTX to SSZ in RA patients who had failed SSZ monotherapyStudy designObservationalOverall N230Duration of study52 wksInclusion CriteriaEarly RA symptoms less than 1 yearTreatment resistant SSZ monotherapyRA according to to 1987 ACR≥18 yrs oldNo prior use of DMARDsExclusion CriteriaUse of concomitant DMARD therapy other than MTX or SSZ at baselineComparisons (dosage and frequency)D1: MTX: 7.5 - 30 mg/weekD2: MTX: 7.5 - 30 mg/weekSSZ: 750- 3000 mg dailyNumber in groupD1: 124D2: 106Mean age (years)D1: 63.8D2: 61.8Sex, % femaleD1: 70D2: 74Race, % whiteD1: NRD2: NRRace, % blackD1: NRD2: NREthnicity, LatinoD1: NRD2: NRMean disease duration, yearsmedian (IQR): D1:14 wks (5.3, 67.3)D2: 47 wks (20.2, 109.0)TJC, meanNRSJC, mean NRCorticosteroid use, %D1: 8D2: 9DMARD use, %: Previous DMARDS other than SSZ:D1: 15D2: 13MTX na?ve, %: NRTreatment resistant, %: D1: 100D2: 100Patients with early RA, three years or less, %: D1: 100D2: 100Baseline DAS scoreD1: 5.1 (1.3)D2: 4.9 (1.3)Required treatment for latent TBD1: NRD2: NROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): At 6 mo:D1: -0.9 (1.3)D2: -0.8 (1.3)Overall: difference b/t groups: -0.05 (0.16); P=0.737At 12 mo:D1: -1.1 (1.3)D2: -0.9 (1.2)Overall: difference b/t groups 0.05 (0.15); P=0.756SF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallOverall attrition/withdrawal (n): D1: 42D2: 53Overall: 95Withdrawals due to adverse events?(n): D1: 23D2: 12Overall: 35Withdrawals due to lack of efficacy?(n): D1: 5D2: 18Overall: 23Serious adverse events:NRMalignancies:NRRespiratory events:NROther infections:NRGI:NROther:NR Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSchneeweiss et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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ADDIN EN.CITE.DATA 152Country and settingUSA, Pennsylvania Medicare beneficiariesSource of fundingEngalitcheff Arthritis Outcomes Initiatives, Baltimore, MarylandResearch objectiveAssess association between initiation of anti-TNF therapy and risk of serious bacterial infections in routine careStudy designCohort StudyOverall N15,597 courses of therapy and 5,676 patient years of exposureDuration of study1/1/1995 - 12/31/2003Quality rating FairInclusion CriteriaMedicare beneficiaries ages 65 and older with RA who initiated use of a DMARD, including anti-TNF and glucocorticoids, between 1995 and 2003; patients had to demonstrate use of health care system by filling at least 1 prescription for any drug and having at least 1 physician service in each of 2 consecutive 6-month periods in addition to being enrolled in PhDaceutical Assistance Contract for Elderly (PACE) programExclusion Criteria< 3 recoreded RA diagnoses: Any cancer (except nonmelanoma skin cancer) or human immuno-deficiency virus/acquired immuno-deficiency syndromeInterventions, DoseD1: MTX: dosage and frequency NRD2: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRD3: Other: Glucocorticoids: dosage and frequency NRD4: LEF: dosage and frequency NROther: cyclosporine, azathioprine: dosage and frequency NRD5: SSZ: dosage and frequency NRHydroxychlorquine: dosage and frequency NROther: gold, penicillamine, minocycline: dosage and frequency NRNumber in groupD1: 1900D2: 469D3: 10617D4: 654D5: 1957Overall: 15,597Mean age (years)D1: 76D2: 75D3: 79D4: 76D5: 76Sex, % femaleD1: 88D2: 91D3: 88D4: 91D5: 89Overall: 89Race, % whiteD1: 92D2: 92D3: 93D4: 92D5: 92Overall: 92.5Race, % blackD1: 7D2: 7D3: 6D4: 7D5: 7Overall: 7Ethnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: 100D2: 100D3: NRD4: 100D5: 100MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROverall: 2 hospitalizations for pulmonary TBOther population characteristics, %,?(CI/SD/P value)Followup, mean years:D1: 0.58D2: 1.29D3: 0.20D4: 0.64D5: 0.73Overall: NRNursing home resident, %:D1: 7D2: 4D3: 7D4: 7D5: 5Overall: 6.5Any hospitalization prior to index date, %:D1: 25D2: 21D3: 30D4: 22D5: 24Overall: 28Charlson comorbidity score, mean ± SDD1: 1.0 ± 1.5D2: 0.5 ± 1.2D3: 1.3 ± 1.9D4: 0.6 ± 1.4D5: 1.1 ± 1.5Overall: NRNo. of physician visits, mean ± SDD1: 6.7 ± 5.3D2: 7.7 ± 5.5D3: 6.0 ± 4.9D4: 7.3 ± 6.0D5: 6.7 ± 5.3Overall: NRNo. of different non-DMARDs used before index date, mean ± SDD1: 6.6 ± 4.4D2: 8.2 ± 5.1D3: 8.4 ± 4.8D4: 8.2 ± 4.9D5: 6.8 ± 4.5Overall: NRNo. of different DMARD classes used before index date, mean ± SDD1: 0.6 ± 0.7D2: 1.4 ± 1.0D3: 0.3 ± 0.5D4: 1.1 ± 0.9D5: 0.5 ± 0.6Overall: NRAny intraarticular procedures, %:D1: 36D2: 46D3: 24D4: 34D5: 34Overall: 27.5Any extraarticular manifestations, %:D1: 3D2: 4D3: 2D4: 4D5: 3Overall: 2.5At least 1 marker of inflammation tested during previous 180 days, %:D1: 37D2: 39D3: 20D4: 36D5: 33Overall: 25.2Any orthopedic surgeries, %:D1: 41D2: 50D3: 28D4: 38D5: 37Overall: 32Diabetes mellitus, %:D1: 8D2: 9D3: 9D4: 10D5: 8Overall: 4At least 1 antibiotic dispensed during previous 180 days, %:D1: 30.5D2: 40D3: 40D4: 43D5: 30Overall: 28Previous hospitalization for serious bacterial infections, %:D1: 3D2: 2D3: 3D4: 3D5: 3Overall: 3.2Vaccination for Influenza, %:D1: 8D2: 20D3: 12D4: 12D5: 7Overall: 11Vaccination for Pneumococcal, %:D1: 3D2:4 D3: 3% D4: 2 D5: 3 Overall: 3.1ACR NR HAQ, NR DAS NR SF-36 NR Radiographic measures NR Quality of life scales NR Others, (please name); mean difference/absolute difference (CI/SD/P Value)NR Overall4.4% of patients dropped out due to disenrollment from PACE plan. Authors also state that most patients dropped out of study because of treatment discontinuation or because they developed study outcome, however, they do not report raw data for that.Overall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsPneumonia, n:D1: No. of events:?16, Event rate per 100 patient years (95% CI):?1.47 (0.75 - 2.18)D2: No. of events:?14, Event rate per 100 patient years (95% CI):?2.33(1.12-3.54)D3: No. of events:?67, Event rate per 100 patient years (95% CI):?3.16 (2.41-3.91)D4: No. of events: 6, Event rate per 100 patient years (95% CI): 1.43 (0.29-2.57)D 5: No. of events: 13, Event rate per 100 patient years (95% CI): 0.91 (0.42-1.40)Overall: No. of events: 116Other infectionsSepticemia or bacteremia, n:D1: No. of events:?24, Event rate per 100 patient years (95% CI):?2.20(1.33-3.07); Osteomyelitis, No. of events:?7, Event rate per 100 patient years (95% CI):?0.27 (0.07-0.48); Any bacterial infection, No. of events:?41, Event rate per 100 patient years (95% CI):?3.77 (2.64-4.9)D2: No. of events:?13, Event rate per 100 patient years (95% CI):?2.16 (1.00-3.32); Osteomyelitis, No. of events:?3, Event rate per 100 patient years (95% CI):?0.49 (000-1.05); Any bacterial infection, No. of events:?29, Event rate per 100 patient years (95% CI):?4.89 (3.15-6.62)D3: No. of events:?133, Event rate per 100 patient years (95% CI):?6.34 (5.3-7.38); Osteomyelitis, No. of events:?17, Event rate per 100 patient years (95% CI):?0.80 (0.42-1.18); Any bacterial infection, No. of events:?196, Event rate per 100 patient years (95% CI):?9.39 (8.14-10.6)D4: No. of events:?15, Event rate per 100 patient years (95% CI):?3.66 (1.84-5.48); Osteomyelitis, No. of events:?2, Event rate per 100 patient years (95% CI):?0.48 (000-1.14); Any bacterial infection, No. of events:?22, Event rate per 100 patient years (95% CI):?5.36 (3.18-7.54)D5: No. of events:?33, Event rate per 100 patient years (95% CI):?2.31 (1.53-3.09); Osteomyelitis, No. of events:?9, Event rate per 100 patient years (95% CI):?0.63 (0.22-1.04); Any bacterial infection, No. of events:?53, Event rate per 100 patient years (95% CI):?3.75 (2.70-4.74)Overall: No. of events:?218; Osteomyelitis, No. of events:?38; Any bacterial infection, No. of events:?341GINR OtherNR Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Setoguchi et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2071</RecNum><DisplayText><style face="superscript">153</style></DisplayText><record><rec-number>2071</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2071</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Setoguchi, S.</author><author>Solomon, D. H.</author><author>Weinblatt, M. E.</author><author>Katz, J. N.</author><author>Avorn, J.</author><author>Glynn, R. J.</author><author>Cook, E. F.</author><author>Carney, G.</author><author>Schneeweiss, S.</author></authors></contributors><auth-address>Division of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02130, USA. ssetoguchi@</auth-address><titles><title>Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2757-64</pages><volume>54</volume><number>9</number><keywords><keyword>Aged</keyword><keyword>Antirheumatic Agents/adverse effects/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ complications/drug therapy</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neoplasms/ epidemiology</keyword><keyword>Proportional Hazards Models</keyword><keyword>Regression Analysis</keyword><keyword>Risk Assessment</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists & inhibitors</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><accession-num>16947774</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4></record></Cite></EndNote>153Country, Setting:US and Canada,3 databasesFunding:Novartis andNIHResearch Objective:To estimate association between treatment with biologic DMARDs and development of cancer in pts with RAStudy Design:Cohort StudyOverall N:7,830Study Duration: 1994 to 2004 in US1996 to 2003 in CanadaInclusion Criteria:Age > 651 claim with a diagnosis of RA and who were dispensed at least 1 prescription of any DMARD or corticosteroid after first RA diagnosisExclusion Criteria:Diagnosis of any cancer (except nonmelanoma skin cancer) or human immuno-deficiency virus infectionInterventions:D1: Biologic DMARDD2: MTXN:D1: 1152D2: 7306Mean age (yrs):D1: 71.4D2: 73.4Sex, % female:D1: 75.3D2: 73.1Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:D1: 51.3D2: 41.5MTX naive, %:NRTreatment resistant %: NRPatients with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRA pts vs. overall populationNon-Hodgkin's lymphoma-PY 33,335.0 Observed 58 Expected 26.0 SIR 2.2 95% CI,1.71-2.87 Multiple myeloma-PY yrs 33,410.0 Observed 19 Expected 9.3 SIR 2.0 95% CI,1.26-3.12Melanoma-PY 33,377.7 Observed 29 Expected 12.8 SIR 2.3 95% CI,1.55-3.22 Colorectal cancer-PY 32,844.9 Observed 118 Expected 97.3 SIR 1.2 95% CI,1.01-1.45 Lung cancer-PY 31,532.8 Observed 169 Expected 95.6 SIR 1.8 95% CI,1.52-2.05 Urinary tract/bladder cancer-PY 33,367.0 Observed 54 Expected 26.4 SIR 2.0 95% CI,1.55-2.65 Biologics vs. MTX Unadjusted Lymphoproliferative HR 1.20 (95% CI,0.57-2.51) Hematologic HR 1.45 (95% CI,0.76-2.74) Solid HR 0.91 (95% CI,0.66-1.25) Overall HR 1.00 (95% CI,0.75-1.33)See health outcomesOverall Attrition Rate, %:NAITT Analysis:Not applicable Observational studyQuality Rating:GoodStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSetoguchi et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI1
ODk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xNTQ8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yNTg5PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNTlhc3hzeHZ5Znh4eHZlZTAycHBheHdm
d2YwZnNmejI5NXY5Ij4yNTg5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikdl
bmVyaWMiPjEzPC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+U2V0b2d1
Y2hpLCBTLjwvYXV0aG9yPjxhdXRob3I+U2NobmVld2Vpc3MsIFMuPC9hdXRob3I+PGF1dGhvcj5B
dm9ybiwgSi48L2F1dGhvcj48YXV0aG9yPkthdHosIEouIE4uPC9hdXRob3I+PGF1dGhvcj5XZWlu
YmxhdHQsIE0uIEUuPC9hdXRob3I+PGF1dGhvcj5MZXZpbiwgUi48L2F1dGhvcj48YXV0aG9yPlNv
bG9tb24sIEQuIEguPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl
c3M+RGl2aXNpb25zIG9mIFBoYXJtYWNvZXBpZGVtaW9sb2d5IGFuZCBQaGFybWFjb2Vjb25vbWlj
cywgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgQnJpZ2hhbSBhbmQgV29tZW4mYXBvcztzIEhvc3Bp
dGFsIGFuZCBIYXJ2YXJkIE1lZGljYWxTY2hvb2wsIEJvc3RvbiwgTUEgMDIxMzAsIFVTQS4gc3Nl
dG9ndWNoaUBwYXJ0bmVycy5vcmcgJmx0O3NzZXRvZ3VjaGlAcGFydG5lcnMub3JnJmd0OzwvYXV0
aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlR1bW9yIG5lY3Jvc2lzIGZhY3Rvci1hbHBoYSBhbnRh
Z29uaXN0IHVzZSBhbmQgaGVhcnQgZmFpbHVyZSBpbiBlbGRlcmx5IHBhdGllbnRzIHdpdGggcmhl
dW1hdG9pZCBhcnRocml0aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSGVhcnQgSjwvc2Vj
b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtZXJpY2FuIEhl
YXJ0IEpvdXJuYWw8L2Z1bGwtdGl0bGU+PGFiYnItMT5BbS4gSGVhcnQgSi48L2FiYnItMT48YWJi
ci0yPkFtIEhlYXJ0IEo8L2FiYnItMj48L3BlcmlvZGljYWw+PHBhZ2VzPjMzNi00MTwvcGFnZXM+
PHZvbHVtZT4xNTY8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+
QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbnRp
cmhldW1hdGljIEFnZW50cy8gYWR2ZXJzZSBlZmZlY3RzL3RoZXJhcGV1dGljIHVzZTwva2V5d29y
ZD48a2V5d29yZD5BcnRocml0aXMsIFJoZXVtYXRvaWQvY29tcGxpY2F0aW9ucy8gZHJ1ZyB0aGVy
YXB5PC9rZXl3b3JkPjxrZXl3b3JkPkNvaG9ydCBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkNv
bmZvdW5kaW5nIEZhY3RvcnMgKEVwaWRlbWlvbG9neSk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxl
PC9rZXl3b3JkPjxrZXl3b3JkPkhlYXJ0IEZhaWx1cmUvIGV0aW9sb2d5L21vcnRhbGl0eTwva2V5
d29yZD48a2V5d29yZD5Ib3NwaXRhbGl6YXRpb24vc3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwg
ZGF0YTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5
d29yZD48a2V5d29yZD5NZXRob3RyZXhhdGUvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3
b3JkPlByb3BvcnRpb25hbCBIYXphcmRzIE1vZGVsczwva2V5d29yZD48a2V5d29yZD5SZXRyb3Nw
ZWN0aXZlIFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Umlzazwva2V5d29yZD48a2V5d29yZD5U
dW1vciBOZWNyb3NpcyBGYWN0b3ItYWxwaGEvIGFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8
L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVzPjxk
YXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwOTctNjc0NCAoRWxlY3Ry
b25pYyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MTg2NTc2NjU8L2FjY2Vzc2lvbi1udW0+PHVybHM+
PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9tMz5P
PC9jdXN0b20zPjxjdXN0b200PktRIDMgLyBnb29kPC9jdXN0b200PjwvcmVjb3JkPjwvQ2l0ZT48
L0VuZE5vdGU+AG==
ADDIN EN.CITE.DATA 154Country and settingUSA, Medicare and drug benefit programs in Pennsylvania and New JerseySource of fundingNot reportedResearch objectiveEstimate risk of heart failure hospitalization in elderly TNFα users with and without previous heart failureStudy designRetrospective Cohort StudyOverall N5593Duration of studyJanuary 1, 1994 - December 31, 2004Quality rating Good: For an observational study, this is quite good with appropriate adjustment and analysisInclusion Criteria≥ 65 years oldAt least one recorded diagnosis of RAFilled at least 1 prescription of any TNFA (ETN, IFX, ADA) or MTX after first RA diagnosisAt least one clinical service during each of 4 consecutive 6-month periods before use of DMARDsExclusion CriteriaPts who had a diagnosis of heart failure in an outpatient file but none noted in a hospital discharge summaryInterventions, DoseD1: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRD2: MTX: dosage and frequency NRD3: ETN: dosage and frequency NRIFX: dosage and frequency NRADA: dosage and frequency NRD4: MTX: dosage and frequency NRNumber in groupD1: 225D2: 808D3: 777D4: 3783Overall: 5593Mean age (years)D1: 73D2: 77D3: 72D4: 74Sex, % femaleD1: 89D2: 84D3: 90D4: 89Race, % whiteD1: 88D2: 92D3: 89D4: 91Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: 67D2: 56D3: 59D4: 48DMARD use, %D1: 100D2: 100D3: 100D4: 100Overall: 100MTX na?ve, %D1: NRD2: 0D3: NRD4: 0Baseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Average follow-up, mean (SD):?1.6 (1.5)RA severity-related covariates RA-related surgery:?7%Extra-articular manifestations:?39%Arthocentesis:?64%Injection (joint, tendon, etc):?23%Corticosteorids:?67%Other cytotoxic DMARDs:?24%Noncytotoxic DMARDs:?35%COX2 inhibitors:?48%MI hospitalization:?17%Ischemic heart disease:?66%Valvular heart disease:?45%Cardiomyopathy:?18%Cardiac surgery:?10%1 Prior HF hospitalization:?13%2 Prior HF hospitalization:?5%3 Prior HR hospitalizations:?1%Vascular surgery:?29%Ventricular arrhythmia/ cardiac arrest:?2%Atrial fibrilation:?39%Other dysrhythmias:?24%Intervention for arrhythmia:?4%Cerebrovascular diseases:?29%Hypertension:?92%Hyperlipidemia:?64%Diabetes:?48%Chronic kidney diseases:?33%Dialysis:?1%Anemia:?64%Hypothyroidism:?17%Chronic airway diseases:?60%Cancer:?22%Anxiety or depression 55% D2: Average follow-up, mean (SD):?1.7 (1.9)RA-related surgery:?4%Extra-articular manifestations:?34%Arthocentesis:?53%Injection (joint, tendon, etc):?12%Corticosteorids:?56%Other cytotoxic DMARDs:?4%Noncytotoxic DMARDs:?22%COX2 inhibitors:?26%MI hospitalization:?15%Ischemic heart disease:?63%Valvular heart disease:?39%Cardiomyopathy:?19%Cardiac surgery:?9%1 Prior HF hospitalization:?17%2 Prior HF hospitalization:?2%3 Prior HR hospitalizations:?1%Vascular surgery:?27%Ventricular arrhythmia/ cardiac arrest:?2%Atrial fibrilation:?37%Other dysrhythmias:?21%Intervention for arrhythmia:?6%Cerebrovascular diseases:?34%Hypertension:?87%Hyperlipidemia:?53%Diabetes:?47%Chronic kidney diseases:?25%Dialysis:?0%Anemia:?52%Hypothyroidism:?17%Chronic airway diseases:?53%Cancer:?19%Anxiety or depression 48% D3: Average follow-up, mean (SD):?1.8 (1.6)RA-related surgery:?10%Extra-articular manifestations:?28%Arthocentesis:?58%Injection (joint, tendon, etc):?16%Corticosteorids:?59%Other cytotoxic DMARDs:?24%Noncytotoxic DMARDs:?32%COX2 inhibitors:?48%MI hospitalization:?3%Ischemic heart disease:?21%Valvular heart disease:?20%Cardiomyopathy:?5%Cardiac surgery:?1%Vascular surgery:?12%Ventricular arrhythmia/ cardiac arrest:?1%Atrial fibrilation:?8%Other dysrhythmias:?8%Intervention for arrhythmia:?1%Cerebrovascular diseases:?13%Hypertension:?72%Hyperlipidemia:?58%Diabetes:?31%Chronic kidney diseases:?15%Dialysis:?0%Anemia:?55%Hypothyroidism:?12%Chronic airway diseases:?34%Cancer:?13%Anxiety or depression:?43% D4: Average follow-up, mean (SD):?2.5 (2.4)RA-related surgery:?6%Extra-articular manifestations:?23%Arthocentesis:?48%Injection (joint, tendon, etc):?11%Corticosteorids:?48%Other cytotoxic DMARDs:?5%Noncytotoxic DMARDs:?26%COX2 inhibitors:?24%MI hospitalization:?3%Ischemic heart disease:?19%Valvular heart disease:?16%Cardiomyopathy:?5%Cardiac surgery:?1%Vascular surgery:?14%Ventricular arrhythmia/ cardiac arrest:?0%Atrial fibrilation:?8%Other dysrhythmias:?6%Intervention for arrhythmia:?1%Cerebrovascular diseases:?16%Hypertension:?70%Hyperlipidemia:?46%Diabetes:?27%Chronic kidney diseases:?10%Dialysis:?0%Anemia:?47%Hypothyroidism:?11%Chronic airway diseases:?29%Cancer:?14%Anxiety or depression:?35% ACR NRHAQ, NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNAOverall adverse events reported, n:NRSerious adverse eventsDeath, n: NR Overall: All TNFA users:?22; All MTX users:?85; Overall:?107Cardiovascular events (specify), n:D1: Heart failure admissions:?33 per 304 person-years, incidence rate:?108D2: Heart failure admissions:?101 per 1333 person-years, incidence rate:?76D3: Heart failure admissions:?26 per 1375 person-years, incidence rate:?19D4: Heart failure admissions: 126 per 9290 person-years, incidence rate: 14Overall: All TNFA users, Heart failure admissions: 59 per 1680 person-years, incidence rate: 35All MTX users, Heart failure admissions: 227 per 10623 person-years, incidence rate: 21MalignanciesNRRespiratory eventsNROther infectionsNRGINROtherEffects of TNFAs compared to MTX on HF and/or death, With previous heart failure, fully adjusted: HR:?1.75, 95% CI (0.86 - 3.56)Without previous heart failure, fully adjusted: HR:?2.07, 95% CI (1.00 - 4.25)2 groups combined: HR:?1.70, 95% CI (1.07 - 2.69)Risk of death among patients with previous HF (TNFA users compared with MTX users): adjusted HR:?4.19, 95% (CI 1.48 - 11.89)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Shin et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1986</RecNum><DisplayText><style face="superscript">155</style></DisplayText><record><rec-number>1986</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1986</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shin, I. S.</author><author>Baer, A. N.</author><author>Kwon, H. J.</author><author>Papadopoulos, E. J.</author><author>Siegel, J. N.</author></authors></contributors><auth-address>State University of New York at Buffalo, USA.</auth-address><titles><title>Guillain-Barre and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1429-34</pages><volume>54</volume><number>5</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Antibodies, Monoclonal/ adverse effects/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/drug therapy</keyword><keyword>Female</keyword><keyword>Guillain-Barre Syndrome/ chemically induced</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Miller Fisher Syndrome/ chemically induced</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists & inhibitors</keyword></keywords><dates><year>2006</year><pub-dates><date>May</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>16645971</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>PT 10-9 (KD 9-13)</custom7></record></Cite></EndNote>155Country, Setting:USFunding:NRResearch Objective:Review occurence and clinical features of Guillan Barre syndrome and Miller Fisher Syndrome during TNF alpha antagonist therapyStudy Design:Database analysis; AERS Overall N:16 casesStudy Duration: NRInclusion Criteria:TNF alpha antagonist therapy in AERS databaseExclusion Criteria:NAInterventions, dose:NRETAINFN:NRMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRGuillain-Barre was temporally associated with INF in 10 pts, ETA in 5 pts. This compares to an annual incidence of Guillain Barre Syndrome of 1-3/100,000 populationNROverall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Slifman, 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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=
ADDIN EN.CITE.DATA 156Country, Setting:Multinational, multicenterFunding:NRResearch Objective:To evaluate postlicensure cases of opportunistic infection, including Listeria monocytogenes, in pts treated with TNFsStudy Design:Database analysis; AERSOverall N:15 casesStudy Duration: VariedInclusion Criteria:Age: 17 to 80Pts with Listeria monocytogenes treated with ETA or INF for RA or Crohn’s diseaseConcurrent use of immuno-suppressant drugs allowedExclusion Criteria:NAInterventions, dose:D1: INF or ETAETA: variedINF: variedN:D1: 15Median age, yrs:D1: 69.5Sex, % female:D1: 53.3Race, % white:D1: NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRA:D1: 64%For all ages and indications, the estimated rate of cases (reporting rates) of listeriosis reported to FDA within first yr of starting txt with inf was 43 cases per 1,000,000 persons (8/186,500)RA pts treated with inf (US cases only), estimated rate of cases of listeriosis reported to FDA was 61 cases per 1,000,000 persons (5/82,000)In 2000, annual incidence of listeriosis in US for all ages was estimated to be 3 cases per 1,000,0006 deaths reported (5 INF, 1 ETA)Among reports from US only, this series included 8 cases of Listeria infection, all of which were associated with INF txtNROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmitten et al., 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI4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=
ADDIN EN.CITE.DATA 157Country and settingUS & UK. mulitcenterSource of fundingData provided by Bristol-Myers Squibb Company and Harvard PhDaco- epidemiology ProgramResearch objectiveDetermine if RA pts have an elevated risk for herpes zoster & if their risk is associated with DMARD txStudy designRetrospective Cohort StudyOverall NPhDetrics (PM) Database: 12272 with RA; UK General Practice Research Database (GPRD) 38621 with RADuration of studyPhDetrics: mean?=?12.3 mosGPRD: mean?=?38.8 mosQuality rating Fair: Matching did not account for Disease Activity or Severity which could confound results. Higher DAS?=?increased disregulation of immune sys? or different dose of drugs could lead to levels of impact on immune system response?Inclusion CriteriaPhDetrics: enrolled on 1/61 health care plans in US, RA Cohort had to be 18+ and have at least 1 ICD-9 code for RA. GPRD: at least 18 years of age at cohort entry who had at least 90 days of up-to-standard dataExclusion CriteriaPhDetrics: RA Cohort - ICD9 714.3 (Juvenile Chronic Polyarthritis), 714.9 (unspecified inflammatory polyarthropathies). Patients who were enrolled in Medicare gap plans, were missing a value for age or sex, had?=?90 days of continuous enrollment, or had a diagnosis of herpes zoster in 90 days prior to cohort entry were excludedInterventions, DoseD1: Oral DMARDSD2: BiologicsD3: CorticosteroidsD4: Combination therapyNumber in groupD1: 1611D2: 11277D3: 1719D4: 12033Overall: NRMean age (years)D1: 55.4D2: 51.1D3: 63.9D4: 60.6Overall: NRSex, % femaleD1: 75.4D2: 73.1D3: 74.1D4: 72.5Overall: NRRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?NRACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherCompared to pts who had not received DMARDS or Corticosteroids, pts in both databases showed an increased risk for herpes zoster if treated with traditional DMARDS alone (PhDetrics: 1.37, 95%CI:1.18-1.59; GPRD 1.27, 95%CI:1.10-1.48), Oral Corticosteroids alone (PhDetrics: 2.51 95%CI: 2.05-3.06; GPRD 1.46 95%CI: 1.24-1.70) and Traditional DMARDS + Corticosteroids (PhDetrics: 2.39 CI:1.99-2.88); GPRD: 1.82 CI:1.46-2.26) PhDetrics pts on biologics DMARDS alone (1.54, 1.04-2.29), Biologic DMARDS + Corticosteroids (2.44, 1.26-4.73), and or Biologics + Traditional DMARDS + Corticosteroids (1.96, 0.99-3.86) showed an increased risk for herpes zoster while pts treated with a combination of Biologics + Traditional DMARDS (1.38,0.83-2.27) did not show a significantly increase risk. (referant for all comparisons - no DMARD or Corticosteroid) Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmitten et al., 2008 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2784</RecNum><DisplayText><style face="superscript">158</style></DisplayText><record><rec-number>2784</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2784</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Smitten, A. L.</author><author>Choi, H. K.</author><author>Hochberg, M. C.</author><author>Suissa, S.</author><author>Simon, T. A.</author><author>Testa, M. A.</author><author>Chan, K. A.</author></authors></contributors><auth-address>Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.</auth-address><titles><title>The risk of hospitalized infection in patients with rheumatoid arthritis</title><secondary-title>J Rheumatol</secondary-title></titles><periodical><full-title>Journal of Rheumatology</full-title><abbr-1>J. Rheumatol.</abbr-1><abbr-2>J Rheumatol</abbr-2></periodical><pages>387-93</pages><volume>35</volume><number>3</number><keywords><keyword>Adolescent</keyword><keyword>Adrenal Cortex Hormones/ adverse effects</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/complications/ drug therapy</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Cross Infection/ etiology/immunology</keyword><keyword>Databases, Factual</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Retrospective Studies</keyword><keyword>Risk</keyword></keywords><dates><year>2008</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0315-162X (Print)</isbn><accession-num>18260176</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / good</custom4></record></Cite></EndNote>158Country and settingUnited StatesSource of fundingData provided by Bristol-Myers Squibb Company and Harvard PhDaco- epidemiology ProgramResearch objectiveAssess whether risk of hospitalized infection in RA pts is higher during use of newer biological DMARDsStudy designRetrospective Cohort StudyOverall N24,530 (RA cohort only)Duration of study26.6 months (mean follow-up time of RA cohort)Quality rating Good: large sample size but unevenly distributed between treatment Ds; disease severity not accounted forInclusion CriteriaAt least 18 years old, with at least 2 physician visits 2 months apart for RA with an ICD-9-CM code of 714Exclusion CriteriaICD-9-CM codes: 714.3 (juvenile chronic polyarthritis), 714.4 (chronic postrheumatic arthropathy), 714.9 (unspecified inflammatory polyarthropathy); subjects missing values for age or sex; experienced an outcome of interest in 90 days period to cohort entry; enrolled in plans that provide supplementary insurance to MedicareInterventions, DoseD1: Biological DMARDs (IFX, ETN, ADA, ANK)D2: MTX: dose NRD3: Hydroxychlorquine: dose NRD4: LEF: dose NRD5: SSZ: dose NRD6: Oral Corticosteroids (separate D)Number in groupD1: 2,248D2: 5,077D3: 2,992D4: 907D5: 858D6: 4,390Overall: 24,530Mean age (years)D1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: Age 18-44: 26.5%; Age 45-64: 66.3%; Age 65+: 7.2%Sex, % femaleD1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: 75.7Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: 17.9DMARD use, %D1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: Traditional: 41.17 Biologic: 9.17MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Overall: 0 comorbid conditions: 77.0%1-2 comorbid conditions: 21.8%; 3+ comorbid conditions: 59.4%ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)OverallNAOverall adverse events reported, n:D1: 254D2: 352D3: 172D4: 90D5: 44D6: 442Overall: 1,993Serious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NR Pneumonia, n:D1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: 434Upper respiratory infection, n: NROther infectionsUrinary tract infection, n:D1: NRD2: NRD3: NRD4: NRD5: NRD6: NROverall: 250Other infections (specify), n:D1: Hospitalized infections: 254D2: 352D3: 172D4: 90D5: 44D6: 442Overall: Overall hospital infections: 1,993Skin: 257Sepsis: 198Opportunistic: 11Serious (requiring outpatient parenteral antibiotics): 3,010GINROtherNumber of Hospitalized Infections-Oral Corticosteroids 5 mg/day or less: 144; 6-10 mg/day: 119; greater than 10 mg/day: 179Unadjusted and Adjusted Rate Ratio (95% CI), respectively, for hospitalized infection in patients with RA:D1: 1.05 (0.91-1.22); 1.21 (1.02-1.43)D2: 0.76 (0.67-0.86); 0.81 (0.70-0.93)D3: 0.68 (0.58-0.81); 0.74 (0.62-0.89)D4: 1.05 (0.84-1.33); 1.02 (0.79-1.32)D5: 0.66 (0.48-0.91); 0.82 (0.58-1.38)D6: 1.83 (1.62-2.07); 1.92 (1.67-2.21)5 mg/day or less oral corticosteroids: 1.28 (1.06-1.55); 1.32 (1.06-1.63); 6-10 mg/day oral corticosteroids: 1.79 (1.44-2.21); 1.94 (1.53-2.46); greater than 10 mg/day oral corticosteroids: 2.89 (2.39-3.49); 2.98 (2.41-3.69)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, year:Smolen et al., 1999; ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1625</RecNum><DisplayText><style face="superscript">159</style></DisplayText><record><rec-number>1625</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1625</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smolen, J S</author><author>Kalden, J R</author><author>Scott, D L</author><author>Rozman, B</author><author>Kvien, T K</author><author>Larsen, A</author><author>Loew-Friedrich, I</author><author>Oed, C</author><author>Rosenburg, R</author></authors></contributors><titles><title>Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>259-66</pages><volume>353</volume><number>9149</number><keywords><keyword>CN-00413583</keyword><keyword>RCT</keyword></keywords><dates><year>1999</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>-- Goes w/ #1626, continuation 1560, 1575, 1571, 1606</custom7></record></Cite></EndNote>159; Smolen et al., 1999 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1626</RecNum><DisplayText><style face="superscript">160</style></DisplayText><record><rec-number>1626</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1626</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smolen, J. S.</author></authors></contributors><titles><title>Efficacy and safety of the new DMARD leflunomide: comparison to placebo and sulfasalazine in active rheumatoid arthritis</title><secondary-title>Scandinavian journal of rheumatology</secondary-title></titles><periodical><full-title>Scandinavian Journal of Rheumatology</full-title><abbr-1>Scand. J. Rheumatol.</abbr-1><abbr-2>Scand J Rheumatol</abbr-2></periodical><pages>15-21</pages><volume>112</volume><number>Supplement</number><keywords><keyword>CN-00275013</keyword></keywords><dates><year>1999</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,3</custom4><custom7>-- Goes w/ #1625; continuation 1560, 1575, 1571, 1606</custom7><research-notes>included in a meta-analysis but abstracted for certain outcomes</research-notes></record></Cite></EndNote>160; Sharp et al., 2000 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1606</RecNum><DisplayText><style face="superscript">161</style></DisplayText><record><rec-number>1606</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1606</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sharp, J T</author><author>Strand, V</author><author>Leung, H</author><author>Hurley, F</author><author>Loew-Friedrich, I</author></authors></contributors><titles><title>Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>495-505</pages><volume>43</volume><number>3</number><keywords><keyword>CN-00478047</keyword><keyword>RCT</keyword></keywords><dates><year>2000</year></dates><label>MA 1430; radiographic results from 1625, 1640, 1929, 1560
abstracted w/ 1625, 1626, 1575</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1</custom4><custom7>PT</custom7><research-notes>Radiographic outcomes only</research-notes></record></Cite></EndNote>161; Larsen et al., 2001 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1571</RecNum><DisplayText><style face="superscript">162</style></DisplayText><record><rec-number>1571</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1571</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larsen, A</author><author>Kvien, T K</author><author>Schattenkirchner, M</author><author>Rau, R</author><author>Scott, D L</author><author>Smolen, J S</author><author>Rozman, B</author><author>Westhovens, R</author><author>Tikly, M</author><author>Oed, C</author><author>Rosenburg, R</author></authors></contributors><titles><title>Slowing of disease progression in rheumatoid arthritis patients during long-term treatment with leflunomide or sulfasalazine</title><secondary-title>Scandinavian journal of rheumatology</secondary-title></titles><periodical><full-title>Scandinavian Journal of Rheumatology</full-title><abbr-1>Scand. J. Rheumatol.</abbr-1><abbr-2>Scand J Rheumatol</abbr-2></periodical><pages>135-42</pages><volume>30</volume><number>3</number><keywords><keyword>CN-00349647</keyword></keywords><dates><year>2001</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1</custom4><custom7>-- goes w/1560, 1575 (continuation); original trial 1625, 1626</custom7></record></Cite></EndNote>162; Scott et al., 2001 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1575</RecNum><DisplayText><style face="superscript">163</style></DisplayText><record><rec-number>1575</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1575</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scott, D L</author><author>Smolen, J S</author><author>Kalden, J R</author><author>van de Putte, L B</author><author>Larsen, A</author><author>Kvien, T K</author><author>Schattenkirchner, M</author><author>Nash, P</author><author>Oed, C</author><author>Loew-Friedrich, I</author></authors></contributors><titles><title>Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine</title><secondary-title>Annals of the rheumatic diseases</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>913-23</pages><volume>60</volume><number>10</number><keywords><keyword>CN-00356399</keyword></keywords><dates><year>2001</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>2</custom4><custom7>-- goes w/1560, 1571 (continuation); original trial 1625, 1626, 1606</custom7></record></Cite></EndNote>163Country, Setting:Multinational, multicenterFunding:Hoechst Marion RousselResearch Objective:Efficacy and safety of LEF was compared to placebo and SSZ Study Design:RCTOverall N:266 (358 including placebo arm)Study Duration: 24 wks (12 and 24 month followup)Inclusion Criteria:Age: > 18Active RA defined by: ≥ 6 tender and swollen joints, based on a 28-joint count, physician and pt global assessments of RA activity of "fair, poor, or very poor", CRP > 2.0 mg/dL or ESR > 28 mm/hFunctional class I – IIIOther DMARDs discontinued > 4 wksStable doses of NSAIDS permitted -acetylsalicylic acid, oral steroids (prednisolone ≤ 10 mg/day), and up to 3 intra-articular steroid injections, not exceeding 60 mg triamcinoloneIntra-articular steroid injections not permitted during first 6 mos Exclusion Criteria:Pregnant or lactatingInterventions:D1: LEFD2: SSZN:D1: 133D2: 133Mean age, yrs:D1: 58.3D2: 58.9Sex, % female:D1: 75.9D2: 69.2Race, % white:NRMean disease duration, yrs:D1: 7.6D2: 7.4TJC, mean:NRSJC, mean:NRDMARD use, %:D1: 60.2D2: 48.9Corticosteroid use, %:D1: 28.6D2: 27.8MTX naive, %:NRTreatment resistant, %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRF positive: D1: 79%D2: 80%At 24 weeks ACR 20, %:D1: 55 D2: 56ACR 50, %:D1: 33 D2: 30Improving HAQ scores, change (%):D1: -0.50 (45) D2: -0.29 (29) (P = 0.0086)Change in Sharp; number, change (SD): D1: 87 1.23 (2.85)D2: 84 2.32 (10.11)Larsen score change: D1: 0.01D2: 0.01 (P = NS)At 1 yearChange in Sharp; number, change (SD): D1: 60 0.97 (6.11) D2: 53 1.38 (2.88)Larsen score change: D1: 0.02D2: 0.02 (P = NS)At 2 yearsLarsen score change: D1: -0.07D2: -0.02 (P = NS)Similar ACR20 response rates D1: 48; D2: 44; P=NRSAEs:D1: 5D2: 7Headache:D1: 7D2: 11Nausea:D1: 10D2: 17URTI:D1: 14D2: 15Diarrhea: D1: 17D2: 9Alopecia:D1: 8D2: 5Rash: D1: 10D2: 9Withdrawal due to AEs: D1: 14D2: 192 cases of reversible agranulocytosis in SSZOverall Attrition Rate, %:33% at 24 wksITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmolen et al., 2008, OPTION ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3570</RecNum><DisplayText><style face="superscript">164</style></DisplayText><record><rec-number>3570</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3570</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Smolen, J. S.</author><author>Beaulieu, A.</author><author>Rubbert-Roth, A.</author><author>Ramos-Remus, C.</author><author>Rovensky, J.</author><author>Alecock, E.</author><author>Woodworth, T.</author><author>Alten, R.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. josef.smolen@meduniwien.ac.at</auth-address><titles><title>Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title><abbr-1>Lancet</abbr-1><abbr-2>Lancet</abbr-2></periodical><pages>987-97</pages><volume>371</volume><number>9617</number><keywords><keyword>Antibodies, Monoclonal/administration & dosage/adverse effects/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/classification/ drug therapy/physiopathology</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Double-Blind Method</keyword><keyword>Drug Administration Schedule</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Quality of Life</keyword><keyword>Severity of Illness Index</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2008</year><pub-dates><date>Mar 22</date></pub-dates></dates><isbn>1474-547X (Electronic)</isbn><accession-num>18358926</accession-num><urls></urls><custom1>I</custom1><custom2>I MTC</custom2><custom3>CT</custom3><custom4>KQ 1, 2, 3 / fair</custom4></record></Cite></EndNote>164Country and settingInternational, multicenterSource of fundingF Hoffman-La Roche and Chugai PharmaceuticalResearch objectiveAssess efficacy of tocilizumab in RA pts who were receiving background MTX therapyStudy designControlled TrialsOverall N622 (623 were randomized, however 1 subject never received study drug and was withdrawn. Data tables have total n of 622)Duration of study24 wks (Safety: 32 wks)Quality rating Fair Inclusion CriteriaTreatment resistant, adult patientsInadequate response to MTXModerate to severe active RA (diagnosed according to ACR criteria) criteria of more than 6 mos' durationInadequate response to MTXActive disease was defined by an SJC of 6 or more plus a TJC of 8 or more and CRP over 10 mg/L or ESR of 28 mm/h or morePatients had to have received MTX for 12 weeks or longer beforestart ofstudy (stable dose of 10-25 mg/week for 8 weeks or longer)Exclusion CriteriaAutoimmune diseases or significant systemic involvement secondary to RA (e.g., vasculitis, pulmonary fi brosis, or Felty's syndrome)Functional class IV RAPrevious or current inflammatory joint disease other than RACurrently active or previous recurrent bacterial, viral, fungal, or other infections including, but not limited to, TB and atypical mycobacterial disease, clinically significant abnormalities on chest radiograph, hepatitis B and C, and recurrent herpes zoster (Also, investigators were encouraged to exclude potential pts if, in their judgment, they had a history of unacceptably frequent recurrent infections.)Active liver disease, indicated by screening and baseline concentrations of alanine or aspartate aminotransferase of 1 - 5 time supper limit of normal or morePrevious unsuccessful treatment with an anti-TNF agent (i.e., lack of efficacy or significant safety issues, terminations due to cost or injection discomfort were not excluded)Interventions, doseD1: MTX: 10 - 25 mg once/weekTocilizumab: 4 mg/kg every 4 wksD2: MTX: 10 - 25 mg once/weekTocilizumab: 8 mg/kg every 4 wksD3: MTX: 10 - 25 mg once/weekPlaceboNumber in groupD1: 213D2: 205D3: 204Overall: 622Mean age, years (SD)D1: 51.4D2: 50.8D3: 50.6Overall: NRSex, % femaleD1: 82D2: 85D3: 78Overall: 82Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 7.4 D2: 7.5 D3: 7.8 Overall: NR Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanD1: 33.2 (15.6)D2: 31.9 (15.5)D3: 32.8 (16.1)Swollen Joint Count, mean D1: 20.0 (10.9)D2: 19.5 (11.3)D3: 20.7 (11.7)Corticosteroid use, %D1: 55D2: 55D3: 54Overall: 55DMARD use, %D1: 100D2: 100D3: 100Overall: 100MTX na?ve, %D1: 0D2: 0D3: 0Overall: 0Baseline DAS scoreD1: 6.8D2: 6.8D3: 6.8Required treatment for latent TBNRACR ACR 20:D1: 48D2: 59D3: 26Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)ACR 50:D1: 31D2: 44D3: 11Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)ACR 70:D1: 12D2: 22D3: 2Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)HAQ, D1: -0.52D2: -0.55D3: -0.34Overall: 4 mg/kg vs. Placebo (P?=?0.0296), 8 mg/kg vs. Placebo (P?=?0.0082)DAS28?=?2.6 (%)D1: 13D2: 27D3: 0.8Overall: 4 mg/kg vs. Placebo (P?=?0.0002), 8 mg/kg vs. Placebo (P?=?0.0001)SF-36 PhysicalD1: 9.7D2: 9.5D3: 5.0Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)MentalD1: 5.7D2: 7.3D3: 2.7Overall: 4Radiographic measures NRQuality of life scales Patient pain VAS (mm):D1: -25.0D2: -29.8D3: -14.0Patient global VAS (mm):D1: -28.8D2: -32.7D3: -17.8FACIT-fatigue score: D1: 7.3D2: 8.6D3: 4.0Others, (please name) EULARGood Response (%)4 mg/kg: 218 mg/kg: 38Placebo: 3Moderate Response (%)4 mg/kg: 418 mg/kg: 41Placebo: 32No response (%)4 mg/kg: 388 mg/kg: 20,Placebo 65Overall: 4 mg/kg vs. Placebo (P?=?0.0001)8 mg/kg vs. Placebo (P?=?0.0001)SJCMean change from baseline 4 mg/kg: -8.58 mg/kg: -10.5Placebo: -4.3Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)TJCMean change from baseline4 mg/kg: -14.58 mg/kg: -17.1Placebo: -7.4Overall: 4 mg/kg vs. Placebo (P?=?0.0001), 8 mg/kg vs. Placebo (P?=?0.0001)Attrition/withdrawalOverall, n:D1: 25D2: 13D3: 12Overall: 50Withdrawals due to adverse events, n:D1: 14D2: 12D3: 6Overall: 32Withdrawals due to lack of efficacy, n:D1: 2D2: 0D3: 3Overall: 5Adherent/compliant, n:D1: 186D2: 191D3: 189Overall: 566Overall adverse events reported, n:D1: 151D2: 143D3: 129Overall: 423Serious adverse eventsCardiovascular events (specify), n:D1: 0D2: 1D3: 1MalignanciesSkin?cancer (basal cell?or squamous cell), n:D1: 0D2: 0D3: 1Other cancer (specify), n:D1: 0D2: 0D3: 1 (unspecified)Respiratory eventsTuberculosis, n: 3,570Pneumonia, n:D1: 0D2: 1D3: 1Overall: Pneumocystis jirovecii pneumonia, n:D1: 0D2: 0D3: 1Overall: D1: 2D2: 1Upper respiratory infection, n:D1: 12D2: 17D3: 13Overall: 42Other infectionsUrinary tract infection, n:D1: 0D2: 0D3: 1Overall: 1Nasopharyngitis, n: D1: 11D2: 12D3: 10GIDyspepsia and abdominal pain, n:D1: 17D2: 20D3: 11Overall: 48Any GI disorder, n:D1: 46D2: 48D3: 44Overall: 138OtherSkin rash, n:D1: 13D2: 11D3: 3Overall: 27Headache, n:D1: 15D2: 14D3: 9Overall: 28Mouth ulcers, n:D1: 4D2: 5D3: 1Overall: 10Peptic ulcers, n: D1: 1D2: 0D3: 2Overall: 3Raised anlanine aminotransferase, n: D1: 12 D2: 11D3: 3Overall: 26Raised aspartate aminotransferase, n: D1: 1D2: 2D3: 1Overall: 4Cough: 4 mg/kg: 78 mg/kg: 3Placebo: 3Overall: 13Pharyngeal pain, 4 mg/kg: 28 mg/kg: 4Placebo: 3Overall: 9Dyspnoea4 mg/kg: 38 mg/kg: 3Placebo: 0Overall: 6Aggravation of RA4 mg/kg: 78 mg/kg: 7Placebo: 13Overall: 27Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmolen et al., 2009, RAPID 2PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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ADDIN EN.CITE.DATA 165Country and settingMultinationalSource of fundingUCBResearch objectiveEvaluate efficacy and safety of CZP vs. placebo, + MTX, in pts with active RAStudy designControlled TrialsOverall N619Duration of study24 weeksQuality rating Good Inclusion Criteria≥ 18 years oldDiagnosis of RA by ACR criteria, prior MTX ≥ 6 mos (stable dose ≥ 10 mg/wk for ≥ 2 mos)Exclusion CriteriaOther biological agent for RA within 6 mos before enrollment (3 mos for ETN and ANK), previous treatement with biological with severe hypersensitivity or anaphylactic reactionNo initial response to previous anti-TNF therapy, chest x-ray findings for TB, positive PPD (unless thought to be due to BCG vaccination).Interventions, doseD1: MTX: ≥ 10 mg/wkPlacebo: saline SC q 2 weeksD2: MTX: ≥ 10 mg/wkCertolizumab 400 mg SC at weeks 0, 2, and 4 then 200 mg q 2 weeksD3: MTX: ≥ 10 mg/wkCertolizumab: 400 mg SC at weeks 0, 2, and 4 then 400 mg q 2 weeksNumber in groupD1: 127D2: 246D3: 246Mean age, years (SD)D1: 51.5 yr (11.8)D2: 52.2 (11.1)D3: 51.9 (11.8)Sex, % femaleD1: 84.3D2: 83.7D3: 78.0Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 5.6 yr (3.9)D2: 6.1 (4.1)D3: 6.5 (4.3)Patients with early RA, three years or less, %NRTreatment resistant, %NRTender Joint Count, meanD1: 30.4 (3.4)D2: 30.1 (14.5)D3: 30.0 (13.9)Swollen Joint Count, mean D1: 21.9 (9.7)D2: 20.5 (9.6)D3: 21.0 (10.2)Corticosteroid use, %D1: 59.8D2: 55.3D3: 61.8DMARD use, %MTX na?ve, %D1: 0D2: 0D3: 0Baseline DAS scoreD1: 6.83 (0.87)D2: 6.85 (0.84)D3: 6.80 (0.79)Required treatment for latent TBOther population characteristics, %,?(SD)MTX (mg/wk) mean: D1: 12.2 (3.3), D2: 12.5 (3.6)D3: 12.6 (3.7)HAQ-DI mean:D1: 1.6 (0.6)D2: 1.6 (0.6)D3: 1.6 (0.6)mTSS mean:D1: 46.5 (58.6)D2: 39.6 (50.1)D3: 46.7 (56.0)ACR mean difference/ absolute difference (CI)ACR 20:D1: 8.7D2: 57.3, OR 14.4 (6.7-31.0), P?=?0.001D3: 57.6, 14.3 (6.7-30.8), P?=?0.001ACR 50:D1: 3.1D2: 32.5, OR 14.8 (5.3-41.6), P?=?0.001D3: 33.1, 15.3 (5.5-42.9), P?=?0.001ACR 70:D1: 0.8D2: 15.9, OR 23.8 (3.2-175.9), P?=?0.01D3: 10.6, 15.5 (2.1-115.4), P?=?0.01HAQ-DI, adj mean change (SE)D1: -0.14 (0.04)D2: -0.50 (0.03), P?=?0.001D3: -0.50 (0.03), P?=?0.001HAQ-DI, % mean % improvement (SD)D1: 3.7 (59.4)D2: 31.8 (38.5), P?=?0.001D3: 32.0 (35.1) P?=?0.001DAS28 (SD)D1: -0.50 (1.05)D2: -2.27 (1.38), P?=?0.001D3: -2.46, P?=?0.001SF-36 PCS, adj mean change, nD1: 0.9D2: 5.2 (P?=?0.001)D3: 5.5 (P?=?0.001)SF-36 PCS, adj mean change, PFD1: 0.6D2: 12.1 (P?=?0.001)D3: 12.4 (P?=?0.001)Radiographic measures (CI)mTSS: D1: 1.2 (0.5-2.0)D2: 0.2 (-0.1-0.6), P?=?0.01D3: -0.4 (-0.7- to 0.1), P?=?0.001Quality of life scales NROverallOverall attrition/withdrawal, n: D1: 110D2: 72D3: 65Withdrawals due to adverse events, n: D1: 2D2: 11D3: 6Withdrawals due to lack of efficacy, n: D1: 107D2: 54D3: 53Adherent/compliant, n:D1: 1D2: 1D3: 2Withdrawal due to patient indecision or other: D1: NRD2: 6D3: 4Overall adverse events reported, n:D1: 66D2: 139D3: 125Serious adverse eventsDeath, n:D1: 0D2: 1D3: 1Hepatotoxicity/elevated liver enzymes, n:D1: 4D2: 3D3: 3Overall: 4MalignanciesNROther cancer (specify), n:D1: 1 (bladder)D2: 1 (testicular)D3: 1 (colon)Respiratory eventsTuberculosis: NRPneumonia, n:D1: 0D2: 0D3: 1Upper respiratory infection, n:D1: 2D2: 11D3: 4Other infectionsUrinary tract infection, n:D1: 9D2: 11D3: 5Other infections (specify), n:D1: 0D2: 1 case each of erysipelas, gastroenteritis, postop wound infection, tooth abscessD3: 1 case of erysipelas, 2 cases of sinusitisGINR OtherHeadache, n:D1: 1D2: 9D3: 8Any other AEs: For safety analysis two patients inplacebo group that received CZP 200 mg were included inCZP 200 mg group.Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmolen et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI2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ADDIN EN.CITE.DATA 166 ASPIRE Country and settingMultinationalUnversity hospitalsSource of fundingCentocorResearch objectiveExamine radiographic progression and disease activity states in pts treated with MTX or INF + MTXStudy designControlled TrialsOverall N1049Duration of study54 wksQuality rating Fair Inclusion Criteria:Age: 18-75Diagnosed according to 1987 ACR criteriaPersistent synovitis for > 3 mos and < 3 yrs> 10 swollen joints, and > 12 tender joints1 or more of following: a positive test result for serum RF, radiographic erosions of hands or feet, or a serum C-reactive protein level of > 2.0 mg/dl Oral corticosteroids; NSAIDS20 mg MTX (required)Exclusion Criteria:Prior txt with: MTX, received other DMARDs within 4 wks of entryUsed ETN, INF, ADA or other anti-TNF-á agenthepatitis B or C virus, CHF, or lymphoma or other malignancy within past 5 yrs (excluding excised skin cancers)Interventions, doseD1: MTX: wk 54 mean:?15.1mg/wkPlaceboD2: MTX wk54 mean:?15.5mg/wkIFX: 3mg/kgD3: MTX: mean wk 54:?14.9mg/wkIFX: 6mg/kgNumber in groupD1: 298D2: 373D3: 378Mean age, years (SD)D1: 50D2: 51D3: 49Sex, % femaleD1: 74.8D2: 71.6D3: 67.7Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsNRPatients with early RA, three years or less, %D1: 100D2: 100D3: 100 Treatment resistant, %NRTJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %D1: 100D2: 100D3: 100Overall: 100MTX na?ve, %NRBaseline DAS-ESR score (SD)D1: 6.69 (1.04)D2: 6.62 (1.07)D3: 6.72 (1.01)Required treatment for latent TBNRACR NRHAQ NRDAS D1: % remission at 54 wks by DAS28-ESR: MTX: 16.3%D2: MTX+INF: 24.7%SF-36 NRRadiographic measures D1: Changes in TSS wk 14/54 by disease activity (remission, low, moderate, high) wk 14/wk54. MTX 0.1, 2.8*, 2.1**, 6.5**/1.1, 2.2**, 3.9**, 5.8**MTX+IFX -0.3, 0.0, 0.3, 1.3/-0.2, -0.4, 0.6, 2.1. [COMPARED TO IFX+MTX *P = 0.05, **P = 0.01] D2: MTX+IFX -0.3, 0.0, 0.3, 1.3/-0.2, -0.4, 0.6, 2.1. Quality of life scales NROthers, (please name) % remission, low, mod, or high disease by SDAI at wk 14/54 MTX: 2.8, 14.6, 45.5, 37.2/ 12.3, 29.5, 29.5, 28.6 (14 & 54 wks between groups, Ps:?0.001)MTX+INF: 10.7, 26.0, 37.4, 25.9/21.3, 35.5, 28.5, 14.7.Attrition/withdrawalNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsTuberculosis: NROther infectionsNRGINRStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSmolen et al., 2009 PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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==
ADDIN EN.CITE.DATA 167 GO-AFTER StudyCountry and settingmultinational; clinics; hospitalsSource of fundingCentocor Research and Development; Schering-Plough Research InstituteResearch objectiveTo assess the efficacy and safety of GOL for patients with active RA who had previously received one or more TNF-alpha inhibitorsStudy designRCTOverall N461Duration of study24 wksQuality rating Fair Inclusion Criteria≥ 18 years oldActive RA≥ 4 tender and swollen jointsTreated with at least 1 alpha-TNF inhibitorExclusion CriteriaInflammatory diseasesSerious AEs with previous TNF-alpha inhibitorEver received natalizumab or RTXReceived ANK < 4 wks or alefacept or efalizumab < 3 mos before the first dose of study drugHad ever received cytotoxic drugsHistory of latent or active granulomatous infection except latent TBBCG vaccination < 12 mos before screeningOpportunistic infection < 6 mos before screeningSerious infection < 2 mos before screeningHistory of chronic infectionDemyelinating diseaseCongestive heart failureSevere, progressive, uncontrolled renal, hepatic, haematological, GI, endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral diseaseHad transplanted organ or malignancy in past 5 yrsInterventions, DoseD1: GOL: 50 mg every 4 wksD2: GO: 100 mg every 4 wksD3: PlaceboNumber in groupD1: 153D2: 153D3: 155Mean age (years)D1: 55D2: 55D3: 54Sex, % femaleD1: 74D2: 80D3: 85Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 9.6 (5.6 - 17.2)D2: 8.7 (5.3 - 13.2)D3: 9.8 (4.9 - 17.6)Patients with early RA, three years or less, %: NR Treatment resistant, %: NRTender Joint Count, meanD1: ≥ 4D2: ≥ 4D3: ≥ 4Swollen Joint Count, mean D1: ≥ 4D2: ≥ 4D3: ≥ 4Corticosteroid use, %NRDMARD use, %: NRMTX na?ve, %: NRBaseline DAS scoreNRRequired treatment for latent TBD1: 10 (7%)D2: 7 (5%)D3: 10 (6%)Other population characteristics: ACR:ACR 20: Week 14D1: 35D2: 38D3: 18Week 24D1: 34D2: 44D3: 17ACR 50: Week 14D1: 16D2: 20D3: 6Week 24D1: 18D2: 20D3: 5ACR 70: Week 14D1: 10D2: 9D3: 2Week 24D1: 12D2: 10D3: 3HAQ: HAQ-DI Week 14D1: -13.4 (-27.3 to 0.0 (P = 0.0005)D2: -17.6 (-43.8 to D3: 0 (-17.6 to 13.3) 0.0 (P < 0.0001)Week 24D1: -13.3 (-33.3 to 0.0 (P = 0.0003)D2: -14.3 (-44.1 to 0.0 (P?<?0.0001)D3: 0 (-25 to 17.6)DAS: Week 14D1: -15.7 (-31.6 to -6.8 (P < 0.0001)D2: -21.5 (-38.3 to -7.5 (P < 0.0001)D3: -4.2 (-19.8 to 8.7)Week 24D1: -18.6 (-36 to -2.6 (P < 0.0001)D2: -25.8 (-40.5 to -12.2 (P < 0.0001)D3: -1.6 (-17.8 to 14.8)SF-36: NRRadiographic measures: NRQuality of life scales: NROthers: OverallOverall attrition/withdrawal (n): D1: 13D2: 15D3: 31Overall: 59Withdrawals due to adverse events?(n): D1: 4D2: 2D3: 10Overall: 16Withdrawals due to lack of efficacy?(n): D1: 6D2: 5D3: 11Overall: 22Adherent/compliant?(n): NROther attrition related comments? Attrition numbers include those that received rescue txOverall adverse events reported (n): D1: 101D2: 119D3: 112Serious adverse events:Cardiovascular events (specify)?(n): HTND1: 5D2: 10D3: 2Malignancies:D1: 1D2: 1D3: 1Respiratory events:Pneumonia (n): D1: 2D2: 0D3: 1Upper respiratory infection?(n): D1: 11D2: 21D3: 10Other infections:Urinary tract infection?(n): D1: 1D2: 0D3: 0Other infections (specify) (n): Infections D1: 53D2: 55D3: 51GI:Bowel obstruction (n): DiaherraD1: 5D2: 12D3: 7GastroenteritisD1: 0D2: 0D3: 1Other:Infusion/injection site reactions?(n): D1: 9D2: 16D3: 6Any other AEs: AE numbers do not include those who received Rescue therapyStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableSokolove et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUy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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUy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==
ADDIN EN.CITE.DATA 168Country and settingUSA; Multicenter registrySource of fundingConsortium of Rheumatology Researchers of North AmericaResearch objectiveTo compare LFT elevations in patients with rheumatoid arthritis receiving ADA, ETN or INF enrolled in the Consortium of Rheumatology Researchers of North America from October 2001 to March 2007.Study designObservationalOverall N6861Duration of studyMean follow-up per person was 17 mosInclusion CriteriaPatients receiving anti-TNF and/or all non- biological DMARDs with normal baseline ALT and/or AST values, including MTX and/or LEF, with available follow-up determinationsExclusion CriteriaPsAComparisons (dosage and frequency)D1: Oral DMARDs: MTX, LEF and all other non-biological DMARDs as a group (SSZ,HCQ, azathioprine, gold, penicillamine).D2: ADA: NRD3: ETN: NRD4: INF: NRNumber in groupD1: 4147D2: 849D3: 1383D4: 1449Mean age (years)D1: 61.2D2: 56.14D3: 55.6D4: 60.4Sex, % femaleD1: 72.8D2: 79.5D3: 79.9D4: 73.7Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 9.8 (9.8)D2: 11.3 (9.6)D3: 12.0 (9.9)D4: 11.3 (9.3)TJC, meanD1: 3.25D2: 4.77D3: 3.81D4: 3.63SJC, mean D1: 4.25D2: 5.67D3: 4.02D4: 5.02Corticosteroid use, %NRDMARD use, %: NRMTX na?ve, %: NRTreatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreD1: 3.47 (1.5)D2: 3.89 (1.7)D3: 3.56 (1.5)D4: 3.56 (1.4)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallNRSerious adverse events:Hepatotoxicity/elevated liver enzymes?(n): LFT >1× ULN, AOR D2: 1.35(95% CI 1.09 to 1.66)D3: 1.00 (95% CI 0.83 to 1.21)D4: 1.58 (95% CI 1.35 to 1.86)ALT and/or AST >2× ULN, AORD2: 1.72 (95% CI 0.99 to 3.01)D3: 1.10 (95% CI 0.64 to 1.88)D4: 2.40 (95% CI 1.53 to 3.76)AST/ALT >2× ULN: 0.7Malignancies:NRRespiratory events:NROther infections:NRGI:NROther:Any other AEs: LFT results (AST/ALT) based on primary model #1 of prevalent TNF-I users in patients on MTX, LEF and other non-biological DMARDQuality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSolomon et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM0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ADDIN EN.CITE.DATA 169Country and settingUS, multicenterSource of fundingMerck, Pfizer, & Savient, NIH, Engalitcheff Arthritis Outcomes InitiativeResearch objectiveInvestigate effects of various immunosuppressive medications on risk CVD in elderly pts with RAStudy designNested Case – Control CohortOverall N3501 (pts could be sampled more than once as controls)Duration of studyNA - median duration 24 mos for cases & 22 mos for controlsQuality rating FairInclusion CriteriaPA Medicare enrollees also beneficiaries in state drug assistance programPts received 2+ diagnoses of RA (diagnoses seperated by min 1 wk)Filled a prescription for immuno-suppressive medsExclusion Criteria<12 mos of registry data prior to study entryInterventions, DoseD1: Case (MI or Stroke)D2: ControlNumber in groupD1: 946D2: 9460Mean age (years)D1: 81D2: 80Sex, % femaleD1: 89D2: 92Race, % whiteD1: 93D2: 94Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Inflamation markers (lab test ordered) D1: 34%D2: 36%Joint aspirations or injections (had 1+ of these procedures) D1: 41% D2: 40%ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNROverall adverse events reported, n:NR - see comments for AE dataSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherAdjusted* risk for CV events (Composite/MI/Stoke) OR, 95% CI. MTX monotherapy 1.0, ref/1.0, ref/ 1.0, refBiologics monotherapy (ADA, ETN, IFX, or AKA) 1.0, 0.5-1.9/ 1.7, 0.5-5.7/ 1.5, 0.6-4.1Biologic + MTX 0.8, 0.3-2.0/ 1.8, 0.5-6.8/ 1.3, 0.4-4.0Glucocorticoid monotherapy 1.5, 1.1-2.1/ 1.5, 0.9-2.5/ 1.7, 1.1-2.6[*adjusted for prior MI, prior CV accident, diabetes, race, n physician visits, n of different medications, use of beta-blockers, use of clopidogrel, and no current use of immunosuppressive agents]Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:St. Clair, 2004;PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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=
ADDIN EN.CITE.DATA 170 Smolen, 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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ADDIN EN.CITE.DATA 171ASPIRE TrialCountry, Setting:Multinational, unversity hospitalsFunding:CentocorResearch Objective:To compare benefits of initiating txt with MTX and anti-TNFá with those of MTX txt alone in pts with RA of < 3 yrs durationStudy Design:RCTOverall N:1049Study Duration: 54 wksInclusion Criteria:Age: 18 to 75Diagnosed according to 1987 ACR criteriaPersistent synovitis for > 3 mos and < 3 yrs > 10 swollen joints, and > 12 tender joints1 or more of following: a positive test result for serum RF, radiographic erosions of hands or feet, or a serum C-reactive protein level of > 2.0 mg/dl Oral corticosteroids; NSAIDS20 mg MTX (required)Exclusion Criteria:Prior txt with: MTX, received other DMARDs within 4 wks of entryUsed ETA, INF, ADA or other anti-TNF-á agentHistory of TB; HIV, hepatitis B or C virus, CHF, or lymphoma or other malignancy within past 5 yrs (excluding excised skin cancers)Interventions, dose:D1: MTX (20 mg/wk) + placeboD2: MTX + INF (3 mg/kg/wk)D3: MTX + INF (6 mg/kg/wk)N:D1: 282D2: 359D3: 363Mean age, yrs:D1: 50D2: 51D3: 50Sex, % female:D1: 75D2: 71D3: 68Race, % white:NRMean disease duration, yrs:D1: 0.9D2: 0.8D3: 0.9TJC, mean:D1: 34D2: 32D3: 33SJC, mean:D1: 22D2: 21D3: 22DMARD use, %:D1: 35D2: 29D3: 32Corticosteroid use, %NRMTX naive, %:Overall: 100Txt resistant, %:NRPts with Early RA (≤3 yrs):Overall: 100Baseline DAS, mean:NRJSN:D1: 3.0D2: 2.9D3: 2.9HAQ: D1: 1.5D2: 1.5D3: 1.5At weeks 30 to 54HAQ:D1: 0.68D2: 0.80D3: 0.88; (D2 vs. D1; P = 0.03) (D3 vs. D1; P < 0.001)At 54 weeksHAQ > 0.22, %:D1: 65.2D2: 76.0 D3: 75.5(D2 vs. D1; P = 0.003) (D3 vs. D1; P < 0.004)ACR20, %: D1: 53.6D2: 62.4D3: 66.2 (D2 vs. D1; P = 0.028) (D3 vs. D1; P < 0.001)ACR50, %: D1: 32.1D2: 45.6D3: 50.4 (D2 vs. D1; P = 0.001) (D3 vs. D1; P < 0.001)ACR70, %: D1: 21.2D2: 32.5D3: 37.2 (D2 vs. D1; P = 0.002) (D3 vs. D1; P < 0.001)ACR-N, %: D1: 26.4D2: 38.9D3: 46.7 (P < 0.001)Modified Sharp: D1: 3.7D2: 0.4D3: 0.5 (P < 0.001)Increase in radiographic score, %: INF: 39 vs. MTX 61(P < 0.001)Employability:INF+MTX (OR 2.4, P < 0.001)MTX (P = 0.56)Combo has higher probability of improvement than MTX aloneNet increase in employability: MTX+INF: 8%MTX-only: 2%Employability status changed from employable to unemployable, %: INF: 8MTX-only: 14 (P = 0.05)SF-36 Physical component summary scoresD1: 11.7D2: 13.2D3: 10.1D3 vs. D1, P = 0.10D3 vs. D2; P = 0.003Modified Sharp/van der Heijde Score change:D1: 3.7D2: 0.4D3: 0.5 P < 0.001Erosion Score change:D1: 3.0D2: 0.3D3: 0.1 P < 0.001JSN Score change:D1: 0.6D2: 0.1D3: 0.2 P < 0.001SAEs:D1: 11D2: 14D3: 14Serious Infections:D1: 2.1D2: 5.6D3: 5.0Infusion or injection reaction:D1: 7D2: 21D3: 15TB:D1: 0D2: 0.8D3: 0.3Nausea:D1: 18D2: 20D3: 17URTI:D1: 21D2: 25D3: 28Overall Attrition Rate, %:14.9ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, year:Strand et al., 1999 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1640</RecNum><DisplayText><style face="superscript">172</style></DisplayText><record><rec-number>1640</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1640</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Strand, V</author><author>Cohen, S</author><author>Schiff, M</author><author>Weaver, A</author><author>Fleischmann, R</author><author>Cannon, G</author><author>Fox, R</author><author>Moreland, L</author><author>Olsen, N</author><author>Furst, D</author><author>Caldwell, J</author><author>Kaine, J</author><author>Sharp, J</author><author>Hurley, F</author><author>Loew-Friedrich, I</author></authors></contributors><titles><title>Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate</title><secondary-title>Archives of Internal Medicine</secondary-title></titles><periodical><full-title>Archives of Internal Medicine</full-title><abbr-1>Arch. Intern. Med.</abbr-1><abbr-2>Arch Intern Med</abbr-2></periodical><pages>2542-50</pages><volume>159</volume><number>21</number><keywords><keyword>CN-00414764</keyword><keyword>RCT</keyword></keywords><dates><year>1999</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>-- goes with 1931; 1577 = continuation phase</custom7></record></Cite></EndNote>172; Strand et al., 1999PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjE5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ADDIN EN.CITE.DATA 173; Cohen et al., 2001 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1577</RecNum><DisplayText><style face="superscript">174</style></DisplayText><record><rec-number>1577</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1577</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cohen, S</author><author>Cannon, G</author><author>Schiff, M</author><author>Weaver, A</author><author>Fox, R</author><author>Olsen, N</author><author>Furst, D</author><author>Sharp, J</author><author>Moreland, L</author><author>Caldwell, J</author><author>Kaine, J</author><author>Strand, V</author></authors></contributors><titles><title>Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of leflunomide in the treatment of rheumatoid arthritis</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1984-92</pages><volume>44</volume><number>9</number><keywords><keyword>CN-00374337</keyword></keywords><dates><year>2001</year></dates><label>MA 1430</label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>-- continuation phase/goes with 1640, 1931</custom7></record></Cite></EndNote>174Country, Setting:US and Canada,multicenter (47 university & private rheumatology practices)Funding:Hoescht Marion RousselResearch Objective: Efficacy and safety of LEF with placebo and MTX in active RA Study Design:RCTOverall N:482 (active arms- 364)Study Duration: 12 mos (w/ 1 year followup)Inclusion Criteria:Age: 18 or olderDiagnosed according to ACR criteria; DMARDs discontinued at least 30 days priorDuration of condition at least 6 mos10 mg stable prednisone (or equivalent)NSAIDs if dosages stable at least 30 days prior to enrollment Exclusion Criteria:Pregnant or lactatingPrior treatment with: MTXInflammatory joint disease not caused by RA,History of clinically significant drug or alcohol abuse, or admitted to consumption of more than 1 alcoholic drink per dayInterventions:D1: LEF (20 mg/week)D2: MTX(7.5 to 15 mg/week)N:D1: 182D2: 182Mean age, yrs:D1: 54.1D2: 53.3Sex, % female:D1: 72.5D2: 75.3Race, % white:NRMean disease duration, yrs:D1: 7.0D2: 6.5TJC, mean:D1: 15.5D2: 15.8SJC, mean:D1: 13.7D2: 13.0DMARD use, %:D1: 55.5D2: 56.0Corticosteroid use, %:D1: 53.8D2: 52.7MTX naive, %:Both groups 100Treatment resistant, %: NRPts with Early RA (≤3 yrs): NRBaseline DAS, mean: NRRF positive: D1: 64.8D2: 59.4MHAQ: D1: 0.8D2: 0.8At 12 mos ACR 20, %D1: 52D2: 46ACR 50, %D1: 34D2: 23ACR 70, %D1: 20D2: 9MHAQ mean change D1: -0.3 D2: -0.2Sharp score change D1: 0.53 (n:131)D2: 0.88 (n= 138) (P = 0.05)Mean change HAQ-DID1: -0.45 (n= 164)D2: -0,26 (n= 168) (P ≤ 0.01)Mean change SF-36 physical component D1: 7.6 (n= 157)D2: 4.6 (n=162) Work productivity mean change D1: 9.8 (n= 138)D2: 7.5 (n= 148)SAEs:D1: 1.1D2: 2.7Infections:D1: 56.6D2: 59.9Abdominal Pain:D1: 13.7D2: 15.4Nausea:D1: 20.9D2: 19.2Back pain: D1: 8 D2: 2Diarrhea: D1: 36.8D2: 21.6Oral Ulcers: D1: 6.8D2: 10.5GI Events: D1: 5.5D2: 1.7Elevated Transaminases: D1: 7.1D2: 4.4Overall Attrition Rate, %:51% at 1 yearITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableStrand et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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 EN.CITE.DATA 175Country and settingMultinationalSource of fundingRoche, GenentechResearch objectiveEvaluate long-term impact on physical function of a single course of rituximab in rheumatoid factor, seropositive patients with active rheumatoid arthritis (RA) despite ongoing methotrexate treatment.Study designControlled TrialsOverall N161Duration of study2 yrs.Quality rating Poor: very high attrition rate Inclusion CriteriaAge 21 yearsFulfillment of revised 1987 American Rheumatism Association criteriaActive disease (defined as 8 swollen and 8 tender joints and at least 2 of following: a serum CRP level 1.5mg/dl, ESR 30mm/h, or morning stiffness 45 minutes) despite treatment with > 10mg of MTX per week; RF 20 IU per ml.; failed at least 1 DMARD.Exclusion CriteriaAutoimmune disorder other than RA (except concurrent Sjogren's)American Rheumatism Association functional class IV diseaseActive rheumatoid vasculitisHistory of systemic diseases associated with arthritisChronic fatigue syndromeSerious & uncontrolled coexisting diseasesActive infectionHistory of recurrent clinically significant infection or of recurrent bacterial infections with encapsulated organismsPrimary or secondary immuno-deficiencyHistory of cancer (except basal cell carcinoma of skin that had been excised).Interventions, DoseD1: Methotrexate 10 mg/wkMedian dose of MTX at study entry was 12.5-15 mg/weekPlaceboD2: Methotrexate: Median dose of MTX at study entry was 12.5-15 mg/weekRituximab1000 mg days 1 and 15D3:Methotrexate: Median dose of MTX at study entry was 12.5-15 mg/weekRituximab1000 mg days 1 and 15 Other: Cyclophosphamide 750 mg days 3 and 17; Median dose of MTX at study entry was 12.5-15 mg/weekD4: Methotrexate > or equal to 10 mg/wk; Median dose of MTX at study entry was 12.5-15 mg/weekRituximab1000 mg days 1 and 15Number in groupD1: 40D2: 40D3: 41D4: 40Mean age (years)D1: 53.7 (11.2) D2: 53.5 (10.2)D3: 52.9 (9.9)D4: 53.5 (11.9)Sex, % femaleD1: 80D2: 72.5D3: 82.9D4: 75.0Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD) yrsD1: 11.0 (7.1) D2: 9.3 (5.5) D3: 9.8 (6.1)D4: 11.5 (7.3)Patients with early RA, three years or less, %D1: 0D2: 0D3: 0D4: 0 Treatment resistant, %NRTender Joint Count, mean (SD)D1: 32 (12.8)D2: 33.8 (14.8)D3: 32.7 (13.8)D4: 32.2 (15.9)Swollen Joint Count, mean (SD)D1: 18.6 (9.6)D2: 20.5 (11.2)D3: 19.4 (10.2)D4: 22.7 (12.7)Corticosteroid use, %NRDMARD DMARDs failed (other than MTX), n (SD)D1: 2.6 (1.3)D2: 2.5 (1.6) D3: 2.6(1.4) D4: 2.5(1.4)MTX na?ve, %NRBaseline DAS28 score, mean (SD)D1: 6.9 (0.7) D2: 6.8 (1.0) D3: 6.9 (0.8) D4: 6.8 (0.9)Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)HAQ-DI baseline mean (± SD):D1: 2.0 (0.5)D2: 2.0 (0.6)D3: 1.8 (0.7)D4: 1.8 (0.6)MD global,(± SD): D1: 66.7 (15.7)D2: 66.7 (16.2)D3: 67.4 (14.5)D4: 65.6 (14.0)Pt global,(± SD): D1: 65.4 (20.3)D2: 67.8 (22.8)D3: 63.4 (20.5)D4: 61.4 (20.4)Pt pain assessment (VAS, mm): D1: 62.6 (16.1)D2: 62.2 (20.2)D3: 57.5 (20.0)D4: 54.6 (17.8)ESR (mm/h): D1: 51.5 (31.8)D2: 46.9 (22.9)D3: 54.9 (28.6)D4: 53.3 (23.4)Week104: 1 (3)Overall: Overall HAQ-DI baseline mean (± SD): (1.8-2.0)ACR mean difference/ absolute difference (%)Week 24ACR 20:D1: 15 (38) D2: 26 (65), P?=?0.05D3: 31 (76), P?=?0.01 based on Fisher's exact test for comparisons with placebo + MTX group; Wk 48: 19 (46%), P <D4: NRACR50:D1: 5 (13)D2: 13 (33)D3: 17 (41), P?=?0.01 based on Fisher's exact test for comparisons with placebo + MTX groupD4: NRACR 70:D1: 2 (5)D2: 6 (15)D3: 6 (15)D4: 9 (23), P?=?0.05Week 48:ACR 20 (%):D1: 8 (20)D2: 12 (30)D3: ACR 50 (%):D1: 2 (5)D2: 5 (13)D3: 10 (24), P?=?0.05ACR 70:D1: 0%D2: 3(8%)D3: 4 (10)D4: 6 (15%), P?=?0.05Week 104:ACR 20:D1: 5 (13%)D2: 3 (8%)D3:NRACR 50:D1: 4 (10%)D2: 3 (8%)D3: 4 (ACR 70:D1: 3 (8%)D2: NRD3: 3 (8)D4: 4 (10%)HAQ, mean difference/ absolute difference (CI/SD/P Value)D1: Mean change from baseline at Wk 12 (n?=?39): -0.3 (P > or equal to 0.0001); Wk 24 (n?=?37): -0.4 (P?=?0.0002); Wk 48 (n?=?25): -0.3 (P > or equal to 0.005); Wk 72 (n?=?15): -0.3 (P > or equal to 0.05)D2: Mean change from baseline at Wk 12 (n ?=?DAS SF-36 Radiographic measures NRQuality of life scales NROthers % of patients continuing protocol participation Week 24:D1: 92.5D2: 95.0D3: 90.2D4: 97.5Week 48:D1: 62.5D2: 77.5D3: 82.9D4: 95.0Week 72:D1: 37.5D2: 42.5D3: 53.7D4: 70.0Week 104:D1: 15.0D2: 10.0 D3: 21.9D4: 45.0% of patients reporting improvements in HAQ-DI that met or exceeded MCID (a reduction of > or equal to 0.25) Week 12:D1: (n?=?39): 38D2: (n?=?39): 63D3: (n?=?40): 61D4: (n?=?40): 55Week 24:D1: (n?=?37): 45D2: (n?=?38): 68D3: (n?=?37): 59D4: (n?=?39): 63Week 48:D1: (n?=?25): 28D2: (n?=?31): 43D3: (n?=?34): 39D4: (n?=?38): 68Week 72:D1: (n?=?15): 18D2: (n?=?17): 18D3: (n?=?22): 22D4: (n?=?28): 48Attrition/withdrawalOverall, n:D1: 34D2: 36D3: 32D4: 22Overall: 124Withdrawals due to adverse events, n:D1: 4D2: **5D3: 4D4: 1Overall: 14Withdrawals due to lack of efficacy, n:D1: 17D2: 5D3: 4D4: 4Overall: 30Adherent/compliant, n: NR*OTHER D1: 13D2: 26D3: 25D4: 17Overall OTHER: 81*The majority of protocol discontinuations classified as 'other' were owing to requirement for retreatment with rituximab under a separate protocol; **includes 1 death due to pneumonia.Overall adverse events reported, n:D1: 4D2: 5D3: 4D4: 1Overall: 14Serious adverse eventsDeath, n:D1: 0D2: 1D3: 0D4: 0Overall: 1MalignanciesNRRespiratory eventsPneumonia, n: D2: 1 (reported above as well as it led to death)Upper respiratory infection, n:D1: 6 (through wk24 for all Ds in this category)D2: 4 D3: 2D4: 4 Other infectionsNRGINausea or vomiting, n:D1: 1D2: 2D3: 4D4: 0OtherInfusion/injection site reactions, n: (through wk24 for all Ds in this category)D1: 12D2: 18 D3: 13 D4: 13 Skin rash, n: (through wk 24 for all Ds in this category)D1: 1D2: 4 D3: 4 D4: 1Other AEs?1, n:D1: Hypotension (through wk24 for all Ds inse categories): 7; hypertension, 6 *a change of more than 30 mm Hg in systolic or diastolic blood pressure from pressure at screening was classified as hypotension or hypertension D2: HypotensionThrough wk 24 for all groups in these categories. Arthralgia, n:D1: 3D2: 3D3: 1D4: 4Back pain:D1: 2D2: 4D3: 3D4: 0Through wk 24 for all groups in these categories. Cough, n:D1: 0D2: 5D3: 1D4: 2Pruritus, nD1: 0D2: 4D3: 4D4: 0Through wk 24 for all groups in this category. Dyspnea, n:D1: 0D2: 4D3: 0D4: 0Any event up to Wk 24: D1: 32D2: 32D3: 30D4: 34Any event up to Wk 48: D1: 34D2: 36D3: 35D4: 35Serious adverse event up to week 24: D1: 3D2: 2D3: 6D4: 3Serious adverse event up to week 48: D1: 4D2: 4D3: 7D4: 4Any event associated with first infusionD1: 12D2: 18D3: 13D4: 13Exacerbation of RA through wk 24: D1: 16D2: 6D3: 6D4: 2Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableStrangfeld et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI0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==
ADDIN EN.CITE.DATA 176Country and settingGerman, multicenterSource of fundingEssex, Wyeth, Abbott, Amgen, Hoffman-La Roche, Bristol-Meyers SquibbResearch objectiveInvestigate if TNF-alpha inhibitors as a class, or by mode of impact, are related to higher rates of herpes zoster in RA ptsStudy designProspective Cohort StudyOverall N5040Duration of studyvaried, up to 36 mos from May 2001 to December 2006Quality rating GoodInclusion CriteriaRA pts initiating biologic therapy or switching to another DMARD (Oral or Biologic)Exclusion CriteriaMissing follow up data (152 patients or 2.9% of eligible)Interventions, DoseD1: Oral DMARDSD2: BiologicsD3: CorticosteroidsD4: Combination therapyNumber in groupD1: 1252D2: 591D3: 1423D4: 1774Mean age (years)D1: 53.8D2: 52.9D3: 54.2D4: 56.2Sex, % femaleD1: 77.8D2: 73.3D3: 80.2D4: 78.6Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: median (IQR): 9 (4-16)D2: 8.5 (4-14) D3: 10 (5-17)D4: 6 (3-12) Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %Glucocorticoid/ Prenisolone:D1: 86.1/35.1D2: 84.4/36.7D3: 81.6/29.2D4: 76.5/19.3DMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)D1: 5.8 (1.3)D2: 5.9 (1.2)D3: 5.7 (1.3) D4: 5.0 (1.3) Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)NRACR ACR 20: No efficacy outcomes reportedACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNROverall adverse events reported, n:D1: NR - see additional comments for germane analysesSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherAdjusted (Age & Propensity score) HR for Herpes Zoster. Glucocorticoids 1-9 mgs 1.86 (95%CI 0.92-3.78)Glucocorticoids 10+mg 2.52 (1.12-5.65) [ref - 0mgs of glucocorticoids]. Anti-TNF combined D1.63 (0.97-2.74), ETN 1.36 (0.73-2.55), IFX or ADA 1.82 (1.05-3.15) [ref - traditional DMARDs]. Results from subsample (N?=?1344) of patients who could act as own control - HR for Herpes Zoster. ETN 1.09 (0.39-3.06); IFX 2.43 (0.94-6.26); ADA 3.01 (1.36-6.64) [ref - traditional DMARDs]Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicableStrangfeld et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx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ADDIN EN.CITE.DATA 177Country and settingGermanySource of fundingEssex Pharma, Wyeth pharma, Amgen, Biovitrum, Abbott, Bristol-Myers Squibb, Roche, UCBResearch objectiveTo investigate the risk of new or recurrent malignancy in patients with RA receiving biologics compared to conventional DMARDsStudy designObservationalOverall N5120Duration of study60 mosInclusion CriteriaTreatment resistant failure of at least one other DMARD Exclusion CriteriaNRComparisons (dosage and frequency)D1: Prior malignancies-conventional DMARDD2: Prior malignancies-biologic (ETN, ADA, INF, ANK)D3: Without prior malignancies-conventional DMARDD4: Without prior malignancies-biologics (ETN, ADA, INF, ANK)Number in groupD1: 55D2: 67D3: 1719D4: 3279Overall: 5120Mean age (years)D1: 63.2D2: 64.0D3: 55.9D4: 53.6Overall: comparison b/t strata: P<0.001Sex, % femaleD1: 74.5D2: 67.2D3: 78.7D4: 78.2Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: median (IQR): 7 (3, 13)D2: median (IQR): 10 (6, 16.5)D3: median (IQR): 6 (2.5, 12)D4: median (IQR): 9 (5, 17)Comparison b/t strata: P=0.286TJC, meanNRSJC, mean NRCorticosteroid use, %NRDMARD use, %: No of previous DMARDs: D1: 1.9 (1.0) D2: 3.7 (1.5) D3: 1.9 (1.1) D4: 3.6 (1.4)Comparison b/t strata: P= 0.656MTX na?ve, %: D1: NRD2: NRD3: NRD4: NROverall: 2.7Treatment resistant, %: NRPatients with early RA, three years or less, %: NR Baseline DAS scoreD1: Mean (SD): 5.4 (1.1)D2: Mean (SD): 5.7 (1.3)D3: Mean (SD): 5.0 (1.3)D4: Mean (SD):5.8 (1.3)Comparison b/t strata: P=0.282Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):NRHAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): OverallOverall adverse events reported (n): D1: 5D2: 9D3: 4D4: 1Overall: 19Serious adverse events:Death (n): D1: 0D2: 0D3: 4D4: 1Overall: 5Malignancies:Recurrent cancerD1: 5; crude incidence rates: 31.4 (95% CI,10.2 to 73.4) D2: 9; crude incidence rates: 45.5 (95% CI, 20.8 to 86.3)D3: NROverall: (incidence rate ratio anti-TNFá agents vs. DMARDs: 1.4 (95% CI, 0.5 to 5.5) P=0.63)74 patients among the 4,998 patients who did not have a prior malignancy developed an incident tumor.Respiratory events:NROther infections:NRGI:NROther:Number of co-morbidities, mean (SD): Pts who developed malignancies during the study: 2.5 (2.1)Pts who did not develop malignancies during the study: 1.7(1.9) COPDPts who developed malignancies during the study: 11/74 (14.9%)Pts who did not develop malignancies during the study: 223/4924 (4.5%)P<0.0001Chronic gastrointestinal diseasesPts who developed malignancies during the study: 13/74 (17.6%)Pts who did not develop malignancies during the study: 406/4924 (8.2%)P=0.008Chronic renal diseases Pts who developed malignancies during the study: (4/74 (5.4%) Pts who did not develop malignancies during the study: 159/4924 (3.2%)P=0.22The univariate analysis showed that patients with a very active disease (DAS28 >5.1, mean: 5.93) during follow-up had a 2 times higher cancer risk than those with low disease activity (DAS28 <3.2, mean: 2.75) Overall number of observed cancers in patients exposed to anti-TNFá agents: non-significantly lower than the expected number from the general population (standardized incidence rate ratio: 0.75, 95% CI 0.54 to 1.01). No difference was found for patients not exposed to biologics.Quality rating for efficacy/effectiveness? NRQuality rating for observational studies FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Suissa et al., 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw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ADDIN EN.CITE.DATA 178Country, Setting:US, 2 large databasesFunding:AventisResearch Objective:Assess risk of hepatic events associated with the use of LEF and other DMARDS compared to MTXStudy Design:ObservationalOverall N:41,885Study Duration: 3 yrsInclusion Criteria:Age: 18 and olderPrevious use of DMARDs: after 9/1/98ICD 9 code for RAExclusion Criteria:< 3 mos eligibility in health insurance planPts with outcome 3 mos before cohort studyInterventions, dose:NRN:NRMean age, yrs:NRSex, % female:NRRace, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRWhen compared to MTX, No increased risk with LEF(rate ratio 0.9, 95% CI, 0.2-4.9), or with traditional DMARDS (RR 2.3; 95% CI, 0.8-6.5)There is an increased risk with biologic DMARDS (RR:5.5; 95% CI, 1.2-24.6)Rate of nonserious hepatic events was also increased with biologic DMARDS (RR 1.5; 95% CI, 1.0-2.3), but not LEF (RR:0.9; 95% CI, 0.7-1.3) and traditional DMARDS (RR 1.1; 95% CI, 0.8-1.4)NROverall Attrition Rate, %:NRITT Analysis:NA: cohortQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Suissa et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1985</RecNum><DisplayText><style face="superscript">179</style></DisplayText><record><rec-number>1985</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1985</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suissa, S.</author><author>Hudson, M.</author><author>Ernst, P.</author></authors></contributors><auth-address>McGill University Health Centre, Montreal, Quebec, Canada. samy.suissa@clinepi.mcgill.ca</auth-address><titles><title>Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1435-9</pages><volume>54</volume><number>5</number><keywords><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Isoxazoles/ adverse effects</keyword><keyword>Lung Diseases, Interstitial/ chemically induced/ epidemiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>May</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>16645972</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>PT 10-9 (DJ 9-13)</custom7></record></Cite></EndNote>179Country, Setting:Canada, PharMetrics claims databaseFunding:Sanofi-Aventis; Canadian Institutes of Health ResearchResearch Objective:To assess risk of ILD in pts with RA treated with LEF.Study Design:Retrospective Cohort StudyOverall N:62,734Study Duration: Sept 1, 1998 through Dec 31, 2003Inclusion Criteria:Age: 18 or olderDMARD-treated cohort defined as all subjects who received at least 1 prescription for a DMARD on or after September 1, 1998, mo LEF was approved in US Exclusion Criteria:No DMARD prescriptionSubjects with outcome of interest during 1-yr period prior to cohort entryInterventions, dose:D1: Cases of ILDD2: ControlsN:D1: 74D2: 7400Mean age, yrs:D1: 62D2: 61Sex, % female:D1: 70D2: 74Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRRisk of ILD in pts treated with LEF compared with those not treated with LEF; adjusted OR 1.9, 95% CI,1.1-3.6 (all ORs reported here were adjusted for the concurrent use of the other DMARDs, the other anti-RA drugs, as well as sex and comorbid conditions)Increase was less and was not significant with use of MTX (OR 1.4; 95% CI,0.8-2.3)No increase in risk of ILD with LEF among pts who had no previous MTX use and no interstitial lung disease prior to cohort entry (37 cases and 4,259 controls); OR 1.2; 95% CI,0.4-3.1. This group did have an increased risk of ILD with MTX treatment (OR 3.1; 95% CI,1.5-6.4). Among those who had previously taken MTX or who had a previous diagnosis of ILD (37 cases and 3,141 controls), the risk of ILD was elevated with LEF treatment (OR 2.6; 95% CI,1.2-5.6) but was decreased with MTX treatment (OR 0.4; 95% CI,0.2-0.9)NROverall Attrition Rate, %:NAITT Analysis:NA: nested case control designQuality Rating:FairNesStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableSuissa et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3170</RecNum><DisplayText><style face="superscript">180</style></DisplayText><record><rec-number>3170</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3170</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Suissa, S.</author><author>Bernatsky, S.</author><author>Hudson, M.</author></authors></contributors><auth-address>McGill University Health Centre, Montreal, Canada. samy.suissa@clinepi.mcgill.ca</auth-address><titles><title>Antirheumatic drug use and the risk of acute myocardial infarction</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>531-6</pages><volume>55</volume><number>4</number><keywords><keyword>Aged</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Case-Control Studies</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Isoxazoles/therapeutic use</keyword><keyword>Male</keyword><keyword>Methotrexate/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Myocardial Infarction/ epidemiology/ prevention & control</keyword><keyword>Random Allocation</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2006</year><pub-dates><date>Aug 15</date></pub-dates></dates><isbn>0004-3591 (Print)</isbn><accession-num>16874796</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>180Country and settingNorth America - claims dataSource of fundingSanofi-AventisCanadian Institutes of Health Research, Fonds de la recherche en sante du QuebecResearch objectiveAssess risk of AMI associated with use of DMARDS and other RA txtStudy designNested Case control CohortOverall N6138 for case-control with 1:10 ratio selected from eligible RA cohort of 107,908 subjectsDuration of studyvaired, mean?=?14 mos (11). All subjects were followed from date of cohort entry until one of following occurred: termination of health plan enrollment, death, end of study period (December 31, 2003), or outcome of interest, namely AMQuality rating FairInclusion CriteriaRA pts with 1 year of eligibility in databaseExclusion CriteriaAMI during 1 year prior to cohort entryInterventions, DoseD1: Other: Case (Acute Myocardial Infarction - AMI)D2: Other: ControlNumber in groupD1: 558D2: 5580Mean age (years)D1: 65 D2: 65Sex, % femaleD1: 55D2: 55Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)NRPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %Glucocorticoid therapy:D1: 15.1D2: 12.0DMARD use, %D1: 25.4D2: 30.4MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: Mean follow up: 14 mos (11)D2: 14 mos (11)ACR ACR 20:D1: Efficacy outcomes NR ACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference NROverallOverall attrition/withdrawal, n: D1: NA, LTF NR for databaseOverall adverse events reported, n:NR - see additional comments for germane analysesSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherAdjusted* RR of AMI for current users of RA medications: MTX monotherapy 0.81 (95%CI 0.60-1.08)LEF 0.28 (0.12-0.64)Biologic Agents (IFX, ETN, & ANA combined) 1.30 (0.92-1.83)All other DMARDS (includes HCQ, SSZ, & 10 other txt) 0.67 (0.46-0.97)Glucocorticoids 1.32 (1.02-1.72)[*Adjusted for age & comorbidities]Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Svennsson et al., 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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 EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEx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 EN.CITE.DATA 181Country, Setting:Sweden, multicenter (5 rheumatologic units covering both urban and rural districts)Funding:Swedish Rheumatism Association and Vardal FoundationResearch Objective:To study and compare outcomes of 2 different DMARD/corticosteroid options in txt of early RA in clinical practiceStudy Design:RCTOverall N:245Study Duration: 2 yrsInclusion Criteria:Diagnosed according 1987 revised ACRDuration of condition: less than 2 yrsConsidered to be in need of Css or DMARDS by treating physician's judgmentNSAIDS and analgesics allowed Exclusion Criteria:Prior txt with: DMARDS or Cxs Per authors--regarded as not suitable for various medical or non-medical reasonsInterventions:D1: PNL + MTXD2: SSZ + PNL at lowest possible doseOverall:PNL: 7.5 to 15 mg daily for 1 to 3 mos. with subsequent reduction to lowest possible doseMTX: 5 to 15 mg per wkSSZ: 2 to 3 grams dailyN:D1: 113D2: 108Mean age (yrs):D1: median 54D2: median 52Sex, % female:D1: 59D2: 67Race, % white: NR Mean disease duration, yrs:D1: 6 mos.D2: 7 mosTJC, mean:NRSJC, mean:NRDMARD use, %:D1: 0D2: 0Corticosteroid use, %:D1: 0D2: 0MTX naive, %: NRTreatment resistant %: NRPatients with Early RA (≤3 yrs): NRDAS28 median:D1: 5D2: 4.9 Larsen:D1: 5D2: 3HAQ:D1: 0.9D2: 0.9RF +:D1: 71D2: 39No significant differences between txt groups for individual response, remission, function, or radiologic progressionResponse (EULAR individual response criteria for good/moderate/no response, %) D1: 30/40/30. D2: 33/30/37% (P = 0.319)Remission, % D1: 29 D2: 19 (P = 0.095)Mean change in HAQ D1: 0.35 D2: -0.38 (P = 0.752)Mean change in Larsen score 6.2 vs. 4.1 (P = 0.298)Completers, %D1: 81% D2: 53% Survival analysis between 2 groups (using withdrawals due to AEs or inefficacy as terminal event) showed a highly significant difference in survival times between 2 groups (P = 0.0005)Overall: D1: 9.9D2: 31.6Overall Attrition Rate, %: 39.6ITT Analysis:No another type of analysis was used (define): Although they state it was an ITT analysis, statistical analysis based on 221 of the 245 pts with available data for clinical outcomes and for about 72% of the cases for Larsen score (based on availableQuality Rating:Poor for efficacy, fair for adverse eventsStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Svensson et al., 2005 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1460</RecNum><DisplayText><style face="superscript">182</style></DisplayText><record><rec-number>1460</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1460</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Svensson, Bjorn</author><author>Boonen, Annelies</author><author>Albertsson, Kristina</author><author> van der Heijde, Desiree</author><author>Keller, Catharina</author><author>Hafstrom, Ingiald</author></authors></contributors><titles><title>Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rate: a two-year randomized trial</title><secondary-title>Arthritis and rheumatism</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>3360-70</pages><volume>52</volume><number>11</number><keywords><keyword>CN-00531519</keyword></keywords><dates><year>2005</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1,2,3</custom4><custom7>PT 9-28 (LM 8-2)</custom7></record></Cite></EndNote>182Country, SettingSweden, multicenterFunding:Swedish Rheumatism Association and othersResearch ObjectiveEfficacy of low-dose PNL on joint damage and disease activity in pts with early RA being treated concomitantly with DMARDsStudy Design:RCTOverall N:250Study Duration: 2 yrsInclusion Criteria:Age 18 to 80 yrsDiagnosed according ARA 1987 revised criteriaDuration ≤ 1 yr: pt in BARFOT studyDAS28 score >3.0Started by treating rheumatologist on first DMARDConcomitant NSAIDS txt permittedIntraarticular steroid injections allowed except 2 wks prior to any clinical evaluationExclusion Criteria:Pregnant or lactatingGlucocorti-coids, DMARDsContraindi-cation for glucocorticoid therapyPrevious fragility fractures, pts < 65 years with T score <-2.5 on bone mineral densitometryInterventions, dose:D1: DMARD (SSZ 2 g/day or MTX mean dose 10 mg/week, dosages NR) + PNL (7.5 mg/d)D2: DMARD onlyN:D1: 119D2: 131Mean age, yrs:D1: 51D2: 59Sex, % female:D1: 65D2: 63Race, % white:D1: NRD2: NRMean disease duration, yrs:D1: 6.5 mosD2: 5.8 mosTJC, mean:NRSJC, mean:NRDMARD use, %:Overall: 100Corticosteroid use, %:NRMTX naive, %:NRTxt resistant, %:NRPts with Early RA (≤3 yrs):Overall: 100Baseline DAS, mean:D1: 5.28D2: 5.42HAQ:D1: 1.01D2: 0.98SOFI: D1: 8D2: 9At 2 yrs: DAS < 2.6 disease remission, % achievedD1: 55.5D2: 32.8 (P = 0.0005)DAS28, scores over time ± SD D1: 5.3 ± 1.1 at baseline to 2.7 ± 1.5 after 1 yr and 2.7 ± 1.3 after 2 yrsD2: 5.4 ± 1.0, 3.3 ± 1.5, and 3.2 ± 1.4HAQ scores mean decrease over time : D1: 1.0 at baseline to 0.4 at 1 year and 0.5 D2: 1.0, 0.6, and 0.7 (P value NR)Improvement in mean SOFI index D1: mean decreased from 8 at baseline to 4 at 1 year and 4 after 2 years D2: 9, 6, and 7 respectively(P value NR)Total sharp score, median IQR change iD1: 1.8 (IQR 0.5-6.0) D2: 3.5 (IQR 0.5-10.0) (P = 0.019)Newly eroded joints per pt, median D1: 0.5 (IQR 0-2) D2: 1.25 (IQR 0-3.25) (P = 0.007)NROverall Attrition Rate, %:6.6%ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicablevan Halm, V.P. et al.; 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE.DATA 183Country and settingAmsterdam, Netherlands; outpatient clinicSource of fundingNot reportedResearch objectiveInvestigate possible associations between CVD and use of conventional DMARDs in RAStudy designCase Control CohortOverall N613Duration of studyRecruitment: 1953 - 2002; Follow-up: 2002 - 2004.Quality rating FairInclusion CriteriaFulfillment of American College of Rheumatology criteria of RA.Exclusion CriteriaNRInterventions, DoseD1: PRED: dosage and frequency NRMTX; dosage and frequency NRSSZ; dosage and frequency NRHydroxychlorquine: dosage and frequency NRD2: PNL: dosage and frequency NRMTX: dosage and frequency NRSSZ: dosage and frequency NRHydroxychlorquine: dosage and frequency NRNumber in groupD1: 541D2: 72Mean age (years)D1: 62, SD 11D2: 67, SD 10P = 0.001Sex, % femaleD1: 72D2: 58P = 0.02Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 7.7 yrs, IQR: 5-11D2: 10.6, IQR: 8-13P = 0.001Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: PRED ever: 31D2: PRED ever: 25Overall: PRED ever: P?=?0.32DMARD use, %D1: Median use: 2 IQR: 2-3SSZ HCQ or MTX never: 5SSZ ever: 78HCQ ever: 40MTX ever: 72D2: Median use: 3, IQR: 1-3SSZ HCQ or MTX never: 17SSZ ever: 65HCQ ever: 38MTX ever: 44 Overall:Median use: P?=?0.01SSZ HCQ or MTX never: P?=?0.001SSZ ever: P?=?0.02HCQ ever: P?=?0.67MTX ever: P?=?0.001MTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1:Erosive pts (%): 80DMARD naive (%): 3Hypertension: 19%Hypercholesterolemia: 2%D2: Erosive pts (%): 92DMARD naive (%): 10Hypertension: 49%Hypercholesterolemia: 21%Overall: Erosive pts: P?=?0.02DMARD naive: P?=?0.002Hypertension: P?=?0.001Hypercholesterolemia: P?=?0.001ACR NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNAOverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherModel 2 OR (95% CI) corrected for age, gender, smoking, RA duration, htn, diabetes, and hypercholesteremia with all comparisons to never MTX, SSZ, or HCQ; MTX 0.47 (0.07-3.23)SSZ 0.31 (0.07-1.33)HCQ 0.45 (0.10-2.04)MTX and SSZ 0.24 (0.07-0.85)MTX and HCQ 0.54 (0.08-3.66)SSZ and HCQ 0.34 (0.05-2.16)MTX, SSZ, and HCQ 0.27 (0.07-0.99)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:van Riel et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1949</RecNum><DisplayText><style face="superscript">184</style></DisplayText><record><rec-number>1949</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1949</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Riel, P. L.</author><author>Taggart, A. J.</author><author>Sany, J.</author><author>Gaubitz, M.</author><author>Nab, H. W.</author><author>Pedersen, R.</author><author>Freundlich, B.</author><author>Macpeek, D.</author></authors></contributors><auth-address>University Medical Center Nijmegen, Netherlands.</auth-address><titles><title>Efficacy and safety of combination etanercept and methotrexate versus etanercept alone in patients with rheumatoid arthritis with an inadequate response to methotrexate: The ADORE study</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><dates><year>2006</year><pub-dates><date>Feb 7</date></pub-dates></dates><accession-num>16464988</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>HRCT</custom3><custom4>1, 3</custom4><custom5>ETA, MTX</custom5><custom6>RA</custom6><custom7>PT 9-28 (KD 8-23)</custom7></record></Cite></EndNote>184Country, Setting:Multinational, multicenterFunding:WyethResearch Objective:Evaluate efficacy and safety of ETA monotherapy vs. ETA + MTX in RA pts with inadequate response to MTXStudy Design:RCT, open-labelOverall N:315Study Duration: 16 wksInclusion Criteria:Age: ≥ 18Diagnosed according to ACR criteriaFunctional class of: I-IIIPrevious use of DMARDsInadequal control of RA symptoms on MTX ≥ 12.5 mg/wk for ≥3 mosExclusion Criteria:DMARDS other than MTX within 12 wks of screening; prednison ≥10 mg/dCorticosteroid injections within 6 wks'Significant' concurrent medical illnessInterventions, dose:D1: ETA (25 mg s.c. twice wkly)D2: ETA (25 mg s.c. twice wkly) + MTX (≥12.5 mg/wk)N:D1: 159D2: 155Mean age, yrs:D1: 53D2: 54Sex, % female:D1: 79.2D2: 76.8Race, % white:D1: 99.4D2: 98.7Mean disease duration, yrs:D1: 10.0D2: 9.8TJC, mean:D1: 14.6D2: 14.7SJC, mean:D1: 11.2D2: 11.9DMARD use, %:NRCorticosteroid use, %D1: 49.1D2: 55.5MTX naive, %:Overall: 0Txt resistant, %:Overall: 100Pts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 6.2D2: 6.3HAQ:D1: 1.6D2: 1DAS28 improvement of > 1.2 units, %:D1: 72.8D2: 75.2Difference -2.3 (95% CI, -13.1-8.2; P = 0.658)EULAR response maintained, %: D1: 80.0D2: 82.4 (P = NR)ACR 20, %: D1: 71.0D2: 67.1Difference 3.9 (95% CI, -6.4- 14,2; P = 0.46)ACR 50, %: D1: 41.9D2: 40.1Difference 1.8,(95% CI, -9.2-12.8?; P = 0.75)ACR 70, %: D1: 17.4D2?: 18.4Difference -1.0 (95% CI, -9.6-7.6; P = 0.82)Overall: D1: 62.9D2: 70.3SAEs:D1: 5.0D2: 4.5Infections:D1: 24.5D2: 32.3Serious Infections:D1: 0.6D2: 0.3Infusion or injection reaction:D1: 6.3D2: 6.5Dizziness:D1: 0.6%D2: 0Headache:D1: 8.8D2: 6.5URTI:D1: 8.2D2: 12.9Overall Attrition Rate, %:17.2ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicablevan Riel et al., 2008,PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE.DATA 185 ADORE trial Country and settingMultinational multicenterSource of fundingWyeth ResearchResearch objectiveAssess efficacy of ETN vs. ETN + MTX in RA patients using pt reported outcomesStudy designControlled TrialsOverall N315Duration of study16 weeksQuality rating Fair Inclusion CriteriaTreatment resistant, unsatisfactory response to MTX 12.5 mg a week for at least 3 mos18 years old or olderACR functional class I-IIIDAS28 of 3.2 or greater or combination of ≥ 5 swollen joints≥ 5 painful jointsESR of 10 mm/h or more16 years old or older during onset of RANo DMARD use other than MTX within 12 weeks of screeningExclusion CriteriaPatients requiring concurrent use of PRED greater than 10 mg/day or equivalentInterventions, DoseD1: ETN: 25 mg twice a weekD2: MTX: 12.5 mg per weekETN: 25 mg twice a weekNumber in groupD1: 160D2: 155Overall: 315Mean age (years)D1: 53D2: 54Sex, % femaleD1: 79.2D2: 76.8Race, % whiteD1: 99.4D2: 98.7Race, % blackD1: 0.0D2: 1.3Ethnicity, LatinoNRMean disease duration, years (SD)D1: 10.0 yrs (NR)D2: 9.8 (NR)Patients with early RA, three years or less, %NR Treatment resistant, %D1: 100D2: 100Overall: 100TJC, mean (SD)D1: 14.6D2: 14.7SJC, mean (SD) D1: 11.2D2: 11.9Corticosteroid use, %D1: 49.1D2: 55.5DMARD use, %NRMTX na?ve, %D1: 0D2: 0Overall: 0Baseline DAS score, mean (SD)D1: 6.2D2: 6.3ACR NAHAQ, mean change from baseline (SD)D1: -0.59 (0.69)D2: -0.59 (0.58)Overall: NS, Difference between groups (95% CI): 0.029 (-0.115, 0.172)DAS NASF-36 NRRadiographic measures NAQuality of life scales EQ-5D VAS (0-100): D1: 19.76 (27.24)D2: 21.00 (26.61) Difference between groups (95% CI): -2.593 (-7.667, 2.482);-EQ-5D (0-1):D1: 0.1883 (0.33)D2: 0.2399 (0.32) Difference between groups (95% CI): -0.024 (-0.82, 0.034 )EQ-5D Usual Activities:D1: 0.3077 (0.61)D2: 0.2867 (0.55)Difference between groups (95% CI): 0.017 (-0.102, OverallOverall attrition/withdrawal, n:D1: 18D2: 13Overall: 30Withdrawals due to adverse events, n:D1: 6D2: 9Overall: 15Withdrawals due to lack of efficacy, n:D1: 9D2: 0Overall: 9Overall adverse events reported, n: NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNRAuthor, year, study name, if applicablevan Riel et al., 2008, ADORE trialPEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy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ADDIN EN.CITE.DATA 185 (original ADORE publication was van Riel 2006)(continued)Presence of known relevant concurrent diseasesUse of bolus corticosteroids within 6 weeks or intra-articular corticosteroid injection within 9 weeks of screeningPrevious treatment with ETN or other biological treatmentsRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)Mean HAQ:D1: 1.6D2: 1.70.137)EQ-5D Self Care: D1: 0.1731 (0.55)D2: 0.3533 (0.55)Difference between groups (95% CI): -0.129 (-0.233, -0.025; (P = 0.0154)EQ-5D Pain/Discomfort:D1: 0.3718 (0.62)D2: 0.4400 (0.65)Difference between groups (95% CI): -0.04 (-0.159, 0.078)EQ-5D Mobility: D1: 0.3077 (0.50)D2: 0.2318 (0.52)Difference between groups (95% CI): 0.058 (-0.047, 0.164)EQ-5D Anxiety/Depression: D1: 0.2323 (0.59)D2: 0.24 (0.65)Difference between groups (95% CI): 0.029 (-0.089, 0.147)Patient global assessment ofdisease (PGAD) (0-10):D1: -2.78 (2.60) D2: -2.95 (2.59)Difference between groups (95% CI): -0.174 (-0.692, 0.345)Pain VAS (0-10):D1: -29.40 (25.09)D2: -29.93 (27.25)Difference between groups (95% CI): -1.327 (-7.039, 4.386)Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, year, study name, if applicablevan Vollenhoven et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM3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ADDIN EN.CITE.DATA 186 Swefot TrialCountry and settingSweden; multicenterSource of fundingSchering-Plough;Swedish Rheumatism AssociationResearch objectiveTo compare the addition of SSZ and HCQ versus the addition of INF to MTX in patients with early RAStudy designControlled TrialsOverall N258Duration of study12 mosInclusion CriteriaEarly RA; symptom duration <1 yrTreatment resistant resistant to 3-4 mos of MTX treatment indicated by DAS28>3.2≥18 yrs oldACR dx of RAno previous treatment with DMARDsNo oral glucocorticoid or stable glucocorticoid therapy for at least 4 wks of at most 10 mg daily PNL or equivalentDAS28 >3.2Exclusion CriteriaContraindications of any trial drugsComparisons (dosage and frequency)D1: MTX: up to 20 mg per wkSSZ: 1000 mg twice a dayHCQ: 400 mg a dayD2: MTX: up to 20 mg a weekINF: 3 mg/kg at wk 0, 2, 6 and every 8 wks thereafterNumber in groupD1: 130D2: 128Overall: 258Mean age (years)D1: 52.9 D2: 51.1Overall: NRSex, % femaleD1: 78D2: 76Overall: NRRace, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 6.3 mos (3.6)D2: 6.2 mos (3.5)Overall: NRTJC, meanNRSJC, mean NRCorticosteroid use, %D1: 8D2: 6Overall: NRDMARD use, %: D1: 100D2: 100Overall: 0MTX na?ve, %: D1: 0D2: 0Overall: 0Treatment resistant, %: D1: 100D2: 100Overall: 100Patients with early RA, three years or less, %: D1: 100D2: 100Overall: 100 Baseline DAS scoreAt baseline:D1: 5.98 (0.96)D2: 5.91 (0.93)At randomizationD1: 4.79 (1.05)D2: 4.91 (0.98)Overall: NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value): NRACR mean difference/ absolute difference?(CI/SD/P Value):ACR 20: ITT population:D1: I28D2: 42Overall: RR 1.48 (1.06 to 2.08; P=0.0266)mITT population:D1: 45D2: 59Overall: RR 1.31 (1.03 to 1.66; P=0.0257)ACR 50: ITT population:D1: 15D2: 25Overall: RR 1.71 (1.02 to 2.86; P=0.0424)mITT population: D1: 34D2: 48Overall: RR 1.43 (1.06 to 1.93; P=0.0226)ACR 70: ITT population: D1: 7D2: 12Overall: RR 1.69 (0.77 to 3.73; P=0.2044)mITT population: D1: 15D2: 28Overall: RR 1.83 (1.12 to 2.98; P=0.0156)HAQ, mean difference/ absolute difference?(CI/SD/P Value): NRDAS, mean difference/absolute difference?(CI/SD/P Value): NRSF-36, mean difference/absolute difference?(CI/SD/P Value): NRRadiographic measures, mean difference/absolute difference?(CI/SD/P Value): NRQuality of life scales, mean difference/absolute difference?(CI/SD/P Value): NROthers, (please name); mean difference/absolute difference?(CI/SD/P Value): NROverallOverall attrition/withdrawal (n):D1: 41D2: 23Overall: 64Withdrawals due to adverse events?(n): D1: 14D2: 10Overall: 24Withdrawals due to lack of efficacy?(n): D1: 18D2: 3Overall: 21Adherent/compliant?(n): D1: NRD2: NROverall: NROther attrition related comments? D1: 5 pts received treatment and 5 switched treatmentD2: 8 never received treatment and 5 switched treatmentOverall adverse events reported (n): D1: 48D2: 32Serious adverse events:Death (n): D1: 0D2: 0Cardiovascular events (specify)?(n): HTND1: 2D2: 0Hepatotoxicity/elevated liver enzymes?(n): LiverD1: 1D2: 5Malignancies:NRRespiratory events:Upper respiratory infection?(n):D1: 2D2: 2Other infections:Other infections (specify) (n): D1: 0D2: 5GI:Other GI symptoms (specify) (n): D1: 15D2: 1Other:Fractures?(n): MusculoskeletalD1: 0D2: 1Skin rash (n): Skin and allergic reactionsD1:3D2: 11Demyelenation or multiple sclerosis?(n): Central and peripheral nervous systemD1: 6D2: 1 Quality rating for efficacy/effectiveness? FairQuality rating for observational studies NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Wallis et al., 2004 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1927</RecNum><DisplayText><style face="superscript">187</style></DisplayText><record><rec-number>1927</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1927</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wallis, R. S.</author><author>Broder, M. S.</author><author>Wong, J. Y.</author><author>Hanson, M. E.</author><author>Beenhouwer, D. O.</author></authors></contributors><auth-address>Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA. r.wallis@umdnj.edu</auth-address><titles><title>Granulomatous infectious diseases associated with tumor necrosis factor antagonists</title><secondary-title>Clin Infect Dis</secondary-title></titles><periodical><full-title>Clinical Infectious Diseases</full-title><abbr-1>Clin. Infect. Dis.</abbr-1><abbr-2>Clin Infect Dis</abbr-2></periodical><pages>1261-5</pages><volume>38</volume><number>9</number><keywords><keyword>Aged</keyword><keyword>Antibodies, Monoclonal/ adverse effects</keyword><keyword>Antirheumatic Agents/adverse effects</keyword><keyword>Communicable Diseases/ chemically induced/epidemiology</keyword><keyword>Female</keyword><keyword>Granulomatous Disease, Chronic/ chemically induced/epidemiology</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/ adverse effects</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Receptors, Tumor Necrosis Factor</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Risk Factors</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists & inhibitors</keyword></keywords><dates><year>2004</year><pub-dates><date>May 1</date></pub-dates></dates><accession-num>15127338</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>OAE</custom3><custom4>3</custom4><custom7>KD 9-6 (SW)</custom7></record></Cite></EndNote>187Country, Setting:Multinational, multicenterFunding:NRResearch Objective:The relationship between the use of tumor necrosis factor antagonists and onset of granulomatous infection was examinedStudy Design:Database analysis;AERSOverall N:649 casesStudy Duration: variousInclusion Criteria:All pts treated with INF or ETAOther meds allowed Concurrent use of immuno-suppressant drugsExclusion Criteria:NAInterventions, dose:D1: INF (various)D2: ETA (various)N:D1: 566 cases (>233,000 treated)D2: 83 cases (>113,000 treated)Mean age, yrs:D1: 60D2: 58Sex, % female:D1: 66D2: 59Race, % white:NRMean disease duration, yrs:NRTJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:D1: 41D2: 66MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 43D2: 41NRGranulomatous infections, rate per 100,000D1: 239 D2: 74 (P < .001) D1 risk of granulomatous infection was 3.25-fold greater among pts than D2. Tuberculosis infections, rate per 100,000D1: 144 D2: 35 (P < .001) Overall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Wasserman et al., 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 188Country, Setting:Canada, Quaternary care centerFunding:Schering-PloughResearch Objective:Description of infusion-related reactions to INF (during or within 1 hour of infusion) in pts with active rheumatoid arthritisStudy Design:Case seriesOverall N:113 pts, 1,183 infusionsStudy Duration: Mean 60.6 wksInclusion Criteria:Age: 18 to 75Diagnosed according to ACR; failed at least 3 DMARDsActive disease; stable doses of corticosteroids (10 mg/d) and/or NSAIDsExclusion Criteria:Biologically-based therapiesCurrent signs and symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, GI, endocrine, pulmonary, cardiac, neurological, or cerebral diseaseHistory of lymphopro-liferative diseaseAny known malignant disease Screened for TBInterventions, dose:D1: INFINF: 3 mg/kg wks 0,2,6 then every 8, dose could be increased to 5 mg/kg at wk 14 based on clinical groundsN:D1: 113 pts; 1,183 infusionsMean age, yrs:D1: 45.7Sex, % female:D1: 87Race, % white:NRMean disease duration, yrs:D1: 13.6TJC, mean:D1: 21.3SJC, mean:D1: 10.8DMARD use, %:NRPRE use, %:D1: 59MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMTX use:D1: 100104 infusion-related reactions out of 1183 infusions performed (8.8%) and 60 of 113 pts (53%) experienced at least one reaction during course of txtInfusion related reactions; Allergic-45 (3.8%); Cardiopulmonary-35 (3.0%); Misc.-24 (2.0%)Reactions following pretxt or not with diphenhydramine at infusions 3 and 4 Pretreated 14.7% vs. Not pretreated 14.3%Overall: D1: 8.8Headache:D1: 9Overall Attrition Rate, %:ITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Weaver et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 189Country, Setting:US, Rheumatology practices (509)Funding:Immunex CorporationResearch Objective:To evaluate effectiveness of select biologics, MTX (MTX), and other DMARDs in management of adult RA in routine clinical practiceStudy Design:Prospective cohort studyOverall N:5,397Study Duration: 12 mosInclusion Criteria:Age: 18 or olderDiagnosed with RA according to ACR criteria: 1987 ACRPts requiring a change in RA txtExclusion Criteria:Pregnant or lactatingActive infection, Concurrent enrollment in a clinical trialInterventions, dose:D1: MTX (10 to 15 mg/wk)D2: ETN (50 mg/wk)D3: ETN (50 mg/wk) +MTXD4: INF (3.8 mg/8wks)D5: INF (3.8 mg/8wks) + MTX (15 mg/wk)D6: LEF (20 mg/d)D7: LEF (20 mg/d) +MTX (15 mg/wk)D8: MTX (15 mg/wk) +HCQ (400 mg/d)D9: MTX (15 mg/wk) +HCQ (400 mg/d) +SSZ (2000 mg/d)N:D1: 941 D2: 1251D3: 1783 D4: 120D5: 540 D6: 204D7: 191 D8: 325D9: 42Mean age, yrs:D1: 56.8 D2: 53.2D3: 52.6 D4: 60.2D5: 58.5 D6: 57.7D7: 55.5 D8: 53.8D9: 47.8 Sex (% female D1: 75 D2: 75 D3: 79 D4: 71 D5: 77 D6: 76D7: 78D8: 80 D9: 79Race, % white:D1: 77 D2: 81 D3: 81D4: 78 D5: 81 D6: 78D7: 82 D8: 83 D9: 79Mean disease duration, yrs:D1: 3.5 D2: 9.2 D3: 7.7 D4: 10.6D5: 9.5 D6: 10.1D7: 7.4 D8: 4.6 D9: 7.2 TJC, mean:D1: 13 D2: 13.4D3: 13.3 D4: 14.8D5: 3.9 D6: 12.8D7: 12.2 D8: 11.8D9: 10.1 SJC, mean:D1: 11.3 D2: 11.1D3: 11.5 D4: 13.9D5: 12.0 D6: 11.8D7: 11.4 D8: 9.2 D9: 10.2DMARD use, %:D1: 25 D2: 75 D3: 96 D4: 85 D5: 96 D6: 75D7: 95 D8: 78 D9: 88Corticosteroid use, %D1: 53 D2: 48 D3: 51D4: 63 D5: 57 D6: 48D7: 56 D8: 50 D9: 48MTX naive, %: NR Treatment resistant, %: NRPts with Early RA (≤3 yrs): NRBaseline DAS, mean: NRRF factor positive:D1: 72 D2: 65 D3: 69 D4: 68 D5: 69 D6: 75D7: 73 D8: 71 D9: 71mACR20, %: D1: 37D2: 41D3: 43D4: 26D5: 35Adjusting for baseline covariates D3: vs. D1(OR, 1.29, 95% CI, 1.09-1.52; P < 0.01)D2 vs. D1 (OR, 1.23, 95% CI, 1.02-1.47; P < 0.05)D1 vs. D5 (OR, 0.96 CI 0.76-1.21 P = 0.72) D1 vs. D4 (OR, 0.66, 95% CI, 0.43-1.02; P = 0.06)Mean change HAQ improvement, % D1: 7D2: 17 (P < 0.001) D3: 17 (P < 0.001) mACR20 responseD5 vs. D1: (OR, 0.68, 95% CI, 0.48-0.96; P < 0.05) D6 vs. D1 (OR, 0.76, 95% CI, 0.54-1.06; P = 0.11)D8 vs, D1: (OR, 0.94, 95% CI, 0.72-1.23; P = 0.64) D9 vs. D1: (OR, 0.57, 95% CI, 0.27-1.18; P = 0.13)SJC % improvement D1 vs. D1: 34 (N/A) D2 vs. D1: 53 (P < 0.0001)D4 vs. D1: 29 (P = NS) D3 vs. D1: 55 (P < 0.0001) D5 vs. D1:48 (P < 0.01)TJC % improvement D1: 34(N/A)D2 vs. D1: 53% (P < 0.001)D4 vs. D1: 29% (P = NS) D3 vs. D1: 55% (P < 0.0001) D5 vs. D1: 48% (P = NS)HAQ % improvement amongst pts < 65 yrs D2: 22 D4: 4 (P = NR) NROverall Attrition Rate, %:33.2ITT Analysis:YesQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Weinblatt et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2031</RecNum><DisplayText><style face="superscript">190</style></DisplayText><record><rec-number>2031</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2031</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weinblatt, M.</author><author>Combe, B.</author><author>Covucci, A.</author><author>Aranda, R.</author><author>Becker, J. C.</author><author>Keystone, E.</author></authors></contributors><auth-address>Brigham and Women's Hospital, Boston, Massachusetts.</auth-address><titles><title>Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>2807-2816</pages><volume>54</volume><number>9</number><dates><year>2006</year><pub-dates><date>Aug 31</date></pub-dates></dates><accession-num>16947384</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>PAE</custom3><custom4>3</custom4><custom7>DJ 9-28 (PT 9-25)</custom7></record></Cite></EndNote>190Country, Setting:MultinationalMulticenterASSURE TrialFunding:Bristol-Myers SquibbResearch Objective:To assess safety of ABA in pts with active RA who had been receiving 1 traditional nonbiologic and/or biologic DMARDsStudy Design:RCTOverall N:1456Study Duration: One yrInclusion Criteria:Age: ≥ 18Diagnosed according to ACR criterial class I-IVDMARDsStable, low-dose oral Css and/or stable doses of NSAIDsStable CHF, asthma, COPD, and DMExclusion Criteria:Pregnant or lactatingHistory of TBImpaired renal or hepatic systemMycophenolate mofetil, CYP, other calcineurin inhibitors, D-penicillamine, cyclophos-phamide, apheresis unstable or uncontrolled diseases, or any autoimmune disorder as the main diagnosisBacterial infectionsActive herpes zoster < 2 mos, hepatitis B or C Interventions, dose:D1: Non-bio and ABAD2: Non-bio and placeboD3: Bio and ABAD4: Bio and placeboABA: 500 mg a body weight <60 kg, 750 mg for 60-100 kg, and 1 gram for >100 kgN:D1: 856D2: 418D3: 103D4: 64Mean age, yrs:D1: 52.2D2: 52.0D3: 54.6D4: 52.8Sex, % female:D1: 83.1D2: 83.7D3: 75.7D4: 75.0Race, % white:D1: 83.9D2: 83.3D3: 97.1D4: 92.2Mean disease duration, yrs:D1: 9.5D2: 9.5D3: 11.3D4: 11.3TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRHAQ:D1: 1.5D2: 1.5D3: 1.5D4: 1.6ABA and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively)Serious infections were more frequent in the ABA group than in the placebo group (2.9% vs. 1.9%)Serious adverse events occurred more frequently in the subgroup receiving ABA plus a biologic agent (22.3%) than in other subgroups (11.7-12.5%)Sub analysis of Pts w/ COPD and DM (placebo vs. ABA)(%)COPDOverall AEs 88.2 vs.97.3Respiratory oriented 23.5 vs. 23.5SAEs 5.9 vs. 27DMOverall AEs 90.3 vs. 93.8Infections 58.1 vs. 50.8SAEs 12.9 vs. 21.5Change in HAQ from baselinePlacebo -0.25 vs. ABA-0.46 (P < 0.001)Overall: D1: 89.7D2: 86.1D3: 95.1D4: 89.1SAEs:D1: 11.7D2: 12.2D3: 22.3D4: 12.5Infections:D1: 54.9D2: 53.6D3: 65.0D4: 57.8Serious Infections:D1: 2.6D2: 1.7D3: 5.8D4: 1.6Malignancies:D1: 3.2D2: 3.8D3: 6.8D4: 1.6Overall Attrition Rate, %:15ITT Analysis:YesQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWeinblatt, M. et al2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIz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ADDIN EN.CITE.DATA 191Country and settingUnited States multicenterSource of fundingBristol-Myers SquibbResearch objectiveInvestigate efficacy and safety of ABA in combination with ETN in patients with active RAStudy designControlled TrialsOverall N121Duration of studyDB Phase: 1 yearLTE: 2 yearsQuality rating Fair Inclusion Criteria≥ 18 years of ageMet criteria ofACR for RAIn functional class, I, II, or IIIMust have received ETN 25 mg twice weekly for ≥ 3 mos and have ≥ 8 swollen joints (66-joint count) and ≥ 10 tender joints (68-joint count). CRP elevation was not required for entry.Exclusion CriteriaActive or latent infectionRecent opportunist infectionTB requiring treatment within previous 3 yearsHistory of cancer within previous 5 yearsHistory of drug or alcohol misusePregnant and nursing women.Interventions, doseD1: ETN: 25 mg twice weeklyAbatacept: 2 mg/kg on days 1, 15 and 30, and every 4 weeks thereafter after 1 year switched to 10 mg/kgD2: ETN: 25 mg twice weeklyPlacebo: after 1 year switch to 10 mg/kg abataceptNumber in groupD1: 85D2: 36Overall: 121Mean age, years (SD)D1: 49.8 (23-73)D2: 54.3 (28-71)Sex, % femaleD1: 78D2: 72Race, % whiteD1: 94D2: 100Race, % blackD1: NRD2: 0Ethnicity, LatinoD1: NRD2: 0Mean disease duration, years (SD)D1: 13 (10.1)D2: 12.8 (8.6)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)D1: 28.7 (14)D2: 29.2 (13.2)Swollen Joint Count, mean (SD)D1: 19.6 (9.4)D2: 20.1 (10.5)Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score (SD)D1: 61.8 (17.2)D2: 62.1 (13.5)Required treatment for latent TBNROther population characteristics, n?(SD)Patient assessment of pain: D1: 66.5 (16.6) D2: 53.2 (23.2) mHAQ:D1: 1.0 (0.5)D2: 0.9 (0.5)ACR Modified ACR 20:At 6 months:D1: 48.2 D2: 30.6 P = 0.072 At 1 year:D1: 48.2D2: 30.6Overall: NRModified ACR 50:At 6 months:D1: 25.9D2: 19.4P = 0.448At 1 year:D1: 28.2D2: 16.7Overall: NRModified ACR 70:At 6 months:D1: 10.6D2: 0.0P = 0.042At 1 year:D1: 9.4D2: 5.6P = 0.481HAQ (SD/P Value)Change from baseline to 1-year D1: -0.3 (0.5, P?=?0.001)D2: -0.2 (0.4, P?=?0.040Change from 1-year to 2-years:D1: -0.1 (0.3, P?=?NS)D2: 0 (0.2, P?=?NS)DAS Change from baseline to 1-year:D1: -25.7 (27.0, P?=?0.001)D2: -18.2 (20.4, P?=?0.001)Change from 1-year to 2-years: D1: -7.6 (20.6, P?=?0.0135)D2: -0.6 (23.1, P?=?NS)SF-36 Change after 1-year of LTEMCS:D1: 7.08D2: 2.14PCS:D1: 9.11D2: 3.19Change after 2 years of LTEMCS:D1: 4.68D2: 7.54PCS:D1: 6.65D2: 3.44Radiographic measures NRQuality of life scales NRAttrition/withdrawalOverall after 1 year, n:D1: 27D2: 14Withdrawals due to adverse events, n:D1: DB Phase: 10 LTE: 8D2: 1Withdrawals due to lack of efficacy, n:D1: 9D2: 12Adherent/compliant after 1 year, n:D1: 58D2: 22Attrition rate difficult to determine b/c they do not clearly indicate how many patients remained in either drug after LTE completion they list only total LTE completion (N?=?61).Overall adverse events reported, n:D1: DB Phase: 79 LTE: 78D2: 32Overall: 189Serious adverse eventsDeath, n:D1: DB Phase: 0LTE: 1D2: 0Overall: 1MalignanciesNRRespiratory eventsTuberculosis: NRUpper respiratory infection, n:D1: DB Phase: 20, LTE: 10D2: 5Overall: 35Other infectionsNRGINausea or vomiting, n:D1: DB Phase: 13, LTE: 12D2: 1Overall: 26Other GI symptoms, n:D1: Diarroea: DB Phase: 12, LTE: 13D2: Diarrhea: 2Overall: 27OtherSkin rash, n:D1: DB Phase: 11 LTE: 10D2: 3Overall: 24Headache, n:D1: DB Phase: 20, LTE: 10D2: 5Overall: 35Dizziness, n:D1: DB Phase: 13, LTE: 8D2: 2Overall: 23Fatigue, n:D1: DB Phase: 14, LTE: 14D2: 6Overall: 34Sinusitis, n:D1: DB Phase: 14, LTE: 18D2: Sinusitis: 3Overall: 35Arthralgia, n:D1: DB Phase: 13, LTE: 5D2: 3Overall: 21Cough, n:D1: DB Phase: 11, LTE: 11D2: 3Overall: 25Vascular disorders: D1: DB Phase: 0, LTE: 6D2: 1MalignanciesD1: DB Phase: 0, LTE: 3D2: 0Gastrointestinal disorders: D1: DB Phase: 0, LTE: 3D2: 0Infections and infestations: D1: DB Phase: 3, LTE: 1D2: 0Nervous system disorders: D1: DB Phase: 2, LTE: 1D2: 0Respiratory, thoracic and mediastinal disorders: D1: DB Phase: 30, LTE: 32D2: 7Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWells et al., 2008; ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2964</RecNum><DisplayText><style face="superscript">192</style></DisplayText><record><rec-number>2964</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2964</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Wells, G.</author><author>Li, T.</author><author>Maxwell, L.</author><author>Maclean, R.</author><author>Tugwell, P.</author></authors></contributors><auth-address>Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, Ontario, KIH 8M5 Canada. gawells@ottawaheart.ca</auth-address><titles><title>Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>260-5</pages><volume>67</volume><number>2</number><keywords><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Double-Blind Method</keyword><keyword>Fatigue/drug therapy</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoconjugates/ therapeutic use</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Quality of Life</keyword><keyword>Sleep Disorders/drug therapy</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2008</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1468-2060 (Electronic)</isbn><accession-num>17846044</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>CT</custom3><custom4>KQ 2 / fair</custom4><custom7>Companions: 2714, 3492 (ATTAIN)</custom7></record></Cite></EndNote>192 Westhovens et al., 2006;PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM0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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM0
OTI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xOTM8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4zNDkyPC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNTlhc3hzeHZ5Znh4eHZlZTAycHBheHdm
d2YwZnNmejI5NXY5Ij4zNDkyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikdl
bmVyaWMiPjEzPC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2VzdGhv
dmVucywgUi48L2F1dGhvcj48YXV0aG9yPkNvbGUsIEouIEMuPC9hdXRob3I+PGF1dGhvcj5MaSwg
VC48L2F1dGhvcj48YXV0aG9yPk1hcnRpbiwgTS48L2F1dGhvcj48YXV0aG9yPlNoZXJyZXIsIFku
PC9hdXRob3I+PGF1dGhvcj5ldCBhbC4sPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz
PjxhdXRoLWFkZHJlc3M+UmVwcmludHM6IFVaIEtVIExldXZlbkRpZW5zdCBSZXVtYXRvbCwgSGVy
ZXN0ciA0OUIsIEItMzAwMCBMb3V2YWluLCBCZWxnaXVtIHJlbmUud2VzdGhvdmVuc0B1ei5rdWxl
dXZlbi5hYy5iZSYjeEQ7VW5pdiBIb3NwIExldXZlbiwgTG91dmFpbiwgQmVsZ2l1bTwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkltcHJvdmVkIGhlYWx0aC1yZWxhdGVkIHF1YWxpdHkgb2Yg
bGlmZSBmb3IgcmhldW1hdG9pZCBhcnRocml0aXMgcGF0aWVudHMgdHJlYXRlZCB3aXRoIGFiYXRh
Y2VwdCB3aG8gaGF2ZSBpbmFkZXF1YXRlIHJlc3BvbnNlIHRvIGFudGktVE5GIHRoZXJhcHkgaW4g
YSBkb3VibGUtYmxpbmQsIHBsYWNlYm8tY29udHJvbGxlZCwgbXVsdGljZW50cmUgcmFuZG9taXpl
ZCBjbGluaWNhbCB0cmlhbDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5SaGV1bWF0b2xvZ3k8L3Nl
Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5SaGV1bWF0b2xv
Z3k8L2Z1bGwtdGl0bGU+PGFiYnItMT5SaGV1bWF0b2xvZ3kgKE94Zm9yZCkuPC9hYmJyLTE+PGFi
YnItMj5SaGV1bWF0b2xvZ3kgKE94Zm9yZCk8L2FiYnItMj48L3BlcmlvZGljYWw+PHBhZ2VzPjEy
MzgtMTI0NjwvcGFnZXM+PHZvbHVtZT40NTwvdm9sdW1lPjxudW1iZXI+T2N0PC9udW1iZXI+PGtl
eXdvcmRzPjxrZXl3b3JkPkFiYXRhY2VwdC0tYXJ0aHJpdGlzLTwva2V5d29yZD48a2V5d29yZD5D
b21iaW5lZCB0aGVyYXB5LS1hYmF0YWNlcHQsIGFudGkgaW5mbGFtbWF0b3J5IGFnZW50cyBhbmQg
c3Rlcm9pZHMsIGNvcnRpY288L2tleXdvcmQ+PGtleXdvcmQ+Q29tYmluZWQgdGhlcmFweS0tYW50
aSBpbmZsYW1tYXRvcnkgYWdlbnRzLCBhYmF0YWNlcHQgYW5kIHN0ZXJvaWRzLCBjb3J0aWNvPC9r
ZXl3b3JkPjxrZXl3b3JkPkNvbWJpbmVkIHRoZXJhcHktLXN0ZXJvaWRzLCBjb3J0aWNvLCBhYmF0
YWNlcHQgYW5kIGFudGkgaW5mbGFtbWF0b3J5IGFnZW50czwva2V5d29yZD48a2V5d29yZD5JbW11
bm9tb2R1bGF0aW5nIGFnZW50cy0tYWJhdGFjZXB0PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub21v
ZHVsYXRpbmcgYWdlbnRzLS1hbnRpIGluZmxhbW1hdG9yeSBhZ2VudHM8L2tleXdvcmQ+PGtleXdv
cmQ+SW1tdW5vbW9kdWxhdGluZyBhZ2VudHMtLXN0ZXJvaWRzLCBjb3J0aWNvPC9rZXl3b3JkPjxr
ZXl3b3JkPlF1YWxpdHkgb2YgbGlmZS0tYWJhdGFjZXB0PC9rZXl3b3JkPjxrZXl3b3JkPkFydGhy
aXRpcy0tYWJhdGFjZXB0PC9rZXl3b3JkPjxrZXl3b3JkPk91dGNvbWVzLS1jbGluaWNhbDwva2V5
d29yZD48a2V5d29yZD5EYXRhIGNvbGxlY3Rpb24tLXBhdGllbnRzPC9rZXl3b3JkPjxrZXl3b3Jk
PlN0ZXJvaWRzLCBjb3J0aWNvLS1hcnRocml0aXM8L2tleXdvcmQ+PGtleXdvcmQ+VHVtb3IgbmVj
cm9zaXMgZmFjdG9yLWFscGhhIGluaGliaXRvcnMtLWFydGhyaXRpczwva2V5d29yZD48a2V5d29y
ZD5BbnRpIGluZmxhbW1hdG9yeSBhZ2VudHMtLW5vbnN0ZXJvaWRhbDwva2V5d29yZD48a2V5d29y
ZD5QYXRpZW50cy0tZGF0YSBjb2xsZWN0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5
ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMC8wMS88L2RhdGU+PC9wdWItZGF0ZXM+
PC9kYXRlcz48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cDovL3NlYXJjaC5lYnNjb2hvc3Qu
Y29tL2xvZ2luLmFzcHg/ZGlyZWN0PXRydWUmYW1wO2RiPWlwYSZhbXA7QU49NDMtMTg3ODQmYW1w
O3NpdGU9ZWhvc3QtbGl2ZSA8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTE+STwv
Y3VzdG9tMT48Y3VzdG9tMj5JPC9jdXN0b20yPjxjdXN0b20zPkNUPC9jdXN0b20zPjxjdXN0b200
PktRIDIgLyBmYWlyPC9jdXN0b200PjxjdXN0b203PkNvbXBhbmlvbnM6IDI5NjQsIDI3MTQgKEFU
VEFJTik8L2N1c3RvbTc+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE.DATA 193 Hassett et al., 2008PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjI3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ADDIN EN.CITE.DATA 194 ATTAINCountry and settingSee 458 (from orignal report)Source of fundingBristol-Meyers SquibbResearch objectiveTo examine impact of ABA on HRQOL To evaluate patient-recorded outcomes including SF-36, activity limitation, fatigueStudy designControlled TrialsOverall N391Duration of study24 weeksQuality rating Fair Inclusion CriteriaTreatment resistant defined as inadequate response to anti-TNF ≥10 swollen and ≥12 tender jointsCRP levels of at least 1 mg/dl (upper limit of normal range:0.5 mg/dl).Exclusion CriteriaPatients not treated with oral DMARDs or ANK for ≥ 3 mos prior to the study or not receiving a stable dose for at least 28 daysUse of myco- phenolate mofetil, cyclosporine, other calcineurin inhibitorsand D-penicillamineWomen who were pregnant or nursing Interventions, DoseD1: Abatacept: 10 mg/kgDMARDSD2: PlaceboDMARDSNumber in groupD1: 258D2: 133Mean age (years)D1: 53.4D2: 52.7Sex, % femaleD1: 77.1D2: 79.7Race, % whiteD1: 96.1D2: 93.2Race, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 12.2 (8.5)D2: 11.4 (8.9)Patients with early RA, three years or less, %NRTreatment resistant, %100%TJC, mean (SD)D1: 22.3 (10.2) D2: 22.0 (10.0)SJC, mean (SD) D1: 31.2 (13.0) D2: 32.8 (13.4)Corticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)D1: 6.5D2: 6.5Overall: 6.5Required treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)ACR NRHAQ, D1: HAQ-DI -0.5 (SD 0.6)D2: -0.1 (0.4)P = 0.0001Treatment difference?=?-0.33, 95% CI, (-0.44 to -0.22)DAS NRSF-36 Physical component score, % (SD):D1: 6.5 (SD 9.6)D2: 1.0 (SD 7.7)Patients doing better (%):D1: 44.6D2: 23.1Patients doing same (%):D1: 45.8D2: 63.1Patients doing worse (%):D1: 9.6D2: 13.9Overall:Mental component score (MCS), % (SD)D1: 5.4 (SD 11.7)D2: 1.7 (SD 10.2)Patients doing better (%):D1: 43.0D2: 31.5Patients doing same (%):D1: 45.840.3D2: 45.4Patients doing worse (%):D1: 16.7D2: 23.1Overall: Physical Component Score, P?=?0.0001, Percentage of Patients Doing Better/Same/Worse, P?=?0.0002, Treatment Difference?=?5.5, 95% CI, (3.6 to 7.4)Mental Component Score, P?=?0.0025, Percentage of Patients Doing Better/Same/Worse, P?=?0.0723, Treatment Difference?=?3.7, 95% CI, (1.3 to 6.1)Radiographic measures NRQuality of life scales NROthers, (please name) Fatigue VAS: ABA?=?-22.1 (SD?=?28.6), Placebo?=?-5.3 (SD?=?27.4), P = 0.0001[From #2964] Fatigue Treatment difference?=?-16.8, 95% CI, (-22.8 to -10.8)[From #2714] Required Help or Care at Baseline: ABA?=?89%, Placebo?=?87%Required Help or Care at Final Visit: ABA?=?70%, Placebo?=?76%Percent Difference in Required Help or Care between Baseline and Final Visit: ABA?=?19%, Placebo?=?11%Psychosocial Independence: Changes in Mean Scores from Baseline to Final Visit in Psychosocial Independence between ABA and Placebo: ABA greater by 0.46 units, 95% CI, (0.17-0.75), P?=?0.002Changes in Mean Scores from Baseline to Final Visit in Physical Independence between ABA and Placebo: ABA greater by 0.59 units, 95% CI, (0.35-0.82), P?=?0.001OverallNROverall adverse events reported, n: NRSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherNR Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Westhovens et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1945</RecNum><DisplayText><style face="superscript">195</style></DisplayText><record><rec-number>1945</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1945</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Westhovens, R.</author><author>Yocum, D.</author><author>Han, J.</author><author>Berman, A.</author><author>Strusberg, I.</author><author>Geusens, P.</author><author>Rahman, M. U.</author></authors></contributors><auth-address>UZ Gasthuisberg, Leuven, Belgium. rene.westhovens@uz.kuleuven.ac.be</auth-address><titles><title>The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial</title><secondary-title>Arthritis Rheum</secondary-title></titles><periodical><full-title>Arthritis and Rheumatism</full-title><abbr-1>Arthritis Rheum.</abbr-1><abbr-2>Arthritis Rheum</abbr-2><abbr-3>Arthritis & Rheumatism</abbr-3></periodical><pages>1075-86</pages><volume>54</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Antibodies, Monoclonal/ adverse effects</keyword><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/ complications/ drug therapy</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infection/epidemiology/ etiology</keyword><keyword>Male</keyword><keyword>Methotrexate/ therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Risk Assessment</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><accession-num>16572442</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>P</custom3><custom4>1, 3 MTC</custom4><custom7>KD 10-9 (DJ 9-13)</custom7></record></Cite></EndNote>195START TrialCountry, Setting:Multinational, multicenterFunding:Centocor Research Objective:The risk of serious infections in INF therapy, and safety in combination with background txts during 1 yr in pts with RA with various comorbiditiesStudy Design:RCTOverall N:1084Study Duration: 54 wks of which 22 wks wast RCT then open label extensionInclusion Criteria:Adults w/ RA according to ACR criteriaMTX > 3 mosChloroquine, AZA, penicillamine, oral or intramuscular goldHCQ, SSZ, LEF, CYP, oral Css, or NSAIDSExclusion Criteria:TBOpportunistic or serious infections, HIV, lympho-proliferative disease or malignancyCHF investigational drug (3 mos or 5 half-lives, whichever was greater), with cyclophos-phamide, nitrogen mustard, chlorambucil, or other alkylating agents more than 5 mg/kg cyclosporine, or biologicInterventions, dose:D1: Placebo + MTX (up to 25 mg/wk)D2: INF 3 mg/kg (at wks 0, 2, 6, and 14) + MTX (up to 25 mg/wk)D3: INF 10 mg/kg (at wks 0, 2, 6, and 14) + MTX (up to 25 mg/wk)D4: D2 + D3N:D1: 363D2: 360D3: 361Mean age, yrs:D1: median 52D2: 53D3: 52Sex, % female:D1: 83.2D2: 80.0D3: 77.8Race, % white:NRMedian disease duration, yrs:D1: 8.4D2: 7.8D3: 6.3TJC, mean:D1: 22D2: 22D3: 22SJC, mean:D1: 15D2: 15D3: 15DMARD use, %:D1: 70D2: 70.8D3: 69.8Corticosteroid use, %:D1: 59.2D2: 59.2D3: 59MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NRMedian HAQ score:D1: 1.5D2: 1.5D3: 1.5% RF positive: D1: 80.7D2: 82.8D3: 76.8At week 22ACR20 response, %D1: 26D2: 58 D3: 61(P < 0.0001)ACR50 response, %D1: 9.7D2: 32.1 D3: 35.4(P < 0.0001)ACR70 response, %D1: 4.7D2: 14.0 D3: 16.1(P < 0.0001)DAS28 , (+/-)D1: 4.4 (1.4) D2 and D3: 3.4 (1.3) (P < 0.001)Remission, %D1: 14D2: 31 D3: 32(P < 0.0001)Overall: D1: 66.2D2: 69.7D3: 72.3D4: 71.0SAEs:D1: 7.5D2: 7.8D3: 7.5D4: 7.8Serious Infections:D1: 1.7D2: 1.7D3: 5.0D4: 3.3Cardiovascular Events: D1: 3.3D2: 4.5 D3: 5.9D4: 5.2Headache:D1: 6.1D2: 9.7D3: 10.2D4: 10.0Hepatotoxicity (ALT increase):D1: 2.8D2: 3.6D3: 5.3D4: 4.4Malignancies:D1: 1.7 D2: 4.2 Nausea:D1: 8.0D2: 6.4D3: 6.4D4: 6.4URTI:D1: 10.5D2: 9.7D3: 11.9D4: 10.8UTI:D1: 0D2: 0D3: 0.6D4: 0.3Overall Attrition Rate, %:17.1ITT Analysis:YesQuality Rating:GoodStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWesthovens et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3886</RecNum><DisplayText><style face="superscript">196</style></DisplayText><record><rec-number>3886</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3886</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Westhovens, R.</author><author>Robles, M.</author><author>Ximenes, A. C.</author><author>Nayiager, S.</author><author>Wollenhaupt, J.</author><author>Durez, P.</author><author>Gomez-Reino, J.</author><author>Grassi, W.</author><author>Haraoui, B.</author><author>Shergy, W.</author><author>Park, S. H.</author><author>Genant, H.</author><author>Peterfy, C.</author><author>Becker, J. C.</author><author>Covucci, A.</author><author>Helfrick, R.</author><author>Bathon, J.</author></authors></contributors><auth-address>(Westhovens) UZ Gasthuisberg, Department of Rheumatology, B-3000 Leuven, Belgium.</auth-address><titles><title>Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Annals of the Rheumatic Diseases</full-title><abbr-1>Ann. Rheum. Dis.</abbr-1><abbr-2>Ann Rheum Dis</abbr-2></periodical><pages>1870-7</pages><volume>68</volume><number>12</number><edition>2009 Jan 5</edition><dates><year>2009</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>16935912</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 1, 2, 3 / good</custom4></record></Cite></EndNote>196Country and settingMultinationalSource of fundingBristol-Myers SquibbResearch objectiveTo assess the efficacy and safety of ABA in MTX-naive patients with early RA and poor prognostic factors.Study designRCTOverall N509Duration of study2 yrsQuality rating Good Inclusion CriteriaMTX naive or previous exposure of 10mg/wk or less for three wks or less, with none administered for 3 mos before providing informed consentEarly RA of 2 yrs or less≥ 12 tender and 10 swollen jointsC-reactive protein (CRP) 0.45 mg/ dl or greaterRF and/or anti-CCP2 seropositivity and radiographic evidence of bone erosion of the hands/ wrists/feetExclusion CriteriaWomen who were pregnant or breastfeedingPatients with active Mycobacterium tuberculosis requiring treatment within 3 yrs.Interventions, DoseD1: MTX: 7.5 mg/wk; 15 mg/wk at wk 4 and 20 mg/wk at wk 8 ABA: 10 mg/kgD2: MTX: 7.5mg/wk; 15 mg/wk at wk 4 and 20mg/wk at wk 8Placebo Number in groupD1: 256D2: 253Overall: 509Mean age (years)D1: 50.1D2: 49.7Overall: NRSex, % femaleD1: 76.6D2: 78.7Overall: NRRace, % whiteD1: 78.9D2: 86.6Overall: NRRace, % blackNREthnicity, LatinoNRMean disease duration, yearsD1: 6.2 (7.5)D2: 6.7 (7.1)Overall: NRPatients with early RA, three years or less, %: 100 Treatment resistant, %: NRTender Joint Count, meanD1: 31.3 (14.8)D2: 30.8 (14.0)Overall: 31.0Swollen Joint Count, mean D1: 22.9 (11.3D2: 21.9 (10.1)Overall: 22.4Corticosteroid use, %D1: 51.2D2: 49.0Overall: NRDMARD use, %: Other non- biological DMARD (HCQ)D1: 1.6 D2: 2.0 Overall: NRSSZD1: 0 D2: 0.4 Overall: NRMTX na?ve, %: 100Baseline DAS scoreD1: 6.3 (1.0)D2: 6.2 (1.0)Overall: 6.3Required treatment for latent TBNROther population characteristics: HAQ-DI mean (SD)D1: 1.7 (0.7)D2: 1.7 (0.7)Overall: NRACR:ACR 20: NRACR 50: Yr 1D1: 57.4D2: 42.3D1 vs. 2: P< 0.001ACR 70: Yr 1D1: 42.6D2: 27.3D1 vs. 2: P< 0.001HAQ: HAQ-DID1: -0.96 (SE 0.04)D2: -0.76 (SE 0.04) DAS: CRPD1: -3.22 (SE 0.09)D2: -2.49 (SE 0.09)P < 0.001SF-36: Mental componentD1: 8.15 (SE 0.64)D2: 6.34 (SE 0.64) D1 vs. 2: P = 0.046Physical componentD1: 11.68 (SE 0.62) D2: 9.18 (SE 0.63) D1 vs. 2: P = 0.005Radiographic measures: Yr 1TSD1: 0.63D2: 1.06D1 vs. 2: P = 0.040ESD1: ES:0.50D2: 0.89D1 vs. 2: P = 0.033JSND1: 0.13D2: 0.17D1 vs. 2: P = 0.353No radiographic progressionD1: (T< or = 0): 61.2% (95% CI, 55.0-67.3)D2: (T< or = 0): 52.9% (95% CI, 46.6-59.2) D1 and D2: 8.3% (95% -1.0 to 17.5)Quality of life scales: NROthers: Yr 1 ACR90D1, 16.4%D2: 6.7%D1 vs D2: P < 0.001OverallOverall attrition/withdrawal (n): D1: 24D2: 26Withdrawals due to adverse events?(n): D1: 9D2: 11Withdrawals due to lack of efficacy?(n): D1: 0D2: 8Overall adverse events reported (n): D1: 217D2: 211Overall: 428Serious adverse events:Death (n):D1: 2D2: 4Overall: 6Malignancies:Other cancer (specify)?(n): PancreaticD1: 1D2: 0Overall: NRRespiratory events:Tuberculosis?(n): D1: 0D2: 0Overall: 0Pneumonia (n): D1: 1D2: 3Overall: 4Upper respiratory infection?(n): D1: 26D2: 26Overall: 52Other infections:Other infections (specify) (n): Infections (not specified)D1: 132D2: 139Serious infections (not including pneumonia)GastroenteritisD1: 1D2: 1CellulitisD1: 1D2: NRPseduomonal lung infectionD1: 1D2: NRPost operative lung infectionD1: 1D2: NRBreast cellulitis/staphycoccal infectionD1: NRD2: 1GI:NROther:Infusion/injection site reactions?(n): D1: 16D2: 5Overall: 21Dizziness (n): D1: 5D2: 2Overall: 7Any other AEs: Most frequently reported adverse events in D1:Nausea:10% ptsUpper respiratory tract infection: 10% ptsHeadache: 10% ptsD2: NRPregnancy (protocol violations)D1: 2D2: NRSpontaneous abortion between days 1 and 30 after 1 infusion of ABAD1: 1D2: NRStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Wolfe and Michaud, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 197Country, Setting:US, 908 practicesFunding:National Data Bank for Rheumatic Diseases (US) funded by pharmaResearch Objective:The rate of and standardized incidence ratio for lymphoma in pts with RA and in RA patient subsets by txt groupStudy Design:Prospective cohort studyOverall N:18,572Study Duration: Up to 3 yrsInclusion Criteria:Participants in National Data Bank for Rheumatic Diseases (NDB) long-term study of outcomes of RACases were identified from this group as those who developed lymphoma during the 2 ? yr observational periodExclusion Criteria:Cases were rejected if not enough information could be obtained to verify patient’s lymphomaInterventions, dose:D1: INF (varied)D2: ETA (varied)D3: MTX (varied)D4: No MTX/ No BiologicsN:D1: 6433D2: 2729D3: 5593D4: 4474Mean age, yrs:D1: 60.7D2: 56.4D3: 61.2D4: 60.4Sex, % female:D1: 77.3D2: 79.3D3: 75.7D4: 75.7Race, % white:NRMean disease duration, yrs:D1: 13.7D2: 14.1D3: 13.5D4: 13.5TJC, mean:NRSJC, mean:NRDMARD use, %:NRCorticosteroid use, %:NRMTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 1.2D2: 1.2D3: 1.1D4: 1.0VAS QoL:D1: 65.8D2: 64.3D3: 66.7D4: 65.9Pain: D1: 4.2D2: 4.3D3: 3.7D4: 3.9SIR for whole population regardless of txt was 1.9 (95%CI, 1.3-2.7); indicating a greater risk for lymphoma in pts with RASIR for pts taking biologics (INF or ETA) was 2.9 (95%CI, 1.7-4.9). No significant differences were observed between txt groupsOnly 233 pts received AKA and no lymphomas occurred in this groupOverall, lymphoma incidence rate per 100,000 PY was 99 (95%CI,69-142); for various durations of RA, rates were: 0-5 yrs: 171 (95%CI,82-360), 5-10 yrs: 70 (95%CI,29-168), 10-15 yrs: 20 (95%CI,3-145), >15 yrs: 121 (95% CI, 74-198)NROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Wolfe and Michaud, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 198Country, Setting:US, multicenter (National Data Bank for Rheumatic Diseases)Funding:Centocor, IncResearch Objective:To determine frequency of heart failure in pts with RA, and to determine its predictors, particularly use of anti-TNF therapyStudy Design:Retrospective cohort studyOverall N:15,739 (RA plus OA subjects)Study Duration: Inclusion Criteria:Participation in National Data Bank for Rheumatic Diseases study of outcomes of arthritis; patient at participating rheumatology clinicExclusion Criteria:NRInterventions, dose:D1: Any Anti-TNFD2: INFD3: ETAD4: No anti-TNFD5: Total PopulationOverallN:NRMean age, yrs:D1: 60D2: 61.5D3: 56.7D4: 61.5D5: 51Sex, % female:D1: 78D2: 77D3: 80D4: 76D5: 77Race, % white:D1: 95D2: 96D3: 92D4: 92D5: 94Mean disease duration, yrs:D1: 14.2D2: 13.8D3: 15.2D4: 15.5D5: 14.9TJC, mean:NRSJC, mean:NRDMARD use, %:Overall: 86PRE use (%)D1: 47D2: 49D3: 39D4: 33D5: 39MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:D1: 3.7D2: 3.7D3: 3.6D4: 3.5D5: 3.6 MTX use:D1: 67D2: 76D3: 44D4: 47D5: 56Heart Failure461 cases in 13,171 pts with RA (overall risk of 3.5%); after adjusting for demographic characteristics; Risk: 3.9% (95% CI,= 3.4% to 4.3%)Among all cases of heart failure, pts receiving anti-TNF therapy were less likely to have heart failure than those not receiving anti-TNF therapy (-1.2%; 95% CI,-1.9 --0.5%)Overall, adjusted frequency of heart failure was 2.8% in those treated with anti-TNF vs. 3.9% in remaining pts (P = 0.03)Frequency of heart failure was 5.2% in men and 3.0% in womenIn examining incident cases of heart failure in pts under age 50, no increase was found (0/1569 pts using anti-TNF vs. 3/1401 not using anti-TNF therapy)NROverall Attrition Rate, %:NRITT Analysis:NAQuality Rating:FairStudy Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Analysis and Quality RatingAuthor, yr:Wolfe et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 199Country, Setting:US, Rheumatology ClinicsFunding:Bristol-Meyers-SquibbResearch Objective:To evaluate txt of RA and risk of hospitalization for pneumoniaStudy Design:Prospective cohort studyOverall N:16,788Study Duration: 3.5 yrsInclusion Criteria:Participants in NDB longitudinal study of RA outcomes including 5,317 enrolled as part of an INF safety registry and 1,852 as part of a LEF safety registryOther meds allowedExclusion Criteria:NAInterventions, dose:D1: CohortPrednisoneMTXLEFSSZHydroxychlorquineETAINFAdalimumabOther various RA txtsN:NRMean age, yrs:D1: 62Sex, % female:D1: 77.2Race, % white:D1: 89.7% white, 4.8% black, 3.0% Hispanic, 1.0 Asian/Pacific Islander, 1.1% American Indian or Alaskan native, 0.5% OtherMean disease duration, yrs:D1: 16.3TJC, mean:NRSJC, mean:NRDMARD use mean (lifetime #): D1: 3.3Corticosteroid use, %:D1: 38.1MTX naive, %:NRTxt resistant %:NRPts with Early RA (≤3 yrs):NRBaseline DAS, mean:NREffect of txt variables on risk of pneumonia (adjusted for demographic variables-age, sex, smoking, education, and enrollment)Prednisone HR 1.7 [95% CI, 1.5-2.1]) LEF HR 1.3 [95% CI, 1.0-1.5], P = 0.036)?SSZ HR 0.7 [95% CI, 0.4-1.0], P = 0.053)ETA HR 0.8 [95% CI, 0.6-1.0], P = 0.051)INF HR 1.1 [95% CI, 0.9-1.4], P = 0.322)Adalimumab HR 1.1 [95% CI, 0.6-1.9], P = 0.747)MTX HR 1.0 [95% CI, 0.8-1.2], P = 0.927)Hydroxychloroquine HR 0.9 [95% CI, 0.7-1.2], P = 0.481)NROverall Attrition Rate, %:NAITT Analysis:NAQuality Rating:FairStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWolfe et al., 2007 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2207</RecNum><DisplayText><style face="superscript">200</style></DisplayText><record><rec-number>2207</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2207</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Wolfe, F.</author><author>Caplan, L.</author><author>Michaud, K.</author></authors></contributors><auth-address>National Data Bank for Rheumatic Diseases, Arthritis Research Center Foundation, Wichita, KS 67214, USA. fwolfe@arthritis-</auth-address><titles><title>Rheumatoid arthritis treatment and the risk of severe interstitial lung disease</title><secondary-title>Scand J Rheumatol</secondary-title><short-title>Rheumatoid arthritis treatment and the risk of severe interstitial lung disease</short-title></titles><periodical><full-title>Scandinavian Journal of Rheumatology</full-title><abbr-1>Scand. J. Rheumatol.</abbr-1><abbr-2>Scand J Rheumatol</abbr-2></periodical><pages>172-8</pages><volume>36</volume><number>3</number><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Antibodies, Monoclonal/adverse effects</keyword><keyword>Arthritis, Rheumatoid/complications/ drug therapy</keyword><keyword>Female</keyword><keyword>Hospitalization</keyword><keyword>Humans</keyword><keyword>Lung Diseases, Interstitial/ etiology</keyword><keyword>Male</keyword><keyword>Methotrexate/adverse effects</keyword><keyword>Middle Aged</keyword><keyword>Risk</keyword></keywords><dates><year>2007</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>0300-9742 (Print)</isbn><accession-num>17657669</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>O</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>200Country and settingUS, multicenterSource of fundingCentocor, Amgen, Abbott, Bristol-Meyers-Squibb, Aventis, NIHResearch objectiveInvestigate association of serious ILD and RA treatmentsStudy designRetrospective Cohort StudyOverall N17598Duration of studyVaried, cohort followed up to 3.5 yrs beginning in 2001Quality rating Fair: Some confounding factors were controlled for but authors assert there are others (e.g. dr.s who prescribed a TNF-therapy to treat ILD, Dr.s prescribe LEF instead of MTX in pts with a history of lung disease) that present problems for assessing cInclusion CriteriaNational Databank for Rheumatic Diseases (NDB) includes patients receiving treatment for RAPatients hospitalized with interstitial lung diease (HILD) were considered casesExclusion CriteriaNRInterventions, DoseD1: Hospitilization for Interstitial Lung Disease (HILD) Case/Control (both Ds include treatment with: PRED, MTX, LEF, IFX, HCQ, ETN, SSZ, ADA, & ANK as well as others drugs not included in this reviewD2: Number in groupD1: 100D2: 17498Mean age (years)D1: 64.4D2: 61.9Sex, % femaleD1: 80.0D2: 77.0Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 15.3 (11.2)D2: 15.9 (11.2)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %NRMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: HAQ/prior lung problems: 1.4 (0.8)/66.7%D2: 1.1 (0.7)/16.7% (for BOTH HAQ & Prior lung problems P?=?0.001)ACR ACR 20:D1: No efficacy outcomes reportedACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallWithdrawals due to adverse events, n:D1: 8% of pts drop from National Data Bank for Rheumatic Diseases every yearOverall adverse events reported, n:D1: NR - see additional comments for germane analysesSerious adverse eventsNRMalignanciesNRRespiratory eventsNROther infectionsNRGINROtherHazard Ratio for HILD from current treatements (adjusted for age, sex, and prior lung disease): PRED 2.5 (95%CI 1.5-4.1, P?=?0.000), INX 0.7 (0.4-1.3), ETN 0.9 (0.4-1.7), LEF (1.3 (0.7-2.3), HCQ 1.0 (0.5-1.9), SSZ 1.4 (0.5-3.7), MTX 1.2 (0.7-1.9). Hazard Ratio for HILD from past treatments (adjusted for age, sex, and prior lung disease): PRED 3.0 (CI: 1.0-8.9, P?=?0.044), IFX 2.1 (CI:1.1-3.8, P?=?0.019), ETN 1.7 (CI: 1.0-3.0, P?=?0.056), LEF 1.4 (0.8-2.4), HCQ 0.7 (0.4-1.2), SSZ 0.7 (0.4-1.2), MTX 0.7 (0.4-1.4), ADA 1.1 (0.4-2.7), AKA 1.0 (0.3-3.3). Odds Ratio for death from ILD by treatment at time of hospitalization (adjusted for age, sex, and baseline HAQ): ETN 4.9* (CI: 1.0-23.1, P?=?0.044), LEF 3.5 (CI: 0.9-13.5, P?=?0.073), MTX 0.4 (0.1-1.4), INX 0.6 (0.1-2.5), PRED 0.9 (0.2-4.1). [*ETN OR for death reported differently in text - 4.0, CI is same in both places]Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWolfe & Michaud, 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIy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==
ADDIN EN.CITE.DATA 201 **UPDATES PREVIOUS REPORT** Wolfe & Michaud, 2004PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz
NDI8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4xOTc8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzQyPC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJm
ejlheDl0YWZ4cGQ1Ij4xMzQyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5Xb2xmZSwgRi48L2F1dGhvcj48YXV0aG9yPk1pY2hhdWQsIEsuPC9hdXRob3I+PC9hdXRob3Jz
PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+TmF0aW9uYWwgRGF0YSBCYW5rIGZvciBSaGV1
bWF0aWMgRGlzZWFzZXMsIEFydGhyaXRpcyBSZXNlYXJjaCBGb3VuZGF0aW9uLCBXaWNoaXRhLCBL
UyA2NzIxNCwgVVNBLiBmd29sZmVAYXJ0aHJpdGlzLXJlc2VhcmNoLm9yZzwvYXV0aC1hZGRyZXNz
Pjx0aXRsZXM+PHRpdGxlPkx5bXBob21hIGluIHJoZXVtYXRvaWQgYXJ0aHJpdGlzOiB0aGUgZWZm
ZWN0IG9mIG1ldGhvdHJleGF0ZSBhbmQgYW50aS10dW1vciBuZWNyb3NpcyBmYWN0b3IgdGhlcmFw
eSBpbiAxOCw1NzIgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QXJ0aHJpdGlzIFJo
ZXVtPC9zZWNvbmRhcnktdGl0bGU+PHNob3J0LXRpdGxlPkx5bXBob21hIGluIHJoZXVtYXRvaWQg
YXJ0aHJpdGlzOiB0aGUgZWZmZWN0IG9mIG1ldGhvdHJleGF0ZSBhbmQgYW50aS10dW1vciBuZWNy
b3NpcyBmYWN0b3IgdGhlcmFweSBpbiAxOCw1NzIgcGF0aWVudHM8L3Nob3J0LXRpdGxlPjwvdGl0
bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFydGhyaXRpcyBhbmQgUmhldW1hdGlzbTwvZnVs
bC10aXRsZT48YWJici0xPkFydGhyaXRpcyBSaGV1bS48L2FiYnItMT48YWJici0yPkFydGhyaXRp
cyBSaGV1bTwvYWJici0yPjxhYmJyLTM+QXJ0aHJpdGlzICZhbXA7IFJoZXVtYXRpc208L2FiYnIt
Mz48L3BlcmlvZGljYWw+PHBhZ2VzPjE3NDAtNTE8L3BhZ2VzPjx2b2x1bWU+NTA8L3ZvbHVtZT48
bnVtYmVyPjY8L251bWJlcj48a2V5d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdv
cmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBNb25vY2xvbmFsL2FkdmVyc2Ug
ZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbnRpcmhldW1hdGljIEFnZW50cy8gYWR2ZXJzZSBl
ZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFydGhyaXRpcywgUmhldW1hdG9pZC8gZHJ1ZyB0aGVy
YXB5LyBlcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RGF0YWJhc2VzLCBGYWN0dWFsPC9r
ZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5Gb2xsb3ctVXAgU3R1ZGll
czwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vZ2xvYnVs
aW4gRy9hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+SW5jaWRlbmNlPC9rZXl3b3Jk
PjxrZXl3b3JkPkx5bXBob21hLCBOb24tSG9kZ2tpbi8gZXBpZGVtaW9sb2d5L2V0aW9sb2d5PC9r
ZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG90cmV4YXRlLyBhZHZl
cnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdv
cmQ+UHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsIFR1bW9y
IE5lY3Jvc2lzIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0LCBOb24t
VS5TLiBHb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48
a2V5d29yZD5TRUVSIFByb2dyYW08L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2YgSWxsbmVz
cyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UdW1vciBOZWNyb3NpcyBGYWN0b3ItYWxwaGEvIGFu
dGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll
YXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPkp1bjwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh
dGVzPjxhY2Nlc3Npb24tbnVtPjE1MTg4MzQ5PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48
Y3VzdG9tMT5JPC9jdXN0b20xPjxjdXN0b20yPkk8L2N1c3RvbTI+PGN1c3RvbTM+T0FFPC9jdXN0
b20zPjxjdXN0b200PjM8L2N1c3RvbTQ+PGN1c3RvbTc+TE0gOC0xNCAoU1cpPC9jdXN0b203Pjwv
cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 197Country and settingUS, multicenterSource of fundingCentocor, Sanofi-Aventis, Bristol-Meyers Squibb, Abbott, Amgen, Wyeth-Australia, Merck, & PfizerResearch objectiveAssess relationship between anti-TNF therapy, MTX, and lymphoma in pts with RAStudy designRetrospective Cohort StudyOverall N19591 (for RA SIR calculation), 19562 for treatment analysisDuration of studymean 3.7 yearsQuality rating Fair: additional information about differences in Case/Control population sociodemographic characteristics & medical history/severity would allow for a better assessment of potential confounding variablesInclusion CriteriaRA diagnosed by rheumatologistExclusion Criteriaincomplete treatment data in registry, completed?=?2 semiannual questionairres, diagnosis of lymphoma prior to database entryInterventions, DoseD1: Case (Lymphoma)/Control (includes pts on MTX, INF, ETA, & ADA)Number in groupD1: 19591Mean age (years)D1: 59.0Sex, % femaleD1: 77.2Race, % whiteNRRace, % blackNREthnicity, LatinoNRMean disease duration, years (SD)D1: 14.1 yrsPatients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %NRDMARD use, %D1: % provided is forMTX na?ve, %NRBaseline DAS score, mean (SD)NRRequired treatment for latent TBNROther population characteristics, %,?(CI/SD/P value)D1: HAQ: 1.1 (0.7)ACR ACR 20:D1: No efficacy outcomes reportedACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallNROverall adverse events reported, n:NRSerious adverse eventsNRMalignanciesLymphoma or leukemia, n:D1: NR, SEE ADDITIONAL COMMENTSRespiratory eventsNROther infectionsNRGINROtherAfter adjusting for inflammatory activity, pts treated with any Anti-TNF (IFX, ETN, or ADA) did not have an increases risk for lymphoma compared to RA pts who had not received Anti-TNFs (OR 1.0, 95%CI: 0.6-1.8, P?=?0.875). IFX vs. all others (OR 1.2 CI:0.6-2.2, P?=?0.646); ETN vs. all others (OR 0.7, CI:0.3-1.6, P?=?0.422); ADA* 4.5 (0.9-23.1, P?=?0.064) *Authors questioned reliability of this result based on small sample (N?=?56) who had only used ADAStudy CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableWolfe & Muchaud, 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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ADDIN EN.CITE.DATA 202Country and settingUS, multicenterSource of fundingAbbott, Amgen, Bristol-Meyers Squibb, Centocor, Merck, Pfizer, and Wyeth AustraliaResearch objectiveAssess risk of malignancy among biologic treated ptsStudy designRetrospective Cohort StudyOverall N13,869 RA patients (13,001 in conditional logistic regression)Duration of studyMean: 4.1 years (minimum 1 year follow up)Quality rating FairInclusion CriteriaRAExclusion Criteria< 1 cancer free phase in NDB prior to initiating study or?=?2 observational periods recorded in NDBPrevious diagnoses for individual cancers (e.g. lung) excluded pt from analysis for that specific outcomeInterventions, DoseD1: All RA pts in NDB database (pts on biologics including INF, ETN, ADA, & ANK)Number in groupD1: 13,001Mean age (years)D1: 58.5Sex, % femaleD1: 78Race, % whiteD1: 92.5Race, % blackD1: 3.9Ethnicity, LatinoD1: 1.9Mean disease duration, years (SD)D1: 16.7 yrs (12.7)Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, mean (SD)NRSwollen Joint Count, mean (SD) NRCorticosteroid use, %D1: PRED: 45.6DMARD use, %D1: combined use ofMTX na?ve, %NRBaseline DAS score, mean (SD)D1: First Patient Activity Scale score: 3.7 (2.2) Required treatment for latent TBNROther population characteristics, %,?NRACR ACR 20:D1: No efficacy outcomes reportedACR 50: NRACR 70: NRHAQ NRDAS NRSF-36 NRRadiographic measures NRQuality of life scales NROthers, (please name); mean difference/absolute difference (CI/SD/P Value)NROverallOverall attrition/withdrawal, n: D1: NA, LTF NR for databaseOverall adverse events reported, n:D1: NR, SEE ADDITIONAL COMMENTSSerious adverse eventsNRMalignanciesOther cancer (specify), n:D1: NR, SEE ADDITIONAL COMMENTSRespiratory eventsNROther infectionsNRGINROtherBiologics were associated with an increased risk of nonmelanotic skin cancer (OR 1.5, 95% CI 1.2-1.8) and melanoma (OR 2.3, 95% CI 0.9-5.4). No other malignancy was associated with biologic use; OR (overall risk) of any cancer was 1.0 (95% CI 0.8-1.2). P?=?NS for all other cancers and all cancers combined (cancer assessed [with 10+ cases]: bladder, breast, colon, esophogas, leukemia, lung, lymphoma, Non-Hodgkins, pancrease, prostate, & solid* [*excludes lymphoma, leukemia, myeloma, and nonmelanoma skil malignancies]. Stratified by tx: Melanoma - IFX 2.6 (1.0-6.7), ETN* 2.4 (1.0-5.8), ADA* 0.8 (0.1-6.6), ANK* 4.2 (0.9-20.0)Skin (excludes melanoma)- IFX 1.7 (1.3-2.2), ETN 1.2 (1.0-1.5), ADA 0.9 (0.5-1.8), ANK 1.4 (0.7-2.8)Other cancers by drug P?=?NS [*indicates less than 10 cases by treatment]Study CharacteristicsInclusion and Exclusion CriteriaCharacteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events, %Author, year, study name, if applicableZhang, et al., 2006PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMz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=
ADDIN EN.CITE.DATA 203Country and settingChina, multicenterSource of fundingNRResearch objectiveReport efficacy and safety of IFX intreatment of active RA in Chinese pts.Study designControlled TrialsOverall N173Duration of study18 weeksQuality rating Fair Inclusion CriteriaTreatment resistant MTXDiagnosis of RA by ACR criteria, and active disease at screening despite treatment with MTX for 3 mos or over and at a stable dose (7.5-20 mg/wk) for at least 4 weeksActive disease based on: 1) 3 or more swollen joints, 2) 8 or more tender joints, 3) 2 offollowing items: morning stiffness greater than or equal to 45 min at screeningESR that exceeded 28 mm/hCRP that was greater than 1.5 times that of upper limit of normalScreening laboratory tests had to meet following criteria: haemoglobin?=?85 g/L, white blood cell count?=?4 times 10^9/L, serum neutrophils?=?1.5 times 10^9/L, platelets?=?100 times 10^9/L, serum aminotrans-ferase concentration?=?1.5 time suppoer limit of normal, serum creatinine of?=?120 umol/LStable dose of glucocorticosteroid for 4 weeks before screening and does not exceed 10 mg/day of PRED or equivalent.Exclusion CriteriaPatients with positive TB skin tests (induration?=?15 mm), hepatitis, AIDS, tumor, infections, congestive heart failure, demyelinating disease, commenced on treatment with other DMARDs within 4 weeks prior to screening, treatment with thalidomide or other TNF antagonists within 3 mos of entry to study.Interventions, doseD1: MTX: stable doseIFX: 3 mg/kg body weight at weeks 0, 2, 6, and 14D2: MTX: stable dose Placebo: 3 mg/kg body weight at weeks 0, 2, 6, and 14Number in groupD1: 87D2: 86Overall: 173Mean age, years (SD)D1: 47.9, SD: 10.1D2: 48.9, SD: 8.0P = 0.461Sex, % femaleD1: 85.1D2: 84.9Race, % whiteNARace, % blackNAEthnicity, LatinoNAMean disease duration, yearsD1: 85.6 months, SD: 74.0D2: 96.0 months, SD: 74.6P?=?0.360Patients with early RA, three years or less, %NR Treatment resistant, %NRTender Joint Count, meanNRSwollen Joint Count, mean NRCorticosteroid use, %D1: Never: 44.8D2: Never: 36.1DMARD use, %NRMTX na?ve, %NABaseline DAS scoreNRRequired treatment for latent TBNRACR At week 18: ACR 20:D1: 75.86D2: 48.84P = 0.0003ACR 50:D1: 43.68D2: 25.58P = 0.011ACR 70:D1: 22.99D2: 13.95P = 0.137HAQ, At week 18 vs. baseline:D1: -0.76D2: -0.45P = 0.0016DAS NRSF-36 NRRadiographic measures NRQuality of life scales NRAttrition/withdrawalOverall, n:D1: 9D2: 15Overall: 24Withdrawals due to adverse events, n:D1: 6D2: 4Overall: 10Overall adverse events reported, n:D1: 57D2: 48Overall: 105Serious adverse eventsHeart failure, n:D1: 0D2: 0MalignanciesTumour, n:D1: 0D2: 0Respiratory eventsTuberculosis: NRPneumonia, n:D1: NAD2: 1Other infectionsUrinary tract infection, n:D1: NRD2: 1GIAbdominal pain, n:D1: 1D2: NAOtherSkin rash, n:D1: 2D2: NADemyelenation or multiple sclerosis, n:D1: 0D2: 0Progressive multifocal leukoencephalopathy, n:D1: 1D2: NA Other AEs?1, n:D1: adult onset of Still's disease: 1D2: edema of lower limb: 1Other AEs?2, n:D1: Pharyngitis: 1D2: Exacerbation of swollen joints: 3 Other AEs?3, n:D1: NRD2: Abnormality in serum alanine transaminase: 1Any other AEsRespiratory:D1: 12D2: 12Liver:D1: 10D2: 7Skin:D1: 9D2: 4Urinary:D1: 7D2: 6Hematological:D1: 7D2: 2Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAdverse Events (%)Analysis and Quality RatingAuthor, yr:Zink, 2005PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz
OTg8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4yMDQ8L3N0
eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMzk4PC9yZWMtbnVtYmVyPjxm
b3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iNWZ4dHcyZXQ2dHZyZndlMHpwczUycHJm
ejlheDl0YWZ4cGQ1Ij4xMzk4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv
dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv
cj5aaW5rLCBBLjwvYXV0aG9yPjxhdXRob3I+TGlzdGluZywgSi48L2F1dGhvcj48YXV0aG9yPkth
cnksIFMuPC9hdXRob3I+PGF1dGhvcj5SYW1sYXUsIFAuPC9hdXRob3I+PGF1dGhvcj5TdG95YW5v
dmEtU2Nob2x6LCBNLjwvYXV0aG9yPjxhdXRob3I+QmFiaW5za3ksIEsuPC9hdXRob3I+PGF1dGhv
cj52b24gSGludWViZXIsIFUuPC9hdXRob3I+PGF1dGhvcj5Hcm9tbmljYS1JaGxlLCBFLjwvYXV0
aG9yPjxhdXRob3I+V2Fzc2VuYmVyZywgUy48L2F1dGhvcj48YXV0aG9yPkFudG9uaSwgQy48L2F1
dGhvcj48YXV0aG9yPkhlcnplciwgUC48L2F1dGhvcj48YXV0aG9yPktla293LCBKLjwvYXV0aG9y
PjxhdXRob3I+U2NobmVpZGVyLCBNLjwvYXV0aG9yPjxhdXRob3I+UmF1LCBSLjwvYXV0aG9yPjwv
YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkdlcm1hbiBSaGV1bWF0aXNtIFJl
c2VhcmNoIENlbnRyZSwgQmVybGluLCBHZXJtYW55LiBaaW5rQERSRlouZGU8L2F1dGgtYWRkcmVz
cz48dGl0bGVzPjx0aXRsZT5UcmVhdG1lbnQgY29udGludWF0aW9uIGluIHBhdGllbnRzIHJlY2Vp
dmluZyBiaW9sb2dpY2FsIGFnZW50cyBvciBjb252ZW50aW9uYWwgRE1BUkQgdGhlcmFweTwvdGl0
bGU+PHNlY29uZGFyeS10aXRsZT5Bbm4gUmhldW0gRGlzPC9zZWNvbmRhcnktdGl0bGU+PHNob3J0
LXRpdGxlPlRyZWF0bWVudCBjb250aW51YXRpb24gaW4gcGF0aWVudHMgcmVjZWl2aW5nIGJpb2xv
Z2ljYWwgYWdlbnRzIG9yIGNvbnZlbnRpb25hbCBETUFSRCB0aGVyYXB5PC9zaG9ydC10aXRsZT48
L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm5hbHMgb2YgdGhlIFJoZXVtYXRpYyBE
aXNlYXNlczwvZnVsbC10aXRsZT48YWJici0xPkFubi4gUmhldW0uIERpcy48L2FiYnItMT48YWJi
ci0yPkFubiBSaGV1bSBEaXM8L2FiYnItMj48L3BlcmlvZGljYWw+PHBhZ2VzPjEyNzQtOTwvcGFn
ZXM+PHZvbHVtZT42NDwvdm9sdW1lPjxudW1iZXI+OTwvbnVtYmVyPjxrZXl3b3Jkcz48a2V5d29y
ZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFn
ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTW9ub2Nsb25hbC9hZG1pbmlzdHJhdGlv
biAmYW1wOyBkb3NhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QW50aXJoZXVtYXRpYyBBZ2VudHMvIGFk
bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5BcnRocml0aXMsIFJo
ZXVtYXRvaWQvIGRydWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5CaW9sb2dpY2FsIFJlc3Bv
bnNlIE1vZGlmaWVycy8gYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3
b3JkPkRydWcgQWRtaW5pc3RyYXRpb24gU2NoZWR1bGU8L2tleXdvcmQ+PGtleXdvcmQ+RHJ1ZyBU
aGVyYXB5LCBDb21iaW5hdGlvbjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl
eXdvcmQ+SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2dsb2J1bGluIEcvYWRtaW5pc3Ry
YXRpb24gJmFtcDsgZG9zYWdlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdv
cmQ+TWV0aG90cmV4YXRlL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5
d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QYXRpZW50IERyb3BvdXRzL3N0YXRp
c3RpY3MgJmFtcDsgbnVtZXJpY2FsIGRhdGE8L2tleXdvcmQ+PGtleXdvcmQ+UHJlc2NyaXB0aW9u
cywgRHJ1Zy9zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3JkPjxrZXl3b3Jk
PlJlY2VwdG9ycywgVHVtb3IgTmVjcm9zaXMgRmFjdG9yL2FkbWluaXN0cmF0aW9uICZhbXA7IGRv
c2FnZTwva2V5d29yZD48a2V5d29yZD5SZWdpc3RyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2Vh
cmNoIFN1cHBvcnQsIE5vbi1VLlMuIEdvdiZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+U2lhbG9n
bHljb3Byb3RlaW5zL2FkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29y
ZD5UcmVhdG1lbnQgRmFpbHVyZTwva2V5d29yZD48a2V5d29yZD5UdW1vciBOZWNyb3NpcyBGYWN0
b3ItYWxwaGEvYW50YWdvbmlzdHMgJmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48L2tleXdvcmRz
PjxkYXRlcz48eWVhcj4yMDA1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHVi
LWRhdGVzPjwvZGF0ZXM+PGFjY2Vzc2lvbi1udW0+MTU3MDg4ODQ8L2FjY2Vzc2lvbi1udW0+PHVy
bHM+PC91cmxzPjxjdXN0b20xPkk8L2N1c3RvbTE+PGN1c3RvbTI+STwvY3VzdG9tMj48Y3VzdG9t
Mz5ITzwvY3VzdG9tMz48Y3VzdG9tND4xLDM8L2N1c3RvbTQ+PGN1c3RvbTc+S0QgOS02IChTVyk8
L2N1c3RvbTc+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjEz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ADDIN EN.CITE.DATA 204Country, Setting:Germany, clincalFunding:Essex Pharma, Wyeth Pharma, Amgen, and AbbottResearch Objective:To compare drug continuation rates in pts. with RA who start on a biological agent or on a DMARD after previous DMARD failureStudy Design:Retrospective cohort studyOverall N:1,523Study Duration: 1 yrInclusion Criteria:Age: 18 to 75Diagnosed with RA according to ACR criteriaPrevious use of DMARDs: at least 2Exclusion Criteria:NRInterventions (dose):D1: ETAD2: INFD3: AKAD4: Total Control GroupD5: LEF D6: LEF + MTXDosages NRN:D1: 511D2: 343D3: 70D4: 599D5: 120 D6: 141Mean age, yrs:D1: 53.7D2: 53.6D3: 54.3D4: 56.5D5: 58 D6: 57.4Sex, % female:D1: 77.9D2: 71.1D3: 77.1D4: 82.8D5: 85.8 D6: 78.0Race, % white:NRMean disease duration (yrs):D1: 9D2: 8.5D3: 13D4: 6D5: 9D6: 7TJC, mean:D1: 13.3 D2: 12.6D3: 12.6 D4: 10D5: 10.6 D6: 10.9SJC, mean:D1: 10.4 D2: 10.7D3: 10.2 D4: 7.7D5: 7.4 D6: 8.5DMARD use (#):D1: 3.9 D2: 3.7D3: 4.2 D4: 2.1D5: 2.4 D6: 2.2Corticosteroid use, %:NRMTX naive, %:NRContinuation rates D1 and D2 similarD3 significantly lowerTxt continuation at 1 yr, %D1: 68.6ETA+ MTX?: 71.6D2: 65.4D6: 66.2D3: 59AKA vs. ETA; P = 0.004; ANA vs. INF; P = 0.03 Txt discontinuation because of adverse events, %: D2: 18.7INF+MTX: 18.2D1: 12.6%ETA+MTX 13.3 D3: 16.3Txt discontinuation because of lack of efficacy, %:D1: 19.9ETA + MTX :16.9;D2: 45INF+MTX: 17.9D3: 29.6NROverall Attrition Rate, %:N/AITT Analysis:N/A: registryQuality Rating:Good ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related searches
- effectiveness of online education
- effectiveness of frontline plus for dogs
- cost of wave therapy for ed
- effectiveness of online learning environments
- effectiveness of online classes
- effectiveness of flu vaccine 2019
- types of therapy for trauma
- effectiveness of immunotherapy for cancer
- side effects of targeted therapy for cancer
- 2019 new drug therapy approvals
- infusion therapy for rheumatoid arthritis
- effectiveness of treatment for stage 2 melanoma