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.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.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.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.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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ADDIN 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.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.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 &amp; 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). 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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 &amp; 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.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.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.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.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.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.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.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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ADDIN 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.DATA 27 ; Keystone et al. , 2008PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZXlzdG9uZTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

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ADDIN EN.CITE.DATA 28; Keystone et al., 2009PEVuZE5vdGU+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.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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ZE5vdGU+

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.DATA 33; subanalysis of Curtis et al., 2007PEVuZE5vdGU+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

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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.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.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 &amp; 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.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.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.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&apos;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 &amp; 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&apos;t</keyword><keyword>Research Support, U.S. Gov&apos;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. 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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 &amp; 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.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 &amp; 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.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.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.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.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.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.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.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

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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.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.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.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.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.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 &amp; 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.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)&#xD;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? 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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.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.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.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.DATA 72; Goekoop-Ruiterman, 2007PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjMy

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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.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.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.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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ADDIN 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.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.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.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

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ADDIN 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.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&apos;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 &amp; 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 &amp; 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.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.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.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.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.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.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.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.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.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.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

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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.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.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.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 &amp; Rheumatism</abbr-3></periodical><dates><year>2010</year><pub-dates><date>Nov 19</date></pub-dates></dates><isbn>1529-0131 (Electronic)&#xD;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? 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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.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&#xD;Parker Institute, Musculoskeletal Statistics Unit, Frederiksberg Hospital, Frederiksberg, Denmark&#xD;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

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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.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.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.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.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.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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ADDIN 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&apos;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.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.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.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.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.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.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.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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ADDIN 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 &amp; dosage/adverse effects/pharmacokinetics</keyword><keyword>Antirheumatic Agents/ administration &amp; 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 &amp; 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 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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.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 &amp; 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 &amp; #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 &amp; 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 &amp; #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 &amp; 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 &amp; #1491, #1620&#xD;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 &amp; 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 &amp; #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 &amp; 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 &amp; #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.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.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.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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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.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&apos;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 &amp; 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.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.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

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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.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.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 &amp; dosage/ therapeutic use</keyword><keyword>Crohn Disease/ drug therapy</keyword><keyword>Gastrointestinal Agents/administration &amp; 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.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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ADDIN 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)&#xD;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? 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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&apos;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 &amp; 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 &amp; 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.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 &amp; 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 &amp; 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. 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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.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 &amp; 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&#xD;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 &amp; 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.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.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.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.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.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.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.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 &amp; 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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ADDIN 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.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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ZE5vdGU+AG==

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.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 &amp; 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&apos;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 &amp; 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 &amp; 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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ADDIN 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 &amp; 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.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.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.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.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&apos;t</keyword><keyword>Risk Factors</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists &amp; 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.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.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&apos;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 &amp; 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.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.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 &amp; 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&apos;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.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.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.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.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.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.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

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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 ................
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