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Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Alonso-Ruiz et al., 2008 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>4701</RecNum><DisplayText><style face="superscript">205</style></DisplayText><record><rec-number>4701</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">4701</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Alonso-Ruiz, A.</author><author>Pijoan, J. I.</author><author>Ansuategui, E.</author><author>Urkaregi, A.</author><author>Calabozo, M.</author><author>Quintana, A.</author></authors></contributors><auth-address>Rheumatology Service (Cruces Hospital), Barakaldo, Spain&#xD;Clinical Epidemiology Section (Cruces Hospital), Baracaldo, Spain&#xD;Health Library (Donostia Hospital), San Sebasti??n, Spain&#xD;Department of Applied Mathematics, Statistics and Operational Research, Faculty of Science and Technology (University of the Basque Country), Leioa, Spain&#xD;Department of Pharmacology, Faculty of Medicine and Odontology (University of the Basque Country), Leioa, Spain</auth-address><titles><title>Tumor necrosis factor alpha drugs in rheumatoid arthritis: Systematic review and metaanalysis of efficacy and safety</title><secondary-title>BMC Musculoskeletal Disorders</secondary-title></titles><volume>9</volume><dates><year>2008</year></dates><urls><related-urls><url> 1, 3 / good</custom4></record></Cite></EndNote>205Country and setting:MultinationalFunding:NRAims of Review:To perform a systematic review of RCTs of anti-TNFα drugs inRA followed by a metaanalysis of the efficacy and safety of different doses of INF, ETN and ADAQuality Rating:GoodStudy design:Systematic Review and meta-analysesNumber of Patients:7087Studies Included:N?=?13Characteristics of Included Studies:RCTs of INF, ETN, or ADA of at least 6 months duration with efficacy measured by ACR responseCharacteristics of Included PopulationsPatients had to satisfy the ACR criteria for dianosis of RA and have active diseaseCharacteristics of Interventions:All were trials of INF, ETN, or ADA. 4 INF + MTX vs. MTX trials (INF doses ranged from 3 mg/kg to 10 mg/kg, administered every 8 wks; 1 trial included a 3 and 10 mg/kg arm administered every 4 wks too.)4 ETN trials: 1 ETN + MTX vs. MTX; 1 ETN vs. placebo; 1 ETN vs. MTX; 1 ETN + MTX vs. MTX vs. ETN (ETN doses were either 10 mg or 25 mg administered twice weekly)5 ADA trials: 2 ADA + MTX vs. MTX; 1 ADA vs. placebo; 1 ADA + DMARD vs. DMARD; 1 ADA + MTX vs. MTX vs. ADA (ADA doses were 20 mg or 40 mg adminstered once per wk or 2 wks; 1 trial included an 80 mg/2 wk arm)Study Results:Any anti-TNFα drug (all doses) vs. control treatment (13 studies):ACR20: RR, 1.81 (95% CI, 1.43-2.29); NNT, 6 (5-7)ACR50: RR, 2.46 (95% CI, 1.75-3.45); NNT, 5 (5-6) ACR70: RR, 2.77 (95% CI, 1.85-4.15); NNT, 7 (7-9)Any anti-TNFα drug (recommended doses) vs. control treatment :ACR20: RR, 1.8 (95% CI, 1.4-2.3); NNT, 5 (5-6)ACR50: RR, 2.4 (95% CI, 1.7-3.4); NNT, 5 (5-6) ACR70: RR, 2.7 (95% CI, 1.8-4.1); NNT, 7 (7-9)ADA (all doses) vs. control treatmentACR20: RR, 1.9 (95% CI, 1.3-2.8); NNT, 6 (5-7)ACR50: RR, 2.7 (95% CI, 1.6-4.4); NNT, 6 (5-7)ACR70: RR, 3.3 (95% CI, 1.8-6.3); NNT, 9 (7-11)ADA (recommended doses) vs. control treatmentACR20: RR, 2.0 (95% CI, 1.3-2.9); NNT, 5 (4-6)ACR50: RR, 2.8 (95% CI, 1.6-4.7); NNT, 5 (5-6)ACR70: RR, 3.5 (95% CI, 1.9-6.7); NNT, 7 (6-8)ETN (all doses) vs. control treatmentACR20: RR, 1.7 (95% CI, 1.1-2.6); NNT, 7 (5-10)ACR50: RR, 2.1 (95% CI, 1.1-3.9); NNT, 6 (5-9)ACR70: RR, 2.0 (95% CI, 0.9-4.4); NNT, NSETN (recommended doses) vs. control treatmentACR20: RR, 1.7 (95% CI, 1.1-2.7); NNT, 6 (5-8)ACR50: RR, 2.2 (95% CI, 1.1-4.3); NNT, 6 (4-7)ACR70: RR, 2.1 (95% CI, 0.9-4.5); NNT, NSINF (all doses) vs. control treatmentACR20: RR, 1.8 (95% CI, 1.2-2.8); NNT, 5 (4-6)ACR50: RR, 2.6 (95% CI, 1.5-4.7); NNT, 5 (5-6)ACR70: RR, 2.9 (95% CI, 1.4-5.8); NNT, 8 (6-10)INF (recommended doses) vs. control treatmentACR20: RR, 1.7 (95% CI, 1.1-2.6); NNT, 5 (4-6)ACR50: RR, 2.2 (95% CI, 1.2-4.1); NNT, 6 (5-7)ACR70: RR, 2.4 (95% CI, 1.2-5.0); NNT, 9 (7-13)Efficacy of anti-TNFα drugs (recommended doses) in combination with MTX compared with MTX alone in patients with insufficient responses to MTXACR20: RR, 2 .6 (95% CI, 2.0 5-3.31)ACR50: RR, 4 .13 (95% CI, 2.59-6 .59)ACR70: RR, 4.14 (95% CI, 2.43-7.05)Efficacy of anti-TNFα drugs (recommended doses) plus MTX compared to MTX alone in patients with no previous resistance to MTXACR20: RR, 1.15 (95% CI, 1.07-1.22)ACR50: RR, 1.56 (95% CI, 1.41-1.72)ACR70: RR, 1.77 (95% CI, 1.52-2.05)Adverse Events:Any anti-TNFα drug vs. control treatmentWithdrawal due to adverse event: RR, 1.25 (95% CI, 0.65-2.39); NNH, NSTotal adverse event: RR, 1.0 (1.0-1.5); NNH 27 (17-59)Serious adverse event: RR, 1.1 (0.8-1.6); NNH, NSInfections: RR, 1.9 (0.9-1.2); NNH, NSSerious infections: RR, 1.4 (0.8-2.2) NNH, NSInfusion Reactions: RR, 3.0 (1.0-8.6); NNH, 8 (7-10)Malignancies: RR, 1.5 (0.8-3.0); NNH, NSMortality: RR, 0.8 (0.3-2.1); NNH, NSADA vs. control treatmentWithdrawal due to adverse event: RR, 1.4 (1.0-2.0); NNH, 47 (26-251)Total adverse event: RR, 1.1 (0.9-1.1); NNH, NSSerious adverse event: RR, 1.0 (0.7-1.4); NNH, NSInfections: RR, 1.1 (0.9-1.2); NNH, NSSerious infections: RR, 1.2 (0.6-2.8); NNH, NSInfusion Reactions: RR, 2.7 (1.7-4.2); NNH, 9 (7-14)Malignancies: RR, 1.1 (0.4-2.7); NNH, NSMortality: RR, 1.3 (0.4-4.7); NNH, NSETN vs. control treatmentWithdrawal due to adverse event: RR, 0.7(0.5-0.9); NNH, -26 (-143 to -14) Total adverse event: RR, 1.0 (0.9-1.1); NNH, NSSerious adverse event: RR, 0.9 (0.5-1.6); NNH, NS Infections: RR, 1.0 (0.9-1.0); NNH, NSSerious infections: RR, 0.9 (0.4-2.3); NNH, NS Infusion Reactions: RR, 5.1 (2.9-8.8); NNH, 5(4-6)Malignancies: RR, 1.9 (0.6-5.7); NNH, NS Mortality: RR, 1.5 (0.2-9.5); NNH, NSINF vs. control treatmentWithdrawal due to adverse event: RR, 2.0 (1.3-3.1); NNH, 24 (17-41)Total adverse event: RR, 1.0 (0.9-1.0); NNH, NS Serious adverse event: RR, 1.4 (1.0-2.0); NNH, 31 (17-167)Infections: RR, 1.2 (1.1-1.3); NNH, 10 (7-24)Serious infections: RR, 1.8 (0.9-3.4); NNH, NS Infusion Reactions: RR, 2.7 (1.7-4.2); NNH, 9 (7-14) Malignancies: RR, 2.6 (0.6-11.6); NNH, NSMortality: RR, 0.5 (0.2-1.4); NNH, NSStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Bergman et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjU0

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ADDIN EN.CITE.DATA 206Country and setting:MultinationalFunding:Hoffmann La-RocheAims of Review:ACR response between TCZ and other biologic agents in patients with rheumatoid arthritis who have inadequate response to disease-modifying antirheumatic drugsQuality Rating:FairStudy design:Systematic review and meta-analysisNumber of Patients:10,419Studies Included:N?=?18Characteristics of Included Studies:Double-blind, randomized, placebo controlled trials, 24 to 30 weeksCharacteristics of Included PopulationsAdults with RACharacteristics of Interventions:RCTs - study duration of at least 6 months;Study Results:Fixed-Effects Model Relative Risk (95% CrI) / Random-Effects Model Relative Risk (95% CrI)Biologic agent vs.placebo, Fixed-Effects Model Relative Risk (95% CrI) ACR20TCZ: 2.0 (1.9-2.2) TNF- inhibitors :1.9 (1.7-2.1) ABA: 1.9 (1.7-2.1) RTX: 1.8 (1.5-2.2) ACR50TCZ: 3.5 (3.0, 4.0)TNF- inhibitors: 2.8 (2.4, 3.2)ABA: 2.7 (2.2, 3.3)RTX: 2.8 (1.8, 4.0)ACR70TCZ: 6.8 (4.9, 9.4)TNF- inhibitors: 3.8 (3.1, 4.8)ABA: 3.4 (2.5, 4.8)RTX: 4.3 (2.2, 8.9)Biologic agent vs.placebo, Random-Effects Model Relative Risk (95% CrI)ACR20TCZ: 2.1 (1.6-2.5)TNF:- inhibitors: 2.0 (1.7-2.3)ABA: 1.9 (1.4-2.3)RTX: 1.9 (1.3-2.5)ACR50TCZ: 3.6 (2.5, 5.0)TNF- inhibitors: 3.2 (2.5, 4.3)ABA: 2.7 (1.7, 4.0)RTX: 2.9 (1.5, 4.9)ACR70TCZ: 6.9 (4.5, 10.8)TNF- inhibitors: 4.0 (3.0, 6.0)ABA: 3.6 (2.2, 6.2)RTX: 4.4 (1.9, 10.5)Pairwise comparison of biologic agentsACR20TCZ vs.TNF- inhibitors 1.1 (1.0, 1.2) / 1.1 (0.8, 1.3)TCZ vs.ABA 1.1 (1.0, 1.2) / 1.1 (0.8, 1.6)TCZ vs.RTX 1.1 (0.9, 1.4) / 1.1 (0.8, 1.7)ABA vs.TNF- inhibitors 1.0 (0.9, 1.1) / 0.9 (0.7, 1.2)RTX vs.TNF- inhibitors 1.0 (0.8, 1.2) / 1.0 (0.6, 1.3)RTX vs.ABA 1.0 (0.8, 1.2) / 1.0 (0.7, 1.5)ACR50TCZ vs.TNF- inhibitors 1.3 (1.1, 1.5) / 1.1 (0.7, 1.6)TCZ vs.ABA 1.3 (1.0, 1.6) / 1.3 (0.8, 2.3)TCZ vs.RTX 1.3 (0.9, 1.9) / 1.2 (0.7, 2.5)ABA vs.TNF- inhibitors 1.0 (0.8, 1.2) / 0.9 (0.5, 1.3)RTX vs.TNF- inhibitors 1.0 (0.7, 1.5) / 0.9 (0.5, 1.6)RTX vs.ABA 1.0 (0.7, 1.5) / 1.1 (0.5, 2.1)ACR70TCZ vs.TNF- inhibitors 1.8 (1.2, 2.6) / 1.7 (1.0, 2.8)TCZ vs.ABA 2.0 (1.3, 3.1) / 1.9 (1.0, 3.6)TCZ vs.RTX 1.6 (0.7, 3.3) / 1.6 (0.6, 4.0)ABA vs.TNF- inhibitors 0.9 (0.6, 1.2) / 0.9 (0.5, 1.5)RTX vs.TNF- inhibitors 1.1 (0.5, 2.4) / 1.1 (0.4, 2.6)RTX vs.ABA 1.3 (0.6, 2.8) / 1.2 (0.5, 3.2)Adverse Events:NAStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Bernatsky et al., 2010 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5428</RecNum><DisplayText><style face="superscript">207</style></DisplayText><record><rec-number>5428</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5428</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bernatsky, S.</author><author>Habel, Y.</author><author>Rahme, E.</author></authors></contributors><auth-address>McGill Univ, Ctr Hlth, 687 Pine Ave W, V Bldg, Room V2-09, Montreal, PQ H3A 1A1, Canada sasha.bernatsky@mail.mcgill.ca</auth-address><titles><title>Observational studies of infections in rheumatoid arthritis: a metaanalysis of tumor necrosis factor antagonists</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>928-931</pages><volume>37</volume><keywords><keyword>Infliximab--toxicity-</keyword><keyword>Toxicity--infliximab</keyword><keyword>Anti inflammatory agents--infliximab</keyword><keyword>Infections--infliximab</keyword><keyword>Research--Clinical studies</keyword><keyword>Clinical studies--meta analysis</keyword></keywords><dates><year>2010</year></dates><isbn>0315162X</isbn><urls><related-urls><url> / fair</custom4><remote-database-name>ipa</remote-database-name><remote-database-provider>EBSCOhost</remote-database-provider></record></Cite></EndNote>207Country and setting:Study conducted in Canada - components are multinationalsFunding:NRAims of Review:a systematic review and synthesis of observational studies of TNF antagonists andinfection risk.Quality Rating:FairStudy design:Systematic review and meta-analysisNumber of Patients:NRStudies Included:N?=?7Characteristics of Included Studies:5 cohort and 2 nested case-control studiesCharacteristics of Included PopulationsPatients with RA and serious infectionsCharacteristics of Interventions:Anti-TNFsStudy Results:Anti-TNF therapy appeared to significantly increase risk of serious infection (pooled adjusted RR1.37, 95% CI, 1.18-1.60).Adverse Events:The summary RR, suggested about a 40% increased risk of serious infections in patients with RA exposed to TNF antagonists (RR, 1.37; 95% CI, 1.18-1.60).Study Characteristics Characteristics of Included Studies ResultsAdverse EventsAssessments, Study Appraisals, and Quality RatingAuthor, year, country, funding:Bongartz, 2006, multinational, Mayo foundation, Abbott & Centocor ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1913</RecNum><DisplayText><style face="superscript">208</style></DisplayText><record><rec-number>1913</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1913</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bongartz, T.</author><author>Sutton, A. J.</author><author>Sweeting, M. J.</author><author>Buchan, I.</author><author>Matteson, E. L.</author><author>Montori, V.</author></authors></contributors><auth-address>Division of Rheumatology and Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA. bongartz.tim@mayo.edu</auth-address><titles><title>Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials</title><secondary-title>JAMA</secondary-title></titles><periodical><full-title>JAMA</full-title><abbr-1>JAMA</abbr-1><abbr-2>JAMA</abbr-2></periodical><pages>2275-85</pages><volume>295</volume><number>19</number><keywords><keyword>Antibodies, Monoclonal/adverse effects/ therapeutic use</keyword><keyword>Antirheumatic Agents/adverse effects/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Biological Response Modifiers/adverse effects/ therapeutic use</keyword><keyword>Humans</keyword><keyword>Infection/epidemiology</keyword><keyword>Neoplasms/epidemiology</keyword><keyword>Randomized Controlled Trials</keyword><keyword>Research Support, Non-U.S. Gov&apos;t</keyword><keyword>Risk</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists &amp; inhibitors</keyword></keywords><dates><year>2006</year><pub-dates><date>May 17</date></pub-dates></dates><accession-num>16705109</accession-num><label>MA but not a base </label><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>S</custom3><custom4>3</custom4><custom7>DJ 9-20 (SW)</custom7></record></Cite></EndNote>208Study Design:Systematic literature search with meta-analysisAims of the Review:To assess extent to which anti-TNF antibody therapy may increase risk of serious infection and malignancies in pts with RA by performing a meta-analysisTo derive estimates of sparse harmful events occurring in randomized trials of anti-TNF therapyNumber of Pts:5014 (9 trials)Studies included:Keystone (2004)St Clair (2004)Furst (2003)Lipsky (2000)van de Putte (2003)Weinblatt (2003)Maini (1998)van de Putte (2004)Westhovens (2004)Characteristics of included studies:RCTs of INF and ADA in which pts had ACR-diagnosed RA and were randomized to anti-TNF vs. placebo (or anti-TNF antibody + traditional DMARD vs. placebo + traditional DMARD)Both pt and observer were maskedTrial had to be at least 12 wks in durationCharacteristics of included populations:Pts with an ACR diagnosis of RA who were randomized to receive Anti-TNF or placeboCharacteristics of interventions:Anti-TNF (dosing varied) or ControlIn pts with RA, anti-TNF treatment leads to increased risk of serious infections and a dose-dependent increased risk of malignancies. Serious infections reported in 126 anti-TNF- treated pts vs. 26 control group pts (OR, 2.0; 95% CI, 1.3-3.1)Malignancies reported in 24 / 3493 (0.8%) pts who received > 1 dose of anti-TNF vs. 2 / 1512 (0.2%) pts on controlPooled OR for malignancies in anti-TNF group vs. placebo group: 3.3 (95% CI, 1.2-9.1)Number needed to harm was 154 (95% CI 91-500) for 1 additional malignancy within a treatment period of 6 to 12 months. For serious infections, the number needed to harm was 59 (39-125) within a treatment period of 3 to 12 monthsOverall AEs reported: Malignancy: Anti-TNF (23/3192)Control (3/1428) OR: 3.3 (95% CI 1.2 – 9.1)Serious Infections: Anti-TNF (126/3493)Control (26/1512) OR: 2.0 (1.3-3.1)Publication Bias Assessed:Not reportedHeterogeneity Assessed:YesStandard Method of Study Appraisals:YesComprehensive Search Strategy:Yes - briefly describe in box: EMBASE, MEDLINE, Cochrane Library, and electronic abstracts of the annual scientific meetings both the European League Against Rheumatism and the American College of Rheumatology – through December 2005Quality Rating: FairStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Bongartz et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5467</RecNum><DisplayText><style face="superscript">209</style></DisplayText><record><rec-number>5467</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5467</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Bongartz, T.</author><author>Warren, F. C.</author><author>Mines, D.</author><author>Matteson, E. L.</author><author>Abrams, K. R.</author><author>Sutton, A. J.</author></authors></contributors><auth-address>Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN, USA. bongartz.tim@mayo.edu</auth-address><titles><title>Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials</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>1177-83</pages><volume>68</volume><number>7</number><keywords><keyword>Antirheumatic Agents/*adverse effects</keyword><keyword>Arthritis, Rheumatoid/*drug therapy</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/*adverse effects</keyword><keyword>Neoplasms/*chemically induced</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Receptors, Tumor Necrosis Factor</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1468-2060 (Electronic)&#xD;0003-4967 (Linking)</isbn><accession-num>19019889</accession-num><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 3 / good</custom4><language>eng</language></record></Cite></EndNote>209Country and setting:MultinationalFunding:WyethAims of Review:To assess the risk of malignancy with ETNQuality Rating:GoodStudy design:Systematic review and meta-analysisNumber of Patients:3316 patients, 2244 who received ETN (contributing 2484 person-years of follow-up) and 1072 who received control therapy (1051 person-years).Studies Included:N?=?9 (8 published, 1 unpublished)Characteristics of Included Studies:RCTS at least 12 weeks longCharacteristics of Included PopulationsPatients with RACharacteristics of Interventions:ETA vs. ControlStudy Results:Adverse Events:Malignancies in 26 patients in the ETN group (incidence rate (IR) 10.47/1000 person-years) and 7 in the control group (IR 6.66/1000 person-years). 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ADDIN EN.CITE.DATA 210, International: Europe, U.S., Canada, Australia, Health Technology Assessment Programme (U.K.)Study Design:Systematic review and meta-analysis analysisAims of Review:To review evidence on clinical benefits, hazards, and cost-effectiveness of AKA in adult RA ptsNumber of Pts:2,905Studies included:Efficacy Trials: Bresnihan (1998)Cohen (2001)Cohen (2002)Unpublished report by Amgen (2001; STN 103950 Clinical Review; low-dose for 3 mos)Safety Trial: Fleischmann (2001)Characteristics of included studies:RCTs (except 1) of AKA or AKA + MTX in pts with highly active RAFleischmann control arm consisted of placebo + DMARD txtCharacteristics of included populations:Mean ages 50sDuration 6 mos to 10 yrsMajority had failed at least 1 DMARD and some were taking MTX up to trial startMajority taking low-dose steroids and NSAIDsCharacteristics of interventions:AKA alone: AKA from 2.5 mg/day to 150 mg/dayAKA + MTX: AKA 0.04 mg/kg per day to 2.0 mg/kg per day or fixed dose 100 mg/dayAdjusted indirect comparisons with anti TNF agents (ETN, INF) suggested that AKA may be significantly less effective at relieving clinical symptoms than anti-TNF agents (-0.21; 95% CI, -0.32 to -0.10) Adjusted indirect comparisons:RD (95% CI)TNF+MTX vs. MTX 0.37 (0.28 to 0.45)AKA+MTX vs. MTX 0.16 (0.09 to 0.23)AKA+MTX vs. TNF+MTX -0.21 (-0.32 to -0.10)Withdrawals due to adverse events: Control: 4.1% to 9%AKA: 5% to 13%Specific adverse events: SAEs:Control: 3.2% to 11.6%AKA: 4.4% to 12.8%Malignancy: Control: 0% to 1.8%AKA: 0% to 1.1%Injection Site Reactions: Control: 3% (low-dose study) to 33%AKA: 19.8% (low-dose study) to 73%Any infection: Control: 13.3% (low-dose study) to 50%AKA: 13.5% (low-dose study) to 48.4%Serious infections: Control: 0.4% to 1.4%AKA: 0.8% to 2.1%Neutropenia: Control: 0% to 4%AKA: 0% to 9%Antibodies to IL-1Ra: Control: 0% to 1.8%AKA: 0.9% to 5%Publication Bias Assessed:NRHeterogeneity Assessed: YesStandard Method of Study Appraisals:YesComprehensive Search Strategy:Yes Quality Rating: GoodStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Devine et al., 2011 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5476</RecNum><DisplayText><style face="superscript">211</style></DisplayText><record><rec-number>5476</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5476</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Devine, E. B.</author><author>Alfonso-Cristancho, R.</author><author>Sullivan, S. D.</author></authors></contributors><auth-address>Pharmaceutical Outcomes Research and Policy Program, Department of Medical Education and Biomedical Informatics, University of Washington, Seattle, Washington 98195-7630, USA. bdevine@uw.edu</auth-address><titles><title>Effectiveness of biologic therapies for rheumatoid arthritis: an indirect comparisons approach</title><secondary-title>Pharmacotherapy</secondary-title></titles><periodical><full-title>Pharmacotherapy</full-title><abbr-1>Pharmacotherapy</abbr-1><abbr-2>Pharmacotherapy</abbr-2></periodical><pages>39-51</pages><volume>31</volume><number>1</number><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1875-9114 (Electronic)&#xD;0277-0008 (Linking)</isbn><accession-num>21182357</accession-num><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 1 / fair</custom4><language>eng</language></record></Cite></EndNote>211Country and setting:MultinationalFunding:NRAims of Review:efficacy of biologic disease-modifyingantirheumatic drugs (DMARDs) vs.placebo with or withoutMTX, in treating rheumatoid arthritis.Quality Rating:FairStudy design:Systematic review and meta-analysisNumber of Patients:6 months: 11,58912 months: 6051Studies Included:6 months: 23 RCTs12 months: 10 RCTsCharacteristics of Included Studies:RCTs at least 22 weeks outcomesCharacteristics of Included PopulationsPatients with RA and and patient populations defined as DMARD-IR or MTX (MTX)-inadequate respondersCharacteristics of Interventions:Biologic DMARDs with or without MTX or other nonbiologic DMARDs, compared with placebo with or without MTX or other nonbiologic DMARDsStudy Results:Log Odds Ratio Estimates for the 6-Month and 12-Month Models by Drug6-month modelCertolizumab μ1 2.60 0.44 1.83-3.59 1TCZ μ2 1.67 0.19 1.31-2.07 2RTX μ3 1.61 0.59 0.55-2.85 3INF μ4 1.57 0.27 1.03-2.10 4ETN μ5 1.43 0.25 1.00-2.00 5ADA μ6 1.37 0.22 0.94-1.83 6GOL μ7 1.36 0.38 0.64-2.14 7ABA μ8 1.16 0.27 0.61-1.68 8ANK μ9 0.98 0.28 0.47-1.58 9MTX 0.78 0.19 0.39-1.17Baseline disease duration 1 0.08 0.04 < 0.01-0.18Baseline HAQ score 2 -0.45 0.53 -1.49-0.63Variance 2 0.05 0.02 < 0.01-0.2812-month modelCertolizumab μ1 2.02 0.44 1.16-2.83 1RTX μ2 1.95 0.90 0.47-4.00 2ADA μ3 1.37 0.28 0.83-1.89 3INF μ4 1.36 0.31 0.80-1.99 4ETN μ5 0.86 0.32 0.28-1.43 5ABA μ6 0.63 0.30 0.08-1.24 6MTX 0.84 0.21 0.42-1.26Baseline disease duration 1 0.10 0.04 < 0.01-0.17Baseline HAQ score 2 0.46 0.78 -1.11-1.89Variance 2 0.02 0.06 < 0.01-0.88Adverse Events:NRStudy Characteristics Characteristics of Included Studies ResultsAdverse EventsAssessments, Study Appraisals, and Quality RatingAuthor, year, country, funding:Gartlehner et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2043</RecNum><DisplayText><style face="superscript">212</style></DisplayText><record><rec-number>2043</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2043</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gartlehner, G.</author><author>Hansen, R.A.</author><author>Jonas, B.L.</author><author>Thieda, P.</author><author>Lohr, K. N.</author></authors></contributors><titles><title>The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis</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>2398-408</pages><volume>33</volume><number>12</number><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>S</custom3><custom4>1,3</custom4><custom7>LL 12/1/06</custom7></record></Cite></EndNote>212USStudy Design:META-ANALYSISanalysis (random effects model); systematic reviewAims of the Review:To assess comparative efficacy and safety of biologic agents for RANumber of Patients:ADA: 2,354ETN: 1,151INF: 704AKA:1,039 (#'s refer to 17 sudies used for adjusted indirect comparisons of efficacy)Studies included:26 controlled trials18 additional studies assessed safetyCharacteristics of included studies:Often limited to 1 year of follow-upReported on DAS-28Radiographic progression, functional capacity, and QOLCharacteristics of included populations:Narrowly defined populationsMean age 53.476% female89% caucasionCharacteristics of interventions:All efficacy studies except 1 were funded by the pharmaceutical industryAll 12 weeks plus of duration (for observational studies it was 3 months or greater and 100 or more patients)Adjusted indirect comparison indicate no significant differences in efficacy between antiTNF drugsAnti-TNF drugs appear to be more efficacious than AKA but do not differ among each other. Inddirect comparisons of INF and of anti-TNF drugs as a class compared to AKA yielded a statistically significant greater efficacy on ACR 20 [RR 0.58 (95%CI 0.38-0.90) and RR 0.61 (95% CI 0.39-0.96), respectively], but not ACR 50Few studies assessed longterm radiographic outcomes. In general, rate of radiographic progression was significantly lower in patients treated with biologics than in placebo-treated patients, regardless of concomitant DMARD therapy. 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ADDIN EN.CITE.DATA 213Country and setting:NRFunding:NRAims of Review:To analyze the literature on the efficacy on signs and symptoms, disability and structure, of oral DMARDS and to assess safety, with a special focus on cancers and infectionsQuality Rating:FairStudy design:Systematic Review and Meta-analysisNumber of Patients:Efficacy studies: 14, 159Adverse event studies: NAStudies Included:Efficacy studies: 97Safety studies: 39Characteristics of Included Studies:RCTs reporting the efficacy on signs and symptoms, disability and/or structure of oral DMARDs vs.placebo (except for MTX) or other nonbiologic DMARDs, in patients with RA*from online supplemental materialCharacteristics of Included PopulationsPatients with RACharacteristics of Interventions:MTX: 17 studies4,147 patientsage: 49.7±3.4% female: 72.4disease duration, yrs: 6.7±4.5LEF:9 studies3,617 patientsage: 54.3±4.2% female: 74.5disease duration, yrs: 6.3±2.5SSZ: 22 trials2,813 patientsage: 52.1±4.0% female: 68.8disease duration, yrs: 5.6 ± 3.6Hydroxychloroquine: 20 studies2,182 patientsage: 45.5±6.0% female: 73.5disease duration, yrs: 3.8±3.0Study Results:MTX vs. LEFSJC (4 studies, 1889 patients): Standardized Response Mean (SRM), 0.09 (95% CI, ?0.12-0.30)Pain (4 studies, 1475 patients): SRM, ?0.04 (95% CI, ?0.33-0.26)Disability (4 studies, 1,465 patients): SRM, ?0.09 (95% CI, ?0.30-0.11) ACR20 response (4 studies, 1889 patients): OR, 1.04 (95% CI, 0.60-1.79)Structure (2 studies, 895 patients): SRM, 0.03 (95% CI, ?0.10-0.16)MTX vs. SSZSJC (2 studies, 206 patients): SRM, 0.59 (95% CI, ?1.96-3.15)Disability (2 studies,208 patients): SRM, 0.62 (95% CI, ?0.86-2.10) ACR50 response (2 studies, 193 patients): OR, 1.57 (95% CI, 0.82-3.00)MTX monotherapy vs. MTX combo, DMARD naive No significant advantage of combo with MTX vs.MTX monotherapy for pain, Health Assessment Questionnaire, or ACR20, 50, or 70ACR20: OR, 0.53 (95% CI, 0.21-1.33)MTX monotherapy vs. MTX combos, DMARD inadequate respondersSJC (3 studies): SRM, ?0.78 (95% CI, ?1.30 to ?0.25)Pain (3 studies): SRM, ?0.64 (95% CI, ?1.01 to ?0.28)HAQ (3 studies) SRM, ?1.21 (95% CI, ?2.07 to ?0.36)ACR20 (2 studies): RR,?=?0.26 (95% CI, 0.16 to 0.40)SSZ monotherapy vs. SSZ comboIn 6 trials (657 patients), no significant difference for SJC, function, or ACR20, 50 or 70. Significant finding: Structural damage (1 trial) favoring the combination MTX+SSZ+hydroxychloro-quine: SRM, ?1.70 (95% CI, ?2.03 to ?1.37)25 Pain (1 trial) favoring SSZ monotherapy: SRM, 4.10 (95% CI, 2.91-5.29)Adverse Events:MTX monotherapy vs. MTX combo, DMARD na?veWithdrawals due to lack of efficacy or toxicity were similar in both groups: RR, 1.16 (95% CI, 0.70-1.93)MTX monotherapy vs. MTX combos, DMARD inadequate responders8 trials show insignificant differences in withdrawals between MTX combo and monotherapy. One exception: O’Dell’s study of 102 DMARD inadequate responders. The combo of MTX + SSZ and hydroxychloroquine showed fewer withdrawals than MTX alone: RR, 0.30 (95% CI, 0.14 to 0.65).Study Characteristics Characteristics of Included Studies ResultsAdverse EventsAssessments, Study Appraisals, and Quality RatingAuthor, year, country, funding:Hochberg et al., 2003PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjIw

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ADDIN EN.CITE.DATA 214MultinationalNRStudy Design:Systematic review and indirect comparisonsAims of the Review:Differences in efficacy of TNF alpha blocking agents, as measured by rate ratios for American College of Rheumatology (ACR) 20/50/70 responses, in patients with RA with an incomplete response to methotrexate.Number of Patients:1053380 placebo673 activeStudies included:Maini et al. 1999Lipsky et al. 2000Weinblatt et al 1999Weinblatt et al. 2003Characteristics of included studies:Placebo controlled, double blind, randomised clinical trials of at least 24 weeks’Characteristics of included populations:NR- assuming that it is adults with active RA with lack of response to MTXCharacteristics of interventions:the addition of TNF blocking agents (INF, ETN and ADA) to methotrexate in a "step-up" strategy Indirect comparisons, Relative Risk (95% CI)ETNnercept vs. adalimumab ACR 20 1.10 (0.57 to 2.12) 2.60 (0.35 to 19.0) Infliximab vs. adalimumab 1.07 (0.66 to 1.73) 1.35 (0.47 to 3.85) ETNnercept vs. infliximab 1.03 (0.49 to 2.18) 1.92 (0.22 to 17.0) NRPublication Bias Assessed:NRHeterogeneity Assessed:YesStandard Method of Study Appraisals:NRComprehensive Search Strategy:Yes - briefly describe in boxQuality Rating: FairStudy CharacteristicsStudy DesignResultsAdverse Events QualityCommentsAuthor:Kirwan, 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2189</RecNum><DisplayText><style face="superscript">215</style></DisplayText><record><rec-number>2189</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2189</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Kirwan, J. R.</author><author>Bijlsma, J. W.</author><author>Boers, M.</author><author>Shea, B. J.</author></authors></contributors><auth-address>Liverpool Women&apos;s Hospital, Crown Street, Liverpool, UK, L8 7SS. John.Kirwan@lwh-tr.nwest.nhs.uk</auth-address><titles><title>Effects of glucocorticoids on radiological progression in rheumatoid arthritis</title><secondary-title>Cochrane Database Syst Rev</secondary-title><short-title>Effects of glucocorticoids on radiological progression in rheumatoid arthritis</short-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><pages>CD006356</pages><number>1</number><keywords><keyword>Adult</keyword><keyword>Antirheumatic Agents/therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/ radiography</keyword><keyword>Disease Progression</keyword><keyword>Glucocorticoids/ therapeutic use</keyword><keyword>Humans</keyword><keyword>Randomized Controlled Trials</keyword></keywords><dates><year>2007</year></dates><isbn>1469-493X (Electronic)</isbn><accession-num>17253590</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>SR</custom3><custom4>KQ 1 / good</custom4></record></Cite></EndNote>215Country and setting:Multi-nationalFunding:Chochrane CollaborationStudy design:Systematic Review and meta-analysesOverall study N:1414Study aims:To perform a systematic qualitative review of studies evaluating glucocorticoid efficacy in inhibiting the progression of radiological damage in rheumatoid arthritis.Main results:Comparison 1. Glucocorticoids vs. comparatorErosion outcomes refer to erosion scores expressed as percentage of max possible score for method used by individual studies.Outcome 1. SMD in progression of erosion scores = 0.40 in favor of glucocorticoids (95% CI 0.27, 0.54) (from abstract)Outcome 2. Change in erosions at 1 year as proportion of maximum score (N = 15, # of Participants = 1421) SMD = 0.39 (95% CI, 0.27, 0.52) in favor of glucocorticoidsOutcome 3. Erosions at 1 year, data from 1 & 2 year studies (N = 10, # of partcipants = 940) SMD = -0.43 (95% CI, -0.62, -0.23) in favor of glucocorticoidsOutcome 4> Erosions at 2 years, data from 1 & 2 year studies (N = 10, # of participants = 967) SMD = -0.40 (95% CI, -0.56, -0.24) in favor of glucocorticoidsOutcome 5. Joint Space Narrowing at 1 year as a proportion of maximum score (n = 6, # of participants = 711) SMD = -0.27 (95% CI, -0.50, -0.04) in favor of glucocorticoidsOutcome 6. Joint Space Narrowing at 2 years as a proportion of maximum score (N = 4, # of participants - 512) SMD = -0.31 -(95% CI, -0.51, -0.11) in favor of glucocorticoidsOutcome 7. Joint Space Narrowing at 1 year data from 1 & 2 year studies (N = 4, # of participants = 473). SMD -0.22 (-0.51, 0.07)Outcome 8. Joint Space Narrowing at 2 years data from 1 & 2 year studies (N = 3, # of participants = 345) SMD = -0.28 (95% CI, -0.57, 0.01)Outcome 9. Proportion of patients progressing at year 1 (N = 4, # of participants = 261). Risk Ratio = 0.60 (95% CI, 0.48, 0.74), in favor of glucocorticoidsAdverse events:NRReview based on focused question of interest:YesDid search strategy employ comprehensive, systematic literature search?YesA search ofMEDLINE (from1966 to 22 February 2005) and Cochrane Central Register of Controlled Trials was undertaken, using terms ’corticosteroids’ and ’rheumatoid arthritis’ expanded according to Cochrane Collaboration recommendations. Identified abstracts were reviewed and appropriate reports obtained in full. Additional reports were identified from reference lists and from expert knowledge.Eligibility criteria clearly described?YesRandomized controlled or cross-over trials in adults with a diagnosis of rheumatoid arthritis in which prednisone or a similar glucocorticoid preparation was compared to either placebo controls or active controls (i.e. comparative studies) and where there was evaluation of radiographs of hands, or hands and feet, or feet by any standardised technique. Eligible studies had at least one treatment arm with glucocorticoids and one without glucocorticoids.Review studies independently reviewed by at least 2 persons?YesStandard method of critical appraisal before including?YesComments:Sensitivity analyses looked at several different ways of combining studies, and in all cases a similar benefit for glucocorticoid therapy was demonstrated (concomitant medication, length of study, when only low dose steroid studies were included, when step-down glucocorticoids were used, etc.)Total of 14 comparisons, each with multiple outcomes, reported in review. Comparison 1 was abstracted; others have not been abstracted. The comparisons are:Comp 1. Glucocorticoids vs comparatorComp 2. Glucocorticoids + DMARD + NSAID vs DMARD + NSAIDComp 3. Glucocorticoids vs NSAIDComp 4. Oral low dose Glucocorticoids + DMARD + NSAID vs DMARD = NSAIDComp 5. Step down Glucocorticoids + DMARD + NSAID vs DMARD = NSAIDComp 6. Studies with less than 26 week of Glucocorticoid treatmentComp 7. Studies with more than 26 weeks of Glucocorticoid treatmentComp 8. Glucocorticoids vs comparator using modelled SDsComp 9. Glucocorticoids vs comparators using only studies with modelled SDsComp 10. Glucocorticoids vs. comparator using original SDs in studies with modelled SDsComp 11. Glucocorticoids vs comparator sensitivity analyses by quality standards - Concealed treatmentComp 12. Glucocorticoids vs. comparator sensitivity analyses by quality standards - Blinding of PatientsComp. 13 Glucocorticoids vs comparator sensitivity analyses by quality standards - Intention to TreatComp 14. Glucocorticoids vs comparator sensitivity analyses by quality standards - Blinded AssessorsStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Kuriya et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUw

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ADDIN EN.CITE.DATA 216Country and setting:NRFunding:NRAims of Review:To examine the efficacy of MTX monotherapy compared withcombination therapy with a biologic when used as initial tx in early RA (ERA) pts.Quality Rating:GoodStudy design:Systematic Review and Meta-analysisNumber of Patients:2,763Studies Included:N?=?7Characteristics of Included Studies:Included studies were double-blind, randomised, active-comparator,controlled clinical trials that studied the efficacy of initial combination therapy (MTX + biologic) compared with MTX monotherapy in adult pts with clinically active ERACharacteristics of Included PopulationsPts were adults with clinically active ERA, defined as disease duration <?3 years, and with no or minimal previous exposure to MTX (≤?4 weeks). Previous treatment with corticosteroids, SSZ or hydroxychloroquine/chloroquine was permitted.Characteristics of Interventions:3 INF trials: 3 mg/kg, q 8 weekly2 ADA trials: 40 mg, q 2 weekly1 ETN trial: 50 mg, q weekly1 ABA trial: 10 mg/kg, q 4 weeklyStudy Results:Clinical Remission (Combo vs. Monotherapy, RR, (95% CI): 1.74 (1.54-1.98)Radiographic Non-progression (Combo vs. Monotherapy, RR, (95% CI): 1.30 (1.01-1.68)Adverse Events:NAStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Leombruno et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5462</RecNum><DisplayText><style face="superscript">217</style></DisplayText><record><rec-number>5462</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5462</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Leombruno, J. P.</author><author>Einarson, T. R.</author><author>Keystone, E. C.</author></authors></contributors><auth-address>University of Toronto, Department of Pharmaceutical Sciences, Toronto, Ontario, Canada. john.leombruno@utoronto.ca</auth-address><titles><title>The safety of anti-tumour necrosis factor treatments in rheumatoid arthritis: meta and exposure-adjusted pooled analyses of serious adverse events</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>1136-45</pages><volume>68</volume><number>7</number><keywords><keyword>Antirheumatic Agents/administration &amp; dosage/*adverse effects</keyword><keyword>Arthritis, Rheumatoid/*drug therapy</keyword><keyword>Humans</keyword><keyword>Infection/chemically induced</keyword><keyword>Neoplasms/chemically induced</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Risk Factors</keyword><keyword>Tumor Necrosis Factor-alpha/*antagonists &amp; inhibitors</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1468-2060 (Electronic)&#xD;0003-4967 (Linking)</isbn><accession-num>18753157</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>217Country and setting:multi-nationalFunding:NRAims of Review:To evaluate the safety of biological treatments for RA using results from RCTsQuality Rating:FairStudy design:Meta-analysisNumber of Patients:8,808Studies Included:N?=?18Characteristics of Included Studies:The study must be an RCT with more than 30 patients randomly assigned to either an anti-TNF or a control group (non-DMARD or placebo) over a minimum of 10 wks. A Jadad score of ≥ 2 was required and tx arms of combination biological therapies were excluded.Characteristics of Included PopulationsPatients with RACharacteristics of Interventions:ADA: 6 trialsdoses: 20-80 mg every wk or 20-80 mg every other wkall but 1 on background of MTX or other DMARD.ETN: 7 trialsdoses: 10-25 mg twice per wk2 on background MTX 1 on background SSZINF: 5 trialsdoses: 1-10 mg/kq every 4 wks or 3-10 mg/kg every 8 wksall on background of MTXStudy Results:Adverse Events:Death, OR (CI) ADA: 2.04 (0.64 - 6.51)ETN: 2.34 (0.67 - 8.12) INF: 0.62 (0.21 - 1.79)Anti-TNF: 1.39 (0.74 - 2.62)Serious adverse events, OR (CI) ADA: 1.12 (0.86 - 1.45)ETN: 1.04 (0.73 - 1.47)INF: 1.17 (0.86 - 1.59)Anti-TNF: 1.11 (0.94 - 1.32)Serious infections, OR (CI) ADA: 1.53 (0.83 - 2.81)ETN: 0.89 (0.56 - 1.42)INF: 1.46 (0.86 - 2.47)Anti-TNF: 1.21 (0.89 - 1.63)Lymphomas, OR (CI) ADA: 1.07 (0.28 - 4.09)ETN: 1.42 (0.27 - 7.61)INF: 1.42 (.27 - 7.62)Anti-TNF: 1.26 (0.52 - 3.06)Non-cutaneous cancers and melanomas, OR (CI) ADA: 1.37 (0.49 - 3.89)ETN: 1.11 (0.42 - 2.96)INF: 1.70 (0.39 - 7.32)Anti-TNF: 1.31 (0.69 - 2.48)Non-melanoma skin cancers, OR (CI) ADA: 1.37 (0.49 - 3.89)ETN: 1.03 (0.38 - 2.77)INF: 1.70 (0.39 -7.32)Anti-TNF: 1.27 (0.67 - 2.42)Study CharacteristicsCharacteristics of Included StudiesResultsAdverse EventsAssessments, Study Appraisals, and Quality RatingAuthor, year, country, funding:Maetzel, et al. 2000 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2106</RecNum><DisplayText><style face="superscript">218</style></DisplayText><record><rec-number>2106</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2106</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maetzel, A.</author><author>Wong, A.</author><author>Strand, V.</author><author>Tugwell, P.</author><author>Wells, G.</author><author>Bombardier, C.</author></authors></contributors><auth-address>University Health Network, Toronto, Ontario, Canada.</auth-address><titles><title>Meta-analysis of treatment termination rates among rheumatoid arthritis patients receiving disease-modifying anti-rheumatic drugs</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>975-81</pages><volume>39</volume><number>9</number><keywords><keyword>Antirheumatic Agents/*therapeutic use</keyword><keyword>Arthritis, Rheumatoid/*drug therapy</keyword><keyword>Humans</keyword><keyword>Hydroxychloroquine/*therapeutic use</keyword><keyword>Methotrexate/*therapeutic use</keyword><keyword>Organogold Compounds</keyword><keyword>Sulfasalazine/*therapeutic use</keyword><keyword>*Treatment Refusal</keyword></keywords><dates><year>2000</year><pub-dates><date>Sep</date></pub-dates></dates><accession-num>10986302</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>S</custom3><custom4>3</custom4></record></Cite></EndNote>218 Multinational Arthritis and Autoimmunity Research Centre, Aventis Canada, Inc.Study Design:Meta-analysisAims of Review: To summarize evidence on treatment withdrawal rates reported in observational studies and RCTs of MTX, SSZ, HCQ (and parenteral gold) among RA patients. Number of Pts:Cannot determineStudies included: 159 studies (71 RCTs, 88 observational studies) (159 satisfied screening criteria; 110 studies included in meta-analysis) Characteristics of included studies: Studies reporting information on number of patients withdrawingCharacteristics of included populations:RA Patients being treated with MTX, parenteral gold (GST), SSZ, and HCQCharacteristics of interventions:MTX, GST, SSZ, and HCQRA patients stay significantly longer on MTX than on other DMARDs. (Higher % stay on MTX vs. SSZ because of toxicity [RR 1.68, P < 0.0001]). Majority of withdrawals from SSZ and HCQ result from lack of efficacy. Withdrawal rates similar in observational studies vs RCTs.See main resultsPublication Bias Assessed:NRHeterogeneity Assessed:NRStandard Method of Study Appraisals:YesComprehensive Search Strategy:Yes Quality Rating: Fair Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Martinez Lopez et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3757</RecNum><DisplayText><style face="superscript">219</style></DisplayText><record><rec-number>3757</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3757</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Martinez Lopez, J. A.</author><author>Loza, E.</author><author>Carmona, L.</author></authors></contributors><auth-address>Research Unit, Fundacion Espanola de Reumatologia, Madrid, Spain. juan.martinez@ser.es</auth-address><titles><title>Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding)</title><secondary-title>Clin Exp Rheumatol</secondary-title></titles><periodical><full-title>Clinical and Experimental Rheumatology</full-title><abbr-1>Clin. Exp. Rheumatol.</abbr-1><abbr-2>Clin Exp Rheumatol</abbr-2><abbr-3>Clinical &amp; Experimental Rheumatology</abbr-3></periodical><pages>678-84</pages><volume>27</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Databases, Bibliographic</keyword><keyword>Embryonic Development/drug effects</keyword><keyword>Female</keyword><keyword>Fertility/drug effects</keyword><keyword>Fetal Development/drug effects</keyword><keyword>Humans</keyword><keyword>Lactation/drug effects</keyword><keyword>Male</keyword><keyword>Maternal Exposure/ adverse effects</keyword><keyword>Methotrexate/ adverse effects</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Outcome</keyword><keyword>Reproduction/ drug effects</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>0392-856X (Print)&#xD;0392-856X (Linking)</isbn><accession-num>19772806</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>219Country and setting:MultinationalFunding:Abbott ImmunologyAims of Review:To analyze the safety of MTX in RA regarding the reproductive system.Quality Rating:FairStudy design:Systematic ReviewNumber of Patients:366Studies Included:N?=?6Characteristics of Included Studies:RCTs, cohort studies, longitudinal observation studies and surveysCharacteristics of Included PopulationsRA patients who were 18 years or older; using MTX at doses usually taken in rheumatology (7.5-25 mg/w)Characteristics of Interventions:No true cohorts, only descriptions of cases obtained from retrospective clinical record searches or from surveys. The studies reported outcomes on male or female fertility; pregnancy complications; malformations, miscarriages, induced abortions, still births and breast feeding complicationsStudy Results:There were 101 MTX exposed pregnancies in the studies. The pooled outcomes (elective abortions not included) demonstrated: 19 miscarriages (23% of preganancies); 55 live births (66% of preganancies) and 5 of these had neonatal malformations (5% of pregnancies). The rate of induced abortions is 18%. No study filled the selection criteria for MTX and lactation or male fertility. However, there were case reports that generated possible indirect evidence of MTX in human breast milk and and reversible infertility.Adverse Events:N/AStudy CharacteristicsStudy DesignResultsAdverse Events QualityCommentsAuthor:Mertens, 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2462</RecNum><DisplayText><style face="superscript">220</style></DisplayText><record><rec-number>2462</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2462</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Mertens, M.</author><author>Singh, J. A.</author></authors></contributors><auth-address>University of Minnesota, 596 Grand Ave., Apt 1, Saint Paul, Minnesota 55102, USA. mtm7575@</auth-address><titles><title>Anakinra for rheumatoid arthritis</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><pages>CD005121</pages><number>1</number><keywords><keyword>Adult</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Humans</keyword><keyword>Interleukin 1 Receptor Antagonist Protein/ therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2009</year></dates><isbn>1469-493X (Electronic)</isbn><accession-num>19160248</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>SR</custom3><custom4>KQ 2, 3 / good </custom4></record></Cite></EndNote>220Country and setting:Multi-national (Europe, USA, Canada, Australia)Funding:Internal sources: Minneapolis VA Medical CenterNIH CTSA Award 1 KL2 RR024151-01 (Mayo Clinic Center for Clinical and Translational Research)National Institute of Health External sources: No sources of support suppliedStudy design:Systematic review and meta-analysisOverall study N:N = 2872 (788 placebo, 2084 ANK) in systematic reviewData not presented for 26 randomized pts (7 placebo, 19 ANK); therefore, N = 2846 (781 placebo, 2065 ANK) for analysisStudy aims:1.What is the clinical effectiveness of Anakinra for the treatment of RA in terms of: a. relieving symptoms?b. delaying disease progression?2.What are the risks (frequency and severity of adverse events) associated with Anakinra treatment in these patients?Main results:Result 1. ANK (< 50 mg/day ) vs. Placebo, Risk Ratio (M-H, Fixed, 95% CI)ACR 20: 1.38 (1.01, 1.89)ACR 50: 3.37 (0.82, 13.77)ACR 70: 4.45 (0.26, 76.62)Withdrawals: 0.85 (0.62, 1.18)Mean Difference (IV, Fixed, 95% CI)Change in pain VAS score: 0.85 (0.62, 1.18)Change in HAQ score: -0.2 (-0.33, -0.07)Change is ESR: -10.0 (-15.67, -4.33)(1 study)Change in CRP: -0.9 (-1.64, -0.16) (1 study)Change in Larsen score: -2.80 (-5.47, -0.13)Result 2.ANK (50 - 150 mg/day ) vs. Placebo, Risk Ratio (M-H, Fixed, 95% CI)ACR 20: 1.61 (1.32, 1.98)ACR 50: 2.51 (1.56, 4.03)ACR 70: 3.71 (1.44, 9.57)Withdrawals: 1.04 (0.86, 1.27)Mean Difference (IV, Fixed, 95% CI)Change in pain VAS score: -0.10 (-0.15, -0.04) Change in HAQ score: -0.19 (-0.30, -0.09)Change is ESR: -10.04 (12.75, -7.33)Change in CRP: -0.6 (-1.26, 0.06) (results from 1 study only)Change in Larsen score: -2.45 (-4.53, -0.36)Adverse events:ANK (50 - 150 mg/day ) vs. Placebo, Risk Ratio (M-H, Fixed, 95% CI)Infections: 1.08 (0.80, 1.45)Serious Infections: 3.15 (0.81, 12.20)Adverse Events: 1.05 (0.94, 1.17)Serious Adverse Events: 1.04 (0.70, 1.56)Injection site reactions: 2.45 (2.17, 2.77)Deaths: 1.01 (0.11, 9.04)Review based on focused question of interest:YesDid search strategy employ comprehensive, systematic literature search?YesSearched Cochrane Central Register of Controlled Trials, MEDLINE (1950 to JanuaryWeek 4 2008), EMBASE (1980 to 2008), and CINAHL (1982 to November 2007); also reviewed reference lists of identified publications, including previous meta-analyses, to identify any additional studies/citations; further information was sought from authors/industry if needed.Eligibility criteria clearly described?YesReview studies independently reviewed by at least 2 persons?YesStandard method of critical appraisal before including?YesComments:Due to large variability in doses, 2 groups were created for analysis: data from doses < 50 mg/day of ANK and data from doses 50 to 150 mg/day. 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ADDIN EN.CITE.DATA 221Country and setting:MultinationalFunding:NRAims of Review:To review the evidence for the effi cacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task ForceQuality Rating:FairStudy design:Systematic review and meta-analysisNumber of Patients:NRStudies Included:87 articles and 40 abstractsCharacteristics of Included Studies:For efficacy 1)double-blind randomised controlled trials (RCTs); (2) trials of ≥6 months’ duration; (3)?studies with ≥?50 patients; (6)?publications in English. And for safety (1) registries and observational studies; (2) inclusion of a control group; (3) report of incidence of events in the context of population-based expected incidencesCharacteristics of Included PopulationsPatients with RACharacteristics of Interventions:Studies evaluating 1 of the 9 biological DMARDsStudy Results:Efficacy - # of patients withdrawn for lack of efficacyTNF inhibitors 5 studies n?=?882 RR, 0.25 (95% CI, 0.13-0.48) P?=?0.0001 Sulfasalazine 5 studies n?=?434 RR, 0.45 (95% CI, 0.23-0.89) P?=?0.02 Gold salts 2 studies n?=?320 RR, 0.25 (95% CI, 0.11-0.53) P?=?0.0003 Leflunomide 1 study n?=?190 RR, 0.44 (95% CI, 0.23-0.83) P?=?0.01 All DMARDs 12 studies n?=?1081 RR, 0.39 (95% CI, 0.27-0.57) P?=?0.00001All treatment 18 studies n?=?2148 RR, 0.35 (95% CI, 0.25-0.49) P?=?0.00001 Adverse Events:Toxicity - Withdrawals for adverse eventsTNF inhibitors 5 studies n?=?882 RR, 2.20 (95% CI, 0.82-5.91) P?=?0.12 NNT/NNH, 0.25Sulfasalazine 5 studies n?=?434 RR, 1.76 (95% CI, 0.98-3.14) P?=?0.06 NNT/NNH, 0.93Gold salts 2 studies n?=?320 RR, 2.34 (95% CI, 1.10-4.97) P?=?0.03 NNT/NNH, 0.79Leflunomide 1 study n?=?190 RR, 3.86 (95% CI, 1.20-12.39) P?=?0.02 NNT/NNH, 0.45All DMARDs 12 studies n?=?1081 RR, 2.32 (95% CI, 1.55-3.47) P?=?0.0001 NNT/NNH, 0.86All treatment 18 studies n?=?2148 RR, 2.33 (95% CI, 1.61-3.37) P?=?0.00001 NNT/NNH, 0.62Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAuthor, year, country, funding:Osiri et al., 2002 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1430</RecNum><DisplayText><style face="superscript">142</style></DisplayText><record><rec-number>1430</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1430</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Osiri, M</author><author>Shea, B</author><author>Robinson, V</author><author>Suarez Almazor, M</author><author>Strand, V</author><author>Tugwell, P</author><author>Wells, G</author></authors></contributors><titles><title>Leflunomide for treating rheumatoid arthritis</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><pages>CD002047</pages><number>3</number><keywords><keyword>CD002047</keyword></keywords><dates><year>2002</year></dates><label>MA</label><urls></urls><custom1>I</custom1><custom2>B</custom2><custom3>S</custom3><custom4>B - 3981</custom4><custom7>GG 10-2 (LL 8-23)</custom7></record></Cite></EndNote>142Multinational Cochrane CollaborationStudy Design:Systematic review of RCTs and CCTsAims of the Review:To determine efficacy and toxicity of LEF compared to placebo or other DMARDs in txt of RAMETA-ANALYSIS-analysis stratified comparison between LEF and Placebo or other DMARDs by outcomes at different length of txtsNumber of Pts:1,144 LEF312 to Placebo680 to MTX132 to SSZOnly 920 used in meta-analysis-analysis 2 yr extension: LEF:158SSZ: 60MTX 101Studies included:6 trialsCharacteristics of included studies:Randomized, double-blind, placebo and/or active controlledCharacteristics of included populations:All with active RACharacteristics of interventions:5,10 or 25 mg/d vs. placebo or MTX or SSZLEF significantly better than placebo at 6,12 and 24 mos. LEF vs. MTXACR 20: Significantly more responders for MTX than LEF at 12 mos; OR: 1.43 (1.15-1.77)No significant differences at 2 yrs but more responders with MTX than with LEF; OR, 1.28 (0.98-1.67)ACR 50, ACR 70: differences in ACR 50/70 repsonses between LEF and MTX were NSTotal withdrawals lower in LEF group (10% greater than Placebo (70/416 vs. 18/311)); LEF not diff in efficacy and tolerability than MTX and SSZ, except that LEF was more efficaious than SSZ at 24 mos; AEs+ GI sympotms, elevated liver funcitn tests, alopecia, and infectionsPublication Bias Assessed:NRHeterogeneity Assessed:YesStandard Method of Study Appraisals:YesComprehensive Search Strategy:Yes Quality Rating: GoodStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Osiri et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3981</RecNum><DisplayText><style face="superscript">222</style></DisplayText><record><rec-number>3981</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3981</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Osiri, M.</author><author>Shea, B.</author><author>Welch, V.</author><author>Suarez-Almazor, M. E.</author><author>Strand, V.</author><author>Tugwell, P.</author><author>Wells, G. A.</author></authors></contributors><titles><title>Leflunomide for the treatment of rheumatoid arthritis</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><pages>Art. No.: CD002047</pages><volume>1</volume><keywords><keyword>Humans [checkword]</keyword><keyword>Anti-Inflammatory Agents, Non-Steroidal [therapeutic use]</keyword><keyword>Antirheumatic Agents [therapeutic use]</keyword><keyword>Arthritis, Rheumatoid [drug therapy]</keyword><keyword>Isoxazoles [therapeutic use]</keyword><keyword>Methotrexate [therapeutic use]</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Sulfasalazine [therapeutic use]</keyword></keywords><dates><year>2003</year></dates><urls><related-urls><url> </url></related-urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 1, 2, 3 / good</custom4><electronic-resource-num>10.1002/14651858.cd002047</electronic-resource-num></record></Cite></EndNote>222Country and setting:MultinationalFunding:Cochrane CollaborationAims of Review:To determine the efficacy and toxicity of LEF (monotherapy or combined with another DMARD) compared to placebo orother DMARDs in the treatment of RA.Quality Rating:GoodStudy design:Systematic Review and meta-analysesNumber of Patients:NRStudies Included:N?=?33Characteristics of Included Studies:All randomized controlled trials (RCTs) or controlled clinical trials(CCTs) comparing LEF as monotherapy or in combinationwith another DMARD to placebo or other DMARDs.Characteristics of Included PopulationsPatients were at least 18 yrs old, had a clinical diagnosis of RA according to the ACR 1987 revised criteria, and had active disease as shown by these outcomes:1) number of 10der joints;2) number of swollen joints;3) duration of morning stiffness;4) acute phase reactants.Characteristics of Interventions:Studies comparing LEF treatment (as monotherapy or incombination with other DMARDs) at a dose of 20 to 25 mg/day (with or without a loading daily dose of 100 mg given in the first1 to 3 days) with placebo or other DMARDs were included. The duration of treatment in the trials must have been at least 3 mos (or 12 wks).Study Results:ACR20, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 3 mos: 0.96 (0.84-1.10)LEF vs. MTX, at 4 mos: 0.95 (0.50-1.81)LEF vs. MTX, at 6 mos (24 wks): 0.96 (0.87-1.06)LEF vs. MTX, at 12 mos: 1.08 (0.75-1.55)LEF vs. MTX, at 2 yrs: 1.05 (0.81-1.37)LEF vs. SSZ, at 6 mos: 1.03 (0.83-1.28)LEF vs. SSZ, at 12 mos: 1.03 (0.83-1.29)LEF vs. SSZ, at 24 mos: 0.73 (0.57-0.93)LEF+MTX vs.MTX, at 24 wks: 0.42 (0.29-0.63)LEF+SSZ vs. placebo+SSZ, at 24 wks: 0.96 (0.49-1.88)LEF vs. anti-TNF+MTX, at 24 wks: 1.14 (0.97-1.34)Lef+ADA vs. ADA, at 12 wks: 0.83 (0.69-0.99)ACR50, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 12 mos: 0.86 (0.52-1.44)LEF vs. MTX, at 2 yrs: 0.82 (0.60-1.10)LEF vs. SSZ, at 6 mos: 0.92 (0.64-1.31)LEF vs. SSZ, at 12 mos: 0.93 (0.63-1.36)LEF vs. SSZ, at 24 mos: 0.48 (0.28-0.80)LEF+MTX vs.MTX, at 24 wks: 0.23 (0.11-0.48)LEF+SSZ vs. placebo+SSZ, at 24 wks: 0.10 (0.01-1.79) LEF vs. MTX, at 24 wks: 0.83 (0.53-1.32)LEF vs. anti-TNF+MTX, at 24 wks: 1.39 (0.97-1.99)Lef+ADA vs. ADA, at 12 wks: 0.84 (0.58-1.20)ACR70, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 12 mos: 0.44 (0.26-0.77)LEF vs. MTX, at 2 yrs: 0.72 (0.44-1.18)LEF vs. SSZ, at 6 mos: 0.66 (0.28-1.55)LEF vs. SSZ, at 12 mos: 1.14 (0.57-2.25)LEF vs. SSZ, at 24 mos: 0.70 (0.34-1.43)LEF+MTX vs.MTX, at 24 wks: 0.23 (0.07-0.77)LEF vs. MTX, at 24 wks: 0.5 (0.10-2.53)LEF vs. anti-TNF+MTX, at 24 wks: 3.75 (1.35-10.43)HAQ, Mean Difference (IV, Fixed, 95% CI)LEF vs. MTX, at 3 mos: 0.01 (-0.12, 0.14)LEF vs. MTX, at 6 mos: -0.01 (-0.11-0.09)LEF vs. MTX, at 12 mos: -0.02 (-0.09-0.05)LEF vs. MTX, at 2 yrs: 0.05 (-0.04-0.14)LEF vs. SSZ, at 6 mos: -0.25 (-0.42- -0.08)LEF vs. SSZ, at 12 mos: -0.14 (-0.33-0.05)LEF vs. SSZ, at 24 mos, -0.29 (-0.57- -0.01)LEF+MTX vs. MTX, at 24 wks: -0.30 (-0.42- -0.18)LEF+SSZ vs. placebo+SSZ, at 24 mos: -0.07 (-0.20-0.06)LEF vs. anti-TNF, at 24 wks: 0.49 (0.34-0.64)HAQ-DI, Mean Difference (IV, Fixed, 95% CI)LEF+SSZ vs. placebo+SSZ, at 24 mos: -0.08 (-0.23-0.07)Lef/lLEF+ MTX vs. placebo/LEF + MTX, at 48 wks: 0.21 (0.05-0.37)MHAQ, Mean Difference (IV, Fixed, 95% CI)LEF vs. MTX, at 6 mos: -0.12 (-0.22- -0.02)LEF vs. MTX, at 12 mos: -0.14 (-0.25- -0.03)LEF vs. MTX, at 24 mos: -0.15 (-0.29- -0.01)LEF vs. MTX, at 4 mos: -2.34 (-7.64-2.96)Chinese disability, Mean Difference (IV, Fixed, 95% CI)LEF vs. MTX, at 3 mos: -0.09 (-0.18- -0.00)LEF vs. MTX, at 6 mos: -0.05 (-0.20-0.10)SF-36, Mean Difference, Physical Component Scores (IV, Fixed, 95% CI) LEF vs. MTX, at 12 mos: -3.0 (-5.41- -0.59)Lef/LEF + MTX vs.placebo/LEF + MTX, at 48 wks: -1.90 (5.14-1.34)SF-36, Mean Difference, Mental Component Scores (IV, Fixed, 95% CI)LEF vs. MTX, at 12 mos: -0.6 (-3.01-1.81)Lef/LEF + MTX vs.placebo/LEF + MTX, at 48 wks: -2.7 (5.63-0.23)Work Productivity Scores, Mean Difference (IV, Fixed, 95% CI)LEF vs. MTX, at 12 mos: -2.30 (-6.37-1.77)DAS28 response rate, Risk Ratio (M-H, Fixed, 95% CI)LEF + SSZ vs. SSZ, at 24 wks: 0.76 (0.47-1.24)DAS28 score change, Mean Difference (IV, Fixed, 95% CI)LEF + SSZ vs. SSZ, at 24 wks: 0.10 (-0.41-0.61)LEF vs. MTX, at 16 wks: 0.57 (0.24-0.90)LEF vs. MTX, at 24 wks: -0.10 (-0.41-0.21)LEF vs. anti-TNF+MTX, at 24 wks: 0.80 (0.43-1.17)DAS28 responders, Risk Ratio (M-H, Fixed, 95% CI) LEF + SSZ vs. SSZ, for 24-wk completers: 0.61 (0.36-1.04)EULAR remission (DAS28 <3.2), Risk Ratio (M-H, Fixed, 95% CI)LEF vs.MTX, at 16 wks: 1.24 (0.64-2.42)DAS28 remission, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 24 wks: 1.0 (0.22-4.56)LEF vs. anti-TNF+MTX, at 24 wks: 1.67 (0.38-7.39)LEF vs. Lef+MTX, at 3 mos: 1.35 (0.18-10.09)DAS28 low disease activity, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. MTX, at 24 wks: 1.0 (0.28-3.63)LEF vs. anti-TNF+MTX, at 24 wks: 3.33 (1.17-9.51)DAS28 moderate disease activity, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 24 wks: 1.05 (0.76-1.44)LEF vs. anti- TNF+MTX, at 24 wks: 0.56 (0.30-1.04)DAS28 high disease activity, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 24 wks: 0.5 (0.05-5.22)LEF vs. anti-TNF+MTX, at 24 wks: 0.33 (0.02-6.44)EULAR good response, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. LEF + MTX, at 3 mos: 0.37 (0.10-1.34)LEF + ADA vs. ADA, at 12 wks: 0.71 (0.47-1.05)EULAR moderate response, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. Lef+MTX, at 3 mos: 0.80 (0.47-1.35)LEF + ADA vs. ADA, at 12 wks: 0.83 (0.73-0.93)EULAR response-no improvement, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. LEF + MTX, at 3 mos: 4.27 (0.64-28.56)EULAR response rate, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. MTX, at 16 wks: 1.05 (0.89-1.23)Adverse Events:Total withdrawals, Risk Ratio (M-H, Fixed, 95% CI) LEF vs.SSZ, at 6 mos: 0.75 (0.53-1.07)LEF vs.SSZ, at 12 mos: 1.07 (0.43-2.63)LEF vs. SSZ, at 24 mos: 0.79 (0.39-1.59)LEF vs. MTX, at 12 mos: 1.26 (1.08-1.48)LEF vs. MTX, at 2 yrs: 1.15 (0.83-1.61)LEF + MTX vs. MTX, at24 wks: 0.93 (0.60-1.43)LEF + SSZ vs. placebo + SSZ, at 24 wks: 1.34 (0.77-2.34)LEF/LEF+ MTX vs. placebo/Lef + MTX, at 48 wks: 1.4 (0.65-3.00)LEF + MTX vs. MTX, at 3mos: 0.75 (0.39-1.43)LEF+ MTX vs. MTX, at 24 mos: 1.25 (0.52,-3.01)Withdrawals due to adverse events, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. SSZ, at 6 mos: 0.77 (0.45-1.33)LEF vs. SSZ, at 12 mos: 0.38 (0.08-1.90)LEF vs. SSZ, at 24 mos: 0.67 (0.25-1.76)LEF vs. MTX, at 6 mos: 0.24 (0.10-0.57)LEF vs. MTX, at 12 mos: 1.43 (1.13-1.83)LEF vs. MTX, at 2 yrs: 1.38 (0.77-2.47)LEF + MTX vs. MTX, at 24 wks: 1.82 (0.83-3.97)LEF/Lef + MTX vs. placebo/LEF + MTX, at 48 wks: 1.0 (0.21-4.83)LEF vs. LEF + MTX, at 3mos: 0.46 (0.03-8.03)LEF + MTX vs. MTX, at 3mos: 0.86 (0.41-1.81)LEF + MTX vs. MTX, at 24 mos: 1.4 (0.46-4.23)Reported adverse events, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. MTX, at 6 mos: 0.55 (0.42-0.73)LEF + MTX vs. MTX, at 24 mos: 3.5 (1.29-9.49)Alopecia, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. SSZ: 1.57 (0.63-3.93)LEF vs. MTX: 1.72 (1.32-2.24)LEF/Lef + MTX vs. placebo/LEF + MTX, at 48 wks: 8.0 (1.02-62.74) GI symptoms, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. SSZ: 0.88 (0.63-1.22)LEF vs. MTX: 0.50 (0.28-0.92)Allergy or rash, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. SSZ: 1.0 (0.52-1.92)LEF vs. MTX: 1.51 (1.19-1.92)LEF + SSZ vs. placebo + SSZ, at 24 wks (rash): 1.12 (0.32-3.93) LEF/LEF + MTX vs. placebo/LEF + MTX, at 48 wks (rash): 0.86 (0.30-2.46) Nausea, Risk Ratio (M-H, Fixed, 95% CI)LEF + SSZ vs. placebo + SSZ, at 24 wks: 3.57 (0.41-30.90)LEF/LEF + MTX vs. placebo/LEF + MTX, at 48 wks: 1.33 (0.31-5.80)Diarrhea, Risk Ratio (M-H, Fixed, 95% CI)LEF + SSZ vs. placebo + SSZ, at 24 wks: 2.68 (0.29-24.93)LEF/LEF + MTX vs. placebo/LEF + MTX, at 48 wks: 5.33 (1.61-17.71)Hyper10sion, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. SSZ: 1.0 (0.21-4.87)LEF vs. MTX: 2.29 (1.42-3.69)W8 loss, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. SSZ: 3.0 (0.62-14.60)LEF vs. MTX: 0.81 (0.39-1.66)Infections, Risk Ratio (M-H, Fixed, 95% CI) LEF vs. SSZ: 0.25 (0.03-2.21)LEF vs. MTX: 0.97 (0.81-1.15)LEF/LEF + MTX vs. placebo/LEF + MTX, at 48 wks: 2.5 (0.81-7.70)Elevated liver function tests, Risk Ratio (M-H, Fixed, 95% CI)LEF vs. SSZ: 0.6 (0.15-2.46)LEF vs. MTX: 0.66 (0.31-1.39)LEF/LEF + MTX vs. placebo/LEF + MTX, at 48 wks: 1.07 (0.53-2.15)Elevated liver function tests, reported as adverse event, Risk Ratio (M-H, Random, 95% CI)LEF vs. SSZ, at 6 mos: 0.6 (0.15-2.46)LEF vs. MTX, at 6 mos: 0.52 (0.24-1.15)LEF vs. MTX, at 1 year: 0.65 (0.17-2.45)LEF vs. MTX, at 2 yrs: 0.80 (0.30-2.14)Elevated liver function tests, withdrawals Risk Ratio (M-H, Random, 95% CI)LEF vs. SSZ, at 6 mos: 1.0 (0.14-6.99)LEF vs. MTX, at 6 mos: 0.18 (0.02-1.63)LEF vs. MTX, at 1 year: 0.90 (0.28-2.86)LEF vs. MTX, at 2 yr: 0.33 (0.08-1.42)Serious adverse events, (M-H, Fixed, 95% CI) LEF + SSZ vs. placebo + SSZ, at 24 wks: 1.79 (0.47-6.77)LEF/Lef + MTX vs. placebo/Lef + MTX, at 48 wks: 0.87 (0.44,-1.72)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAuthor, yr, country, funding:Rheumatoid Arthritis Clinical Trial Archive Group, 1995, ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>1754</RecNum><DisplayText><style face="superscript">223</style></DisplayText><record><rec-number>1754</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">1754</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rheumatoid Arthritis Clinical Trial Archive Group,</author></authors></contributors><titles><title>The effect of age and renal function on the efficacy and toxicity of methotrexate in 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>218-23</pages><volume>22</volume><number>2</number><keywords><keyword>CN-00113693</keyword></keywords><dates><year>1995</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>S</custom3><custom4>4</custom4><custom7>PT 9-26 (DJ 8-16) Goes w #1912</custom7><research-notes>Subgroups only--no systematic lit search</research-notes></record></Cite></EndNote>223Multinational, NIH grantsStudy Design:Systematic reviewAims of the Review:To evaluate whether age and renal impairment affect rate of side effects or efficacy of MTX in RA ptsNumber of Pts:496Studies included:11 MTX clinical trials: Weinblatt, et al., 1985Furst, et al., 1989Schmid, et al., unpublished studyWilliams, et al., 1985Wilke, et al., unpublished studyWeinblatt, et al., 1990Williams, et al., 1992Suarez et al 1988Morassut, et al., 1989Hamdy, et al., 1987Bell, et al., 1988.Characteristics of included studies:RCTsPlacebo control or comparative trialMTX as 1 treatment armAdult RA ptsTrial completed (although not necessarily published) by end of 1991, and trial 12 weeks or longer (to end or to crossover)Characteristics of included populations:Adult RA pts treated with MTXCharacteristics of interventions:All pts treated with MTX (doses NR)Study compares subgroups of pts treated with MTXNeither age nor renal impairment had any effect on efficacy of MTXOdds of major clinical improvement by age were 1.0 for < 60 yr old group (referent), 1.4 (0.7, 2.6) for 60-64, 1.0 (0.5, 2.2) for 65-69, and 0.7 (0.3, 1.7) for ≥ 70 (efficacy regression analyses controlled for age group, sex, renal function, study of origin, initial tender joint count, grip strength, steroid dose, NSAID used at baseline, and maximum MTX dose)Odds of major clinical improvement by creatinine clearance were 1.0 for ≥99.8 ml/min (referent), 0.6 (0.3, 1.0) for 78.6-99.9 ml/min, 1.1 (0.6, 2.0) for 62.6-78.6 ml/min, and 1.0 (0.5, 2.1) for < 62.6 ml/minAge did not affect rate of toxicity. Those in the oldest group were not at a higher risk of side effects from MTXNo significant difference for liver toxicity between different creatinine clearance groups1.0 (referent)1.8 (1.0, 3.4)1.2 (0.6, 2.3)1.8 (0.8, 3.7)Toxicity regressions adjusted for age, sex, creatinine clearance, baseline NSAID use (yes/no), maximum MTX dose, and study of originPublication Bias Assessed:NRHeterogeneity Assessed:YesStandard Method of Study Appraisals:NRComprehensive Search Strategy:Yes Quality Rating: FairStudy CharacteristicsStudy DesignResultsAdverse Events QualityCommentsAuthor:Salliot, 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2806</RecNum><DisplayText><style face="superscript">224</style></DisplayText><record><rec-number>2806</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">2806</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Salliot, C.</author><author>Dougados, M.</author><author>Gossec, L.</author></authors></contributors><auth-address>Rene-Descartes University, Medicine Faculty, AP-HP, Cochin Hospital, Rheumatology B Department, Paris, France. carinesalliot@wanadoo.fr</auth-address><titles><title>Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised placebo-controlled trials</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>25-32</pages><volume>68</volume><number>1</number><keywords><keyword>Antibodies, Monoclonal/adverse effects</keyword><keyword>Antirheumatic Agents/ adverse effects</keyword><keyword>Arthritis, Rheumatoid/ drug therapy/microbiology</keyword><keyword>Bacterial Infections/ complications</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoconjugates/adverse effects</keyword><keyword>Interleukin 1 Receptor Antagonist Protein/adverse effects</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Odds Ratio</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Risk</keyword><keyword>Tumor Necrosis Factor-alpha/ antagonists &amp; inhibitors</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1468-2060 (Electronic)</isbn><accession-num>18203761</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>SR</custom3><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>224Country and setting:NRFunding:NRStudy design:Systematic Review and meta-analysesOverall study N:N = 4,767 (745 rituximab, 1960 abatacept, 2062 anakinra), 2112 placeboStudy aims:To assess if biological agents, ie rituximab, abatacept, and anakinra increase risk of serious infections.Main results:Pooled ORs Regardless of Dose:Rituximab Pooled OR = 1.45 (0.56 - 3.73)Abatacept Pooled OR = 1.35 (0.78 - 2.32)Anakinra Pooled OR = 2.75 (0.90 - 8.35)Pooled ORs Stratified by High and Low Dose:RituximabHigh Dose v Placebo 1.68 (0.64 - 4.35)Low Dose V Placebo 0.24 (0.01 - 4.33)High Dose v Low Dose 7.20 (0.43 - 120.66)Abatacept High Dose v Placebo 1.35 (0.78 - 2.33)Excluding patients receiving concominant treatment with other biologic DMARDs, pooled OR = 1.24 (0.70 - 2.29)Low Dose v Placebo 0.84 (0.13 - 5.30)High Dose v Low Dose 2.16 (0.52 - 8.98)Excluding patients receiving concominant treatment with other biologic DMARDs, pooled OR = 2.0 (0.48 - 8.33)AnakinraHigh Dose v Placebo 3.40 (1.11 - 10.46)Excluding patients with comorbidity factors, pooled OR = 1.67 (0.51 - 5.41)Low Dose v Placebo 0.51 (0.03 - 8.27)High Dose v Low Dose 9.63 (1.31 - 70.91)Excluding patients with comorbidity factors, pooled OR = 6.41 (0.81 - 50.30)Adverse events:Rituximab:Among 17 patients who had 1 serious infection: 5 had bronchopneumonia (1 presented with 2 episodes of Pseudomonas aeruginosa pneumonia), 2 septic arthritis (of whom one Staphylococcus aureus septicaemia), 3 pyelonephritis and 2 gastroenteritis and 1 each epiglottitis, cellulitis of a toe, and acute hepatitis B. One fatal bronchopneumonia occurred in a patient receiving rituximab.Abatacept:49 serious infections occurring with abatacept were mainly bronchopulmonary, streptococcal and pyogenic septicaemia, staphylococcal arthritis, abscesses, gastrointestinal (6 of whom 3 diverticulitis), dermatological infections (6 of whom 1 was a cellulitis) and pyelonephritis. One case of unconfirmed tuberculosis and 1 case of pulmonary aspergillosis were reported. Last patient (who had history of tuberculosis and pulmonary fibrosis) died of aspergillosis and of Pseudomonas aeruginosa septicaemia.Anakinra:Among 30 serious infections occurring in anakinra-treated groups, 11 were pneumonia. Others were osteomyelitis, cellulitis, bursitis, herpes zoster, infected bunion and gangrene (1 of each). No related death or opportunistic infections were described.Review based on focused question of interest:YesDid search strategy employ comprehensive, systematic literature search?Yes.A systematic literature search of literature published up to December 2007 was performed in PUBMED, EMBASE and Cochrane library databases; without limitation of years of publication or journal, using followings key-words: “rheumatoid arthritis,” “abatacept,’ “rituximab,” “anakinra,” “clinical controlled trials,” “clinical trials,” “randomised controlled trials,” “clinical trials phase II, III, IV”. We also included congress abstracts of American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) meetings from 2004 to 2006, because we assumed that any abstract published prior to 2004 had been published in a formal fulllength work. Moreover, to complete our search with unpublished data, Food and Drug Administration (FDA), European Agency for Evaluation of Medicinal Products (EMEA) and manufacturers (Roche, Amgen and Bristol- Myers Squibb) were contacted.Eligibility criteria clearly described?Yes.Inclusion criteria were randomised placebo controlled trials in adult patients with RA according to ACR criteria. Publications had to be written in English, French or Spanish. Patients had to be randomised to receive placebo or 1 of 3 biological agents (rituximab, anakinra and abatacept), as monotherapy or with concomitant biological or non-biological DMARDs. Reviews and articles reporting trials that were not placebo-controlled were excluded.Review studies independently reviewed by at least 2 persons?No. One reviewer selected studies and abstracted data.Standard method of critical appraisal before including?NRComments:NRStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Schipper et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3770</RecNum><DisplayText><style face="superscript">225</style></DisplayText><record><rec-number>3770</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3770</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>Van Riel, P. L.</author></authors></contributors><auth-address>Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. LSchipper@reuma.umcn.nl</auth-address><titles><title>Methotrexate in combination with sulfasalazine is more effective in rheumatoid arthritis patients who failed sulfasalazine than in patients naive to both drugs</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>828-33</pages><volume>48</volume><number>7</number><keywords><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Double-Blind Method</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Methotrexate/ therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Sulfasalazine/ therapeutic use</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2009</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1462-0332 (Electronic)&#xD;1462-0324 (Linking)</isbn><accession-num>19458163</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>225Country and setting:MultinationalFunding:NRAims of Review:To review the effects of the combination of MTX and SSZ in na?ve patients and patients with an insufficient response, using the results of published parallel and add-on clinical trials in RA.Quality Rating:FairStudy design:Systematic ReviewNumber of Patients:NRStudies Included:N?=?4Characteristics of Included Studies:RCT of at least 12 weeks duration with a parallel or an add-on design,Characteristics of Included PopulationsRA patients fulfilling the ACR 1987 revised criteria; either na?ve to MTX and SSZ (parallel trials) or had failed to 1 of them (add-on trials).Characteristics of Interventions:Placebo-controlled, double blind RCTs and compared the efficacy of combined MTX and SSZ to each individual agent and randomized open study comparing the combination of MTX and SSZ with MTX alone.Study Results:Trials with naive patients:Mean DAS changes: sub-additive efficacy (1.3 and 1.9 respectively)ACR 20: 80%ACR50: 33%ACR70: 3% Trials with patients who failed SSZ: Mean DAS changes: additive efficacy. ACR 20: 29%ACR50: 11%ACR70: 4%Adverse Events:From the 2 parallel trials, the first RCT showed more toxicity (nausea) of the MTX-SSZ combination compared with the single-drug arms. The second study showed more adverse events (nausea) in the combination group. The 2 add-on trials showed that the addition of MTX to SSZ in patients who had failed to the latter drug was clinically significantly superior to a switch to MTX alone, without increased toxicity.Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Singh et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjM5

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ADDIN EN.CITE.DATA 226Country and setting:MultinationalFunding:GovernmentAims of Review:To provide estimates of the benefits and safety of biologics in patients with RAQuality Rating:GoodStudy design:Overview of SERs using ne2rk meta-analyses of Cochrane SERsNumber of Patients:NRStudies Included:6 SERs; 31 studiesCharacteristics of Included Studies:In most of the included trials, each biologic was compared with a placebo, usually in combination with traditional DMARDs (usually MTX) or other biologicsCharacteristics of Included PopulationsEligibility criteria and patient populations weresimilar across reviews: adults with RA who met the ACR criteria for RACharacteristics of Interventions:ADA: All RCTs or CCTs comparing ADA (alone or combo with DMARDs) with placebo or other DMARDsABA: All RCTs comparing ABA (alone or combo with DMARDs) with placebo or other DMARDs; no restrictions on dosage or duration of the interventionANK: All RCTs comparing ANK (alone or combo with DMARDs or other biologics) with placebo or other DMARDs or biologicsETN: All RCTs or CCTs of at least 6 months’ duration comparing ETN with placebo, ETN with MTX, or ETN + MTX with MTX aloneINF: All RCTs comparing INF (1, 3, 5 or 10 mg/kg) + MTX with MTX alone, or INF with placebo, with a minimum duration of 6 months and at least 2 infusionsRIT: All RCTs comparing RIT (300, 350, 500 or 600 mg/m2) (alone or combo with DMARD) with placebo or other DMARDs or biologicStudy Results:Benefit (ACR 50), Biologic vs. Placebo, OR (95% CI), NNTABA: 2.98 (1.79-4.97), NNT, 4 (3-9)ADA: 3.70 (2.4-5.7), NNT, 4 (3-6)ANK: 1.68 (0.83-3.41), NNT, NSETN: 4.97 (2.70-9.13), NNT, 3 (2-5)INF: 2.92 (1.37-6.24), NNT, 4 (2-18)RIT: 4.10 (2.02-8.33), NNT, 3 (1-7)Overall (all biologics vs. placebo): 3.35 (2.62-4.2) Indirect comparison of ACR 50 between biologics, Ratio of odds ratios (95% CI)ABA vs. ADA: 0.81 (0.43-1.49)ABA vs. ANK: 1.77 (0.78-4.00)ABA vs. ETN: 0.60 (0.29-1.25)ABA vs. INF: 1.02 (0.43-2.40)ABA vs. RIT: 0.73 (0.32-1.65)ADA vs. ANK: 2.20 (1.01-4.75)ADA vs. ETN: 0.74 (0.37-1.48)ADA vs. INF: 1.26 (0.56-2.86)ADA vs. RIT: 0.90 (0.41-1.96)ANK vs. ETN: 0.34 (0.14-0.81)ANK vs. INF: 0.58 (0.22-1.52)ANK vs. RIT: 0.41 (0.16-1.05)ETN vs. INF: 1.70 (0.68-4.22)ETN vs. RIT: 1.21 (0.51-2.90)INF vs. RIT: 0.71 (0.27-1.89)ACR50 Subgroup data, OR (95% CI):Concomitant use of MTX Yes: 3.16 (2.40-4.16) No: 4.18 (2.48-7.06) Rheumatoid arthritis duration Early: 2.05 (1.24-3.38) Established: 3.47 (2.26-5.33) Late: 4.02 (2.89-5.59) Biologic is TNF-inhibitor Yes: 3.57 (2.57-4.97) No: 3.10 (2.12-4.53) Prior drugs failed Biologic: 4.09 (2.17-7.69) DMARD: 3.27 (2.46-4.35) None: 3.00 (1.11-8.13) Combination biologic therapy Yes: 1.00 (0.45-2.23) No: 3.60 (2.89-4.49) Duration of randomized trial Short: 4.03 (2.93-5.54) Intermediate: 2.92 (1.91-4.46) Long: 1.73 (0.78-3.82) Prior failure of TNF biologic Yes: 4.11 (2.21-7.63) No: 3.24 (2.48-4.22) Adverse Events:Safety (withdrawal due to an adverse event), OR (95% CI), NNTABA: 1.24 (0.88-1.76), NNT, NSADA: 1.54 (1.12-2.12), NNT, 39 (19-162)ANK: 1.67 (1.22-2.29), NNT, 31 (17-92)ETN: 0.82 (0.56-1.19), NNT, NSINF: 2.21 (1.28-3.82), NNT, 18 (8-72)RIT: 1.34 (0.65-2.76), NNT, NSOverall: 1.39 (1.13-1.71)Indirect comparison of withdrawal due to adverse events between biologics, Ratio of odds ratios (95% CI)ABA vs. ADA: 0.80 (0.51-1.26)ABA vs. ANK: 0.74 (0.47-1.17)ABA vs. ETN: 1.52 (0.93-2.49)ABA vs. INF: 0.56 (0.30-1.05)ABA vs. RIT: 0.93 (0.43-2.02)ADA vs. ANK: 0.92 (0.60-1.42)ADA vs. ETN: 1.89 (1.18-3.04)ADA vs. INF: 0.70 (0.38-1.28)ADA vs. RIT: 1.15 (0.54-2.48)ANK vs. ETN: 2.05 (1.27-3.29)ANK vs. INF: 0.76 (0.41-1.39)ANK vs. RIT: 1.25 (0.58-2.69)ETN vs. INF: 0.37 (0.19-0.70)ETN vs. RIT: 0.61 (0.28-1.35)INF vs. RIT: 1.66 (0.69-3.98)Withdrawal due to adverse event Subgroup data, OR (95% CI):Concomitant use of MTX Yes: 1.30 (1.02-1.65) No: 1.70 (1.12-2.57) Rheumatoid arthritis duration Early: 1.45 (0.92-2.28) Established: 1.25 (0.87-1.78) Late: 1.52 (1.09-2.11) Biologic is TNF-inhibitor Yes: 1.27 (0.94-1.69) No: 1.55 (1.14-2.11) Prior drugs failed Biologic: 1.74 (1.02-2.96) DMARD: 1.41 (1.11-1.79) None: 0.85 (0.41-1.76) Duration of randomized trial Short: 1.46 (1.07-1.99) Intermediate: 1.31 (0.94-1.82) Long; 1.47 (0.71-3.03) Prior failure of TNF biologic Yes: 1.76 (1.01-3.06) No: 1.34 (1.06-1.69) Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Singh et al., 2009PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx

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ADDIN EN.CITE.DATA 227Country and setting:NRFunding:Cochrane Collaboration; The Oak Foundation, Switzerland; NIH CTSA AwardAims of Review:To compare the efficacy and safety of ABA, ADA, ANK, ETN, INF, and RIT in RA ptsQuality Rating:FairStudy design:Systematic ReviewNumber of Patients:NRStudies Included:N=6 (Note - 6 Cochrane reviews; data from 7 studies on ABA, 8 on ADA, 5 on ANK, 4 on ETN, 4 on INF, 4 on RIT)Characteristics of Included Studies:Systematic reviews containing at least 1 RCT, with clinically relevant outcomes, and clear inclusion/exclusion criteria; completed, updated, and available Cochrane Systematic reviews of biologic DMARDs as of May 30, 2009Characteristics of Included Populations18 yo or older; RA according to 1987 ACR criteria (populations characteristics similar among reviews)Characteristics of Interventions:Biologic DMARDs along or in combo with other biologics/traditional DMARDs compared to placebo along or placebo + biologics/traditional DMARDs. Biologics were of the following dosing regimens: ADA: 500 mg IV q 4 weeks for 2 weeks if <60 kg (750 mg if 60-100kg; 1000 mg if >100 kg)ADA: 40 mg SQ q 2 wksANK: 100 mg SQ QDETN: 25 mg SQ twice a wkINF: 3 mg/kg IV q 8 wksRIT: 2-1000 mg IV doses 2 wks apartStudy Results:ACR50 (OR, 95% CI, reference group is placebo) ABA: 2.98 (1.79 to 4.97)ADA: 3.70 (2.40 to 5.70)ANK: 1.68 (0.83 to 3.41)ETN: 4.97 (2.70 to 9.13)INF: 2.92 (1.37 to 6.14)RIT: 4.10 (2.02 to 8.33)Indirect comparions (only significant OR reported): ANK less efficacy than ETN: 0.34 (0.14 to 0.81, P?=?0.05)ADA greater efficacy than ANK: 2.20 (1.01 to 4.75, P?=?0.046)Adverse Events:Withdrawals due to ADEs (OR, 95% CI, reference group is placebo): ABA: 1.24 (0.88-1.76)ADA: 1.54 (1.12-2.12)ANK: 1.67 (1.22-2.24)ETN: 0.82 (0.56-1.19)INF: 2.21 (1.28-3.82)RIT: 1.34 (0.65-2.76)Indirect comparisons (only signficant OR reported): ADA more withdrawals due to ADEs than ETN: 1.89 (1.18 to 3.04; P?=?0.009)ANK more withdrawals due to ADE than ETN: 2.05 (1.27 to 3.29; P?=?0.003)ETN less withdrawals due to ADEs than INF: 0.39 (0.19 to 0.70; P?=?0.002)Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Singh et al., 2010 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5108</RecNum><DisplayText><style face="superscript">228</style></DisplayText><record><rec-number>5108</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5108</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Singh, J. A.</author><author>Noorbaloochi, S.</author><author>Singh, G.</author></authors></contributors><auth-address>Medicine, Minneapolis VA Medical Center, 1 Veterans Drive, Rheumatology (111R), Minneapolis, Minnesota, USA, 55417.</auth-address><titles><title>Golimumab for rheumatoid arthritis</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><pages>CD008341</pages><number>1</number><edition>2010/01/22</edition><keywords><keyword>Adult</keyword><keyword>Antibodies, Monoclonal/ therapeutic use</keyword><keyword>Antirheumatic Agents/ therapeutic use</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Drug Therapy, Combination/methods</keyword><keyword>Humans</keyword><keyword>Methotrexate/ therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2010</year></dates><isbn>1469-493X (Electronic)&#xD;1361-6137 (Linking)</isbn><accession-num>20091667</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 1, 2, 3 / good</custom4><electronic-resource-num>10.1002/14651858.CD008341 [doi]</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>228Country and setting:MultinationalFunding:NIHAims of Review:To compare the efficacy and safety of GOL in adults withrheumatoid arthritis.Quality Rating:GoodStudy design:Systematic ReviewNumber of Patients:1714Studies Included:N?=?4Characteristics of Included Studies:(RCTs) or Controlled Clinical Trials (CCTs) (methods of allocating participants to a treatment which are not strictly random, e.g., date of birth, hospital record number or alternation)Characteristics of Included PopulationsAdults 18 years or older, with RA meeting the 1987 American College of Rheumatology Classification criteria for RA. 1 study was prior mtx failure and biologic failure (smolen 99), 3 studies were na?ve populationsCharacteristics of Interventions:Interventions compared are GOL alone or in combination with DMARDs or biologics vs.placebo plus MTX or GOL alone or in combination with DMARDs or biologics compared to other DMARDs or biologics. There were no restrictions with regard to dosage or duration of intervention.Study Results:Compared to patients treated with placebo+MTX, patients treated with the FDA-approved dose of GOL+MTX (50 mg every 4 weeks) were 2.6 times more likely to reach ACR50 at 14-24 wks (95%confidence interval (CI) 1.3 to 4.9; P?=?0.005 and NNT?=?5, 95% CI, 2-20). GOL pts were 1.5 times more likely to reach ACR20 (CI) 1.3-4.9. GOL pts were 2.8 times more likely to reach ACR70 (CI) 1.3-5.98. GOL-treated patients were significantly more likely to achieve DAS remission (RR, 5.1 (CI) 1.7-15.7): Absolute risk difference?= 10% (95% CI, 6%-14%). NNTB?= 6 (95% CI, 2-35). GOL treated patients had a significantly greater change in DAS28 scores compared to placebo (P?=?0.0003). GOL +MTX pts had greater improvement in functional ability (HAQ) and HAQ score decrease RR, 1.79 (CI) 1.38-2.31,P?<?0.0001: Absolute risk difference, -20% (95% CI, -25%- -15%). Relative percent change, 11% (95% CI, -14% to-8.3%) NNT, 3 (95% CI, 3-4) compared to MTX + placebo (all statistically significant).Adverse Events:Patients treated with the FDA-approved dose of GOL+MTX (50 mg every 4 weeks) no more likely to have any adverse event (relative risk 1.1, 95% Cl, 0.9-1.2; P?=?0.44), and 0.5 times as likely to have overall withdrawals (95% Cl 0.3-0.8; P?=?0.005). No significant differences were noted between GOL and placebo regarding serious adverse events, infections, serious infections P?=?0.8, lung infections P?=?0.9, tuberculosis P?=?0.5, cancer P?=?0.8, withdrawals due to adverse events P?=?0.2 and inefficacy P?=?0.1 and deaths P?-0.99. No radiographic data were reported. GOL 100 mg every 4 weeks + MTX vs.placebo + ethotrexate: There was no significant difference between the number of adverse events and serious adverse events occurring for GOL treated patients compared to placebo treated patients with (P?= 0.14) and (P?=?0.9) respectively.There was no statistically significant difference between the number of infections between the GOL and placebo groups (P?=?0.7).There was no statistically significant difference between the number of serious infections between the GOL and placebo groups (P?=?0.3). There were no patients experiencing tuberculosis in either treatment or placebo groups. There was no statistically significant difference between the number of lung infections between the GOL and placebo groups (P?=?0.1). There was no statistically significant difference between the GOL and placebo groups (P?=?0.7) for cancer. Patients treated with GOL were 0.7 times less likely to withdraw compared to placebo.There was no statisticallysignificant difference between the number of patients withdrawing due to inefficacy in the placebo and treatment groups (P?=?0.41), adverse eventss P?=?0.24 or deaths P?=?0.99. GOL 50 mg every 2 weeks + MTX vs.placebo + MTX: No significant differences were noted between GOL and placebo regarding serious adverse events, infections, serious infections P?=?0.97, cancer P?=?0.5, withdrawals due to adverse events P?=?0.97 and inefficacy P?=?0.3. No deaths in either group. GOL 100 mg every 2 weeks + MTX vs.placebo + MTX: No significant differences were noted between GOL and placebo regarding serious adverse events P?=?0.7, infections, serious infections P?=?0.5, withdrawals due to adverse events P?=?0.3 and inefficacy P?=?0.3. No deaths in either group. GOL 100 mg every 4 weeks + placebo (oral) vs.placebo (injections) + MTX: No significant differences were noted between GOL and placebo regarding serious adverse events P?=?0.7, infections P?=?0.3, serious infections P?=?0.7, withdrawals due to adverse events P?=?0.4 and deaths P?=?0.5. There were no inefficacy withdrawals.Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Singh et al., 2010 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>5148</RecNum><DisplayText><style face="superscript">229</style></DisplayText><record><rec-number>5148</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">5148</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Singh Jasvinder, A.</author><author>Beg, Saba</author><author>Lopez-Olivo Maria, Angeles</author></authors></contributors><titles><title>Tocilizumab for rheumatoid arthritis</title><secondary-title>Cochrane Database of Systematic Reviews</secondary-title></titles><periodical><full-title>Cochrane Database of Systematic Reviews</full-title><abbr-1>Cochrane Database Syst. Rev.</abbr-1><abbr-2>Cochrane Database Syst Rev</abbr-2></periodical><number>7</number><keywords><keyword>Hm-muskel</keyword></keywords><dates><year>2010</year></dates><pub-location>Chichester, UK</pub-location><publisher>John Wiley &amp; Sons, Ltd</publisher><accession-num>CD008331</accession-num><urls><related-urls><url> 1, 2, 3 / fair</custom4><electronic-resource-num>10.1002/14651858.CD008331.pub2</electronic-resource-num></record></Cite></EndNote>229Country and setting:NRFunding:Cochrane Collaboration; NIH CTSA K12 AwardAims of Review:To assess the efficacy and safety of TCZ in RA ptsQuality Rating:FairStudy design:Systematic ReviewNumber of Patients:3,334Studies Included:N?=?8Characteristics of Included Studies:All multi-center trials; RCTs (or quasi-randomized trials)Characteristics of Included Populations18 yo or older (some studies 20 yo or older); 1987 ACR criteria for RA for 6 months or more; mean age in early 50sCharacteristics of Interventions:TCZ alone or in combination with DMARDs or biologics vs.placebo or other DMARDs or biologics; no restriction with dosage and duration of intervention; all patients on stable dose of MTX (10-25 mg a week)Study Results:All results reported for 8 mg/kg TCZ +MTX vs. placebo +MTX. ACR50 (RR, 95% CI, TCZ vs. placebo): 3.17 (2.72 to 3.67); DAS remission (DAS<2.6): 8.74 (6.26 to 11.8); clinically significant HAQ decrease (HAQ improvement of >0.3 or MHAQ decease >0.22): 1.79 (1.62 to 1.94)Adverse Events:TCZ 1.2 times more likely to have ADE vs.placebo (74% vs. 65%); serious ADEs: 1.17 (0.83 to 1.64); withdrawals due to ADEs: 1.43 (0.95 to 2.12)Study Characteristics Inclusion and Exclusion Criteria Characteristics and InterventionsBaseline Disease and Treatment CharacteristicsHealth OutcomesAuthor, year, country, funding:Wailoo et al., 2006 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>2094</RecNum><DisplayText><style face="superscript">230</style></DisplayText><record><rec-number>2094</rec-number><foreign-keys><key app="EN" db-id="5fxtw2et6tvrfwe0zps52prfz9ax9tafxpd5">2094</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wailoo, A.</author><author>Brennan, A.</author><author>Bansback, N.</author><author>Nixon, R.</author><author>Wolfe, F.</author><author>Michaud, K.</author></authors></contributors><titles><title>Modeling the cost effectiveness of etanercept, adalimumab and anakinra compared to infliximab in the treatment of patients with rheumatoid arthritis in the Medicare program. AHRQ Technology Assessment Program</title></titles><dates><year>2006</year></dates><urls></urls><custom1>I</custom1><custom2>I</custom2><custom3>S</custom3><custom4>1</custom4><research-notes>This is the Sheffield Report</research-notes></record></Cite></EndNote>230AHRQStudy Design:Decision analytic model and meta-analysisanalysisAims of the Review:Cost effectiveness of ETN, ADA,, ANA and INF alone and in sequenceNumber of Patients:17,000 in disease registry (National Databank for Rheumatic Diseases) and 6694 in RCTsStudies included:Disease registry (National Databank for Rheumatic Diseases) and 6694 in 13 RCTsCharacteristics of included studies:Treatment duration of at least 6 monthsCharacteristics of included populations:Adult patients with RACharacteristics of interventions:Placebo and MTX controlledOdds ratio of ACR50INF/ETN 1.17 (0.68, 2.08)ADA/ETN 1.02 (0.54, 1.97)ADA/INF 0.87 (0.47, 1.57)NRPublication Bias Assessed:YesHeterogeneity Assessed:NRStandard Method of Study Appraisals:NRComprehensive Search Strategy:Yes Quality Rating: FairStudy Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Wiens et al., 2009 ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1" ExcludeYear="1"><RecNum>3707</RecNum><DisplayText><style face="superscript">231</style></DisplayText><record><rec-number>3707</rec-number><foreign-keys><key app="EN" db-id="59asxsxvyfxxxvee02ppaxwfwf0fsfz295v9">3707</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Wiens, A.</author><author>Correr, C. J.</author><author>Pontarolo, R.</author><author>Venson, R.</author><author>Quinalha, J. V.</author><author>Otuki, M. F.</author></authors></contributors><auth-address>Universidade Federal do Parana, Pharmacy Department, Curitiba, Parana, Brazil.</auth-address><titles><title>A systematic review and meta-analysis of the efficacy and safety of etanercept for treating rheumatoid arthritis</title><secondary-title>Scand J Immunol</secondary-title></titles><periodical><full-title>Scandinavian Journal of Immunology</full-title><abbr-1>Scand. J. Immunol.</abbr-1><abbr-2>Scand J Immunol</abbr-2></periodical><pages>337-44</pages><volume>70</volume><number>4</number><keywords><keyword>Adult</keyword><keyword>Arthritis, Rheumatoid/ drug therapy</keyword><keyword>Humans</keyword><keyword>Immunoglobulin G/ adverse effects/ therapeutic use</keyword><keyword>Methotrexate/therapeutic use</keyword><keyword>Middle Aged</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Receptors, Tumor Necrosis Factor/ therapeutic use</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2009</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1365-3083 (Electronic)&#xD;0300-9475 (Linking)</isbn><accession-num>19751268</accession-num><urls></urls><custom1>I</custom1><custom2>I</custom2><custom4>KQ 3 / fair</custom4></record></Cite></EndNote>231Country and setting:NRFunding:NRAims of Review:To evaluate the efficacy and safety of ETN for treating RAQuality Rating:FairStudy design:Systematic review and meta-analysisNumber of Patients:2385Studies Included:N?=?8Characteristics of Included Studies:RCTsCharacteristics of Included PopulationsMean age: 47.5 to 54 yoMean disease duration: 0.7 to 13 yearsMean no. of previous DMARDs: 0.5 to 3.3Mean no. of swollen joints: 13.2 to 25Mean no. of 10der joints: 14 to 35% on steroids: 39 to 81Mean baseline HAQ score: 1.1 to 1.9note: n ot all baseline characteristics reported in all studiesCharacteristics of Interventions:SQ doses of ETN compared to placebo group, with or without MTX. ETN dose was 25 mg twice a week or 50 mg weekly.Study Results:ETN vs. control at 6 monthsACR20: 55% vs. 19%; RR, 2.94 (95% CI, 2.27-3.81)ACR50: 26% vs. 6%; RR, 5.28 (95% CI, 3.12-8.92)ACR70: 7% vs. 1%;RR, 4.83 (95% CI, 1.74-13.47)ETN vs. control at 12 monthsACR20: 77% vs. 67%;RR, 1.14 (95% CI, 1.07-1.23)ACR50: 59% vs. 43%; RR, 1.36 (95% CI, 1.21-1.53)ACR70: 34% vs. 21%; RR, 1.56 (95% CI, 1.30-1.88)Adverse Events:ETN vs. controlSerious AEs: RR, 0.88 (95% CI, 0.66-1.17; P?=?0.38)Serious infections: RR, 0.87 (95% CI, 0.60-1.26; P?=?0.57)Malignancy: RR, 1.48 (95% CI, 0.66-3.35); P?=?0.32)Deaths: RR, 1.51 (95% CI, 0.34-6.63; P?=?0.58)Study Characteristics, Quality RatingStudy InformationStudy Characteristics ResultsAdverse EventsAuthor, Year:Wiens et al., 2010PEVuZE5vdGU+PENpdGUgRXhjbHVkZUF1dGg9IjEiIEV4Y2x1ZGVZZWFyPSIxIj48UmVjTnVtPjUx

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ADDIN EN.CITE.DATA 232Country and setting:MultinationalFunding:Brazilian National Council of Scientific and Technological Development.Aims of Review:To evaluate the efficacy and safety of using the anti-tumor necrosis factor- (anti-TNF- ) drugs ADA, ETN, and INF for the treatment of rheumatoid arthritis.Quality Rating:FairStudy design:Systematic ReviewNumber of Patients:6503Studies Included:N?=?21Characteristics of Included Studies:RCTsCharacteristics of Included PopulationsMean age 48-57, Disease duration 0.6 to 12 yrs, prior DMARDs 0-3, Treatment duration 12-2yrsCharacteristics of Interventions:Studies that compared the anti-TNF- drug with placebo, with or without concomitant MTX in both groups. From these RCTs, those that used the usual dosages for each of the anti-TNF- drugs—ADA 20 mg once/week or 40 mg every other week subcutaneously, ETN 25 mg twice/week or 50 mg once/week subcutaneously, and INF 3 mg/kg intravenously at weeks 0, 2, 6, and then every 8 weeks.Study Results:With short-term treatment (12-30 wks), ETN demonstrated the highest risk ratios (RRs) for reaching ACR20 and ACR50. ADA demonstrated the highest RR, for achieving ACR70 ACR 20ETN: 2.94, 95% CI: 2.27-3.81 ADA: 2.26, 95% CI: 1.82-2.81INF 1.87, 95% CI: 1.43, 2.45ACR 50ETN: 5.28, 95% CI: 3.12-8.92ADA: 3.50, 95% CI: 2.75-4.44INF: 2.68, 95% CI: 1.79-3.99ACR 70ETN: 4.83, 95% CI: 1.74-13.47ADA: 5.36, 95% CI: 3.76-7.64INF: 2.68, 95% CI: 1.78-4.03Over a long-term treatment course (1-3 yrs), ADA demonstrated the highest RRs (95% CIs) for these parameters: 1.85 (1.07-3.19), 2.80 (1.16-6.77), and 3.23 (1.37-7.61) for ACR20, ACR50, and ACR70, respectively.Adverse Events:No statistically significant differences were noted in the safety of any of the 3 drugs compared with placebo (P > 0.05 for all parameters). INF had the highest RRs for withdrawing from the study due to lack of efficacy (2.05, 95% CI, 1.33-3.16) and adverse events (0.41, 95% CI, 0.18-0.95). ................
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