title: Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis.
abstract: BACKGROUND
  Methotrexate (MTX) is among the most effective disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) with less toxicity and better tolerability.
  
  
  OBJECTIVE
  To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA.
  
  
  METHODS
  Trials were identified in MEDLINE (1950 to 2009), EMBASE (1980 to 2009), the Cochrane Controlled trials Registry (CENTRAL) (up to 2009), the American and European scientific meeting abstracts 2005-9, the reference lists of all relevant studies, letters, and review articles.
  
  
  METHODS
  Randomized controlled trials comparing MTX monotherapy versus MTX combined with other non-biologic DMARDs of at least 12 weeks of trial duration in adult RA patients.
  
  
  METHODS
  Two reviewers independently identified eligible studies,extracted the data, and assessed the risk of bias of relevant studies.The efficacy analysis was stratified into 3 groups based on previous DMARDs use: DMARD naive, MTX inadequate response, and non-MTX DMARDs inadequate response. The toxicity analysis was stratified by DMARD combination and pooled across trials for each combination. Our prespecified primary analysis was based on total withdrawal rates for efficacy or toxicity.
  
  
  RESULTS
  A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (risk ratio (RR) 1.16, 95% CI.0.70 to 1.93, absolute risk difference(ARD) 5%, 95%CI-3% to 13%). Trials in MTX or non-MTX DMARDs inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups with RR 0.86 95% CI 0.49 to1.51, ARD -2 %, 95% CI-13 % to 8 % and RR 0.75 95% CI 0.41 to 1.35, ARD -10%, 95% CI -31% to 11%, respectively. Significant reductions of pain and improvement in physical function (measured by Health Assessment Questionnaire or HAQ) were found in the MTX combination group, but only in MTX-inadequate responders (absolute risk difference -9.72%, 95%CI -14.7% to -4.75% for pain and mean difference (MD) -0.28, 95%CI -0.36 to -0.21 (0-3) for HAQ).
  
  
  CONCLUSIONS
  When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy. Trials are needed that compare currently used MTX doses and combination therapies.
authors.affiliation: Rheumatology Division, Department of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok road, Siriraj hospital, Bangkoknoi, Bangkok, Thailand, 10700.
authors.forename: Wanruchada
authors.initials: W
authors.lastname: Katchamart
authors.forename: Judith
authors.initials: J
authors.lastname: Trudeau
authors.forename: Veerapong
authors.initials: V
authors.lastname: Phumethum
authors.forename: Claire
authors.initials: C
authors.lastname: Bombardier
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004359:Drug Therapy, Combination / Q000379:methods; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate
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