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The efficacy and toxicity of Methotrexate (MTX) monotherapy vs. MTX combination therapy with non-biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: A systematic review and metaanalysis
  1. Wanruchada Katchamart (wanda.katchamart{at}
  1. University of Toronto, Canada
    1. Judith Trudeau (judithtrudeau{at}
    1. Hospital Notre-Dame, Department of Rheumatology, Canada
      1. Veerapong Phumethum (doctorvee2519{at}
      1. University of Toronto, Canada
        1. Claire Bombardier (claire.bombardier{at}
        1. Institute for Work and Health, Canada


          Objective: To evaluate the efficacy and toxicity of Methotrexate (MTX) monotherapy compared to MTX combination with non-biologic disease-modifying anti-rheumatic drugs (DMARDs) in adult with rheumatoid arthritis.

          Method: We performed a systematic review of randomized trials comparing MTX alone and in combination with other non-biologic DMARDs. Trials were identified in MEDLINE, EMBASE, the Cochrane Library and ACR/EULAR meeting abstracts. Primary outcomes were withdrawals for adverse events or lack of efficacy.

          Results: A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomized. 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 (Relative Risk: RR 1.16, 95% CI.0.70-1.93). Trials in MTX or non MTX DMARDs inadequate responder patients, also showed no difference in withdrawal rates between the MTX combo vs mono groups (RR 0.86; 95% CI 0.49 to1.51 and RR 0.75; 95% CI 0.41 to 1.35) but in one study the specific combination of MTX with sulfasalazine and hydroxychloroquine showed better efficacy/ toxicity ratio over MTX alone with RR of 0.3 (95%CI 0.14 to 0.65). Adding leflunomide to MTX non-responders improved efficacy but increased the risk of gastrointestinal side effect and liver toxicity. Withdrawals for toxicity were most significant with cyclosporine and azathioprine combinations.

          Conclusion: In DMARD naive patients the balance of efficacy/toxicity favours MTX monotherapy. In DMARD inadequate responders the evidence is inconclusive. Trials are needed that compare currently used MTX doses and combination therapies.

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