Background/Purpose: To compare methotrexate based disease-modifying anti-rheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naïve to or after an inadequate response (IR) to methotrexate.  

Methods: We conducted a systematic review and Bayesian random-effects network meta-analysis of trials assessing methotrexate used alone or in combination with other conventional synthetic DMARDs (csDMARDs), biologics (bDMARDs) or tofacitinib in adult patients with rheumatoid arthritis. The major outcomes were ACR50 response (major clinical improvement), radiographic progression and withdrawals due to adverse events (WDAE). Trials were identified from MEDLINE, EMBASE and CENTRAL databases from inception to August 13, 2014, abstracts from 2 major rheumatology meetings from 2009-2014, 2 trial registers, and hand-searches of Cochrane reviews. The risk of bias of each study was evaluated using the Cochrane risk of bias tool, separately for each outcome. Trials judged at high overall risk of bias were excluded.

Results:   150 trials with over 34,000 patients were included. Methotrexate naïve: In methotrexate-naïve patients, ‘triple therapy’ (the combination of methotrexate + sulphasalazine + hydroxychloroquine), and methotrexate + several bDMARDs (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab) were similar to each other and significantly superior to oral methotrexate for ACR50 response. There was a 61% probability of an ACR50 response with triple therapy (moderate quality evidence), which was similar to the probability of an ACR50 response for the MTX + bDMARDs that were statistically significantly superior to oral MTX (range: 55%-67%, moderate to high quality evidence). Only methotrexate + adalimumab and methotrexate + etanercept were significantly superior to oral MTX for inhibiting radiographic progression. Triple therapy had significantly fewer WDAE compared to methotrexate + infliximab. Methotrexate-IR: In methotrexate-IR patients, several treatments were significantly superior to oral methotrexate for ACR50 response, including csDMARD combinations (triple therapy, methotrexate + hydroxychloroquine, methotrexate + leflunomide, methotrexate + intramuscular gold), methotrexate + most bDMARDs, and methotrexate + tofacitinib. There was a 61% probability of an ACR50 response with MTX + sulphasalazine + hydroxychloroquine, compared to 27% to 65% for the MTX + bDMARDs that were statistically significantly superior to oral MTX. No treatment was significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + abatacept had fewer WDAE than several treatments.

Conclusion:   Triple therapy and most regimens combining biologic DMARDs with methotrexate were similarly effective in controlling disease activity and all generally well tolerated in both methotrexate-naive and methotrexate-exposed patients. Given cost considerations, these findings support a therapeutic trial of low-cost triple therapy prior to using biologic DMARDs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/methotrexate-monotherapy-and-methotrexate-combination-therapy-with-traditional-and-biologic-dmards-for-rheumatoid-arthritis-a-cochrane-systematic-review-and-network-meta-analysis/