Researchers from the University of Calgary found moderate to high quality evidence that triple therapy with methotrexate + sulfasalazine + hydroxycholoroquine or combining methotrexate + most biologic disease-modifying antirheumatic drug (DMARDs) or tofacitinib demonstrated similar efficacy in controlling disease activity in methotrexate-naive patients or after an inadequate response to methotrexate.
Methotrexate is the preferred DMARD for treating rheumatoid arthritis but its added benefits and harms when combined with other DMARDs is still debated. Study authors compared methotrexate and methotrexate-based DMARD combinations for the treatment of rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate. They identified all randomized-controlled trials with methotrexate as monotherapy or in combination with any conventional synthetic DMARD, biologic DMARDs, or tofacitinib.
The review’s major outcomes included ACR50 response, radiographic progression, and withdrawals due to adverse events; several minor outcomes were evaluated as well. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability. A total of 158 studies involving >37,000 patients were included.
Among methotrexate-naive patients, methotrexate + sulfasalazine + hydroxychloroquine (“triple therapy”), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib proved statistically superior to oral methotrexate for ACR50 response. The estimated probability response was similar between these treatments compared with methotrexate (moderate to high quality evidence).
Methotrexate + adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression but the estimated mean change over 1 year with all treatments was less than the minimal clinically important difference of 5 units on the Sharp-van der Heijde scale.
Methotrexate + azathioprine resulted in statistically more withdrawals due to adverse events vs. oral methotrexate. In contrast, triple therapy resulted in statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio: 0.26, 95% CI: 0.06–0.91).
Among patients with inadequate response to methotrexate, triple therapy, methotrexate + hydroxychloroquine, methotrexate + leflunomide, methotrexate + intramuscular gold, methotrexate + most biologics, and methotrexate + tofacitinib were statistically significantly superior to oral methotrexate for ACR50 response. With triple therapy, there was a 61% probability of an ACR50 response vs. a range of 27–64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate.
In regards to inhibition of radiographic progression, no treatment was statistically significantly superior to oral methotrexate. In addition, methotrexate + cyclosporine and methotrexate + tocilizumab had a statistically higher rate of withdrawals due to adverse events vs. oral methotrexate. Methotrexate + abatacepthad a statistically lower rate of withdrawals due to adverse events than several treatments, the authors added.
Methotrexate + some biologic DMARDs were superior to methotrexate alone in preventing joint damage in methotrexate-naive patients but the magnitude of these effects were small over 1 year.
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