The quality of evidence is downgraded by study limitations (unclear allocation concealment and lack of blinding).
A Cochrane review [Abstract] 1 and network meta-analysis included 158 studies with over 37 000 subjects. People who had not taken methotrexate before: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine (“triple therapy”), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression but the estimated mean change over one year with all treatments was less than the minimal clinically important difference. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval 0.06 to 0.91). Patients with an inadequate response to methotrexate: Several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy, methotrexate + hydroxychloroquine, methotrexate + leflunomide, methotrexate + intramuscular gold, methotrexate + most biologics, and methotrexate + tofacitinib. There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments.
A systematic review 2 included 36 studies (13 step-up, 16 parallel and 7 step-down trials) with a total of 5 289 subjects. Nine assessed early rheumatoid arthritis (RA) and 27 established RA. Seven added steroids to disease-modifying anti-rheumatic drugs (DMARD) monotherapy and one study added steroids to DMARD combinations. Six assessed methotrexate (MTX) plus tumour necrosis factor (TNF) inhibitors. Efficacy was assessed by the numbers of patients withdrawn due to lack of efficacy. Toxicity was assessed by the numbers of patients withdrawn due to adverse events.
Overall, combination DMARD therapy was more effective than monotherapy (RR 0.35, 95% CI 0.28 to 0.45). The combination of methotrexate with TNF inhibitors was more effective than methotrexate monotherapy (RR 0.22, 95% CI 0.14 to 0.32; 6 studies, n=1 530). Methotrexate plus sulphasalazine and/or antimalarials was more effective than methotrexate monotherapy (RR 0.41, 95% CI 0.24 to 0.70; 8 studies, n=946). There was no significant difference between corticosteroids added to one DMARD as bridging therapy and DMARD alone (7 studies, n=289). Other non-biological DMARD combinations were effective (RR 0.37, 95% CI 0.27 to 0.51) with insufficient trials of specific combinations for further sub-analyses. Combination therapy was significantly better than monotherapy in early RA (9 studies, n=1 031), established RA (22 studies, n= 4 258) and the benefit remained after excluding studies involving TNF inhibitors (21 studies, n=2 728). The meta-analysis of ACR20 response reported in 18 trials showed a significant difference in favour of combination therapy (RR 1.53, 95% CI 1.26 to 1.86), as did the meta-analysis of ACR70 response or remission reported in 14 trials (RR 2.06, 95% CI 1.55 to 2.74).
Combination therapy resulted in more withdrawals for toxicity than monotherapy (RR 1.37, 95% CI 1.16 to 1.62).Combining MTX with sulphasalazine or anti-malarials or both appeared less toxic than monotherapy, although the difference was not significant (RR 0.81, 95% CI 0.52 to 1.27).
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