Fifteen RCTs were included in the review (n=4,200 patients); thirteen RCTs used a parallel design, one RCT used a step-up design, and one RCT used a tight-control design. Sample sizes ranged from 20 to 1,049. The mean Jadad score was 3.9 points. Four RCTs scored the maximum number of points; two RCTS were described as low quality (2 out of 5 points). Follow-up periods ranged from one to two years.
Significant beneficial effects in favour of disease-modifying antirheumatic drugs (DMARD) combinations compared with methotrexate monotherapy were reported for American College of Rheumatology (ARC) 20-70 responses (ACR20, OR 2.02, 95% CI 1.27 to 3.20, six RCTs; ACR 50, OR 1.64, 95% CI 1.15 to 2.34, five RCTs; ACR70, OR 1.84, 95% 1.31 to 2.57, five RCTs), withdrawals due to inefficacy (OR 0.52, 95% CI 0.33 to 0.82; eight RCTs), disability measured on the Health Assessment Questionnaire (WMD -0.17, 95% CI -0.33 to -0.01; two RCTs), and annual X-ray progression (WMD -1.20%, 95% CI -1.36 to -1.04; five RCTs). However, DMARD combinations were associated with increased withdrawals for toxicity (OR 2.69, 95% CI 1.49 to 4.83; eight RCTs);
Significant beneficial effects in favour of tumour necrosis factor inhibitors/methotrexate compared with methotrexate monotherapy were reported for ACR20-70 responses (ACR 20, OR 2.03, 95% CI 1.63 to 2.54, six RCTs; ACR50, OR 2.17, 95% CI 1.78 to 2.64, five RCTs; ACR70, OR 2.30, 95% CI 1.89 to 2.79, five RCTs), withdrawals due to inefficacy (OR 0.29, 95% CI 19 to 0.44; seven RCTs), disability measured on the Health Assessment Questionnaire (WMD -0.16, 95% CI -0.26 to -0.04; two RCTs), and annual X-ray progression (WMD -0.84%, 95% CI -1.23 to -0.45; four RCTs). There was no difference for withdrawals due to toxicity.
There was little evidence of significant statistical heterogeneity.
Further sensitivity analyses, numbers needed to treat and numbers needed to harm were reported in the review and showed similar findings.
All forest plots and some of the tables were only available as supplementary online material (see URL for Additional Data).