OBJECTIVES: To compare ACR responses between novel DMARDs, either as monotherapy or in combination with methotrexate (MTX), including subcutaneous (SC) abatacept and SC tocilizumab (TCZ), in RA patients with an inadequate response to conventional DMARDs (DMARD-IR). METHODS: A systematic literature review identified 30 randomized clinical trials (RCTs) that evaluated abatacept (intravenous [IV] and SC), anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tofacitinib, and TCZ (IV and SC). Reported treatment effects--ACR responses at 24 weeks--were synthesized by means of Bayesian network meta-analyses to compare the different treatments as monotherapy and combination therapy. The effects of anti-tumor necrosis factor (aTNF) therapy were assumed to be interchangeable. aTNF data were pooled. RESULTS: The combination therapies aTNFs + MTX, tofacitinib + MTX, abatacept IV/SC + MTX, and TCZ IV/SC + MTX demonstrated comparable ACR responses while anakinra + MTX was less efficacious. Among biologic monotherapies, greater ACR20/50/70 responses were observed with TCZ IV than with aTNFs and tofacitinib. When comparing biologics + MTX with biologic monotherapies, ACR20, ACR50, and ACR70 responses with TCZ + MTX were similar to TCZ as monotherapy (OR=1.04, 95% CI, 0.39-2.80; OR=1.28, 95% CI, 0.46-3.51; OR=0.97, 95% CI, 0.38-2.49, respectively). Greater ACR20/50/70 responses were observed with aTNF + MTX than with aTNF monotherapy (OR=2.22; 95% CI, 0.46-10.83, probability better=84%; OR=3.12, 95% CI, 0.60-16.32, probability better=92%; OR=1.39, 95% CI, 0.26-6.78, probability better=68%, respectively). Sensitivity analyses showed conflicting results for the indirect comparison of tofacitinib + MTX versus tofacitinib. CONCLUSIONS: Results suggest that most of the novel DMARDs, in combination with MTX, have similar levels of efficacy in DMARD-IR patients. As monotherapy, TCZ is likely to have a greater response than aTNFs and tofacitinib. TCZ monotherapy also shows comparable efficacy compared to TCZ + MTX, whereas aTNFs in combination with MTX showed greater ACR responses compared with aTNF monotherapy at 24 weeks.