Given the availability of a number of alternative biologic treatment options and other novel disease-modifying antirheumatic drugs (DMARDs) for the treatment of patients with rheumatoid arthritis (RA), clinicians are faced with an increasingly challenging choice regarding optimal treatment. Biologics are usually combined with traditional DMARDs, primarily methotrexate (MTX), but some biologics and tofacitinib (together referred to in this article as novel DMARDs) have been shown to be efficacious as monotherapy as well. In real-world practice, approximately one-third of RA patients receiving biologics are on monotherapy, primarily because of intolerance of, or noncompliance with, MTX. Limited data, however, are available analyzing the effectiveness of monotherapy compared with combination therapy across novel DMARDs.
To compare American College of Rheumatology (ACR) responses to approved novel DMARDs used as monotherapy or as combination therapy with methotrexate (MTX) at 24 weeks in RA patients who have shown inadequate response to conventional DMARDs (DMARD-IR). 
Through a systematic review of the literature, we identified randomized controlled trials that assessed approved novel DMARDs used as monotherapy or as combination therapy with MTX in DMARD-IR RA patients. Twenty-eight RCTs were identified that evaluated abatacept, anakinra, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib. ACR responses at 24 weeks were extracted and combined by means of Bayesian network meta-analyses. 
With the exception of anakinra plus MTX, which was less efficacious, most novel DMARDs, when used in combination with MTX, demonstrated comparable ACR responses. When novel DMARDs were used as monotherapies, greater ACR20/50/70 responses were observed with tocilizumab than with anti-tumor necrosis factor agents (aTNF) or tofacitinib. Furthermore, ACR20/50/70 responses with tocilizumab plus MTX were similar to those with tocilizumab monotherapy (odds ratio [OR] for the indirect comparison = 1.08, 95% credible interval [CrI] = 0.40-2.84; OR = 1.24, CrI = 0.44-3.61; OR = 0.95, CrI = 0.33-2.72, respectively), whereas greater responses were observed with aTNF plus MTX than with aTNF monotherapy (OR = 2.41, CrI = 0.51-11.61; OR = 2.85, CrI = 0.51-17.67; OR = 1.28, CrI = 0.21-8.42, respectively). Relative efficacy estimates for the indirect comparison of tofacitinib plus MTX with tofacitinib monotherapy were very uncertain.
Results suggest that in combination with MTX most of the available novel DMARDs have similar levels of efficacy in DMARD-IR patients. As monotherapy, however, tocilizumab displayed higher ACR responses than aTNF or tofacitinib. ACR responses with tocilizumab plus MTX were similar to those with tocilizumab as monotherapy, whereas aTNF in combination with MTX demonstrated greater ACR responses than aTNF as monotherapy.