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Randomized clinical trials are needed to show efficacy and safety, and are needed to back up the claims and indications for a particular drug. The issue of treatment choice has become challenging, especially when choosing to start or augment therapy. Do I aim for monotherapy or continue to advocate for combination therapy to achieve superior outcomes? This systematic analysis identified 28 RCTs evaluating abatacept, anakinra, adalimumab, certolizumab, etanercept, golimumab, infliximab, tocilizumab, or tofacitinib. Using indirect comparisons of ACR 20/50/70 data, nearly all of these novel therapies had similar effects, especially if used in combination with methotrexate, in incomplete DMARD responders. However, when when used as monotherapy, greater responses were seen with tocilizumab, compared with tofacitinib or TNF inhibitors. Responses to tocilizumab monotherapy was similar to tocilizumab plus MTX. Its unclear from the available data if tofacitinib monotherapy is equivalent to tofacitinib plus MTX.