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The comparative effectiveness of available targeted immunomodulators for moderate-to-severe psoriasis has not been evaluated.To evaluate the comparative effectiveness of targeted immunomodulators for adults with moderate-to-severe plaque psoriasis.Systematic literature review of placebo-controlled and head-to-head randomized trials of 8 targeted immunomodulators that evaluated clinical benefits or harm. The primary outcome was a 75% improvement on the Psoriasis Area and Severity Index. We also conducted a network meta-analysis adjusted for placebo response to perform indirect comparisons between agents.In the network meta-analysis, the targeted immunomodulators ordered by increasing relative risk (demonstrating greater likelihood) of achieving a 75% improvement on the Psoriasis Area and Severity Index relative to placebo were as follows: apremilast (6.2), etanercept (9.6), adalimumab (13.0), ustekinumab (14.0), secukinumab (15.4), infliximab (16.2), brodalumab (17.3), and ixekizumab (17.9). Ixekizumab, brodalumab, and infliximab were all statistically superior to ustekinumab, adalimumab, etanercept, and apremilast; results were similar to those of head-to-head studies where data were available.Much of the evidence is short-term (covering 10-16 weeks); limited direct comparisons.The interleukin 17A inhibitors are more effective in achieving clearance than ustekinumab, and they are generally more effective than etanercept, adalimumab, and apremilast.