Background This review’s goals were to investigate apremilast’s efficacy versus placebo in palmoplantar psoriasis (PP) and palmoplantar pustulosis (PPP), and apremilast’s efficacy versus methotrexate in PP. Methods A literature search was conducted in PubMed, clinicaltrials.gov, and Embase in July 2022. Publications investigating subjects with PP or PPP, treated with apremilast, which reported palmoplantar-specific outcomes were used. Exclusion criteria included cases of drug-induced PP/PPP, case studies, non-English texts, omission of palmoplantar-specific outcomes, and incomplete publications. Studies were assessed for risk of bias using Cochrane Review Manager application and CASP checklist. Primary endpoints were a 50% improvement of the Palmoplantar Psoriasis/Pustulosis Area and Severity Index (PPPASI 50) and improvement of the Palmoplantar Physician Global Assessment (PPPGA) to 0 or 1 in patients with baseline PPPGA ≥ 3. Results Seventeen original studies including five placebo-controlled randomized clinical trials (RCTs), one phase II clinical trial, two randomized methotrexate comparative trials, six cohort studies, and three case series were analyzed, totaling 1117 participants. Meta-analysis of four placebo-controlled RCTs investigating PP found apremilast treatment to be superior to placebo in achieving a PPPGA of 0/1 (baseline PPPGA of ≥ 3) after 16 weeks of treatment ( n = 244; OR = 2.69 [1.39–5.22]). Apremilast was superior to placebo in achieving PPPASI 50 at week 16 in the only placebo-controlled RCT of PPP (78.3 vs. 40.9%) [ P = 0.0003]. Apremilast was comparable to methotrexate in achieving PPPASI 50 at week 16 in PP (59.5 vs. 64.3%; n = 84; [ P = 0.65]). Non-randomized studies generally showed marked improvement in PPPASI, PPPGA, and DLQI scores following apremilast treatment. Discussion Apremilast treatment in PP and PPP resulted in significant improvement in objective, palmoplantar-specific clinical parameters versus placebo, and comparable efficacy with methotrexate in PP. Limitations in interpreting these results include variations in palmoplantar-specific metrics used and risk of bias of included studies. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-022-00877-w.

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