Upadacitinib for Palmoplantar Pustulosis: An Open-label, Assessor-blinded Feasibility Study Using Historic Control Data (JAKPPPOT).

BACKGROUND: Palmoplantar pustulosis (PPP) is a rare, disabling inflammatory skin disease with substantial unmet need. Janus kinase inhibitors (JAKi) target inflammatory pathways implicated in PPP. High smoking prevalence and rare disease status mean that a randomised controlled trial (RCT) to evaluate the efficacy and safety of JAKi in PPP may be challenging. OBJECTIVES: To determine the feasibility of a future RCT of JAKi therapy in PPP and generate an exploratory estimate of treatment effect. METHODS: This open-label, assessor-blinded feasibility trial, conducted at a UK national specialist dermatology centre, enrolled adults (≥18 years) with moderate-to-severe PPP and treated them with upadacitinib 30 mg once daily for 8 weeks (15 mg for higher-risk individuals). Primary feasibility endpoints were recruitment (consent rate), adherence (≥80% of days covered), and acceptability ('completely acceptable'/'acceptable' on post-treatment 5-point Likert scale). Secondary outcomes included change from baseline in Palmoplantar Pustulosis-Psoriasis Area and Severity Index (PP-PASI) and safety. Study procedures were harmonised with a previous RCT in PPP, permitting comparison with historic placebo data. Analyses were descriptive with baseline-adjusted PP-PASI change estimated with a linear (Gaussian) mixed-effects model. RESULTS: All prespecified feasibility criteria were met. Of 67 contacted individuals, 28 consented (41.8%), and 20 started treatment (71.4%; mean age 46.0 years; 85% female). Adherence ≥80% was achieved by 19/20 participants (95%), with a mean proportion of days covered of 95.7% (SD 9.7). 18/19 participants (94.7%) viewed treatment as acceptable. Mean PP-PASI decreased from 20.3 (SD 10.6) at baseline to 4.6 (SD 4.5) at week 8 with upadacitinib, versus 18.0 (SD 10.4) to 15.4 (SD 10.1) with historic placebo. Baseline-adjusted PP-PASI change at week 8 for upadacitinib relative to historic placebo was -12.3 (95% CI -15.8 to -8.9) in favour of upadacitinib. PP-PASI50 and PP-PASI75 responses with upadacitinib relative to historic placebo were 100% vs 16.1% and 65.0% vs 3.2%. The most common adverse events were headache, acne, and upper respiratory tract infections. CONCLUSIONS: This study demonstrates that a definitive trial of JAK inhibition in PPP is feasible and identifies an encouraging exploratory efficacy signal. The findings support progression to a multicentre active-comparator randomised controlled trial.