Ivarmacitinib is associated with rapid clinical improvement and immune remodeling in palmoplantar pustulosis: A multicenter, single-arm clinical trial

BACKGROUND: Palmoplantar pustulosis (PPP) carries substantial burden with limited treatments. Selective JAK1 inhibition is promising, yet prospective, immune-integrated data remain scarce. OBJECTIVES: To evaluate the efficacy, safety, and immunomodulatory effects of ivarmacitinib in PPP and to explore baseline predictors of response. METHODS: Prospective, single-arm, 12-week study across 3 centers. Sixty patients received oral ivarmacitinib 4 mg daily; 58 (96.7%) completed follow-up. PRIMARY ENDPOINT: PPPASI change at week 12. Exploratory endpoints included peripheral T lymphocyte subsets, neutrophil phenotypes, and plasma proteomics. RESULTS: Mean PPPASI decreased from 11.3 (95%CI: 9.9-12.6) to 3.9 (3.4-4.4) (P < .001); 85.0% achieved PPPASI50 and 13.3% achieved PPPASI75 after 12 weeks. Pruritus, pain, and quality of life improved by week 2 (all P < .05). Treatment partially normalized Th2/Th17-skewed polarization and activated neutrophil phenotypes. Early response correlated with lower baseline CD4/CD8 ratio, Th2/Th1 ratio, and plasma IL10RA/IL2RB; sustained response with lower CD4+ effector memory and CD8+ central memory proportions, and higher GDNF. Twenty-two grade 1-2 adverse events occurred and 2 patients discontinued treatment. LIMITATIONS: Single-arm design. CONCLUSIONS: Ivarmacitinib achieved rapid improvement with favorable safety and partial immune remodeling in PPP. Baseline immune profiles may stratify response, supporting selective JAK1 inhibition and biomarker-guided patient selection.