BackgroundPalmoplantar pustulosis (PPP) is a chronic inflammatory skin disorder that affects palms and soles. Patients suffer significant pain, itching and daily activity impairment. Guselkumab, an interleukin-23 inhibitor, has been approved for PPP treatment in Japan. However, there is no effective therapy licensed for PPP in Europe and the USA. ObjectiveTo explore the efficacy and safety of guselkumab in patients with moderate-to-severe PPP in the Caucasian population. MethodsA multicenter, single-arm, phase II study involving 50 patients with moderate-to-severe PPP treated with 100 mg guselkumab subcutaneously for 24 weeks was conducted (GAP). Primary endpoint was the reduction of palmoplantar-pustulosis psoriasis area and severity index (PPPASI) at week 24 compared to baseline. Secondary endpoints included physician-assessed and patient-reported measures. Serum samples were taken for exploratory studies. ResultsThe primary endpoint was met with a significant median PPPASI reduction by 59.6% at week 24 compared to baseline (p<0.001). The proportions of patients achieving PPPASI-50 and PPPASI-75 at week 24 were 66.0% and 34.0%, respectively. Median DLQI dropped from 15 at baseline to 5 at week 24 (p<0.001). Week-4 changes in IL-19 serum levels predicted week-24 clinical response. ConclusionGuselkumab may be a promising therapeutic option for PPP in Caucasian patients.