BACKGROUND: The IL-36 pathway plays a key role in the pathogenesis of 
generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, 
treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid 
skin and pustular clearance in patients presenting with GPP flares.
OBJECTIVE: We sought to compare the molecular profiles of lesional and 
nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with 
skin from healthy volunteers, and to investigate the molecular changes after 
spesolimab treatment in the skin and blood of patients with GPP flares.
METHODS: Pre- and post-treatment skin and blood samples were collected from 
patients with GPP who participated in a single-arm, phase I study (n = 7). Skin 
biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were 
obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, 
histopathology, and immunohistochemistry.
RESULTS: In GPP and PPP lesions, 1287 transcripts were commonly upregulated or 
downregulated. Selected transcripts from the IL-36 signaling pathway were 
upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 
pathway-related signatures, TH1/TH17 and innate inflammation signaling, 
neutrophilic mediators, and keratinocyte-driven inflammation pathways were 
downregulated by spesolimab as early as week 1. Spesolimab also decreased 
related serum biomarkers and cell populations in the skin lesions from patients 
with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing 
cells.
CONCLUSIONS: In patients with GPP, spesolimab showed rapid modulation of 
commonly dysregulated molecular pathways in GPP and PPP, which may be associated 
with improved clinical outcomes.