049 Generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP) both show upregulation of the IL-36, neutrophil chemokine, and innate pathways that are modulated by spesolimab, an anti-IL-36 receptor antibody, treatment

Pustular psoriasis comprises a spectrum of inflammatory skin conditions, including GPP and PPP, characterized by neutrophilic infiltration of the epidermis and development of visible sterile pustules. GPP is a rare, multisystemic, potentially life-threatening, flaring disease, whereas PPP is a localized, relapsing, debilitating, chronic disease. Here, gene and protein expression of lesional and non-lesional skin from 7 patients with a moderate GPP flare, 8 patients with moderate-to-severe PPP, and skin samples from the thigh/back (n=10) or palm/sole (n=6) of healthy donors were compared. In lesional skin samples, 7,614 genes in GPP and 1,651 in PPP were found to be differentially expressed compared with healthy donors. In GPP and PPP, 1,287 transcripts were commonly up- or downregulated (adjusted p ≤0.01, absolute fold-change ≥2). Markedly upregulated genes in lesional vs non-lesional skin include IL36a, KRT6A, defensin4b, IL6, CXCL1, CXCL8, IL17A, IL23A, and IL1b; common molecular pathways included increased Th1 and Th17 signaling, keratinocyte-driven inflammation, and a strong upregulation of neutrophil attractants, inflammatory mediators, and the IL-36 pathway. Treatment of 7 GPP patients with a single 10 mg/kg IV dose of spesolimab (BI 655130; NCT02978690) led to rapid clinical improvements and modulation of the transcriptomic profile and select proteins in the skin (NE and lipocalin 2) and blood (IL-6, CRP, CXCL1, IL1RN, CCL20) common to GPP and PPP.