Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases

Abstract

Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). To identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. We performed bulk RNA sequencing of lesional PPP (n=33), palmPP (n=5), and DPE (n=28) samples, as well as 5 healthy non-acral and 10 healthy acral skin samples. Acral skin shows a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared with healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of pro-inflammatory cytokines (TNF, IL36), chemokines, and T cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the three disease states. These identified putative key upstream immunological switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. We demonstrate the molecular overlap between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment, yet highlighting the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.