IL-4/IL-13 Inhibitors for Atopic Dermatitis Induce Psoriatic Rash Transcriptionally Close to Pustular Psoriasis

Abstract

Dupilumab is a therapeutic antibody targeting IL-4 and IL-13 receptor subunit alpha used for the treatment of atopic dermatitis (AD) patients. Cases of psoriasis-like reactions induced under dupilumab treatment (DI-Pso) for AD were recently reported. To understand the pathogenesis of DI-Pso, we performed gene expression profiling studies on skin biopsies of DI-Pso (n=7) compared with plaque psoriasis (PSO), AD and healthy controls (HC) (n=4 each). Differential gene expression was performed using enrichment and gene ontology analysis. Gene expression was validated by qPCR and protein levels assessed by immunohistochemistry. Transcriptomic and protein analysis of DI-Pso compared with HC, PSO and AD skins revealed an activation of Th17/IL-23 pathways associated with a significant expression of IL-36, surrogate marker of pustular psoriasis (PP). By contrast, Th2 representative genes' expression were strongly decreased in DI-Pso across comparison. Matching analysis with public data of PP skin corroborated that DI-Pso and PP upstream regulators overlap, greater than with PSO. Furthermore, DI-Pso showed strongly decreased expression of many barrier skin genes compared with HC, PSO and AD. Our data indicate that pathogenesis of DI-Pso relied on a shift of skin immune responses from a Th2 to an IL-36 and Th17 polarization and on intensified skin barrier alterations.