IL-36-driven pustulosis: Transcriptomic signatures match between generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP).

Abstract

Background: Due to similarities, the distinction between generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP) has been a matter of debate for long time.

Objective: Our aim was to define the molecular features of GPP and AGEP.

Methods: We analyzed skin biopsy samples and clinical data from 125 patients with AGEP, GPP, palmoplantar pustulosis (PPP), plaque psoriasis (PSO), and non-pustular cutaneous adverse drug reactions (ADRs), as well as from healthy skin controls using RNA sequencing and blinded histopathological analyses.

Results: The transcriptome and histopathologic features of AGEP and GPP samples exhibited significant overlap (177 differentially expressed genes (DEGs) in GPP and AGEP compared to healthy skin, only 2 DEGs comparing AGEP and GPP), yet displayed marked differences from those of PPP, PSO, and ADR samples, with a notable number of DEGs (131 DEGs comparing AGEP and PSO, 75 DEGs comparing AGEP and PPP and 52 DEGs comparing AGEP and ADR) and pathways. A transcriptome profile subgroup evaluation of more than 13,000 analyzed genes did not reveal any differentially expressed genes in drug-induced GPP and AGEP. Moreover, the immune response pattern and immune cell composition did not differ between drug-induced GPP and AGEP, whereas non-drug-induced GPP had higher expression of Th17-related genes and a higher neutrophil count than AGEP.

Conclusion: We propose that AGEP is a drug-induced variant of GPP and therefore part of IL-36-related pustulosis. A key signature overarching this spectrum was identified, thereby opening the therapeutic approach of IL-36 inhibition to all subtypes of the disease.