BACKGROUND: Due to similarities, the distinction between generalized pustular psoriasis (GPP) and acute generalized exanthematous pustulosis (AGEP) has been a matter of debate for a long time. OBJECTIVES: 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 nonpustular cutaneous adverse drug reactions (ADRs), as well as from healthy skin controls using RNA-sequencing and blinded histopathologic 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, they 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). A transcriptome profile subgroup evaluation of >
13,000 analyzed genes did not reveal any DEGs 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 T CONCLUSIONS: 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.