Understanding the Pathogenesis of Generalized Pustular Psoriasis Based on Molecular Genetics and Immunopathology

Abstract

Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules. Clinical and genetic evidence indicates that the pathogenesis of GPP both overlaps and is separate from psoriasis vulgaris (PV). Interleukin (IL)-23/IL-17 immune pathway is well known to play a critical role in the immunopathogenesis of PV, while the inflammation of GPP is more inclined to involve the innate immune response via the IL-1/IL-36–chemokine pathway. Mutations in IL36RN, CARD13, AP1S3, MPO, TNIP1, SERPINA3, and SERPINA1 have been shown to be associated with GPP, among which loss-of-function mutation in IL36RN is the dominant mutation with the highest prevalence. Recent studies have shown that interaction of the IL-36 pathway and the IL-23/IL-17 axis underlies the immunological disturbances of GPP, indicating that innate and adaptive immune responses intertwine in the pathogenesis of GPP. With this deeper understanding of the pathogenesis of GPP, treatment by biologics targeting the IL-1/IL-36 pathway appears to be promising. IL-1 inhibitors, anakinra, canakinumab, and gevokizumab have reportedly been effective in some cases. Spesolimab and imsidolimab, which are antibodies to the IL-36 receptor, are undergoing investigation in a phase II trial and showing promising results. In the present review, we illustrate the current understanding of the pathogenesis of GPP based on recent updates on the molecular genetics and immunopathology of GPP and review recent clinical trials and case reports of novel biologics in the treatment of GPP.