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Psoriasis is a chronic, immune‐mediated skin disease that affects over 3% of adults in the United States. Psoriasis can present in several clinical forms. Of these, generalized pustular psoriasis is an acute, severe form, associated with increased morbidity and mortality. Unlike the more common plaque psoriasis, which is thought to feature dysregulation of the adaptive immune system, generalized pustular psoriasis reflects heightened autoinflammatory responses. Recent advances in genetic and immunological studies highlight a key role of the IL‐36 immune axis in the pathogenesis of generalized pustular psoriasis. In this article, we review the psoriatic subtypes and discuss diagnostic criteria of generalized pustular psoriasis, discuss several newly identified genetic variants associated with pustular disease in the skin, and discuss how these mutations shed light on pustular disease mechanisms. Furthermore, we gather insights from recent transcriptomic studies that similarly implicate a pathogenic role of the IL‐36 immune axis in generalized pustular psoriasis. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disorder characterized by recurrent flares associated with skin erythema, desquamation, and widespread superficial sterile pustules, which may be severe ("lakes of pus"). Systemic symptoms are often present, including malaise, fever, and skin pain. In GPP, innate immune responses are driven by abnormal activation of the interleukin (IL)-36-chemokine-neutrophil axis and excessive neutrophil infiltration. This review highlights the IL-36 pathway in the context of the IL-1 superfamily and describes how unopposed IL-36 signaling can lead to the development of GPP. Targeted inhibition of the IL-36 receptor (IL-36R) is an attractive therapeutic strategy in the treatment of GPP, including flare prevention and sustained disease control. Spesolimab is a first-in-class, humanized, monoclonal antibody that binds specifically to the IL-36R and antagonizes IL-36 signaling. Spesolimab was approved by the US Food and Drug Administration in September 2022 to treat GPP flares in adults and was subsequently approved for GPP flare treatment in other countries across the world. Anti-IL-36R therapy, such as spesolimab, can mitigate flares and address flare prevention in GPP, presumably through rebalancing IL-36 signaling and modulating the pro-inflammatory response of the downstream effectors., Competing Interests: JH serves on the medical board and scientific advisory committee of the National Psoriasis Foundation, is a councilor for the International Psoriasis Council, and has been a paid consultant for AbbVie, Arcutis, BMS, Boehringer Ingelheim, Eli Lilly and Company, Janssen, LEO, Novartis, Pfizer, Regeneron-Sanofi, Sun Pharmaceutical, UCB, VisualDx, and UpToDate. SV is an employee of Boehringer Ingelheim Pharmaceuticals, Inc. JK has received grants from and been an investigator for Boehringer Ingelheim; received personal fees from AbbVie, Baxter, Biogen Idec, Delenex Therapeutics, Kineta, Sanofi, Serono, and XenoPort; and received grants from Amgen, Bristol Myers Squibb, Dermira, Innovaderm Research, Janssen, Kadmon, Kyowa Kirin, Eli Lilly, Merck, Novartis, Parexel, and Pfizer., (Copyright © 2023 Hawkes, Visvanathan and Krueger.)