Generalized Pustular Psoriasis: A Review on Clinical Characteristics, Diagnosis, and Treatment

Abstract

Generalized pustular psoriasis (GPP) is a rare, chronic, and severe inflammatory skin disorder characterized by sudden eruption of sterile pustules, often accompanied by systemic inflammation. GPP flares can be life-threatening if untreated, owing to potential serious complications such as sepsis and cardiovascular failure. Diagnosis and clinical measurement of disease severity in GPP are often difficult. Lack of standardized criteria in the international guidelines and the heterogeneity of cutaneous and extracutaneous symptoms make the diagnosis of GPP difficult. Clinical criteria for description and diagnosis of pustular conditions, including GPP, are variable and there is no specific agreement on commonly sustained concepts. Differentiation of GPP from other similar conditions/diseases is important and requires careful assessments. The evidence that supports current topical or systemic therapies is largely based on case reports and small studies. Some biologic agents that target key cytokines involved in the activation of inflammatory pathways have been used as treatments for GPP. Recently, spesolimab, an IL-36R antagonist, has been approved in the USA and Japan for the treatment of GPP flares in adults, but there are no currently approved treatments for GPP in Europe. The IL-36 pathway has recently emerged as a central axis driving the pathogenic inflammatory mechanisms of GPP. Biologic agents that inhibit the IL-36 pathway have shown efficacy and safety in patients with GPP, addressing a generally considered unmet medical need.

Keywords: Biologic agents; Diagnosis; Generalized pustular psoriasis; IL-36; Treatment.

Fig. 1

Schematic representation of the signal transduction pathway activated by cytokines and genes involved in IL-36 autocrine and autoinflammatory circuits. The pathogenesis of GPP is related to mutations in multiple genes, such as the human IL-1Ra gene (IL1RN), IL-36Ra (IL36RN), caspase recruitment domain-containing protein 14 (CARD14), adapter protein complex 1 subunit sigma 3 (AP1S3), TNFAIP3-interacting protein 1 (TNIP1), and the gene coding for alpha-1 antichymotrypsin, also known as serine protease inhibitor gene serpin family A member 3 (SERPINA3). IL-1, TNF, and IL-17A promote the expression of IL-36 by keratinocytes. IL-36 cytokines are released as precursors requiring enzymatical cleavage by neutrophil-derived proteases (elastase, cathepsin G, or protease 3) and keratinocyte-derived cathepsin S. Mature IL-36 cytokines have 500-fold greater biological activity than their precursors and bind to IL-36R on the keratinocyte cell surface, acting in an autocrine manner to further induce IL-36 expression. In addition, they induce the production and secretion of neutrophil chemokines CXCL1, CXCL2, CXCL6, and CXCL8 (IL-8), increasing the attraction of neutrophils to the skin. Serine protease inhibitors such as alpha-1 antitrypsin or alpha-1 antichymotrypsin (encoded by SERPINA1 and SERPINA3, respectively) can inhibit neutrophil proteases. Adapted from Iznardo et al. [26]

Fig. 2

Generalized Pustular Psoriasis Area and Severity Index (GPPASI). Reproduced with permission from Burden et al. [33]

Fig. 3

Components and methodology of the GPPGA score for evaluation and follow-up of GPP patients. Adapted from Choon et al., AAD-VMX 2021 [34]. GGPGA, Generalized Pustular Psoriasis Physician Global Assessment. AAD-VMX American Academy of Dermatology—Virtual Meeting Experience