American Journal of Clinical Dermatology (2022) 23 (Suppl 1):S13–S19 https://doi.org/10.1007/s40257-021-00655-y REVIEW ARTICLE Pathophysiology of Generalized Pustular Psoriasis Slaheddine Marrakchi1 · Lluis Puig2 Accepted: 26 October 2021 / Published online: 21 January 2022 © The Author(s) 2022 Abstract Generalized pustular psoriasis (GPP) is a rare, severe form of pustular psoriasis characterized by widespread, recurrent epi- sodes of neutrophil-rich pustule formation in the epidermis, which can be accompanied by fever and systemic inflammation. Recent clinical, histologic, and genetic evidence indicates that GPP is a distinct entity from plaque psoriasis, with different cytokine pathways predominant in the manifestation of each disease. The interleukin-36 (IL-36) signaling cascade plays a key role in regulating the innate immune system, and its dysregulation appears central to the pathogenesis of GPP. The altered expression of various IL-36 pathway constituents has been shown to cause a positive feedback loop of uncontrolled signaling and excess production of inflammatory cytokines, which in turn leads to chemokine induction and neutrophil recruitment in the epidermis. Given the potentially life-threatening nature of GPP episodes, drug interventions that rapidly achieve disease resolution are required. Early phase data indicate that treatments targeting various components of the IL-36 inflammatory cascade represent promising areas of research. However, there are currently no therapeutic agents specifically approved for GPP in the USA or Europe. Understanding the inflammatory pathways, associated risk factors, and role of neutrophils in the manifestation and perpetuation of GPP flares remains a key goal in developing effective therapeutics. In this article, we summarize the current understanding of GPP, describe novel therapeutic opportunities, and detail how the unique pathophysiology of the disease may inform future treatment strategies. Digital Features for this article can be found at https://​doi.​org/​ Key Points 10.​6084/​m9.​figsh​are.​16823​503. Generalized pustular psoriasis (GPP) is a rare, neutro- philic skin disease characterized by sudden episodes of widespread rash and sterile pustules. While GPP can present with pre-existing plaque psoriasis, it is now recognized as a separate clinical entity with clear distinctions in genetic and immunologic determinants and response to treatment. Identifying a key role for the interleukin-36 immune signaling pathway in the pathogenesis of GPP has paved the way for the development of new therapies. * Slaheddine Marrakchi 1 Introduction slaheddine.marrakchi@tunet.tn 1 Department of Dermatology, Hedi Chaker University There are several subtypes of psoriasis, the most com- Hospital, Sfax, Tunisia mon of which is plaque psoriasis, which is characterized 2 by scaly, sharply demarcated plaques affecting the extensor Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain surfaces [1]. Pustular psoriasis, a rarer form of psoriasis, Vol.:(0123456789) S14 S. Marrakchi, L. Puig represents approximately 1% of all clinical cases; it is an characterized by inflammation in the epidermis, hyperkera- immune-mediated systemic skin disorder, distinguished by tosis, and primary genetic causative factors associated with sterile, neutrophil-rich pustules with a variety of distribu- the hyperactivation of innate immunity (autoinflammation) tion patterns [2]. Pustular psoriasis can be further divided [15]. By contrast, plaque psoriasis has both innate and adap- into specific subtypes based on the clinical presentation and tive immunopathogenic responses and is considered an auto- location of the pustules; it can be classified as either local- immune condition [16, 17]. Studies have identified different ized, comprising palmoplantar pustulosis (PPP) and acroder- cytokine pathways that are predominant in the manifestation matitis continua of Hallopeau, or generalized, comprising of each disease. For example, while the interleukin (IL)-23/ generalized pustular psoriasis (GPP), pustular psoriasis of IL-17 axis appears to drive plaque psoriasis [18, 19], a grow- pregnancy, and infantile/juvenile pustular psoriasis [1]. ing body of evidence implicates the IL-36 pathway as central The pathogenesis of GPP appears to be driven by a com- to the development of GPP [16, 20]. bination of select genetic loci, predominantly inflammatory IL-36 cytokines belong to the IL-1 family and are cytokine signaling constituents, and environmental risk fac- expressed by and act upon various cell types, including tors, including viral infections, medications, and discontinu- keratinocytes, epithelial cells, and immune cells, in an auto- ation of corticosteroids [3]. Histologic examination of GPP crine or paracrine manner [21]. With a key role in regulating lesions reveals parakeratosis, substantial mononuclear and the innate immune system, the uncontrolled expression and neutrophilic infiltration into the epidermis, and epidermal activation of IL-36 cytokines can lead to self-perpetuating edema and hyperplasia [4, 5]. Spongiform pustules of Kogoj, inflammatory cascades [22, 23]. IL-36 signaling occurs via hyperplasia of the suprapapillary capillaries, and Munro’s a complex of IL-36 receptor (IL-36R) and IL-1R accessory microabscesses typical of plaque psoriasis are also seen. protein, propagating inflammatory responses in the epithe- Presentation of GPP may occur in parallel with plaque psori- lium. Dysregulation of this signaling pathway appears cen- asis, which can impede accurate clinical identification [4–6]. tral to the immunopathogenesis of GPP [23, 24] (Fig. 1). Greater understanding of the pathophysiology of GPP Overexpression of IL-36 agonists (IL-36α, β, or γ) or is required to develop effective, targeted, disease-specific expression of a dysfunctional IL-36R antagonist (IL-36RA), therapies. In this article, we summarize current understand- encoded by IL36RN, can lead to a positive feedback loop of ing of GPP and describe how its unique pathophysiology uncontrolled signaling and excess production of inflamma- may inform future treatment strategies. tory cytokines [20, 25]. This in turn leads to the induction of chemokines such as CXCL1 and CXCL8 (IL-8), producing a chemokine gradient that attracts a high number of neutro- 2 Immunopathology of GPP phils into the epidermis [20]. Here, spongiform pustules of Kogoj and sub-corneal accumulation of neutrophils manifest GPP is a rare, neutrophilic skin disease characterized by as “lakes of pus,” which are characteristic of patients with sudden episodes of widespread rash and sterile pustules that GPP [3, 7, 16] (Fig. 1). The video (available online) gives an can occur with or without systemic inflammation, as denoted overview of IL-36 autocrine and autoinflammatory circuits by fever, leukocytosis, and elevated C-reactive protein lev- (MP4 29712 KB). els [7]. A key characteristic of GPP is repeated episodes of Further evidence on the differences in immunopathologic generalized sterile pustule formation caused by extensive determinants driving GPP and plaque psoriasis pathogen- neutrophilic and mononuclear inflammatory infiltrates in the esis comes from gene expression analyses. Compared with epidermis [5, 8]. Severe flares typically require intensive healthy controls, levels of tumor necrosis factor-α, IL-1, hospital treatment [9, 10]. IL-17A, and IL-36 are increased in skin biopsy samples GPP may present with pre-existing plaque psoriasis, and from patients with GPP or plaque psoriasis; however, GPP closely interlinked immunologic pathways appear to under- lesions were shown to have higher levels of IL-1 and IL-36 pin the pathogenesis of both conditions [11, 12]. However, and lower levels of IL-17A and interferon-γ compared with GPP has also been shown to present independently and is plaque psoriasis lesions [16]. Immunohistochemical analysis now recognized as a clinical entity separate from plaque also revealed that IL-36 expression localizes to keratino- psoriasis, with clear distinctions in genetic and immunologic cytes that surround the neutrophilic pustules in GPP [16]. determinants as well as in response to treatment [13, 14]. Furthermore, GPP lesions contain higher levels of neutro- Understanding these distinctions is key to the development philic chemokines and neutrophil and monocyte transcripts of effective, targeted treatments for this disease. GPP is pre- compared with plaque psoriasis lesions [16]. It is impor- dominantly characterized by innate immune inflammation tant to note that IL-36 and IL-23 cytokine pathways closely and is considered an autoinflammatory pustular neutrophilic interact and may crosstalk extensively, and dysregulation of disease. In this respect, GPP is considered representative either pathway is capable of perpetuating an inflammatory of autoinflammatory keratinization diseases, which are response [19]. Pathophysiology of Generalized Pustular Psoriasis S15 IL-36α, IL-36β, IL-36γ Neutrophil, T cell, and monocyte recruitment IL-1RAcP IL-36RA into the epidermis leads to pustule formation IL-36R CD4+ T cell IL-36α IL-36β IL-36γ AP1S3 NF-κB Neutrophil- MAPK derived proteases CARD14 Monocytes IL-1β IL-6 IL-17A NF-κB AP-1 IL-23 CEBP SERPINA3 TNF-α IL-1 NF-κB IL-36 mRNA AP-1 NETs Neutrophils Keratinocyte Pre-IL-36α Pre-IL-36β Neutrophil chemokines Lymphokines Pre-IL-36γ CXCL1, CXCL2, CXCL8 CCL3 Dendritic cells Fig. 1  IL-36 autocrine and autoinflammatory circuits. Keratino- and lymphokines, which further propagate this pro-inflammatory cytes are the major source of IL-36 in the skin. IL-36 cytokines are cycle [23, 24]. AP-1 activating protein-1, CARD caspase recruit- secreted from keratinocytes as precursors that require processing ment domain, CCL chemokine (C–C motif) ligand, CXCL chemokine by neutrophil-derived proteases. Upon protease cleavage, mature (C–X–C motif) ligand, IL interleukin, MAPK mitogen-activated pro- IL-36 agonists have > 500-fold biological activity and bind to IL- tein kinase, mRNA messenger RNA, NET neutrophil extracellular 36R on the surface of keratinocytes, inducing an inflammatory cas- trap, NFκB nuclear factor kappa-light-chain-enhancer of activated B cade that promotes IL-36 expression. IL-36 cytokines also induce cells, R receptor RA receptor antagonist, RAcP receptor accessory the expression of numerous cytokines (IL-1β, IL-17A, IL-23, and protein, TNF tumor necrosis factor TNF-α), neutrophilic chemokines (CXCL1, CXCL2, and CXCL8), In addition to histologic analyses, the central role of the in the pathophysiology of GPP. GPP may often present IL-36 pathway in GPP is supported by the identification of with existing or prior plaque psoriasis but can also arise in associated mutations in patients with the disease. To date, patients with no history of plaque psoriasis [7]. Evidence IL36RN mutations appear to be the main determinant of that GPP alone is a distinct subtype of psoriasis, with its pathology in individuals whose disease has a recognized own etiology, comes from a study in Japanese patients in genetic component [26]. These genetic mutations induce which IL36RN mutations were observed in a much higher a response pathway whereby IL-36R-activating ligands proportion of patients with GPP alone compared with those (IL-36α, β, and γ) are not regulated by IL-36RA, leading presenting with GPP and plaque psoriasis [30]. IL36RN to self-amplifying IL-36 production, notably in highly dif- mutations are also associated with an earlier age of onset ferentiated epidermal keratinocytes [27] (Fig. 1). IL36RN and more severe GPP [26]; furthermore, the onset of GPP mutations leading to an aberrant IL-36RA with decreased has been found to be substantially delayed in individuals affinity for its receptor were discovered in a study of with monoallelic compared with biallelic IL36RN mutations, Tunisian families with a severe form of GPP (with some suggesting a gene dosage effect [28]. phenotypical variation even in members of one given family) Despite the strong correlation between IL36RN mutations known as deficiency of IL-36R antagonist (DITRA) [25]. and GPP, not all patients with GPP have evidence of muta- In an international cohort, 7.7% of patients with GPP were tions in this gene [31]. The pathogenesis of GPP also appears heterozygous and 21% had biallelic mutations in IL36RN to be mediated by transcripts of alternative genetic mutations [28], whereas in a study of Chinese patients, IL36RN muta- associated with the IL-36-mediated inflammatory cascade tions were identified in 75% of patients with GPP [29, 30]. [20]. Gain-of-function mutations in CARD14, which facili- Therefore, the occurrence of IL36RN mutations may differ tates activation of nuclear factor-κB (NF-κB) in keratino- by ethnicity, indicating the likelihood of genetic diversity cytes, are associated with GPP in Japanese populations S16 S. Marrakchi, L. Puig [32]. CARD14 mutations have also been reported in patients III studies [41, 45, 47]. Furthermore approval of the tumor with GPP and pre-existing plaque psoriasis, but are rarely necrosis factor inhibitors adalimumab [48, 49], infliximab reported in patients with GPP alone [33]. Furthermore, loss- [50, 51], and certolizumab pegol for the treatment of GPP of-function mutations in AP1S3 are associated with pustular in Japan was based largely on case studies [52]. psoriasis in individuals of European origin, but are rarely Phase II and III clinical trials investigating the effects of seen in individuals from East Asia [34]. AP1S3 encodes a IL-36R-blocking monoclonal antibodies in patients with protein implicated in autophagosome formation and AP1S3- GPP are ongoing. Interim results from a phase II study of deficient cells demonstrate NF-κB activation, upregulated imsidolimab (ANB019, NCT03619902) suggest a favora- IL-1 signaling, and overexpression of IL-36α [35]. ble safety profile [53]; phase III trails were due to begin In addition, overproduction of IL-36 agonists is observed in the third quarter of 2021. Spesolimab (BI 655130) has in patients with GPP with mutations in SERPINA3, which demonstrated efficacy in a phase I, open-label, proof-of- encodes alpha-1-antichymotrypsin, an inhibitor of cathepsin concept study of seven biologic-naive adult patients pre- G, a protease secreted by neutrophils that cleaves (and acti- senting with a moderate or severe GPP flare [54], with vates) IL-36 precursors [36]. Several proteases secreted by phase II trials currently underway (NCT04399837) [55]. neutrophils (cathepsin G, proteinase 3, elastase), and even Both imsidolimab and spesolimab are also under inves- keratinocytes (cathepsin S), have been found to activate tigation for other putative indications, including PPP IL-36, which may further contribute to positive inflamma- (AB019, NCT03633396; BI 655130, NCT03633396) [56, tory feedback [37]. Mutations in myeloperoxidase, a neu- 57]. In addition, phase I development of an antibody tar- trophil-associated lysosomal hemoprotein, have also been geting the IL-36R for the treatment of PPP is underway identified in patients with GPP [38], although not recog- (REGN6490). nized as the initial trigger of the disease. Overall, while the Regarding the treatment of other psoriatic conditions, evidence indicates that the IL-36 pathway is central to the IL-36γ blockade with a small IL-36γ-binding molecule has development of GPP, a greater understanding of the associ- been shown to inhibit inflammation in plaque psoriasis by ated immunologic components, as well as the pathogenic preventing interactions with IL-36R [58]. In addition, the contribution of genetic and ethnic variations, is required. IL-36 cytokine pathway has been identified as an impor- tant factor in the pathogenesis of psoriatic arthritis, and therefore may be a suitable therapeutic target [59]. Fur- 3 Therapeutic Perspectives ther studies of additional components of the IL-36-related pathways have been initiated, with the IL-1β inhibitor There is no globally accepted therapeutic guidance for GPP, gevokizumab having shown promise on treatment of two and treatment often reflects the recommendations for plaque patients with GPP [60]. psoriasis [9]. Therefore, there is an urgent need for well- designed trials to provide clinical evidence on the safety and efficacy of therapies specifically for GPP. Given the poten- tially life-threatening nature of GPP flares, ideal therapeutic 4 Conclusions agents should have a rapid onset of action, a rapid time to disease clearance, the ability to prevent flares, and a favora- GPP places a considerable burden on patients, and while ble safety profile [7]. However, there is a lack of robust ther- efforts have been made to better understand the disease apeutic data available, which is an inevitable consequence and its management, progress is slowed by the small of the rarity of the disease, and the sudden, self-limiting, number of cases. As a result, there are many important episodic nature of pustular flares limits the availability of knowledge gaps and unmet treatment needs. Identification suitable patients with active disease to power randomized of the key role of the IL-36 pathway in the immunopathol- controlled trials [39]. ogy of GPP has paved the way for new therapies targeting To date, biologics have only been approved for the treat- disease-associated genetic and molecular pathways, and ment of GPP in a limited number of countries, with no these agents have shown promise in patients presenting GPP-specific therapeutic agents approved in the USA or with GPP flares. Further elucidation of the unique patho- Europe [7]. The IL-17/IL-17R inhibitors secukinumab and genesis of GPP may identify additional genetic variants ixekizumab [40–44] and the IL-23 inhibitors risankizumab that could provide effective therapeutic targets. Accurate and guselkumab [45, 46] are approved for use in Japan, knowledge of the pathophysiology of GPP and its genetic and the IL-17 antagonist brodalumab is approved for use determinants will help physicians to personalize treat- in Japan, Taiwan, and Thailand [8, 47]. Approval of these ment and more effectively manage patients with this rare IL-17/IL-17R and IL-23 inhibitors was based on data from disease. prospective but small-scale, open-label, single-arm, phase Pathophysiology of Generalized Pustular Psoriasis S17 Electronic supplementary material The online version of this article References (https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40257-0​ 21-0​ 0655-y) contains supplementary material, which is available to authorized users. 1. Benjegerdes KE, Hyde K, Kivelevitch D, Mansouri B. 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