FormalPara Key Summary Points

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules.

Several therapeutic approaches are utilized to treat GPP, including a number which are approved for other types of psoriasis.

This review summarizes the published literature on efficacy, safety and quality of life outcomes associated with current treatment of GPP with both approved and non-approved products.

Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials.

There is a need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

Introduction

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease [1, 2], characterized by the eruption of widespread sterile pustules, with or without systemic inflammation. GPP occurs in infants and, more frequently, in adults [1, 3, 4]. It is more prevalent in Asian (14.03 and 7.46 per million people in China and Japan, respectively) than European populations (1.76 per million people in France) [4,5,6].

GPP is an extremely heterogeneous condition, with wide variation in nomenclature, classification, diagnosis and treatment as well as clinical variation between patients and between episodes in the same patient [2, 7, 8]. According to the International Classification of Diseases, GPP is classified as a subtype of psoriasis and is differentiated from plaque psoriasis/psoriasis vulgaris by the eruption of sterile pustules which are not restricted within psoriasis plaques [2, 9, 10]. However, GPP has also been classified as an autoinflammatory disease (autoinflammatory keratinization disease or AIKD) or as neutrophilic dermatosis [7, 11]. The presentation and genetic drivers of plaque psoriasis and GPP differ. GPP displays an acute presentation with flares resulting from hyperactivation of innate immunity and neutrophilic inflammation [12,13,14]. Many cases of GPP are familial and are associated with loss-of-function mutations in the interleukin (IL)-36 receptor in 21–24% of cases [12]. Other genetic causes have been identified, but it is notable that all result in dysregulation of IL-36 signalling in the innate immune system indicating that this is the key driver of GPP pathogenesis (Fig. 1) [12, 13, 15]. In contrast, the pathogenesis of plaque psoriasis is driven by the adaptive immune system with a central role played by the IL-23/IL-17 axis [2, 12, 15]. However, the efficacy of biologics targeting IL-23/IL-17 has been reported by some studies [16,17,18,19,20,21,22,23,24,25,26], indicating potential overlap with both the innate and adaptive immune responses playing a role in GPP pathogenesis [15]. Additionally, recent evidence indicates a role for expression of IL-26 by neutrophils as a driver of autoinflammation in forms of pustular psoriasis, including GPP [27]. Without appropriate treatment, GPP often results in hospitalization and can be life-threatening in severe cases [1, 7, 28].

Fig. 1
figure 1

Pathophysiology of GPP and treatments targeting the pathway. Dysregulation of IL-36 signalling results in secretion of keratinocyte cytokines and IL-36-mediated recruitment of neutrophils to the epidermis, leading to the formation of sterile pustules [12]. The stimulation of TH17 and dendritic cells by keratinocyte cytokines leads to release of IL-17A, TNF and IL-23, further increasing IL-36 levels and activating IL-36 receptors, resulting in the release of pro-inflammatory cytokines in a positive loop. Biologic treatments have been developed which target specific components of these pathways (noted in coloured boxes within the figure). GPP generalized pustular psoriasis, IFN interferon, IL interleukin, IL-36Ra interleukin 36 receptor antagonist, TNF tumour necrosis factor

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Treatments for GPP include a number of therapies that have been approved for other indications and are utilized to treat GPP; they can be broadly classified into three categories: biologics, non-biologic systemic therapies and other therapies (Fig. 1 and Table 1). There are few GPP-specific guidelines, and those available note that high-level evidence for GPP treatments are scarce [29,30,31]. These guidelines were published 2012–2019, and so do not include more recent treatment advances and evidence, and recommend non-biologic systemic therapies including acitretin, cyclosporine and methotrexate, and the biologic therapy infliximab as first-line treatment options, with the biologic therapies adalimumab and etanercept, or psoralen plus ultraviolet A (PUVA), as second-line treatments [29, 30]. A Delphi consensus has recently been published which includes statements on clinical course and flare definition, diagnosis, treatment goals and multidisciplinary management of GPP [10]. This consensus also noted the lack of high-level evidence for treatments commonly used for GPP and highlighted the need for GPP-specific therapies. In the absence of GPP-specific guidelines in most countries, clinical practice often follows plaque psoriasis guidelines, which do not address the key clinical presentations of GPP. These guidelines recommend topical treatments, such as corticosteroids, as a first line, followed by phototherapy and then systemic therapies, such as methotrexate and cyclosporine, and finally biologics [32]. Therefore, off-label use of plaque psoriasis medicines to treat GPP is common despite the evidence for the use of these treatments in GPP being limited and usually based on data from small, open-label studies and case reports. Adaptation of plaque psoriasis treatments to GPP may not consider the apparent differences in pathogenesis and disease evolution. In particular, different interleukin pathways are implicated in plaque psoriasis versus GPP, and GPP may have systemic involvement leading to medical emergencies and fatalities. Reuse of approaches to plaque psoriasis in GPP also occurs with clinical measures: there is currently no standardized method for monitoring treatment response in GPP, with studies frequently using endpoints such as the Physician Global Assessment (PGA), Psoriasis Area and Severity Index (PASI) or Clinical Global Impression (CGI) scale [16,17,18,19,20, 22, 24,25,26, 33,34,35,36,37,38,39]. As well as hampering the comparison of results between studies due to the variety of disease measures used in published studies, these measures do not include a pustulation component (the hallmark of GPP) and so are not specific to patients with GPP.

Table 1 Therapies cited for use in GPP
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Additionally, there are limitations associated with the current treatments suggested for GPP [33]. Resolution of GPP flares is often slow and pustular and skin clearance incomplete [34]. An important aspect of current management strategies is supportive care, often including hospital admission. Improvements in GPP treatment, including the development of specific therapies, could reduce the need for such approaches and so may reduce the burden on both the healthcare system and patient. As a chronic disease, GPP has an acute negative impact on patients’ quality of life (QoL), which is not alleviated by current therapies. Given the potentially life-threatening nature of GPP, there is an unmet need both for treatments with rapid onset of efficacy and favourable safety profiles to treat flares and for treatments that can prevent or reduce the occurrence of new flares to alleviate the disease burden [10, 29].

By conducting this review, our objective was to provide a summary of the efficacy, safety and QoL impact of current treatments and understand how these interventions are used in clinical practice.

Methods

A systematic search was conducted in September 2023 to identify articles reporting on outcomes relating to the treatment of GPP. The protocol was registered online in the PROSPERO international prospective database of systematic reviews (register ID CRD42021215437). This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Cochrane Handbook for Systematic Reviews. As this article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors, ethics approval was not necessary.

Embase and MEDLINE databases were searched via ProQuest to identify articles published between 1980–September 2023 using search terms covering the following parameters: disease, treatment patterns, treatment guidelines, clinical outcomes and safety, clinical burden, QoL and economic burden. The full search strategy is provided in Table S1. Publications were included in this review if they met the criteria detailed in Table S2. No restrictions were made regarding intervention, comparator, study design, geography or language. Due to the number of publications which included patients with GPP, it was decided to focus on articles in peer-reviewed journals for the purposes of this review.

Primary screening of publication titles and abstracts was performed by two independent reviewers using the eligibility criteria before full-text articles were obtained for potentially relevant studies. Secondary screening was then performed by the two independent reviewers using the same criteria. Uncertainty regarding inclusion was adjudicated by a third reviewer.

The search identified 1847 citations (Fig. 2), 372 of which were eligible for full-text review: 118 are included in this review and the majority (81%) were post 2010 (Table S3). Most of the publications were descriptions of case series/reports (61%) followed by retrospective or prospective studies (20%) and clinical trials (19%). Figure 3 shows the proportion of each type of study featured in articles published for each treatment group. For the narrative summary of the identified articles, we have presented the information in order of quality of data available, focussing on clinical trials, prospective and retrospective studies, in that order. Where this level of data has not been published for a particular treatment, information is included from case series/reports (if available).

Fig. 2
figure 2

PRISMA flow chart of study selection. PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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Fig. 3
figure 3

Types of study in published articles for each treatment group. *Four publications describing one RCT are included for spesolimab [43,44,45,46]. †Four publications describing two open-label trials are included for ixekizumab [16,17,18,19]. ‡One publication describing an RCT of etretinate with a subset of pustular psoriasis patients (n = 4) is included for etretinate [70]. GMA granulocyte and monocyte adsorption, PUVA psoralen plus ultraviolet A, RCT randomized controlled trial

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To assess the quality of evidence for each treatment, the level of evidence was graded based on the types of study data published, in line with previous criteria for assessing the evidence in guidelines (Table S4) [35].

Biologic Therapies for GPP

Details of the treatment outcomes for articles included in the narrative summary (excluding case series/reports) are given in Table 2, and information on all relevant articles, including case series/reports identified by the systematic search, are in Table S3. A summary of the levels of evidence available for biologic therapies is given in Table S5 and illustrated in Fig. 4.

Table 2 Summary of outcomes for biologic therapies
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Fig. 4
figure 4

Levels of evidence available for biologic therapies. BR Brazil, CA Canada, CN China, EU Europe, IN India, JP Japan, PRO patient-reported outcome, QoL quality of life, TH Thailand, TW Taiwan, US United States. *Where patient age was not specified for the relevant treatment patients are assumed to be adult. †Level of evidence definitions are provided in Table S4. ‡The Effisayil™ 2 study included adolescent patients. §Results for the imsidolimab clinical trial were not available at the time of the literature search. ‖Study specified treatment courses rather than patient numbers

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IL-36R Inhibitors

IL-36R inhibitors bind to IL-36R, disrupting the IL-36 signalling pathway and its subsequent role in the pathogenesis of GPP. As of April 2024, spesolimab has been approved for the treatment of GPP flares in adults in key regions such as the USA, Japan, China and the EU [36,37,38,39] and has recently been approved for expanded indications in the USA and China [40, 41]. Rapid pustular and skin clearance with spesolimab in an open-label, proof-of-concept study (N = 7) has been published, with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) achieved within 1 week by 71.4% of patients and in 100% of patients by Week 4 [42]. This was the first study to use the validated GPP-specific score GPPGA as the efficacy endpoint rather than the non-disease specific PGA, PASI or CGI scales, which do not include a pustulation component. Data from a multicentre, randomized, double-blind, placebo-controlled study in patients with GPP (N = 53) have been published [43,44,45,46]. In this study, 54% of patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (no visible pustules; primary endpoint) at Week 1 compared with 6% receiving placebo (p < 0.001) [43]; this was accompanied by improvements in patient-reported outcomes that were sustained to Week 12 [43, 44]. Serious adverse events (SAEs) and infections were reported in 6% and 17%, respectively, of patients treated with spesolimab at Week 1 compared with 0% and 6% of patients receiving placebo [43]. Similar results were reported in the subset of Asian patients with GPP flares (N = 29) [45]. GPPGA pustulation subscore of 0 and GPPGA total score of 0 or 1 were sustained above 60% for up to 12 weeks; at least one adverse event (AE) was experienced by 11 (68.8%) and 8 (61.5%) of spesolimab- and placebo-treated patients, respectively [45]. To evaluate GPP flare prevention with spesolimab, a further multinational, randomized, placebo-controlled trial was conducted in 123 patients diagnosed with GPP [47]. By Week 48, fewer patients in the spesolimab treatment arms experienced GPP flares (low dose: 23%; medium dose: 29%; high dose: 10%) compared with the placebo arm (52%), and a non-flat dose-response relationship was established for spesolimab compared with placebo. The high-dose spesolimab regimen was significantly superior to placebo for time to first GPP flare (hazard ratio 0.16, 95% confidence interval [CI] 0.05–0.54, p = 0.0005) and flare occurrence (risk difference − 0.39, 95% CI − 0.62 to − 0.16, p = 0.0013). Additionally, no flares were observed in the high-dose spesolimab groups after the first 300 mg dose at Week 4. The incidence of severe AEs and investigator-defined drug-related AEs was similar between patients who received spesolimab and placebo (18/93 [19%] vs 7/30 [23%] and 37/93 [40%] vs 10/30 [33%], respectively).

Imsidolimab is an immunoglobulin G4 antibody that inhibits the function of IL-36R, and is currently in development for patients with GPP. Data from an open-label, single-arm, multiple dose study with eight patients have been published [48]. In this study, 75% of patients were reported as CGI responders at Weeks 4 and 16, among whom 50% were classed as ‘very much improved’. Overall, 6/8 (75%) of patients experienced at least one treatment-emergent adverse event (TEAE), two patients reported TEAEs that were deemed moderate in severity and possibly related to study drug treatment and two SAEs were reported [48].

TNF Inhibitors

Tumour necrosis factor (TNF) is a proinflammatory cytokine that can increase IL-36 production in keratinocytes, and so inhibition of TNF may disrupt inflammatory pathways in GPP [13]. Certolizumab pegol is approved for GPP treatment in Japan [49]. In an exploratory analysis of a randomized open-label trial in Japanese patients with GPP (n = 7) and erythrodermic psoriasis (n = 15), treatment with certolizumab pegol for 16 weeks resulted in improvements in GPP as measured by CGI, Dermatology Life Quality Index, Itch Numeric Rating Scale and Global Improvement Score (GIS) response, which were maintained through Week 52 of the study [50]. SAEs were reported in two of seven patients (neutropenia and pustular psoriasis).

Seven publications reported use of infliximab in GPP [51,52,53,54,55,56,57]. In a single-arm, open-label study, all patients (N = 7) achieved a response (global improvement) at Weeks 2 and 6; AEs led to treatment discontinuations in two patients [53]. A non-interventional retrospective patient chart review in Germany reported an ‘excellent’ response (defined in the source article as based on subjective clinician assessment implied by the inclusion in the patient’s medical record of phrases such as “complete” or “marked response”, “remission”, “dramatic improvement” and “near” or “complete clearance”) in 46.7% (7/15) of treatment courses and a 69.2% discontinuation rate due to AEs [51].

Adalimumab is approved for the treatment of GPP in Japan [58]. Four publications reported adalimumab efficacy in GPP [51, 56,57,58], including a multicentre, open-label study in Japanese patients (N = 10) that reported a clinical response rate (defined as remission [total skin score 0] or improvement from baseline [reduction of  ≥ 1 point from baseline total skin score of 3 or ≥ 2 points from a baseline total skin score of ≥ 4] with reference to Japanese Dermatological Association [JDA] severity index of GPP) of 50% at Week 2 and 70% at Week 16, which was maintained through Week 52 [58]. SAEs were reported in three of ten patients (30%), and two patients discontinued the study because of AEs. A non-interventional retrospective patient chart review reported an ‘excellent’ response (as previously described) in 42.9% (3/7) of treatment courses, although 75% of patients (9/12) discontinued treatment because of lack of efficacy and one patient discontinued because of AEs [51].

Among three publications concerning etanercept, a non-interventional retrospective patient chart review reported ‘excellent’ responses (as previously described) in 50.0% (6/12) of treatment courses, a chart review reported 75.0% (3/4) of patients free of GPP flares for 12 months, and the final retrospective study included one patient treated with etanercept and reported pustule clearance within 7 days [51, 56, 57]. One of the retrospective studies reported that AEs led to treatment discontinuation in 6 of 14 patients [51].

IL-17A Inhibitors

IL-17 is a cytokine with an important role in both the pathogenesis of inflammatory skin disease and inducing neutrophil recruitment; additionally, the proinflammatory functions of IL-36 are reinforced by a feedback loop with the IL-17/IL-23 axis [13]. Ixekizumab is approved for GPP in Japan [17]. Evidence was reported in six publications [16,17,18,19, 51, 59], with a multicentre, single-arm, open-label study in Japan reporting that all patients (N = 5) had a GIS of resolved or improved from Week 12 onwards [17,18,19]. All patients reported at least one TEAE; however, no SAEs were reported. In an open-label study in Japan, the primary endpoint (number of patients who had improvement in their GIS by ≥ 1 point from Week 12 through to Week 20 and with ≤ 2 of GIS) was met by 50% (1/2) of patients and no AEs were reported [16].

Secukinumab is approved in Japan for the treatment of GPP [20], with supporting evidence reported in five publications [20,21,22,23, 51]. In a single-arm, open-label study, 75% of patients with GPP (N = 12) had a CGI score of ‘very much improved’ at Week 16, and this response was noted in 58.3% of patients at Week 52 [20]. SAEs were reported in 25% of patients, and two patients discontinued because of an AE. A non-interventional retrospective patient chart review reported ‘excellent’ responses in 60% (6/10) of treatment courses (as previously described) [51], while according to a second, all treated patients (N = 20) achieved a JDA score of 0/1 within 3 weeks [21]. In an open-label, prospective study, 100% (2/2) of patients with GPP achieved PASI 50 and 50% (1/2) achieved PASI 75 at 25 weeks [22].

IL-17RA Inhibitors

As noted above, IL-17 represents a key target for reducing inflammation and neutrophil recruitment in GPP [13]. Brodalumab is an approved GPP treatment in Japan, Taiwan and Thailand [60]. In an open-label, multicentre study in Japan (N = 12), brodalumab led to a CGI response of ‘improved’ or ‘remission’ in 75% of patients at Week 2 and 91.7% at Week 52. In addition, 91.7% of patients had a Pustular Symptom Scale of 0 or 1 at Week 52; 25% reported SAEs [24].

IL-23 Inhibitors

The IL-23 pathway regulates the synthesis of IL-17 and so could impact on IL-36 signalling in patients with GPP [13]. Guselkumab is approved for GPP in Japan [61]. Evidence was reported in a single-arm, open-label study and a non-interventional retrospective patient chart review [25, 51]. In the single-arm, open-label study in Japan (N = 10), 77.8% of patients achieved a CGI score response at Week 16 and median PASI score improvement was 86.8% at Week 52 [25]. All patients reported at least one AE during the study, and two patients treated with guselkumab reported SAEs (fall and loss of consciousness and squamous cell carcinoma). In the patient chart review, a partial response (defined as “some improvement” in the medical records) after treatment with guselkumab was reported in 100% (1/1) of treatment courses and AEs were experienced by 20% of patients (1/5) [51].

Risankizumab was recently approved in Japan for adults with GPP [62, 63]; a randomized, open-label study showed improvement in JDA score, with all patients (N = 8) achieving clinical response (defined as ‘slightly improved’ in the overall improvement rating from baseline according to the JDA total score) by Week 16, regardless of dose [26]. SAEs were reported by 25% of patients, and two patients experienced an AE leading to discontinuation from the study.

IL-1 Inhibitors

IL-1 is among the cytokines that stimulate IL-36 production in keratinocytes [13]. Use of gevokizumab has been reported in two patient cases from an open-label, expanded-access study where the GPP-specific mean Generalized Pustular Psoriasis Area and Severity Index (GPPASI) scores were reduced by 79% at Week 4 in one patient and by 65% at Week 12 in a second patient [64].

Evidence was available from three case reports regarding the use of anakinra in patients with GPP, all of which reported no/limited efficacy [65,66,67] as well as renal and hepatic abnormalities [67].

IL-12/23 Inhibitors

IL-12 and IL-23 are key cytokines involved in the activation of inflammatory pathways [13]. Evidence for the use of ustekinumab was reported as part of a non-interventional retrospective patient chart review [51]. The majority (5/6 patients, 83%) achieved an ‘excellent’ (as previously described) or ‘partial’ (defined as implied by phrasing such as “some improvement”) response to ustekinumab, with AEs occurring in 21% (3/14) of treatment courses and treatment discontinuation due to AEs occurring in 33% (2/6) of treatment courses.

Anti-CD6 Monoclonal Antibody

Itolizumab is a monoclonal antibody which recognises the distal domain of CD6, a membrane protein expressed on lymphocytes, and inhibits the release of cytokines [68]. Evidence was available from a case series of three patients with GPP who all experienced improvement in lesions and a decrease in disease severity (as measured by pustular symptom score evaluation and scoring system in pustular psoriasis, both based on assessment of symptoms and laboratory parameters) during therapy with itolizumab [68].

Non-Biologic Systemic Therapies for GPP

Details of the treatment outcomes for articles included in the narrative summary (excluding case series/reports) are given in Table 3 and information on all relevant articles, including case series/reports identified by the systematic search are in Table S3. A summary of the levels of evidence available for non-biologic systemic therapies is given in Table S5 and illustrated in Fig. S1.

Table 3 Summary of outcomes for non-biologic systemic therapies
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Retinoids

Two articles (a randomized, double-blind study [N = 4 + 6 additional cases] and a retrospective study [N = 188]) reported on etretinate [69, 70], with complete or almost complete clearance rates reported in 80% of patients and an effective response (‘remarkably effective’ or ‘effective’ on a 4-point clinical effectiveness scale) in 84% of patients, respectively [69, 70]. In the retrospective study, AEs were reported in 46% of patients [69].

Use of acitretin was reported in seven publications (six retrospective studies [N = 10 to 98] and one prospective study [N = 40]) as monotherapy or in combination [21, 51, 57, 71,72,73,74]. Efficacy outcome definitions varied widely, and response rates ranged from 40.9 to 100% [21, 51, 57, 71,72,73,74]. The reported rate of AEs was 80% (8/10) in one retrospective study [71], while a non-interventional retrospective patient chart review reported treatment discontinuation due to AEs in 17.6% (3/17) of patients [51]. A prospective study noted AEs in 8–15% of patients (N = 40), depending on dose [73].

Immunosuppressant Agents

Among the studies reporting use of hydroxyurea, ‘good’ or ‘excellent’ responses (> 50–75% or > 75–95% clearance of lesions, respectively) after 12 weeks of treatment were reported in 4/6 patients in a prospective non-randomized study [75]. The prospective study noted that all patients had lesional pigmentation [75]. Across five retrospective studies methotrexate showed clinical efficacy in 58.3–100% of patients, although endpoints varied considerably [51, 57, 69, 76, 77]. Liver toxicity was observed in 14% of patients receiving methotrexate maintenance treatment [77]. Use of cyclosporine was reported in four retrospective studies [51, 78,79,80], with varying response rates (72.7–100%) [51, 78, 80]. Reported AEs included hypertension [79].

Corticosteroids

Two retrospective studies reported on corticosteroid use in patients with GPP [57, 81]. Efficacy endpoints in one retrospective study focussed on mortality, morbidity and intensive care unit admission, while the other evaluated pustule clearance [57, 81]. A retrospective cohort study in Japan found that treatment with corticosteroids alone was associated with significantly higher in-hospital mortality (p < 0.001) and morbidity (p = 0.02) than treatment with biologics or oral agents without biologics [81]. The retrospective study in China noted a skin lesion clearance rate of 75%, second only to biologics (80%) [57].

Fumarates

The non-interventional retrospective patient chart review reported ‘excellent’ responses (as previously described) with fumaric acid ester in 33.3% (2/6) of treatment courses [51]; however, 56.3% of patients discontinued treatment because of AEs.

Phosphodiesterase-4 Inhibitor

A non-interventional retrospective patient chart review of apremilast reported an ‘excellent’ response (as previously described) in 100% (n = 1) of treatment courses with no reported AEs [51].

Other Therapies for GPP

Details of the treatment outcomes for articles included in the narrative summary (excluding case series/reports) are given in Table 4 and information on all relevant articles, including case series/reports identified by the systematic search, are in Table S3. A summary of the levels of evidence available for other therapies is given in Table S5 and illustrated in Figure S2.

Table 4 Summary of outcomes for other therapies
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Apheresis

A multicentre study examined the effectiveness of granulocyte and monocyte adsorption apheresis (GMA) in patients with GPP in Japan, judging 12 of the 14 patients who completed the study to have responded to the treatment [82]. AEs were reported in three of the patients, none of which were considered serious. GMA was approved for the treatment of GPP in Japan in 2012 [83].

Phototherapy

Three retrospective studies have reported a ‘clinical response’ to phototherapy using oral or topical PUVA [51, 69, 84]. One study reported side effects in 16% of patients [69].

Other Treatments

Combination therapies including glycyrrhizin were described in a retrospective chart review, with all patients (N = 9) achieving ≥ 77% improvement in the severity score of GPP at Week 2, with no significant side effects during treatment or follow-up [85]. The use of colchicine to treat GPP was only reported in one case series, where three of four patients treated were in ‘total remission’ (without fever or pustules) within 2 weeks [86]. One case series reported topical steroid use in GPP, with treatment effective in 62.5% (5/8) of patients [87]. Topical application of vitamin D3 (in combination with brodalumab and corticosteroid) showed good control of skin lesions in a case report [88]. Zinc acetate also achieved good outcomes in an adult patient in one case report [89].

Antibiotics

One publication reported antibiotics as therapy for GPP management, but evidence of clinical efficacy was inconsistent: dapsone showed ‘moderate to good’ (n = 5/26) or ‘excellent’ (n = 19/26) responses (> 50% or total clearance of lesions, respectively) as combination therapy in patients while thiamphenicol efficacy was ‘poor’ (symptoms still existed or < 50% of pustules cleared) (n = 2) [90]. AEs of gastrointestinal disturbances were reported with both drugs.

Discussion

This literature review was performed to gain greater understanding of the GPP treatment landscape and evidence supporting current treatment options. Given the rarity of the disease, we used a broad search strategy and eligibility criteria; however, we identified very few clinical trials, and over half of the relevant publications were case reports/series. Overall, the level of evidence for each treatment was low, with the highest level of evidence seen for IL-36R inhibitors. Although of great educational value, data from such small populations, which lack comparators, provide only low- or very-low-quality evidence to support treatment decisions. It was also notable that many of the publications identified described studies which were not conducted in an exclusively GPP population but instead included patients with other forms of psoriasis, with only a small subset of patients with GPP within each of these studies. In the absence of global treatment guidelines and high-quality evidence to support a defined optimal strategy for GPP management, we found that treatment options were largely adapted from other dermatological regimens [70, 84, 91, 92].

Greater understanding of the mechanisms underlying the pathogenesis of GPP have led to the development of targeted biologic treatments [13]. Japan is one of the few countries where several biologic agents are approved for the treatment of GPP; as noted previously, the prevalence of GPP is higher in Japan than Europe [12]. Approved biologic agents include (at the time of writing) spesolimab, adalimumab, infliximab, certolizumab pegol, secukinumab, ixekizumab, brodalumab, risankizumab and guselkumab. For a number of these agents, the approval is based on limited evidence generated from small (≤ 12 patients), open-label, uncontrolled clinical trials [16,17,18,19,20, 24,25,26, 42, 50, 53, 54, 58]. The IL-36R inhibitor spesolimab is the exception, with results published from two multicentre, randomized, double-blind, placebo-controlled trials in a total of 176 patients diagnosed with GPP [43, 47].

Identification of IL36RN mutations as the key driver of GPP in a high proportion of cases [12] has led to the development of the first GPP-specific treatments targeting the IL-36 pathway. Following the initial proof-of-concept trial [42], spesolimab was evaluated in the pivotal Effisayil™ 1 trial, showing rapid and sustained pustular and skin clearance, accompanied by QoL benefits [43, 44]. This was the first randomized, placebo-controlled study to be conducted in a GPP-specific global population focussing on the treatment of flares and demonstrated superiority to placebo, with a higher incidence of lesion clearance at one week [43]. Based on the results of this trial, approval for the treatment of GPP flares and acute symptoms was granted in key regions, including the USA and Japan in September 2022, and conditional marketing authorization in the EU and approval for marketing in mainland China in December 2022 [36,37,38,39]. The results of a further randomized placebo-controlled study (Effisayil™ 2) focussing on flare prevention have recently been published, demonstrating that spesolimab treatment reduced the risk of GPP flares by 84% over 48 weeks compared with placebo [47]. Given the chronic and potentially life-threatening nature of GPP, the approval of spesolimab for the treatment of GPP flares is particularly important. Currently, spesolimab is approved in 48 countries for the treatment of GPP flares and was recently approved for expanded indications of GPP in China and the USA (for patients ≥ 12 years of age [weighing ≥ 40 kg]), providing acute and chronic treatment [40, 41]. At the time of writing, further clinical trials are completed or ongoing for the IL-36R inhibitors spesolimab (NCT05200247, NCT05239039, NCT05670821 and NCT03886246), a randomized placebo-controlled study has completed for imsidolimab (NCT05352893) with a further trial ongoing (NCT05366855), and a phase 1 study of a recombinant humanized anti-IL-36R monoclonal antibody has completed (NCT05512598).

Historically, the rarity of GPP and its heterogeneous symptoms posed considerable challenges to the development of comprehensive accurate disease measures for the evaluation of new treatments. Accordingly, this review found that psoriasis disease measures remain the most commonly used methods for evaluating patients with GPP, despite their limitations due to lack of assessment of pustules (a hallmark of GPP), systemic inflammation and disease symptoms. More recently, the validation of GPP-specific assessment tools (GPPGA and GPPASI) has been published [93], and these tools were implemented in the Effisayil™ 1 and Effisayil™ 2 spesolimab studies allowing efficacy to be evaluated using dedicated GPP-specific endpoints. International consensus on using such quantitative tools in the development of new treatments is needed to advance patient care.

The limitations associated with this systematic review reflect the challenges faced when conducting clinical research into a rare disease. A limited number of relatively low-quality studies reporting outcomes of interest were identified. Because of the small sample sizes, diverse study designs and lack of standardization of endpoints and assessment tools across studies, it was difficult to quantitatively analyse the results and draw definitive conclusions regarding the comparative efficacy of individual therapeutic approaches. Additionally, the exclusion of abstracts may mean that very recent data presented at congresses have not been included in this review.

Conclusion

Findings from this review highlight the lack of a clear treatment paradigm for GPP. Targeted biologic treatments have the potential to transform the GPP treatment landscape, as has been seen in other autoimmune inflammatory conditions; however, much of the current evidence in the published literature is based on small open-label studies and case reports. This review is limited by the lack of standardization and limitations of the studies identified, making it difficult to compare the therapies evaluated. This lack of high-quality evidence presents a major barrier to development of consensus on the most effective treatments, which is further confounded by non-standardization of clinical outcomes across studies. Prospective randomized studies with GPP-specific endpoints are needed to support the development of an optimal treatment strategy for patients with GPP.