Current Treatments for Generalized Pustular Psoriasis: A Narrative Summary of a Systematic Literature Search

Abstract

Generalized pustular psoriasis (GPP) is a rare, chronic and potentially life-threatening autoinflammatory skin disease characterized by widespread eruption of sterile pustules, with or without systemic inflammation. GPP can significantly reduce patients’ quality of life (QoL). Several therapeutic approaches have been described in the literature, but there is no consensus on optimal treatment. In this review, we summarize published literature on efficacy, safety and QoL outcomes associated with current treatment of GPP with both approved and non-approved products. Embase and MEDLINE databases were searched (1980–September 2023). A search protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on the PROSPERO database (CRD42021215437). Details on publication, population, intervention, efficacy, safety and QoL were captured and checked by independent reviewers. In total, 118 publications were included, with only 19% of publications reporting on the results of clinical trials. Treatment modalities reported for GPP included non-biologic systemic therapies such as retinoids, cyclosporine and methotrexate, topical agents, biologics and small molecules, among others. Results were highly heterogeneous and methodological quality was very low, with only the interleukin-36R inhibitor spesolimab reporting results from placebo-controlled randomized trials; based on this, spesolimab is now approved for GPP treatment in regions including the USA, Japan, China, the EU and several other countries. Some other biologics are approved exclusively in Japan and Taiwan for the treatment of GPP based on open-label studies with small patient numbers in lieu of double-blind studies. Non-standardization of clinical outcomes across studies remains a major hurdle in reaching a consensus on optimal treatment. However, recently trials have been conducted using well-defined, disease-specific endpoints to evaluate GPP-targeted treatments, which will hopefully advance patient care. In conclusion, this review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the optimal treatment strategy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-024-01230-z.

Plain Language Summary

Generalized pustular psoriasis (GPP) is a rare, chronic skin condition characterized by painful, sterile pustules that can occur all over the body. These pustules may also be accompanied by systemic inflammation, which can lead to serious health complications. GPP significantly impacts patients’ quality of life and can even be life-threatening. Because the disease is so rare, treatment guidelines have typically been based on those for plaque psoriasis. However, these guidelines do not specifically address the unique needs of GPP. In this review, we analysed the published literature on GPP management, focussing on treatment efficacy, safety and quality of life outcomes. We searched the literature databases Embase and MEDLINE for articles published between 1980 and September 2023. In total, we identified 118 publications on this topic, covering a wide range of therapies; only one of these therapies, spesolimab, reported results from placebo-controlled randomized trials. Based on these trials, spesolimab is now approved for GPP treatment in the USA, Japan, China, the EU and several other countries. Some other therapies are approved exclusively in Japan and Taiwan based on small, open-label studies in the absence of higher-quality data. To date, comparing treatments has been challenging because of different clinical outcomes used to measure effectiveness. However, well-defined endpoints specific to GPP have recently been developed and used in trials. In conclusion, our review highlights the need for prospective randomized studies with GPP-specific endpoints to determine the best treatment strategy.

Supplementary Information

The online version contains supplementary material available at 10.1007/s13555-024-01230-z.

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) [4–6].

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 [12–14]. 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 [16–26], 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.

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

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 [29–31]. 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 [16–20, 22, 24–26, 33–39]. 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

Biologics	Non-biologic systemic therapies	Other therapies
• TNF inhibitors o Adalimumab o Certolizumab pegol o Etanercept o Infliximab • IL-17A inhibitors o Ixekizumab o Secukinumab • IL-17R antagonists o Brodalumab • IL-12/23 inhibitors o Ustekinumab • IL-1 inhibitors o Anakinra o Canakinumab o Gevokizumab • IL-23 inhibitors o Guselkumab o Rizankizumab • IL-36R inhibitors o Imsidolimab o Spesolimab o Anti-IL-36R monoclonal antibody • Anti-CD6 monoclonal antibody o Itolizumab	• Corticosteroids • Immunosuppressant agents o Hydroxyurea o Leflunomide o Methotrexate o Mycophenolate mofetil o Cyclosporine o Tacrolimus • Retinoids o Acitretin o Etretinate/Ro-10-9359 o Isotretinoin • Fumarates o Fumaric acid esters • PDE-4 inhibitor o Apremilast	• Phototherapy o PUVA • Apheresis o GMA • Other o Colchicine o Glycyrrhizin o Topical steroids o Vitamin D o Zinc acetate • Antibiotics o Dapsone o Thiamphenicol

GMA granulocyte and monocyte adsorptive apheresis, IL interleukin, PDE-4 phosphodiesterase 4, PUVA psoralen plus ultraviolet A, TNF tumour necrosis factor

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.

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

Fig. 3.

Types of study in published articles for each treatment group. *Four publications describing one RCT are included for spesolimab [43–46]. ^†Four publications describing two open-label trials are included for ixekizumab [16–19]. ^‡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

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

References	Study type	Patient population (overall/GPP)	Treatment	Efficacy outcomes	Study duration	Safety outcomes	QoL/PRO outcomes
Spesolimab
Bachelez et al. [42]	Multicentre, single-arm, open‐label, proof-of-concept study (NCT02978690)	Patients with GPP flares (N = 7)	Single, open-label, 10 mg/kg IV dose of spesolimab	Mean improvement in the GPPASI score from baseline was 79.8% at Week 4 GPPGA score of 0 or 1 was achieved within 1 week in five patients (71.4%) and in all patients by Week 4	20 weeks	Any AE: 7 (100%) Severe AE: 0 TRAE: 4 (57.1%) AE leading to drug discontinuation: 0 SAE: 0	Mean (SD) change from baseline to Week 2 Pain VAS: − 45.9 (32.3) FACIT-F: 12.3 (10.1) PSS: − 5.14 (3.18) All maintained to Week 4
Bachelez et al. [43] Navarini et al. [44] Burden et al. [46]	Multicentre, randomized, double-blind, placebo-controlled trial (Effisayil™ 1; NCT03782792)	Patients with GPP flares (N = 53)	900 mg IV dose of spesolimab (n = 35) or placebo (n = 18) on Day 1 Optional open-label 900 mg IV dose of spesolimab on Day 8 for persistent flare Additional open-label 900 mg IV dose of spesolimab for a new flare	GPPGA pustulation subscore of 0, spesolimab vs placebo Week 1: 54% (19/35) vs 6% (1/18); p < 0.001 GPPGA total score 0/1 Week 1: Spesolimab: 43% (15/35) Placebo: 11% (2/18); p = 0.02	12 weeks	Week 1, spesolimab vs placebo: AEs: 66% vs 56% Severe AE: 6% vs 6% Infections: 17% vs 6% TRAEs: 29% vs 28% SAE: 6% vs 0% AE leading to drug discontinuation: 0 Week 12, spesolimab: AEs: 82% Infections: 47% TRAEs: 55% SAE: 12%	GPPASI 75, n (%) (95% CI) Week 1: 4.0 (11.4%) (4.5, 26.0) Week 4: 18.0 (51.4%) (35.6, 67) PROs, median score (IQR): Pain VAS Baseline: 79.8 (70.5, 87.8) Week 1: − 21.3 (− 55.3, − 3.1) Week 4: − 53.4 (− 77.9, − 20.2) PSS Baseline: 11.0 (9.0, 12.0) Week 1: − 4.0 (− 7.0, 0.0) Week 4: − 7.0 (− 10.0, − 3.0) FACIT-Fatigue Baseline: 14.0 (7.0, 28.0) Week 1: 7.0 (1.0, 20.0) Week 4: 22.0 (1.0, 31.0) DLQI Baseline: 19.5 (16.0, 25.0) Week 1: − 2.5 (− 8.0, 1.0)
Morita et al. [45]	Multicentre, randomized, double-blind, placebo-controlled trial (Effisayil™ 1; NCT03782792)	Asian patients with GPP flares (N = 29)		GPPGA pustulation subscore of 0, spesolimab vs placebo Week 1: 62.5% (10/16) vs 7.7% (1/13) Week 12: 68.8% in spesolimab group GPPGA total score 0/1 Week 1: 50.0% (8/16) vs 15.4% (2/13) Week 12: 68.8% in spesolimab group		Week 1, spesolimab vs placebo: AEs: 68.8% (11/16) vs 61.5% (8/13) SAE: 1 patient in the spesolimab group experienced 3 SAEs; resolution occurred within 10 days Week 12 AE: 74.1% (20/27) of patients who received ≥ 1 dose of spesolimab	PROs, score (IQR Q1, Q3): Pain VAS Baseline: 77.1 (64.7, 84.2) Week 12: − 63.5 (− 75.45, − 5.24) FACIT-Fatigue Baseline: 15.5 (12.0, 27.5) Week 12: 26.5 (7.5, 9.5) DLQI Baseline: 19.5 (15.5, 25.5) Week 12:  − 13.5 (− 16.5, − 5.0) PSS Baseline: 11.0 (10.0, 12.5) Week 12: − 7.5 (− 10.0, − 2.5) All PRO scores surpassed the threshold for MCIDs at Week 12
Morita et al. [47]	Multicentre, randomized, double-blind, placebo-controlled trial (Effisayil™ 2; NCT04399837)	Patients with GPP (N = 123)	Low dose: 300 mg SC spesolimab loading dose, followed by 150 mg SC spesolimab every 12 weeks Medium dose: 600 mg SC spesolimab loading dose, followed by 300 mg SC spesolimab every 12 weeks High dose: 600 mg SC spesolimab loading dose, followed by 300 mg SC spesolimab every 4 weeks Placebo: SC placebo loading dose, followed by maintenance SC placebo every 4 weeks	Patients with GPP flares at Week 48 Low dose: 7/31 (23%) Medium dose: 9/31 (29%) High dose: 3/30 (10%) Placebo: 16/31 (52%) Hazard ratio for time to GPP flare vs placebo Low dose: 0.35 (95% CI 0.14–0.86; nominal p = 0.0057) Medium dose: 0.47 (95% CI 0.21–1.06; p = 0.027) High dose: 0.16 (95% CI 0.05–0.54; p = 0.0005) Risk difference for the occurrence of a GPP flare vs placebo over 48 weeks Low dose: − 0.31 (95% CI − 0.54 to − 0.08; nominal p = 0.0068) Medium dose: − 0.23 (95% CI − 0.46 to 0.01; nominal p = 0.036) High dose: − 0.39 (95% CI − 0.62 to − 0.16; p = 0.0013) Hazard ratio for risk of PSS worsening over 48 weeks vs placebo Low dose: 0.46 (95% CI 0.22–0.95; nominal p = 0.0079) Medium dose: 0.56 (95% CI 0.28 to 1.10; nominal p = 0.052) High dose: 0.42 (95% CI 0.20–0.91; p = 0.013)	48 weeks	Any AE All treatment arms combined: 84 (90.3%) Placebo: 26 (86.7%) Severe AE All treatment arms combined: 18 (19.4%) Placebo: 7 (23.3%) Investigator-defined drug-related AE All treatment arms combined: 37 (39.8%) Placebo: 10 (33.3%) AE leading to drug discontinuation All treatment arms combined: 5 (5.4%) Placebo: 0 SAE All treatment arms combined: 9 (9.7%) Placebo: 1 (3.3%)	NA
Imsidolimab
Warren et al. [48]	Open-label, single-arm, multiple-dose study (GALLOP; NCT03619902)	Patients with GPP (N = 8)	IV imsidolimab 750 mg on Day 1, followed by three doses of SC imsidolimab 100 mg on Days 29, 57 and 85	At Weeks 4 and 16, 75% of patients were CGI responders	12 weeks	Patients with at least 1 TEAE: 6 (75%) Related or possibly related TEAE: 3 (37.5%) Severe TEAE: 1 (12.5%) Serious TEAE: 2 (25.0%) TEAE leading to discontinuation of study drug: 1 (12.5%)	DLQI Baseline: 15.8 Day 29: 11.7 Day 141: 9.7
Certolizumab pegol
Okubo et al. [50]	Exploratory analysis of open-label randomized trial	Japanese patients (N = 22)/patients with GPP (N = 7)	Patients with GPP Certolizumab 400 mg Q2W (N = 3) and certolizumab 200 mg Q2W (N = 4)	At Week 2 CGI-I Response: 86% (N = 6) DLQI 0/1: none INRS 0 and Score: none GIS Response: 100% At Week 16 CGI-I Response: 100% DLQI 0/1: 29% (N = 2) INRS 0 and Score: 14% (N = 1) GIS Response: 100% At Week 52 CGI-I Response: 86% (N = 6) DLQI 0/1: 57% (N = 4) INRS 0 and Score: 29% (N = 2) GIS Response: 86% (N = 6)	52 weeks	TEAEs: reported in 100% of patients Most common TEAE was nasopharyngitis, 29% (n = 2) Serious TEAEs: neutropenia (n = 1); pustular psoriasis (n = 1)	Improvements in patient HRQoL was measured by DLQI 0/1 and observed for both CZP-treated groups at Week 16
Infliximab
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 18 treatment courses	Infliximab: standard maintenance dosage	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 46.7% (n = 7 treatment courses) Partial response (patient records note some improvement): 40.0% (n = 6 treatment courses)	Patients treated between January 2005 and May 2019	Any AE: 55.6% (n = 10 treatment courses) Discontinuation due to AEs: 69.2% (n = 9 patients)	NA
Poulalhon et al. [52]	Prospective follow-up study	N = 28/Patients with GPP refractory to ≥ 3 treatments (N = 3)	Infliximab 5 mg/kg at Weeks 0, 2 and 6, and then every 8 weeks	Rapid improvement of clinical and biological signs was observed in all three patients Two of three patients relapsed at 12 and 22 months after the last infliximab infusion	September 2001 to February 2005	All three patients had to discontinue therapy due to: suspected delayed transfusion reaction (1), flare of severe plaque-type psoriasis (1) and loss of vascular access (1)	NA
Torii et al. [53]	Multicentre, open-label, uncontrolled study	N = 64/Patients with pustular psoriasis (N = 7)	Infliximab 5 mg/kg at Weeks 0, 2 and 6, and then every 8 weeks up to Week 46	Response rate (global improvement): Weeks 2 and 6: 100% (n = 7/7) Week 50: 100% (n = 4/4) Last week: 57.1% (n = 4/7) Median PASI response rate at Week 10 vs baseline: 72.4% From Weeks 14 to 50, the improvement was maintained by continuous treatment	62 weeks	SAEs: 28.6% (n = 2/7) AEs leading to discontinuation: 28.6% (n = 2/7)	At Week 10, 83.3% of patients (n = 5/6) had a decrease of ≥ 5 in DLQI from baseline
Torii et al. [54]	Multicentre, single-arm, open-label trial	N = 51/Patients with pustular psoriasis and loss of efficacy of infliximab 5 mg/kg (N = 7)	Infliximab 10 mg/kg every 8 weeks from Weeks 0–32	Median (IQR) improvement in PASI score from baseline to Week 40 (observed): 82.6% (77.5%, 83.9%)	40 weeks	SAEs: 14% (1/7) AEs leading to discontinuation: 14% (1/7)	Mean (SD) change in DLQI at Week 40:  − 9.6 (7.2)
Trent and Kerdel [55]	Retrospective study	Patients with GPP (N = 4)	Infliximab 5 mg/kg intravenously over 3 h	At 24–48 h after infliximab, pustules resolved in all patients, and no new pustules formed Two patients required additional infliximab infusions at Weeks 0, 2 and 6, and then monthly thereafter	NA	No major AEs occurred	NA
Viguier et al. [56]	Retrospective chart review	N = 11 patients from France with GPP/N = 10	Infliximab	8/10 with clinical improvement	NA	Any AE: 32% (n = 6/19)	NA
Zheng et al. [57]	Retrospective study	N = 110/patient from China with GPP (N = 1)	Infliximab	Pustule clearance: 1 Partial pustule clearance: 0 Treatment failure: 0 Time to pustule clearance: 2 weeks Treatment efficacy rate: 1/1 (100%)	Patients treated between 2014 to 2019	NA	NA
Adalimumab
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 17 treatment courses	Adalimumab: standard maintenance dosage	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 42.9% (n = 3/7) Non-response: 57.1% (n = 4/7) Response not reported: 58.8% (n = 10/17) Treatment discontinuation due to ineffectiveness: 75.0% (n = 9/12)	Patients treated between January 2005 and May 2019	AEs: 5.9% (n = 1/17) Treatment discontinuation due to AEs: 8.3% (n = 1/12)	NA
Morita et al. [58]	Multicentre, open-label, 52-week study (NCT02533375)	Patients with GPP (N = 10), with total skin score of ≥ 3, erythema with pustules (skin score ≥ 1), and JDA GPP score < 14	Adalimumab 80 mg at Week 0, followed by 40 mg every other week until Week 50	Primary end point: CR, 70% (n = 7) at Week 16 CR rates remained relatively stable through Week 52 PASI 50 response rates increased between baseline and Week 4 (approximately), and then stabilized PASI 75 and PASI 90 response rates increased more gradually One patient achieved remission (i.e., total skin score 0) at Week 4	52 weeks	Three patients discontinued the study prematurely because of lack of efficacy, and two because of AEs Mild or moderate AEs: 70% (n = 7) Severe AEs: 20% (n = 2) Serious AEs: 30% (n = 3) No deaths	DLQI score decreased (improved) from baseline to Week 16, and from Week 24 to Week 52
Viguier et al. [56]	Retrospective chart review	N = 11 patients from France with GPP/N = 4	Adalimumab	Free of GPP flare: 100% (n = 3) (follow-up for individual patients: 10, 17 and > 18 months) Remission achieved in 2/3 patients (times to remission, 7 and 28 days)	NA	No AEs	NA
Zheng et al. [57]	Retrospective study	N = 110/patient from China with GPP (N = 1)	Adalimumab + acitretin	Pustule clearance: 1 Partial pustule clearance: 0 Treatment failure: 0 Time to pustule clearance: 11 days Treatment efficacy rate: 1/1 (100%)	Patients treated between January 2014 and December 2019	NA	NA
Etanercept
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients with GPP from Germany/N = 18 treatment courses	Etanercept: standard maintenance dosage	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 50% (n = 6/12) Partial response (patient records note some improvement): 25.0% (n = 3/12) Treatment discontinuation due to remission: 7.1% (n = 1/14) Treatment discontinuation due to ineffectiveness: 35.7% (n = 5/14)	Patients treated between January 2005 and May 2019	AEs: 33.3% (n = 6/18) Treatment discontinuation due to AEs: 42.9% (n = 6/14)	NA
Viguier et al. [56]	Retrospective chart review	N = 11 patients from France with GPP/N = 4	Etanercept	Three of four patients treated with etanercept were free of disease flares for 3, 6 and 12 months	NA	No AEs were reported	NA
Zheng et al. [57]	Retrospective study	N = 110/patients from China with GPP (N = 13)	Etanercept monotherapy (n = 1) Etanercept + acitretin (n = 9) Etanercept + MTX (n = 3)	Etanercept monotherapy (n = 1) Pustule clearance: 1 Partial pustule clearance: 0 Treatment failure: 0 Time to pustule clearance: 7 days Treatment efficacy rate: 1/1 (100%) Etanercept + acitretin (n = 9) Pustule clearance: 8 Partial pustule clearance: 0 Treatment failure: 0 Withdrawal (due to financial reasons): 1 Mean time to pustule clearance: 12.6 days Treatment efficacy rate: 8/8 (100%) Etanercept + MTX (n = 3) Pustule clearance: 2 Partial pustule clearance: 0 Treatment failure: 1 Mean time to pustule clearance: 9 days Treatment efficacy rate: 2/3 (67%)	Patients treated between 2014 to 2019	NA	NA
Ixekizumab
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 7 treatment courses	Ixekizumab: standard maintenance dosage	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 50.0% (n = 3/6) Partial response: 33.3% (n = 2/6) Non-response: 16.7% (n = 1/6) Response not reported: 14.3% (n = 1/7)	Patients treated between January 2005 and May 2019	Any AE: 28.6% (n = 2/7) Discontinuations: 28.6% (n = 2/7) Treatment discontinuation due to AEs: 50.0% (n = 1/2)	NA
Morita et al. [16]	Multicentre, open-label clinical trial (UNCOVER-J2; NCT03942042)	N = 12/Patients with GPP (N = 7)	Induction (n = 7): 160 mg ixekizumab as 2 × SC injections at Week 0 followed by 80 mg at Weeks 2, 4, 6, 8 and 10 Maintenance for patients with GIS ≥ 2 (n = 2) at PI discretion: Ixekizumab 80 mg SC Q2W at Weeks 12, 14, 16 and 18	Four patients achieved GIS = 1 at Week 12 and completed the study Two patients entered maintenance: primary endpoint (number of patients with improvement in GIS by ≥ 1 point from Week 12–20, and with GIS ≤ 2) achieved by 1/2 patients PASI 75 response rate: 50% (Week 12), 100% (Week 20) PASI 90 response rate: 50% (Week 12), 50% (Week 20) PASI 100 response rate: 50% (Week 20)	20 weeks	One patient discontinued the study during induction due to lack of efficacy During induction: 4 of 7 patients reported TEAEs (mild or moderate); 1 patient had a TRAE No SAEs or AEs leading to discontinuation AESIs were nasopharyngitis (n = 1) and upper respiratory tract infection (n = 1)	Ixekizumab (Weeks 12–20; n = 2) maintained responses for DLQI total score, DLQI (0,1), and DLQI (0) At Week 20, one patient reported itch NRS ≥ 4-point reduction
Okubo et al. [17] Saeki et al. [18] Saeki et al. [19]	Multicentre, single-arm, open-label study (UNCOVER-J; NCT01624233)	N = 91/Patients from Japan with GPP (N = 5)	Week 0: ixekizumab 160 mg dose Weeks 2–12: ixekizumab 80 mg every 2 weeks Maintenance dose: 80 mg every 4 weeks	PASI score (mean ± SD): - Baseline: 12.8 ± 5.5 - Week 12 (change from baseline): – 9.8 ± 1.4 - Week 52 (change from baseline): – 11.0 ± 3.1 - PASI 75, n (%): 4 (80.0) - PASI 90, n (%): 3 (60.0) - PASI 100, n (%): 2.0 (40.0) - Week 52 (LOCF): 1.8 - Week 244 (LOCF): 1.6 Improvements from baseline in PASI observed as early as Week 1 (– 6.9 ± 3.0) sPGA at: - Baseline (mean ± SD): 3.4 ± 0.9 - Week 52: sPGA (0), n (%): 2 (40.0) sPGA (0,1), n (%): 3 (60.0) GIS at Week 12: resolved, n = 1 (20.0%); improved, n = 4 (80.0%) DSS: - Baseline: 2.8 - Week 52 (LOCF): 0.8 - Week 244 (LOCF): 0.6 Assessment of skin symptoms, GIS, NAPSI, PSSI improved from baseline to Week 52	244 weeks	Patients with ≥ 1 TEAE: n = 5 (100%) AESIs: 80% (n = 4/5) included infections (4), allergic reaction/hypersensitivity (2), injection-site reaction (1), and depression (1) No severe TEAEs, serious AEs or deaths were reported	DLQI score [mean (SD)]: - Baseline: 9.6 (6.5) - Week 12: 4.2 (6.6) - Week 52: 3.8 (4.4) - Week 244: 3.6 (4.8) Change from baseline at: - Week 2: – 5.0 ± 3.5 - Week 12: – 5.4 ± 3.9 - Week 24: – 5.4 ± 4.0 - Week 52: – 5.8 ± 3.9 Itch NRS [mean (SD)]: - Baseline: 7.2 (2.4) - Week 12: 2.0 (1.7) - Week 52: 1.8 (3.0) - Week 244: 1.6 (2.1) - Change from baseline at Week 52: – 5.4 ± 3.1
Zheng et al. [59]	Prospective study	N = 38/Chinese patient with GPP (N = 1)	Ixekizumab	Baseline PASI score: 23.0 Achieved PASI 75 after 4 weeks and PASI 90 after 8 weeks At Week 52 PASI score: 4.0	52 weeks	NA	NA
Secukinumab
Imafuku et al. [20]	Interventional, multicentre, single-arm, open-label study (NCT01952015; JAPIC JapicCTI-132305)	Japanese adults with GPP (N = 12)	Secukinumab 150 mg once weekly at Weeks 0, 1, 2, 3, and 4, and then every 4 weeks until Week 52	Median (range) PASI at baseline: 17.4 (6.1–26.5) Week 52 - PASI 75: 72.7% (n = 8/11); onset of PASI 75 response was at approximately Weeks 3–4, reached a maximum at approximately Week 16 (83.3%, n = 10/12), and was sustained until Week 52 - PASI 90: 63.6% (n = 7/11) - PASI 100: 27.3% (n = 3/11) CGI score ‘very much improved’: - Week 16: 75% (n = 9/12) - Week 52: 58.3% (n = 7/12) JDA total score was rapidly reduced from Weeks 1–3, and the decrease was sustained until Week 52	52 weeks	Any AE: 100% (n = 12) Non-fatal SAE: 25% (n = 3) Discontinued due to any AE: 16.7% (n = 2)	NA
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 210 treatment courses in patients from Germany with GPP/N = 14 treatment courses	Secukinumab	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 60% (n = 6/10) Partial response (patient records note some improvement): 30% (n = 3/10) Non-response (disease exacerbation): 10% (n = 1/10)	Patients treated between January 2005 and May 2019	AEs: 28.6% (n = 4/14) Discontinuations: 23.1% (n = 3/14) Discontinuations due to AEs: 66.7% (n = 2/3)	NA
Miao et al. [21]	Retrospective study	N = 36 paediatric patients from China with GPP/N = 20	Secukinumab	All patients demonstrated a significant response JDA Score Baseline: 8.95 ± 3.49 Week 1: 2.8 ± 1.74 Week 2: 1.25 ± 0.97 Week 12: 0	Patients treated between January 2019 and January 2022	Short-term AEs Abnormal liver enzyme: 10% (N = 2) Herpes simplex: 5% (N = 1) EO% increase: 10% (N = 2) Atopic dermatitis-like lesions: 10% (N = 2) Neutropenia: 10% (N = 2)	NA
Tariq et al. [22]	Prospective study	Patients with psoriasis (N = 11)/patients with GPP (N = 2)	Secukinumab 150 mg Weeks 0–4, and then monthly for 5 months	PASI 50 achieved at 25 weeks: 100% (2/2) PASI 75 achieved at 25 weeks: 50% (1/2)	5 months	NA	Reduction in DLQI > 10 points At 5 weeks: 100% (2/2) At 25 weeks: 100% (2/2)
Wu et al. [23]	Prospective study	Patients with acute GPP (N = 13)	Adults: weekly dose of secukinumab 300 mg Weeks 0–4, and every 4 weeks thereafter Paediatrics: secukinumab 150 mg Week 0, Week 2 and every 4 weeks thereafter	Week 2: 76.2% of patients achieved improvement in GPPASI Week 24: 92.3% of patients achieved IGA 0/1	May 2020–September 2021	AE of leucopenia: 15% (n = 2/13)	NA
Brodalumab
Yamasaki et al. [24]	Open-label, multicentre study (NCT01782937)	N = 30/patients from Japan with GPP (N = 12)	Brodalumab 140 mg at Day 1, Weeks 1 and 2, and then every 2 weeks until Week 52	PASI score - Baseline (mean ± SD): 15.01 ± 12.08 - Week 12: 5.24 ± 8.55 - PASI 75, n (%): 7 (58.3) - PASI 90, n (%): 4 (33.3) - PASI 100, n (%): 3 (25.0) Week 52 (LOCF) – PASI score (mean ± SD): 1.83 ± 4.86 - PASI 75, n (%): 10 (83.3) - PASI 90, n (%): 10 (83.3) - PASI 100, n (%): 7 (58.3) 75.0% of patients (n = 9/12) and 83.3% of patients (10/12) achieved a CGI response of ‘improved’ or ‘remission’ at Weeks 2 and 12, respectively At Week 52 (LOCF), 91.7% of patients (11/12) achieved a response of ‘improved’ or ‘remission’ Improvements seen across PSS, NAPSI and PSSI scores	52 weeks	Any AEs: 91.7% (n = 11/12) Grade 3 AEs: 8.3% (n = 1/12) SAEs: 25.0% (n = 3/12) Discontinuations: n = 1	Baseline DLQI (mean ± SD): 7.9 ± 5.5 DLQI change from baseline (mean ± SD): Week 12: – 3.8 ± 6.3 Week 52 (LOCF): – 5.5 ± 6.6 DLQI score (0 or 1), n (%): Week 12: 4 (33.3%) Week 52 (LOCF): 8 (66.7%) Baseline PDI score (mean ± SD): 11.2 ± 8.8 PDI change from baseline (mean ± SD): Week 12: – 5.4 ± 8.0 Week 52 (LOCF): – 7.8 ± 9.9
Guselkumab
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 5 treatment courses	Guselkumab: standard maintenance dosage for psoriasis	Partial response (patient records note some improvement): 100% (n = 1 treatment course) Response not reported: n = 4 treatment courses	Patients treated between January 2005 and May 2019	Any AE: n = 1 (20%)	NA
Sano et al. [25]	Single-arm, open-label, multicentre study	N = 21/Japanese adults with GPP (N = 10)	Guselkumab 50 mg at Weeks 0, 4 and then Q8W From Week 20, the dose was increased to 100 mg Q8W if patients met the dose-escalation criteria	CGI score (Week 16): Very much improved: 22.2% (n = 2) Much improved: 22.2% (n = 2) Minimally improved: 33.3% (n = 3) - Baseline PASI total score, mean (SD): 29.3 (20.0) - Week 8: Mean reduction in PASI, n = 9; Δ, – 13.8 (12.7) - Week 52: 8 patients achieved a mean absolute PASI of 4.8 (6.4), with median improvement of 86.8%; Δ, – 22.3 (12.9) Reduction in JDA severity index total score from baseline; treatment success was 100% (n = 8/8) for patients who completed Week 52	52 weeks	All patients had ≥ 1 TEAE Two patients had serious TEAEs (fall and loss of consciousness [n = 1]; squamous cell carcinoma of skin [n = 1]). All TEAEs were mild to moderate, except for squamous cell carcinoma, which was severe	DLQI improvement as early as Week 8 Mean (SD) DLQI score improved from 10.1 (6.2) at baseline to 6.2 (8.0) at Week 8, and 0.5 (0.6) at Week 52 DLQI score of 0/1 (indicating no impact of disease on QoL) at Week 52 was achieved by 42.9% of patients (n = 3/7) Improved HRQoL, as measured by SF-36 MCS and PCS scores, was observed through Week 48
Risankizumab
Yamanaka et al. [26]	Randomized, open-label, multicentre study (NCT03022045)	N = 17/Japanese patients with GPP (N = 8)	Risankizumab 150 mg at Week 0 and Week 4 and every 12 weeks thereafter through Week 160	All patients achieved the primary end point of clinical response at Week 16, regardless of dose Reduction of JDA total scores from baseline was observed as early as Week 4 (mean change =  − 3.5 [SD 1.9]) and continued to decrease through Week 52. JDA total scores were generally maintained through Week 160 PASI 90 was achieved by 87.5% of patients at Week 16, and most patients maintained PASI 90 through Week 160	160 weeks	Any AE: 100% (N = 8) SAE: 25% (N = 2) AE leading to discontinuation: 25% (N = 2) Possible drug-induced liver injury: 38% (N = 3)	DLQI 0/1 was achieved by 75.0% of patients after 16 weeks of treatment. Most of the continuing patients achieved DLQI 0/1 by Week 160
Gevokizumab
Mansouri et al. [64]	Patient cases from an open-label, expanded-access study	Patients with severe recalcitrant GPP (N = 2) Patient 1: 6-month history of acute-onset GPP Patient 2: 6-month history of severe recalcitrant GPP	Gevokizumab 60 mg every 4 weeks for 12 weeks	Reduction in GPPASI scores: 79% at Week 4 (Patient 1); 65% at Week 12 (Patient 2)	12 weeks	Patient 1: discontinued at Week 5 for other reasons (flank abscess), despite reduction in overall pustulosis	DLQI at Weeks 0, 2, 4, 8 and 12: - Patient 1: 30, 30, 26, discontinued - Patient 2: 30, 30, 23, 17, 17
Ustekinumab
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 14 treatment courses	Ustekinumab: standard maintenance dosage	Excellent response (patient records note complete or marked response, remission, dramatic improvement, and near or complete clearance): 33.3% (n = 2/6) Partial response (patient records note some improvement): 50% (n = 3/6) Non-response (disease exacerbation): 16.7% (n = 1/6)	Patients treated between January 2005 and May 2019	Treatment discontinuations: 46.2% (n = 6/13 treatment courses) AEs: 21.4% (n = 3/14 treatment courses) Discontinuations due to AEs: 33.3% (n = 2/6)	NA

AE adverse event, AESI adverse event of special interest, CGI Clinical Global Impression score, CI confidence interval, CR clinical response, CZP certolizumab, DLQI Dermatology Life Quality Index, DSS dermal symptoms score, EO% percentage of eosinophils, EP erythrodermic psoriasis, FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue, GIS Global Improvement Score, GPP generalized pustular psoriasis, GPPASI Generalized Pustular Area and Severity Index, GPPGA Generalized Pustular Psoriasis Physician Global Assessment, HRQoL health-related quality of life, IGA Investigator’s Global Assessment, IQR interquartile range, Itch NRS/INRS Itch Numeric Rating Scale, IV intravenous, JDA Japanese Dermatological Association, LOCF last observation carried forward, MCID minimal clinically important differences, MCS Mental Component Summary, MTX methotrexate, NA not available, NAPSI Nail Psoriasis Severity Index, PASI Psoriasis Area and Severity Index, PASI 50/75/90/100 proportion of patients achieving ≥ 50%, ≥ 75%, ≥ 90% or ≥ 100% PASI improvement from baseline, PCS Physical Component Summary, PDI Psoriasis Disability Index, PI principal investigator, PRO patient-reported outcome, PSS Psoriasis Symptom Scale, PSSI Psoriasis Scalp Severity Index, Q2W/Q8W once every 2/8 weeks, QoL quality of life, SAE serious adverse event, SC subcutaneous, SD standard deviation, SF-36 36-Item Short Form Health Assessment Questionnaire, sPGA static Physician Global Assessment, TEAE treatment-emergent adverse event, TRAE treatment-related adverse event, VAS visual analogue scale

Fig. 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

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 [36–39] 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 [43–46]. 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 [51–57]. 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, 56–58], 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 [16–19, 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 [17–19]. 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 [20–23, 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 [65–67] 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

References	Study type	Patient population (overall/GPP)	Treatment	Efficacy outcomes	Study duration	Safety outcomes	QoL/PRO outcomes
Etretinate
Ozawa et al. [69]	Retrospective multicentre study	N = 385 patients from Japan with GPP/N = 188	Etretinate 1 mg/kg/day	84.1% of patients (158/188) treated with etretinate (1 mg/kg/day) had an effective response (‘remarkably effective’ or ‘effective’ on a 4-point clinical effectiveness scale)	Patients treated between 1987 to 1996	AEs were reported in 59 patients (46.46%)	NA
Wolska et al. [70]	Randomized, double-blind study	N = 40/Patients with GPP (N = 10; 4 in double-blind study; 6 additional, subsequent cases)	Etretinate: 0.3–1.0 mg/kg/day	After 1–4 months of etretinate therapy: Almost complete clearing: n = 2 Complete clearing: n = 6 Moderate improvement: n = 1 No improvement: n = 1	NA	NA	NA
Acitretin
Chen et al. [71]	Retrospective study and literature review	N = 15/Children with GPP (N = 10)	Initial acitretin dose: 0.6–1.0 mg/kg/day for 4–6 weeks Transition dose: 0.2–0.4 mg/kg/day for 4–6 weeks Maintenance dose: 0.2–0.3 mg/kg/day	Excellent response (> 90% clearing): 90% (n = 9) Good response (60–90% clearance) but with a relapse after stopping treatment: 10% (n = 1) Skin lesion remission was observed after 5–7 days of treatment	10–32 months	AEs: 80% (n = 8) Dry skin: n = 6 Itching: n = 4 Cheilitis: n = 1	NA
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 28 treatment courses	Acitretin: mean 0.4 mg/kg/day	Excellent response (patient records note complete or marked response, remission, dramatic improvement and near or complete clearance): 40.9% (n = 9 treatment courses) Partial response (patient records note some improvement): 31.8% (n = 7 treatment courses) Non-response (exacerbation of disease): 27.3% (n = 6 treatment courses)	Patients treated between January 2005 and May 2019	Discontinuation due to: AEs: 17.6% (n = 3) Ineffectiveness: 41.2% (n = 7) Remission: 17.6% (n = 3) Other: 23.5% (n = 4)	NA
Lau et al. [72]	Retrospective chart review	N = 27 patients with juvenile GPP treated in Malaysia/N = 16	Acitretin 1 mg/kg	Acitretin was effective in controlling acute flares in all 16 patients	Data collection November 2015 to April 2016	NA	NA
Lu et al. [73]	Prospective comparative study	Chinese patients with GPP (N = 54, where N = 40 treated with acitretin and N = 14 treated with MTX)	MTX: 10 mg/week maintained until 52nd week Acitretin Low dose: 0.3 mg/kg/day, maintained to 52 weeks (N = 13) Medium dose: 0.4 mg/kg/day, maintained to 52 weeks (N = 13) High dose: 0.5 mg/kg/day, maintained to 52 weeks (N = 14)	Effective rates of treatment in the four groups as assessed by GPPASI regression were 69.1%, 86.9%, 88.2% and 91.9%, respectively (markedly effective) BSA scores of the four groups were not significantly different before treatment and were significantly reduced after treatment. The decrease was more significant in the high-dose acitretin group	52 weeks	AEs MTX: 16.2% Acitretin Low dose: 8.1% Medium dose: 10.3% High dose: 14.7%	DLQI scores of the four groups were not significantly different before treatment and were significantly reduced after treatment. The decrease was more significant in the high-dose acitretin group
Miao et al. [21]	Retrospective study	N = 36 paediatric patients from China with GPP/N = 16	Acitretin 0.5 mg/kg (10–30 mg/kg) daily	JDA Score Baseline: 10.13 ± 2.33 Week 1: 6.06 ± 2.32 Week 2: 2.81 ± 1.72 Week 12: 0.69 ± 0.87	Patients treated between January 2019 to January 2022	Short-term AEs Abnormal liver enzyme: 25% (N = 4) Dyslipidaemia: 37.5% (N = 6) Mucocutaneous dryness: 75% (N = 12)	NA
Zheng et al. [57]	Retrospective study	N = 110/Patients from China with GPP (N = 98)	Acitretin 0.5–1.0 mg/kg/day (maximum dose did not exceed 40 mg/day)	Pustule clearance: 70 Partial pustule clearance: 9 Treatment failure: 19 Mean ± SD time to pustule clearance: 8.5 ± 5.2 days (n = 70) Treatment efficacy rate: 70/98 (71.4%)	Patients treated between 2014 to 2019	Leucocytosis: 13/66 (19.7%) Hypoalbuminaemia: 35/66 (53.0%) Abnormal liver function: 11/66 (16.7%) Hyperuricaemia: 15/66 (22.7%) Hyperlipidaemia: 26/55 (47.3%) Elevated hs-CRP: 9/19 (47.4%) Hypocalcaemia: 1/7 (14.3%)	NA
			Etanercept + acitretin (n = 9)	Pustule clearance: 8 Partial pustule clearance: 0 Treatment failure: 0 Withdrawal (due to financial reasons): 1 Mean ± SD time to pustule clearance: 12.6 ± 7.1 days Treatment efficacy rate: 8/8 (100%)		NA	NA
Zhu et al. [74]	Retrospective cohort study	Patients in Beijing with GPP (N = 61)	Acitretin 0.5 mg/kg/day	Therapeutic efficacy (complete response [complete disappearance of rashes, pustules, erythema, scales] or marked response [disappearance of 75% of rashes, pustules, erythema, scales]): 18/25 patients (72.0%) with HOMG mutation 4/7 patients (57.1%) with HEMG mutation 14/29 patients (48.3%) with no mutation Frequency of recurrence (moderate [3/4 per year] or severe [5 per year]): 9/25 patients (36.0%) with HOMG mutation 2/7 patients (28.6%) with HEMG mutation 4/29 patients (13.8%) with no mutation	Patients treated between 2012 and 2014	NA	NA
Hydroxyurea
Das et al. [75]	Prospective, non-randomized study	N = 76/patients with GPP (N = 6)	Hydroxyurea 500 mg two or three times daily for 12 weeks, then once daily for another 12 weeks	At 12 weeks: • Complete response (> 95% lesions cleared): 33.2% (n = 2) • Excellent response (> 75–95% clearance): 16.7% (n = 1) • Good response (> 50–75% clearance): 16.7% (n = 1) • No response (< 25% clearance): 16.7% (n = 1) • Disease worsened: 16.7% (n = 1)	6 months	All patients had lesional pigmentation One patient became sick and switched to another treatment	NA
Juanqin et al. [90]	Retrospective analysis	Patients hospitalized with childhood GPP (N = 30)/number receiving hydroxyurea not specified	Hydroxyurea 20 mg/kg/day	Stated as effective for GPP but no data presented	Patients treated between 1985 and 1996	NA	NA
Methotrexate
Collins et al. [76]	Retrospective review	N = 40/patients with GPP (N = 6)	MTX (orally in most cases in a single weekly dose)	Excellent response: n = 4 Good response (disease measure not defined): n = 2	NA	Treatment discontinuation in patients with psoriasis: Severe nausea (n = 2); abnormal laboratory tests (n = 5) Toxic epidermal necrolysis and subsequent death: n = 2	NA
Haustein and Rytter [77]	26-year retrospective single-centre study	N = 157/patients with GPP (N = 24)	MTX dosage range: 7.5–50.0 mg/week	Good response (clear or almost clear skin): n = 19 (80%) Moderate response (recurrence during treatment): n = 3 (13%) Poor response (no improvement): n = 2 (7%)	January 1972 to December 1998	Main AEs in patients with psoriasis included: Abnormal liver function tests (25%), gastrointestinal symptoms (24%) and bone marrow suppression (11%) One of the 24 patients with GPP (4.2%) developed lung cancer, possibly in relation to long-term MTX treatment	NA
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 42 treatment courses	MTX (mean dose 13 mg/week) (42 of a total 201 treatment courses [20.9%] were for MTX)	Number of treatment courses Excellent response: n = 6 Partial response: n = 8 No response: n = 10	Patients treated between January 2005 and May 2019	Any AE: n = 13 treatment courses (31.0%) Treatment discontinuation: n = 31 treatment courses (77.5%)	NA
Ozawa et al. [69]	Retrospective study	N = 385 patients from Japan with GPP/N = 41	MTX 2.5–5.0 mg orally at 12-h intervals 3 times/week	Remarkably effective or effective in 76% (n = 31)	Patients treated between 1987 and 1996	NA	NA
Zheng et al. [57]	Retrospective study	N = 110/patients from China with GPP: MTX (N = 8)	MTX 7.5–15.0 mg/week	Pustule clearance: 5 Partial pustule clearance: 2 Treatment failure: 1 Mean (SD) time for pustule clearance: 5.0 ± 4.4 days (n = 5) Treatment efficacy rate: 5/8 (62.5%)	Patients treated between 2014 to 2019	Leucocytosis: 1/7 (14.3%) Hypoalbuminaemia: 1/7 (14.3%) Abnormal liver function: 4/7 (57.1%) Hyperuricaemia: 3/7 (42.9%) Hyperlipidaemia: 0/3 (0%) Elevated hs-CRP: 3/5 (60.0%) Hypocalcaemia: 0/0 (0%)	NA
		Etanercept + MTX (N = 3)	Etanercept + MTX	Pustule clearance: 2 Partial pustule clearance: 0 Treatment failure: 1 Median (range) time for pustule clearance: 9 (5–13) days Treatment efficacy rate: 2/3 (67%)		NA	NA
Cyclosporine (CyA)
Cohen Barak et al. [80]	Retrospective chart review	N = 10/one patient with GPP	CyA monotherapy (2–4 mg/kg) initially	Inadequate cutaneous response; dose reduction resulted in flare Etanercept 50 mg twice weekly was added; CyA was tapered over 6 weeks, and the patient had a complete response (> 75% improvement)	7 months	NA	NA
Choon et al. [79]	Retrospective chart review	N = 102 patients with adult onset GPP in a tertiary hospital in Malaysia/N = 8	CyA	Average time to resolution of pustules, 14 days	Between 1989 and November 2011	Hypertension requiring antihypertensive treatment: 37.5% (n = 3) Patients were weaned off antihypertensive medication after stopping CyA	NA
Dogra et al. [78]	Retrospective chart review	N = 10/one patient with GPP	CyA: 100 mg/day Tapered and then stopped	Baseline PASI: 18.2 Week 4 PASI: 3.2 Week 8 PASI: Cleared	8 weeks	NA	NA
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 17 treatment courses	CyA: mean 2.6 mg/kg/day	Excellent response (patient records note complete or marked response, remission, dramatic improvement or complete clearance): 45.5% (n = 5) Non-response: 27.3% (n = 3) Partial response: 27.3% (n = 3)	Patients treated between January 2005 and May 2019	Any AE: 23.5% (n = 4) All treatment withdrawals: 76.5% (n = 13) AE reported as a reason for treatment discontinuation: 15.4% (n = 2)	NA
Corticosteroids
Miyachi et al. [81]	Retrospective cohort study	N = 1516 patients from Japan with GPP who required hospitalization/N = 274	Corticosteroids	In-hospital mortality: 9.1% (vs 1% in biologics group and 3.7% in oral agents group); p < 0.001 In-hospital morbidity: 12% (vs 5.4% in biologics group and 8.2% in oral agents group); p = 0.02 ICU admission within 2 days: 2.2% (vs 0.7% in biologics group and 1.2% in oral agents group)	Patients treated between July 2010 to March 2019	NA	NA
Zheng et al. [57]	Retrospective study	N = 110/patients from China with GPP (N = 8)	Corticosteroids	Pustule clearance: n = 6 Partial pustule clearance: n = 2 Treatment failure: n = 0 Mean (SD) time for pustule clearance: 12.9 (6.0) days Treatment efficacy rate: 6/8 (75%)	Patients treated between 2014 to 2019	Leucocytosis: 4/5 (80.0%) Hypoalbuminaemia: 2/5 (40.0%) Abnormal liver function: 2/5 (40.0%) Hyperuricaemia: 2/5 (40.0%) Hyperlipidaemia: 2/4 (50.0%) Elevated hs-CRP: 1/3 (33.3%) Hypocalcaemia: 0/1 (0%)	NA
Fumaric acid ester
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 19 treatment courses	FAEs: mean 1.5 tablets, 120 mg/day	Excellent response (patient records note complete or marked response, remission, dramatic improvement and near or complete clearance): 33.3% (n = 2 treatment courses) Partial response (patient records note some improvement): 33.3% (n = 2 treatment courses) No response (disease exacerbation): 33.3% (n = 2 treatment courses) Remission: 6.3% (n = 1 patient) Response not reported: 68.4% (n = 13 treatment courses) Ineffectiveness reported as a reason for treatment discontinuation: 12.5% of patients	Patients treated between January 2005 and May 2019	Any AE: 47.4% of treatment courses Treatment withdrawals: 88.9% of treatment courses AE reported as a reason for treatment discontinuation: 56.3% of patients	NA
Apremilast
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 2 treatment courses	Apremilast: licensed maintenance dosage	Excellent response (n = 1); response not reported (n = 1)	Patients treated between January 2005 and May 2019	Treatment discontinuation: 2/2 (100%) Any AEs: 0%	NA

AE adverse event, BSA body surface area, CyA cyclosporine, DLQI dermatological quality of life index, FAE fumaric acid ester, GPP generalized pustular psoriasis, GPPASI Generalized Pustular Psoriasis Area and Severity Index, HEMG heterozygous mutation group, HOMG homozygous mutation group, hs-CRP high-sensitivity C-reactive protein, ICU intensive care unit, JDA Japanese Dermatological Association, MTX methotrexate, NA not available, PASI Psoriasis Area and Severity Index, PRO patient-reported outcome, QoL quality of life, SD standard deviation

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, 71–74]. Efficacy outcome definitions varied widely, and response rates ranged from 40.9 to 100% [21, 51, 57, 71–74]. 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, 78–80], 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

References	Study type	Patient population (overall/GPP)	Treatment	Efficacy outcomes	Study duration	Safety outcomes	QoL/PRO outcomes
GMA
Ikeda et al. [82]	Single-arm, unblinded study	Patients with moderate-to-severe GPP despite receiving conventional medications (N = 15)	One GMA session per week	Responders: 85.7% (12/14) Extent of erythroderma (n = 14, p = 0.0042), pustules (n = 14, p = 0.0031) and oedema (n = 14, p = 0.0014) was significantly improved Pustules and oedema disappeared in 7 and 10 patients, respectively	5 weeks	16 AEs in three patients; none considered serious One patient had an allergic reaction to nafamostat mesylate, which is an anticoagulant used in GMA in Japan	NA
PUVA
Braun-Falco et al. [84]	Retrospective case series	N = 18/patients with GPP from Germany (N = 7); 1 patient received PUVA	0.6 mg/kg MOP followed by UV-A irradiation (with initial doses between 0.5 and 1 J/cm2). Total dose 48 J/cm2	Good clinical response in 3 weeks and complete remission in 7 months (disease measure not defined)	Patients treated between 1969 and 1981	NA	NA
Kromer et al. [51]	Non-interventional retrospective patient chart review	N = 201 treatment courses in patients from Germany with GPP/N = 6 treatment courses	Treatment courses of acitretin and MTX were combined with PUVA: - Acitretin + PUVA: 17.9% (n = 5 treatment courses) - MTX + PUVA: 2.4% (n = 1 treatment course)	NA	Patients treated between January 2005 and May 2019	NA	NA
Ozawa et al. [69]	Retrospective, multicentre study	N = 385 patients with GPP from Japan/N = 81	PUVA: ~ 40 mg of 8-MOP administered 2 h before UV-A irradiation. Exposure dose gradually increased up to 2 to 3 MPD 1–3 times per week	Effective clinical response (remarkably effective or effective): n = 41	Patients treated between 1987 and 1996	Side effects: n = 13 (16.05%, N = 81)	NA
Glycyrrhizin
Yu et al. [85]	Retrospective case series	Patients with GPP and liver test abnormalities (N = 9)	Combination of oral acitretin (0.5 mg/kg/day) and intravenous glycyrrhizin (80 mg/day) for 2 weeks, followed by oral acitretin (20–30 mg/day) and oral glycyrrhizin (150 mg/day) over a 12-month follow-up period	Mean baseline severity score of GPP was 13.3 ± 2.6 (range 9–16) At Week 2, patients achieved ≥ 77% improvement (range 77–94%) in the severity score of GPP Clinical remission persisted at the 12-month follow-up in all but two patients	12 months	No significant side effects occurred during treatment or in the follow-up period	NA
Dapsone
Juanqin et al. [90]	Retrospective analysis	Patients hospitalized with childhood GPP (N = 30)/N = 26 (severe and mild disease: n = 6 and n = 20, respectively)	Combination therapy (TDE) of Chinese herb Lei-Gong-teng (Tripterygium wilfordii) 2–6 tablets per day, dapsone 25 to 75 mg/day and erythromycin 0.45 to 0.9 g/day	Total effective rate: 92% Excellent response (total clearing of the lesions): n = 19/26 Moderate to good response (> 50% clearance): n = 5	Patients treated between 1985 and 1996	Leukopenia (n = 2) Gastrointestinal discomfort (n = 7)	NA
Thiamphenicol
Juanqin et al. [90]	Retrospective analysis	Patients hospitalized with childhood GPP (N = 30)/N = 2	Thiamphenicol 20 mg/kg/day	Poor response (symptoms still existed or < 50% of the pustules cleared): n = 2	Patients treated between 1985 and 1996	Gastrointestinal disturbance in all patients (n = 2)	NA

AE adverse event, GMA granulocyte and monocyte adsorption apheresis, GPP generalized pustular psoriasis, MOP methoxypsoralen, MPD minimum phototoxic dose, MTX methotrexate, NA not available, PRO patient-reported outcome, PUVA psoralen plus UV-A, QoL quality of life, UV-A ultraviolet A

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 [16–20, 24–26, 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 [36–39]. 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.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Lluis Puig, Hideki Fujita, Diamant Thaçi, Min Zheng, Ana Cristina Hernandez Daly, Craig Leonardi, Mark G. Lebwohl and Jonathan Barker contributed to the conceptualization of the study; investigation; validation and visualization of the results; review and editing of the manuscript content; and approved the final version for submission.

Funding

The study and the Rapid Service Fee was supported and funded by Boehringer Ingelheim as part of the initiative PIONEERS^® Partnering for Innovation and Excellence in Rare Skin Diseases.

Data Availability

To ensure independent interpretation of clinical study results and enable authors to fulfil their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to clinical study data pertinent to the development of the publication. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data when it becomes available on Vivli – Center for Global Clinical Research Data (https://vivli.org/), and earliest after publication of the primary manuscript in a peer-reviewed journal, regulatory activities are complete and other criteria are met. Please visit MyStudyWindow at www.mystudywindow.com/msw/datasharing for further information.

Declarations

Conflict of Interest

Lluís Puig has received consultancy/speaker’s honoraria from and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Celgene, Gebro Pharma, Janssen, JS BIOCAD, LEO Pharma, Lilly, Merck Serono, MSD, Mylan, Novartis, Pfizer, Regeneron, Roche, Sandoz, Samsung Bioepis, Sanofi and UCB. Hideki Fujita has received honoraria or fees for serving on advisory boards, as a speaker and as a consultant, as well as grants as an investigator from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Chugai Pharmaceutical, Eisai, Eli Lilly, Janssen, Japan Blood Products Organization, JMEC, Kaken, Kyorin, Kyowa Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe Pharma, Nihon Pharmaceutical, Novartis, Sanofi, Sun Pharma, Taiho, Torii, UCB and Ushio. Diamant Thaçi declares having attended advisory boards and/or received consultancy fees and/or receiving grants as an investigator from AbbVie, Almirall, Amgen, Beiersdorf, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Galapagos, Janssen-Cilag, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Samsung, Sanofi, Sun Pharmaceutical Industries and UCB. Min Zheng has received grants, consulting fees and/or speaker’s fees from AbbVie, Boehringer Ingelheim, Janssen-Cilag, LEO Pharma China, Novartis, Pfizer and Xian-Janssen. Ana Cristina Hernandez Daly is an employee of Boehringer Ingelheim. Craig Leonardi has received honoraria or fees for serving on advisory boards, as a speaker and as a consultant, as well as grants as an investigator from AbbVie, Actavis, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Eli Lilly, Galderma, Janssen, Merck, Novartis, Pfizer, LEO Pharma, Sandoz, Stiefel, UCB, Vitae and Wyeth. Mark G. Lebwohl is an employee of Mount Sinai and receives research funds from: AbbVie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Cara Therapeutics, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc., and is a consultant for Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Arena Pharmaceuticals, Aristea Therapeutics, Avotres Therapeutics, BiomX, Brickell Biotech, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Celltrion, Corevitas, Dermavant Sciences, Evommune, Inc., Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Hexima Ltd, Incyte, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, Trevi, Vial, and Verrica. Jonathan Barker declares having attended advisory boards and/or received consultancy fees and/or spoken at sponsored symposia, and/or received grant funding from AbbVie, Almirall, Amgen, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Samsung, Sienna, Sun Pharmaceutical Industries and UCB.

Ethical Approval

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.