Generalised pustular psoriasis (GPP) is a rare, chronic and life-threatening inflammatory skin disease characterised by widespread eruption of sterile pustules. With the approval of a GPP flare treatment in several countries occurring only recently, the socioeconomic burden associated with GPP is not well established. To highlight current evidence for patient burden, healthcare resource utilization (HCRU) and costs associated with GPP. Patient burden results from serious complications including sepsis and cardiorespiratory failure causing hospitalization and death. HCRU is driven by high hospitalization rates and treatment costs. The mean duration of a GPP hospital stay ranges from 10 to 16 days. A quarter of patients require intensive care, and the mean intensive care stay is 18 days. In comparison to patients with plaque psoriasis (PsO), patients with GPP have: a 64% higher score on the Charlson Comorbidity Index; higher hospitalization rates (≤36.3% vs. ≤23.3%); lower overall quality of life, and higher symptom scores for pain, itch, fatigue, anxiety and depression; direct costs associated with treatment 1.3- to 4.5-fold higher; higher rates of disabled work status (20.0% vs. 7.6%); and increased presenteeism (i.e. worse impairment at work), impaired daily activities, and medically related absenteeism. Current medical management and drug treatment utilising non-GPP-specific therapies impose a significant patient and direct economic burden. GPP also imposes an indirect economic burden by increasing work productivity impairment and medically related absenteeism. This high level of socioeconomic burden reinforces the need for new therapies with proven efficacy in the treatment of GPP.

The aim of this study was to analyse sick leave in generalized pustular psoriasis, the most severe form of pustular psoriasis. Prolonged sick leave of >14 days was analysed for 502 patients with generalized pustular psoriasis compared with controls with psoriasis vulgaris and matched controls from the general population. Using data from the Swedish National Patient Register, and the Longitudinal integrated database for health insurance and labour market studies, the study estimated the mean number of sick leave days in the year of first diagnosis of generalized pustular psoriasis (index year) and for 2 years before and after the index year. Patients with generalized pustular psoriasis were on sick leave to a larger extent than both control populations for all study years. The number of sick leave days peaked in the index year and then reduced. Compared with the control populations, sick leave in generalized pustular psoriasis was already higher prior to diagnosis, indicating delayed diagnosis and/or a comorbidity burden.

Generalized pustular psoriasis (GPP) is a rare, chronic, neutrophilic inflammatory skin disease characterized by episodes of widespread eruption of sterile, macroscopic pustules that can be accompanied by systemic inflammation and symptoms. A systematic literature review and narrative synthesis were conducted to determine the impact of GPP on patients' health-related quality of life (HRQoL) and patient-reported severity of symptoms and to compare its impact to patients with plaque psoriasis (plaque PsO). Searches were undertaken in Embase, MEDLINE and the Cochrane Library from 1 January 2002 to 15 September 2022. Screening was carried out by two reviewers independently. Outcome measures included generic (e.g. EQ-5D, SF-36) and dermatology-specific (e.g. DLQI) clinical outcome assessments, and other relevant patient-reported outcome measures (PROMs) (e.g. severity of pain measured by a numerical rating scale). Overall, 20 studies were found to be eligible for inclusion, of which seven also had data for plaque PsO. The DLQI was the most frequently reported outcome measure (16 out of 20 studies). When reported, mean DLQI (SD) scores varied from 5.7 (1.2) to 15.8 (9.6) across the studies, indicating a moderate to very large effect on HRQoL; the wide range of scores and large SDs were explained by the small population sizes (n ≤ 12 for all studies except two). Similar ranges and large SDs were also observed for other measures within individual studies. However, in general, people with GPP reported a greater impact of their skin condition on HRQoL, when compared to people with plaque PsO (i.e. higher DLQI scores) and higher severity for itch, pain and fatigue. This systematic review highlighted the need for studies with a larger population size, a better understanding of the impact of cutaneous and extracutaneous symptoms and comorbidities on HRQoL during and between GPP flares, and outcome measures specifically tailored to the unique symptoms and the natural course/history of GPP.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening skin disease and the clinical heterogeneity of which is largely unknown. Retrospective cohort analysis was conducted on hospitalized GPP patients between January 2010 and November 2022. A total of 416 patients with GPP and psoriasis vulgaris (PV) respectively were included, matched 1:1 by sex and age. The heterogeneity of GPP was stratified by PV history and age. Compared with PV, GPP was significantly associated with prolonged hospitalization (11.7 vs. 10.3 day, p < 0.001), elevated neutrophil lymphocyte ratio (NLR) (5.93 vs. 2.44, p < 0.001) and anemia (13.9% vs. 1.2%, p < 0.001). Moreover, GPP alone (without PV history) was a relatively severer subtype with higher temperature (37.6°C vs. 38.0°C, p = 0.002) and skin infections (5.2% vs. 11.4%, p = 0.019) than GPP with PV. For patients across different age, compared with juvenile patients, clinical features support a severer phenotype in middle-aged, including higher incidence of anaemia (7.5% vs. 16.0%, p = 0.023) and NLR score (3.83 vs. 6.88, p < 0.001). Interleukin-6 (r = 0.59), high density lipoprotein cholesterol (r = -0.56), albumin (r = -0.53) and C-reactive protein-to-albumin ratio (r = 0.49) were the most relevant markers of severity in GPP alone, GPP with PV, juvenile and middle-aged GPP, respectively. This retrospective cohort suggests that GPP is highly heterogeneous and GPP alone and middle-aged GPP exhibit severe disease phenotypes. More attention on the heterogeneity of this severe disease is warranted to meet the unmet needs and promote the individualized management of GPP.

Generalized pustular psoriasis is a rare presentation of psoriatic disease and is characterized by the acute onset of diffuse superficial pustules on the skin. These pustules can often coalesce, forming what's known as 'lakes of pus' that are most often seen on the trunk and on skin folds. GPP flares are often accompanied by systemic symptoms, including fever, malaise, and edema. The interleukin (IL)-36 pathway plays a central role in the development of GPP, although several other genes may be associated. The rarity of GPP makes its diagnosis challenging and it could be mistaken for an infectious condition or other types of pustular psoriasis, including unstable forms of plaque psoriasis that may present with pustules. Performing a thorough skin examination and obtaining a detailed history are vital to exclude these differential diagnoses. Incorrect or late diagnosis, inadequate or delayed treatment, and lack of specialist referrals may contribute to increased disease severity and can have a debilitating impact on patients' quality of life. In this podcast, two US-based dermatologists discuss the clinical characteristics of GPP, highlight the central role of IL-36 in immunopathogenesis, and share practical approaches to recognizing and diagnosing the disease.

This study aimed to validate the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) and the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) as reliable measures for assessing the severity of Generalized pustular psoriasis (GPP), a rare and potentially life-threatening skin disease. The GPPASI and GPPGA were developed to assess key cutaneous manifestations of GPP, namely erythema, scaling, and pustulation. The study involved the evaluation of photographs from patients with GPP by GPP-experienced dermatologists, who scored the images using an online portal. The intra-rater and inter-rater reliability of the GPPGA was assessed and found to be generally excellent. The study concluded that the GPPGA is a robust, reliable, and reproducible assessment of GPP severity and should be considered a suitable clinical endpoint for future GPP trials. It also suggested that the GPPGA has the potential to become a standard assessment for GPP severity, along with markers of systemic inflammation and patient-reported outcomes.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare form of psoriasis (less of 1% of cases). Currently, GPP is recognized as a clinical entity, distinguished from plaque psoriasis. However, there are not guidelines for GPP management and treatments are often derived from plaque psoriasis. Therefore, conventional systemic drugs are usually used as first-line treatment options, and biologics are still used off label. Recently, spesolimab, an anti-IL36 receptor humanized IgG1 monoclonal antibody, has been specifically approved for GPP disease, revolutionizing treatment scenario. AREAS COVERED: The aim of this review is to investigate current literature on the use of spesolimab for GPP management to underline its potential role in GPP and offer a current clinical perspective. Literature research using the Google Scholar, Pubmed, Embase, Cochrane Skin, and clinicaltrials.gov databases was performed, selecting the most relevant manuscripts. EXPERT OPINION: Spesolimab is efficacious and has a consistent and favorable safety profile in patients presenting with a GPP flare. However, despite excellent results in terms of safety and efficacy have been reported by both clinical trials and very limited real-life experiences, long-term data, especially in flare-up prevention, are scant. Thus, while the available data are encouraging, further research is warranted to understand the efficacy, safety, and long-term outcomes associated with spesolimab treatment in GPP.

Generalized pustular psoriasis (GPP) is a rare skin disease characterized by generalized sterile pustules with or without severe systemic symptoms. In China, systemic treatment with ciclosporin, retinoids and methotrexate is the main management strategy, but with poor outcomes and frequent recurrences. Several studies have indicated that the interleukin (IL)-36 pathway plays an important role in the occurrence and development of this disease,1 which is further demonstrated by the efficacy and safety results for spesolimab (a monoclonal antibody, IL-36 receptor inhibitor) from some clinical trials.2–4 Previous randomized controlled trials for spesolimab have limited patient numbers, especially participants from the Chinese population, here we share our experience with spesolimab in five Chinese patients with GPP flare. We treated five Chinese adult patients with spesolimab in our department from August 2022 to January 2023 who presented with a GPP flare. All the patients were diagnosed with GPP according to the European consensus statement.5 We used the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) and the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) for the evaluation of efficacy of spesolimab at week 0, week 1, week 4 and week 16. Safety events were documented throughout the follow-up period.

Generalized pustular psoriasis (GPP) is a severe and rare form of psoriasis, being a potentially life-threatening condition, characterized by recurring episodes or flares of widespread cutaneous erythema with macroscopic sterile pustules. An irregular innate immune response is linked to GPP, which is considered an auto-inflammatory disorder, while innate and adaptive immunopathogenic responses are involved in psoriasis pathogenesis. In consequence, different cytokine cascades have been suggested to be mainly involved in the pathogenesis of each different psoriasis form, with the interleukin (IL)23/IL17 axis implied in plaque psoriasis, and the IL36 pathway in the GPP. As regards GPP treatment, conventional systemic drugs available for plaque psoriasis are usually used as the first-line treatment option. However, contraindications and adverse events often limit the use of these therapies. In this scenario, biologic drugs may represent a promising treatment option. To date, even if 12 different biologics have been approved for plaque psoriasis, none of these is approved for GPP where they are employed off-label. Recently, spesolimab, an anti-IL36 receptor monoclonal antibody, has been recently approved for GPP. The purpose of this article is to assess the current literature about the use of biological therapies for the treatment of GPP to establish the basis for a shared GPP management algorithm.

BACKGROUND: Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved to treat generalised pustular psoriasis (GPP) flares. We aimed to assess the efficacy and safety of spesolimab for GPP flare prevention. METHODS: This multicentre, randomised, placebo-controlled, phase 2b trial was done at 60 hospitals and clinics in 20 countries. Eligible study participants were aged between 12 and 75 years with a documented history of GPP as per the European Rare and Severe Psoriasis Expert Network criteria, with a history of at least two past GPP flares, and a GPP Physician Global Assessment (GPPGA) score of 0 or 1 at screening and random assignment. Patients were randomly assigned (1:1:1:1) to receive subcutaneous placebo, subcutaneous low-dose spesolimab (300 mg loading dose followed by 150 mg every 12 weeks), subcutaneous medium-dose spesolimab (600 mg loading dose followed by 300 mg every 12 weeks), or subcutaneous high-dose spesolimab (600 mg loading dose followed by 300 mg every 4 weeks) over 48 weeks. The primary objective was to demonstrate a non-flat dose-response curve on the primary endpoint, time to first GPP flare. FINDINGS: From June 8, 2020, to Nov 23, 2022, 157 patients were screened, of whom 123 were randomly assigned. 92 were assigned to receive spesolimab (30 high dose, 31 medium dose, and 31 low dose) and 31 to placebo. All patients were either Asian (79 [64%] of 123) or White (44 [36%]). Patient groups were similar in sex distribution (76 [62%] female and 47 [38%] male), age (mean 40·4 years, SD 15·8), and GPP Physician Global Assessment score. A non-flat dose-response relationship was established on the primary endpoint. By week 48, 35 patients had GPP flares; seven (23%) of 31 patients in the low-dose spesolimab group, nine (29%) of 31 patients in the medium-dose spesolimab group, three (10%) of 30 patients in the high-dose spesolimab group, and 16 (52%) of 31 patients in the placebo group. High-dose spesolimab was significantly superior versus placebo on the primary outcome of time to GPP flare (hazard ratio [HR]=0·16, 95% CI 0·05-0·54; p=0·0005) endpoint. HRs were 0·35 (95% CI 0·14-0·86, nominal p=0·0057) in the low-dose spesolimab group and 0·47 (0·21-1·06, p=0·027) in the medium-dose spesolimab group. We established a non-flat dose-response relationship for spesolimab compared with placebo, with statistically significant p values for each predefined model (linear p=0·0022, emax1 p=0·0024, emax2 p=0·0023, and exponential p=0·0034). Infection rates were similar across treatment arms; there were no deaths and no hypersensitivity reactions leading to discontinuation. INTERPRETATION: High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks. Given the chronic nature of GPP, a treatment for flare prevention is a significant shift in the clinical approach, and could ultimately lead to improvements in patient morbidity and quality of life.FUNDING: Boehringer Ingelheim.

BACKGROUND: Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that can be severe, debilitating and life threatening. Uncontrolled activation of interleukin (IL)-36 proinflammatory activity may underlie the pathogenesis of GPP. Currently, GPP-specific treatment options are limited. OBJECTIVES: To evaluate the efficacy and safety of the anti-IL-36 receptor antibody imsidolimab in patients with GPP. METHODS: In an open-label, single-arm, multiple-dose study, patients with GPP were treated with imsidolimab to assess clinical efficacy, tolerability and safety. Patients received an intravenous dose of imsidolimab 750 mg on day 1, followed by three subcutaneous doses of imsidolimab 100 mg administered on days 29, 57 and 85. The primary efficacy endpoint was the proportion of patients who achieved a clinical response at weeks 4 and 16 following treatment with imsidolimab, as measured by the Clinical Global Impression scale. RESULTS: Eight patients were enrolled and six completed the study. Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29 and through day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. No patient discontinued the study owing to a nonserious TEAE. Two patients experienced serious adverse events (SAEs); no deaths were reported. CONCLUSIONS: Imsidolimab demonstrated a rapid and sustained resolution of symptoms and pustular eruptions in patients with GPP. It was generally well tolerated, with an acceptable safety profile, and is advancing to phase III trials. These data support the targeting of IL-36 signalling with a specific antibody - imsidolimab - as a therapeutic option for this severely debilitating condition.

Generalized pustular psoriasis (GPP) is a rare, debilitating autoinflammatory disorder that presents with flares of widespread sterile pustules and erythema, and is accompanied by systemic inflammation. GPP follows a relapsing or persisting course, and is often recalcitrant to treatment.1,2 Dysregulated interleukin (IL)-36 signalling has been implicated as a key pathogenic driver of disease.3 A randomized placebo-controlled trial of spesolimab indicated that therapeutic IL-36 receptor (IL-36R) blockade results in rapid, clinically meaningful benefit.4 In the spesolimab trial, the primary endpoint was measured at 1 week, so further research is required on the role of IL-36 blockade for ongoing disease control. In this issue of the BJD, Warren et al. report on their open-label, single-arm, phase II study of imsidolimab, a monoclonal antibody that inhibits IL-36R.5 Eight participants were recruited, with six completing the trial. Fifty per cent were female, with a mean (SD) age of 51.3 (14.9) years and a mean (SD) time since GPP diagnosis of 4.0 (6.5) years. Baseline severity was mild (n = 1), moderate (n = 5) or severe (n = 2). Five had concomitant plaque psoriasis. All participants had homozygous wild-type IL36RN, CARD14 and AP1S3 alleles.