People with generalized pustular psoriasis experience underlying skin inflammation, even in the absence of flares. Spesolimab treatment helps control the inflammation and prevent future flares.

We used two-step Mendelian randomization to investigate the inflammatory mediators underlying the effects of cigarette smoking on palmoplantar pustulosis (PPP). We first examined the causal effects of smoking on plasma cytokine levels and then those of smoking-associated cytokines on PPP risk. We identified OX40 as potential mediator of the effects of smoking on PPP.

EFFISAYIL 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus treatment with placebo in approximately half of the patients. In this study, we present histologic, transcriptomic, and proteomic analyses of lesional and nonlesional skin and whole- blood samples collected from EFFISAYIL 1. Treatment with spesolimab led to a transition toward a nonlesional profile, with a downregulation of gene expressions in the skin of IL-36 transcripts (IL36a, IL36b, IL36g) and those associated with neutrophil recruitment (CXCL1, CXCL6, CXCL8), proinflammatory cytokines (IL6, IL19, IL20), and skin inflammation (DEFB4A, S100A7, S100A8). Changes were manifest at week 1 and sustained to week 8. At the systemic level, reductions in serum biomarkers of inflammation (IL-17, IL-8, IL-6) were sustained until 12 weeks after spesolimab treatment. Considerable overlap was observed in the spesolimab-induced changes in gene and protein expressions from skin and blood samples, demonstrating the molecular basis of the effects of spesolimab on controlling local and systemic inflammation. Data are consistent with the mode of action of spesolimab, whereby inhibition of the IL-36 pathway leads to subsequent reductions in the key local and systemic pathologic events associated with generalized pustular psoriasis flares.

Background: Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disease associated with considerable patient burden. The Psoriasis Symptom Scale (PSS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and pain-Visual Analogue Scale (pain-VAS) are patient-reported outcomes (PROs) that have not yet been validated in patients with GPP. Objectives: To evaluate the psychometric properties of the PSS, FACIT-Fatigue and pain-VAS using data from Effisayil 1, a randomised trial of spesolimab in patients with moderate-to-severe GPP. Methods: Inter-item correlations and confirmatory factor analysis (CFA) were performed using Week 1 data. Internal consistency was assessed with Cronbach's alpha coefficient using baseline and Week 1 data. Test-retest reliability was assessed using intraclass correlation coefficients (ICCs); change data for the GPP Physician Global Assessment total score and pustulation subscore were used to define a stable population. Convergent validity was assessed at baseline and Week 1 using Spearman's rank-order correlations. Known-groups validity was measured by analysis of variance using Week 1 data. Ability to detect change from baseline to Week 1 was evaluated by analysis of covariance. Results: Inter-item and item-to-total correlations were moderate or strong for most PSS and FACIT-Fatigue items. CFA demonstrated the unidimensionality of the PSS and FACIT-Fatigue, with high factor loadings for most items (PSS range, 0.75-0.94; FACIT-Fatigue range, 0.11-0.93) and acceptable fit statistics. Both scores demonstrated internal consistency (Cronbach's alpha, 0.71 and 0.95, respectively). The PSS, FACIT-Fatigue and pain-VAS demonstrated test-retest reliability (ICCs >= 0.70) and good evidence of convergent validity. Furthermore, the PROs could differentiate between known groups of varying symptom severity (range, p < 0.0001-0.0225) and detect changes in symptom severity from baseline to Week 1 (range, p < 0.0001-0.0002). Conclusions: Overall, these results support the reliability, validity and ability to detect change of the PSS, FACIT-Fatigue and pain-VAS as PROs in patients with GPP.

Prof. Morita presents the EFFISAYIL® 2 clinical trial, which investigated spesolimab treatment for the prevention of GPP flares.

Importance:Generalized pustular psoriasis (GPP) lacks internationally accepted definitions and diagnostic criteria, impeding timely diagnosis and treatment and hindering cross-regional clinical and epidemiological study comparisons. Objective:To develop an international consensus definition and diagnostic criteria for GPP using the modified Delphi method. Evidence Review:The rarity of GPP presents a challenge in acquiring comprehensive published clinical data necessary for developing standardized definition and criteria. Instead of relying on a literature search, 43 statements that comprehensively addressed the fundamental aspects of the definitions and diagnostic criteria for GPP were formulated based on expert reviews of 64 challenging GPP cases. These statements were presented to a panel of 33 global GPP experts for voting, discussion, and refinements in 2 virtual consensus meetings. Consensus during voting was defined as at least 80% agreement; the definition and diagnostic criteria were accepted by all panelists after voting and in-depth discussion. Findings:In the first and second modified Delphi round, 30 (91%) and 25 (76%) experts participated. In the initial Delphi round, consensus was achieved for 53% of the statements, leading to the approval of 23 statements that were utilized to develop the proposed definitions and diagnostic criteria for GPP. During the second Delphi round, the final definition established was, "Generalized Pustular Psoriasis is a systemic inflammatory disease characterized by cutaneous erythema and macroscopically visible sterile pustules." It can occur with or without systemic symptoms, other psoriasis types, and laboratory abnormalities. GPP may manifest as an acute form with widespread pustules or a subacute variant with an annular phenotype. The identified essential criterion was, "Macroscopically visible sterile pustules on erythematous base and not restricted to the acral region or within psoriatic plaques." Conclusions and Relevance:The achievement of international consensus on the definition and diagnostic criteria for GPP underscores the importance of collaboration, innovative methodology, and expert engagement to address rare diseases. Although further validation is needed, these criteria can serve as a reference point for clinicians, researchers, and patients, which may contribute to more accurate diagnosis and improved management of GPP.

BackgroundPalmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. While the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets.ObjectivesTo identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis.MethodsWe performed a genome-wide association meta-analysis of three North-European cohorts (n=1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP.ResultsWe found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P<5X10-6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and Th2-mediated diseases like atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP.ConclusionsThe first genome-wide association study of PPP points to a pathogenic role for deregulated Th2 responses and cigarette smoking.

This article presents the results of the UK extension of a previously conducted global Delphi panel on generalised pustular psoriasis (GPP). Five UK based dermatologists experienced in GPP management have expressed their level of agreement on 101 questionnaire statements addressing four aspects of GPP: clinical course and flare definition, diagnosis, treatment goals, and holistic management. Consensus was achieved for 89 of 101 statements (88%). Disagreement was detected on issues around the prognostic value of age, QoL assessment tools and the nature of comorbidities associated with GPP. Overall, the panelists corroborated the results of the global study and confirmed that the clinical algorithm derived from the global study is in accordance with the UK clinical practice.

The article provides a pragmatic update of the British Association of Dermatologists guidelines for biologic therapy for psoriasis.

Introduction: Generalized pustular psoriasis (GPP) is characterized by flares of widespread pustulation and erythema that may be fatal. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved to treat GPP flares. Effisayil 2 trial (NCT04399837) assessed efficacy and safety of spesolimab for prevention of GPP flares over 48 weeks. Here we show the efficacy of high-dose subcutaneous (SC) spesolimab for GPP flare prevention in prespecified subgroups in Effisayil 2. Methods: Eligible patients were randomized 1:1:1:1 to receive placebo, or low- (300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (600 mg LD; 300 mg q12w) or high-dose (600 mg LD; 300 mg every 4 weeks) SC spesolimab over 48 weeks. We assessed the efficacy of high-dose spesolimab versus placebo across prespecified subgroups (including IL36RN mutation, comorbid plaque psoriasis [PsV], and body mass index [BMI] status) for the primary endpoint, time to first GPP flare by Week 48 (defined as a ≥2 GPPGA total score increase from baseline and ≥2 GPPGA pustulation score increase from baseline; subsequent use of rescue SC spesolimab also indicated a GPP flare), using a Cox regression analysis stratified by systemic use of GPP medications at randomization. Key secondary endpoint was proportion of patients with ≥1 GPP flare by Week 48. Results: 123 patients were randomized (placebo, N=31; high-dose spesolimab, N=30). Hazard ratios (95% CI) for the primary endpoint favored high-dose spesolimab vs placebo in most prespecified subgroups, including: with IL36RN mutation, 0.04 (0.002, 1.152); without IL36RN mutation, 0.41 (0.109, 1.537); PsV absent at baseline, 0.14 (0.031, 0.629); PsV present at baseline, 0.22 (0.025, 1.883); and BMI <25 kg/m2, 0.22 (0.057, 0.816); 25 to <30 kg/m2, 0.12 (0.005, 2.817); and ≥30 kg/m2, 0.23 (0.008, 6.033). For the key secondary endpoint, adjusted risk differences (95% CI) by Week 48 were lower in those receiving high-dose spesolimab vs placebo in these prespecified subgroups: with IL36RN mutation, -0.75 (-1.000, -0.326); without IL36RN mutation, -0.22 (-0.504, 0.074); PsV absent at baseline, -0.41 (-0.672, -0.154); PsV present at baseline, -0.32 (-0.830, 0.191); and across all BMI subgroups. Conclusion: Over 48 weeks, high-dose spesolimab was effective at preventing GPP flares irrespective of IL36RN mutation, comorbid PsV and BMI status at baseline.

A 69 year-old female patient presented with a reddish-brown, enlarging lesion on her right lower eyelid. Physical exam revealed a 4-5mm, oval-shaped, reddish-brown, shiny, exophytic papule on the right lower eyelid. Shave biopsy of the lower eyelid papule was performed, which revealed nests of cells with prominent cribriform arrangements, focally surrounded by small pools of blue stringy mucinous material and papillary architecture. Cells stained positive for EMA, synaptophysin, and chromogranin, which confirmed the diagnosis of endocrine mucin-producing sweat gland carcinoma (EMPSGC). The lesion was fully removed with negative margins via Mohs micrographic surgery. Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade, cutaneous adenocarcinoma that typically arises on the eyelids of elderly women. EMPSGC may be associated with invasive mucinous carcinoma.

Effisayil 1 was a multicentre, randomized, double‐blind, placebo‐controlled study of the anti‐interleukin (IL)‐36 receptor monoclonal antibody, spesolimab, in patients presenting with a generalized pustular psoriasis (GPP) flare. Previously published data from this study revealed that within 1 week, rapid pustular and skin clearance were observed in patients receiving spesolimab versus placebo. In this pre‐specified subgroup analysis, the efficacy of spesolimab was evaluated according to patient demographic and clinical characteristics at baseline in patients receiving spesolimab (n = 35) or placebo (n = 18) on Day 1. Efficacy was by assessed by achievement of primary endpoint (Generalized Pustular Psoriasis Physician Global Assessment [GPPGA] pustulation subscore of 0 at Week 1) and key secondary endpoint (GPPGA total score of 0 or 1 at Week 1). Safety was assessed at Week 1. Spesolimab was found to be efficacious and had a consistent and favourable safety profile in patients presenting with a GPP flare, regardless of patient demographics and clinical characteristics at baseline.

INTRODUCTION:Generalized pustular psoriasis (GPP) is a rare cutaneous and systemic inflammatory disease which is characterized by flares of widespread painful pustulation of the skin, often associated with fever and elevated inflammatory markers. Although it has historically been regarded as a severe variant of plaque psoriasis, genetic and immunological developments over the past decade have revealed that it is a distinct auto-inflammatory entity, in which over-activity of the interleukin-36 signaling pathway is fundamental. Treatments targeting the IL-36 pathway are under investigation, and in 2022 spesolimab, a monoclonal antibody against the IL-36 receptor, was licensed for treating flares of GPP.AREAS COVERED:In this review I discuss the epidemiology, clinical features, genetics, patho-mechanisms, and current treatment options for GPP. I describe the results of clinical trials that led to the licensing of spesolimab for flares of GPP.EXPERT OPINION:The marked efficacy of spesolimab in GPP opens a new era of highly effective, scientifically-rational, and evidence-based treatment for this orphan disease, and has implications for other diseases in which interleukin 36 signaling is involved.

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 rare and life-threatening skin disease often accompanied by systemic inflammation. There are currently no standardized or validated GPP-specific measures for assessing severity. OBJECTIVE:To evaluate the reliability, validity and responder definitions of the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) and Generalized Pustular Psoriasis Area and Severity Index (GPPASI). METHODS:The GPPGA and GPPASI were validated using outcome data from Week 1 of the Effisayil™ 1 study. The psychometric analyses performed included confirmatory factor analysis, item-to-item/item-to-total correlations, internal consistency reliability, test-retest reliability, convergent validity, known-groups validity, responsiveness analysis and responder definition analysis. RESULTS:Using data from this patient cohort (N = 53), confirmatory factor analysis demonstrated unidimensionality of the GPPGA total score (root mean square error of approximation <0.08), and GPPGA item-to-item and item-to-total correlations ranged from 0.58 to 0.90. The GPPGA total score, pustulation subscore and GPPASI total score all demonstrated good test-retest reliability (intraclass correlation coefficient: 0.70, 0.91 and 0.95 respectively), and good evidence of convergent validity. In anchor-based analyses, all three scores were able to detect changes in symptom and disease severity over time; reductions of -1.4, -2.2 and - 12.0 were suggested as clinically meaningful improvement thresholds for the GPPGA total score, GPPGA pustulation subscore and GPPASI total score respectively. Anchor-based analyses also supported the GPPASI 50 as a clinically meaningful threshold for improvement. CONCLUSIONS:Overall, our findings indicate that the GPPGA and GPPASI are valid, reliable and responsive measures for the assessment of GPP disease severity, and support their use in informing clinical endpoints in trials in GPP.

Generalized pustular psoriasis (GPP), a rare and potentially life-threatening neutrophilic skin disease, is characterized by recurrent flares of pustulation on nonacral skin with associated erythema, crusting and scaling. There are no agreed or validated measurements for assessing GPP severity or symptom improvement; clinically validated endpoints that incorporate key manifestations of GPP, and are meaningful and reliable for the evaluation of treatment response, are needed.

Targeted biologic therapies can elicit an undesirable host immune response characterized by the development of antidrug antibodies (ADA), an important cause of treatment failure. The most widely used biologic across immune-mediated diseases is adalimumab, a tumor necrosis factor inhibitor. This study aimed to identify genetic variants that contribute to the development of ADA against adalimumab, thereby influencing treatment failure. In patients with psoriasis on their first course of adalimumab, in whom serum ADA had been evaluated 6–36 months after starting treatment, we observed a genome-wide association with ADA against adalimumab within the major histocompatibility complex (MHC). The association signal mapped to the presence of tryptophan at position 9 and lysine at position 71 of the HLA-DR peptide-binding groove, with both residues conferring protection against ADA. Underscoring their clinical relevance, these residues were also protective against treatment failure. Our findings highlight antigenic peptide presentation via MHC class II as a critical mechanism in the development of ADA against biologic therapies and downstream treatment response.

Generalized pustular psoriasis (GPP) is a rare skin disease, characterized by recurrent flares of extensive, sterile pustular eruption. In patients with a GPP flare in the Effisayil 1 study (NCT03782792), treatment with intravenous spesolimab led to rapid pustular and skin clearance within 1 week. Patients completing Effisayil 1 were offered maintenance treatment with subcutaneous spesolimab (300 mg every 4, 6 or 12 weeks) in the open-label, long-term extension study, Effisayil ON (NCT03886246). We report interim data for patients who received open-label intravenous spesolimab 900 mg treatment for recurrent GPP flares during maintenance treatment in Effisayil ON. Of 39 patients from Effisayil 1 who entered Effisayil ON, 10 were treated for a new flare by the cut-off date for this analysis. Five of the 10 patients had one flare, four had two flares, and one had four flares in Effisayil ON (i.e., 17 flare treatment periods in total). One week after the first flare treatment with intravenous spesolimab in Effisayil ON, 5/10 patients (50.0%) achieved a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0. Patients achieved a GPPGA pustulation subscore of 0 in 7/17 flare treatment periods (41.2%). During the first flare treatment period, nine patients reported any adverse event; one patient each reported having a severe or serious adverse event. The rapid pustular clearance 1 week after flare treatment in Effisayil ON was consistent with the Week 1 results of Effisayil 1, further supporting spesolimab treatment as an effective option for controlling flares, even if they recur.

Background: Generalized pustular psoriasis (GPP) is a rare, neutrophilic skin disease that can become life-threatening if flares are untreated. There are limited data describing the characteristics and clinical course of GPP disease flares with current treatment options. Objective: The aim of the study was to describe the characteristics and outcomes of GPP flares using historical medical information from patients enrolled in the Effisayil™ 1 trial. Methods: Investigators collected retrospective medical data characterizing patients’ GPP flares prior to clinical trial enrollment. Data on overall historical flares were collected, as well as information on patients’ typical, most severe, and longest past flares. This included data on systemic symptoms, flare duration, treatment, hospitalization, and time to clearance of skin lesions. Results: In this cohort (N = 53), patients with GPP experienced a mean of 3.4 flares per year. Flares were painful, associated with systemic symptoms, and often triggered by stress, infections, or treatment withdrawal. Resolution of flares was longer than 3 weeks in 57.1%, 71.0%, and 85.7% of documented (or identified) typical, most severe, and longest flares, respectively. GPP flares led to patient hospitalization in 35.1%, 74.2%, and 64.3% of patients for their typical, most severe, and longest flares, respectively. For the majority of patients, pustules took up to 2 weeks to clear for a typical flare and 3–8 weeks to clear for the most severe and longest flares. Conclusion: Our findings highlight that current treatment options are slow to control GPP flares and provide context for assessing the efficacy of new therapeutic strategies in patients with a GPP flare.

Palmoplantar pustulosis (PPP) is a severe pustular eruption that affects the palms and/or soles, with detrimental effects on quality of life. The disease is notoriously difficult to treat because its immune and genetic determinants remain poorly defined (Twelves et al., 2019). Although mutations of the IL36RN and myeloperoxidase MPO genes have been convincingly associated with generalized pustular psoriasis, they are rarely found in patients with PPP (Haskamp et al., 2020; Twelves et al., 2019; Vergnano et al., 2020).