Generalized Pustular Psoriasis Research Articles

Clinical course and disease burden of patients with generalized pustular psoriasis in Portugal: a multicenter retrospective cohort study

Objectives Generalized pustular psoriasis (GPP) is a rare, life-threatening skin inflammatory disorder. This study aimed to describe the disease course, treatment strategies, and healthcare utilization among patients with GPP in Portugal. Methods This multicentric, observational, retrospective study included consecutive adult patients with GPP undergoing a dermatology evaluation in different reporting institutions by experienced dermatologists between 2002 and 2023. Results A total of 59 patients were assessed. Most of the cohort had a previous history of plaque psoriasis (71%) and 83% presented at least one comorbidity. At the initial encounter, 64% of the cohort needed hospitalization. Systemic involvement was common, including fever (37%), and elevated white blood cell count and erythrocyte sedimentation rate/C-reactive protein (49%). Nearly, 73% of patients initiated systemic drugs, and 70% had to discontinue the first treatment. During the study, 98% of patients experienced at least one flare. At the last visit, 3.4% of patients had died, and 71.2% exhibited signs of active disease despite undergoing treatment. Conclusions Our study demonstrates that GPP is a chronic, debilitating condition associated with systemic involvement, frequent flares, and hospitalizations, despite receiving multiple systemic treatments. Improved disease awareness and new treatments are needed to improve patient care and decrease the burden of the disease.

Rapid and sustained resolution in generalized pustular psoriasis with IL-17A inhibitors required high adherence: a 96-week analysis in a real-life setting.

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening skin disease often requiring long-term therapy. We aimed to evaluate the use of Interleukin (IL)-17A inhibitors (secukinumab and ixekizumab) in GPP patients over 96 weeks. We retrospectively analyzed a case series of 18 patients with GPP who received secukinumab (n = 13) and ixekizumab (n = 5) therapy with a 96-week follow-up period. The primary effectiveness analysis included determining the percentage of patients who achieved ≥90% or 100% improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score. Adherence was captured using the medication possession ratio (MPR). Using the as-observed (AO) method, 87% and 67% of patients treated with secukinumab or ixekizumab achieved GPPASI 90and 100responses, respectively. At Week 96, the mean GPPASI improvements from baseline GPPASI were 96.3% (95% CI: 0.91-1.01) using the AO method. After Week 48, 14 patients tapered (n = 8) or terminated (n = 6) the treatment. High-adherence therapy (MPR ≥ 80%) was significantly superior to the low-adherence group in the rate of patients achieving a GPPASI 100 response (AO, 100% vs. 38%, P < 0.05). By Week 96, 5 (27.8%) patients had new GPP flares, and 4 (80%) were in the low-adherence group. No new safety signals occurred. IL-17A inhibitors led to effective and sustained improvement in GPP patients, and high-adherence therapy had long-term positive effects on skin clearance. Given its relapsing nature, improving compliance is beneficial for long-term clinical management.

Burden of illness and unmet needs in generalized pustular psoriasis: report of four cases

Generalized pustular psoriasis (GPP), the most severe form of pustular psoriasis, is a rare autoinflammatory skin disease that manifests with the rapid and widespread eruption of small, sterile pustules and surrounding skin erythema, often accompanied by systemic symptoms. GPP is frequently painful and distressing and adversely affects patients’ quality of life. Until recently, systemic treatment for GPP in the United States mainly involved the off-label use of agents approved to treat plaque psoriasis. In September 2022, spesolimab was approved in the United States as a first-in-class treatment for GPP flares in adults, making a GPP-specific therapy available. Here, we describe 4 cases from our respective clinical practices that highlight the difficulties faced by patients with GPP in receiving an accurate diagnosis and obtaining effective treatment and demonstrate the associated physical and psychological disease burdens. The potential severity and consequences of untreated GPP necessitate a prompt diagnosis, initiation of effective treatment, and regular follow-up and monitoring of patients’ conditions. When managing GPP, a multidisciplinary approach is recommended to ensure that patients receive appropriate social and emotional support and effective medical care.

Combination of secukinumab and acitretin for generalized pustular psoriasis: A case report and review of literature.

Generalized pustular psoriasis (GPP) is characterized by painful and occasionally disfiguring cutaneous manifestations with sepsis-like systemic symptoms, and is a rare severe variant of psoriasis. Currently, there is no standard treatment for GPP. Here, we report a case of a female patient with ankylosing spondylitis (AS) and mild scalp psoriasis, who developed GPP and alopecia following three courses of adalimumab therapy. The patient's condition gradually improved following cessation of adalimumab and treatment with secukinumab and acitretin. After eight weeks of treatment, the patient achieved almost complete clearance of her psoriasis, her alopecia improved, and her AS was relieved. Therefore, we believe that a combination of secukinumab with acitretin may be a rational approach for the treatment of severe GPP.

Effect of smoking cessation on psoriasis vulgaris, palmoplantar pustulosis, and generalized pustular psoriasis.

Smoking is a known risk factor for psoriasis; however, the impact of smoking cessation on psoriasis has seldom been evaluated. We aimed to examine the effects of smoking cessation on the development of psoriasis vulgaris (PsV), palmoplantar pustulosis (PPP), and generalized pustular psoriasis (GPP). Using the Korean National Health Insurance Service database, we retrospectively compiled a cohort of 5,784,973 participants without psoriasis, analysed their changes in smoking status from 2004 to 2007 and followed up new cases of psoriasis until 2021. The psoriasis risks were compared with those of sustained smokers, smoking quitters, sustained ex-smokers, and never smokers using multivariate Cox proportional hazards models. The mean age of the participants was 47.1 years (standard deviation, 13.5), and 3,092,426 (53.5%) were male. During 77,990,688 person-years, 67,364 psoriasis cases were identified. Compared with sustained smokers, smoking quitters showed a reduced risk of developing psoriasis (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.87-0.95), specifically PsV (aHR 0.92; 95% CI 0.88-0.97) and PPP (aHR 0.71; 95% CI 0.63-0.79). The reduction in risk due to smoking cessation was more prominent in sustained ex-smokers (psoriasis: aHR 0.77, 95% CI 0.74-0.79; PsV: aHR 0.76, 95% CI 0.73-0.79; PPP: aHR 0.56, 95% CI 0.51-0.61; GPP: aHR 0.64; 95% CI 0.52-0.78). When conducting sensitivity analyses to address the potential for changes in smoking habits after 2007, the results and trends were consistent with the main findings, and a more pronounced significance was observed. Compared with continuous smoking, smoking cessation was associated with a decreased risk of developing psoriasis. The risk-reducing effect of smoking cessation was more pronounced in those maintaining a smoke-free status. Smoking cessation and the maintenance of a smoke-free status should be encouraged to prevent the development of psoriasis and all other smoking-related diseases.

Effect of Spesolimab on Achieving Sustained Disease Remission in Patients with Generalized Pustular Psoriasis: Results from the Effisayil 2 Study

 Introduction: Generalized pustular psoriasis (GPP) is a chronic, rare disease characterized by flares of widespread skin pustulation. Intravenous (IV) spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved for GPP flare treatment; however, the optimal dosing and long-term efficacy of subcutaneous (SC) spesolimab treatment in patients with GPP has not yet been reported. We report the effect of SC spesolimab on achieving sustained disease remission in Effisayil 2 (NCT04399837), a 48-week trial that evaluated the efficacy and safety of SC spesolimab in preventing GPP flares.&#x0D;  Methods: Patients with a history of GPP were randomized (1:1:1:1) to receive placebo (n=31), low- (n=31, 300 mg loading dose [LD]; 150 mg every 12 weeks [q12w]), medium- (n=31, 600 mg LD; 300 mg q12w) or high-dose (n=30, 600 mg LD; 300 mg every 4 weeks [q4w]) SC spesolimab over 48 weeks. Sustained remission was defined as GPP Physician Global Assessment (GPPGA) total score of 0 or 1 at all visits up to Week 48, or GPPGA total score of 0 or 1 and all GPPGA subscores ≤2 at all visits up to Week 48. Sustained pustular clearance was defined as GPPGA pustulation subscore of 0 at all visits from Week 4 to Week 48. Any use of IV spesolimab or another standard of care for GPP worsening was considered a failure of remission. Missing data were imputed by a sequential logistic regression multiple imputation method. Adjusted risk differences (RD) were calculated by the Mantel−Haenszel type-weighted average of differences.&#x0D;  Results: 31 patients received placebo, and 30 patients received high-dose spesolimab. Compared to placebo, more patients had sustained remission in the high-dose arm using both GPPGA total score 0 or 1 (63.3% vs 29.0%; RD [95% CI] 0.35 [0.10–0.59]), and GPPGA total score 0 or 1 and all GPPGA subscores ≤2 (60.4% vs 29.0%; RD [95% CI] 0.32 [0.07–0.56]). Compared to placebo, more patients in the high-dose arm had sustained pustular clearance over 48 weeks (63.6% vs 25.8%; RD [95% CI] 0.38 [0.14–0.62]).&#x0D; Conclusion: Overall, high-dose SC spesolimab q4w is effective for the long-term management of GPP skin symptoms.

Real-World Efficacy of Spesolimab: Reports from Four Patients with Generalized Pustular Psoriasis

 Introduction: Generalized pustular psoriasis (GPP) is a rare, chronic, autoinflammatory skin disease characterized by widespread pustular eruptions that may be accompanied by systemic symptoms. GPP is painful, distressing, and adversely affects patient quality of life (QoL). Spesolimab is a first-in-class anti-IL-36 receptor monoclonal antibody approved for the treatment of GPP flares. Methods: We describe 4 cases from our respective clinical practices, where individuals with GPP were treated successfully with spesolimab. Results: Four patient cases of GPP were included; an 18-year-old male, a 58-year-old female; a 36-year-old male, and a 40-year-old female. One patient had a history of GPP, and had experienced 3 prior flares in the preceding year. Two patients had a history of plaque psoriasis. Events preceding the current GPP flare included hydroxychloroquine treatment (n=2), and corticosteroid treatment (n=3). All patients presented with sudden onset of worsening pustular rash (affecting lower extremities [n=1]; extremities and trunk [n=1]; whole body [n=2]). Two patients had systemic symptoms at presentation (1 case: fever, chills, malaise, fatigue; 1 case: severe weakness), and required hospitalization. Two patients received an initial mis-diagnosis of acute generalized exanthematous pustulosis (AGEP). Significant impacts on QoL were reported; all 4 patients were unable to perform normal daily activities; the 18-year-old patient was targeted at school because the skin lesions were perceived to be contagious. The 4 patients received multiple therapies prior to, and concomitantly with, spesolimab treatment, including topical agents, antibiotics, corticosteroids, retinoids, immunosuppressants, and biologics. All 4 patients received two 900 mg intravenous infusions of spesolimab with treatment intervals between 7 and 20 days. Treatment was given at an outpatient infusion center (n=3*), or using a home infusion service (n=1); *1 patient received their first infusion as an inpatient. Significant clinician-assessed improvement in pustules occurred within 1 week of the first spesolimab infusion in 3 patients; the remaining patient reported improvement 1-2 weeks after the second infusion. One of the hospitalized patients experienced 75% improvement in itching, pain, and pustules within 24 hours of the first spesolimab infusion, and was discharged the next day. Spesolimab treatment also improved QoL, with patients experiencing rapid improvements in pain, and their ability to resume their normal daily activities. Conclusions: These cases demonstrate the efficacy of spesolimab in the real-world, highlighting the ability of spesolimab treatment to rapidly improve GPP symptoms and patient QoL. Administration of spesolimab in an inpatient setting allowed for rapid patient improvement and discharge the next day. These cases also highlight the association of certain drugs as triggers for GPP flares, as well as the importance of AGEP in the differential diagnosis of GPP

Measuring GPPGA, Pain, Symptom, and Quality of Life Index Scores in Untreated Generalized Pustular Psoriasis: Results from the Placebo Group of the Effisayil-2 Trial

Introduction &amp; Objectives: Generalized pustular psoriasis (GPP) is a chronic inflammatory, and potentially life-threatening skin disease, characterized by flares of sterile pustules. Spesolimab is approved to treat GPP flares in adults. Effisayil 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous spesolimab in preventing GPP flares. Here, we report on the underlying disease burden of untreated GPP by longitudinally analyzing patients in the placebo group who did not experience a GPP flare.&#x0D; Materials &amp; Methods: Eligible patients with a history of GPP were randomized (1:1:1:1) to receive one of three subcutaneous spesolimab regimens or placebo for 48 weeks. Patients were assessed for measures of chronic disease burden through the use of Generalized Pustular Psoriasis Physician Global Assessment (GPPPGA) Total Score, Pain Visual Analog Scale (VAS), and Psoriasis Symptom Scale (PSS) at baseline and at 4-week intervals during the trial, and Dermatology Quality of Life Index (DLQI) at baseline and weeks 4, 8, 12, 24, 36, and 48.&#x0D; Results: 16/31 placebo-treated patients experienced a GPP flare over the 48-week observational period of the trial, defined as an increase in GPPPGA score by ≥2 from baseline and the pustular component of GPPPGA ≥2. Of the remaining (“non-flaring”) 15 patients, 40% (6/15) had at least one GPPPGA Total Score value of 2 (skin not clear or almost clear); 4/6 reported such score at ≥4 visits. Pain scores ranged from 0 to 92.47, with 47% (7/15) and 20% (3/15) of patients having at least one “moderate” and “severe” VAS score over 48 weeks, respectively. Most of the 7 patients’ pain scores fluctuated with episodic peaks and valleys. 47% (7/15) and 13% (2/15) of patients had at least one “moderate” and “severe” PSS score, respectively. “Moderate” and “very large” effect on quality of life was reported, at least once, in 67% (10/15) and 40% (6/15) of patients, respectively.&#x0D; Conclusion: Acute flare was reported in more than 50% (16/31) of patients in the placebo group over 48 weeks. Despite not meeting the trial’s definition of GPP flare, most of the 15 “non-flaring” placebo-treated patients showed clear evidence of underlying GPP disease activity – nearly half did not have “clear” or “almost clear” skin and had moderate pain and symptoms; a small subset reported severe pain and symptoms. Majority of patients experienced a moderate to very large impact on quality of life over the 48 weeks. These findings suggest that untreated GPP negatively affects patients even in the absence of acute flare events.

Spesolimab Use for Generalized Pustular Psoriasis Flare Prevention in Patients with Concomitant Plaque Psoriasis: Results from the Effisayil 2 Trial

Introduction &amp; Objectives: Generalized pustular psoriasis (GPP) is a chronic inflammatory, potentially life-threatening skin disease, characterized by flares of sterile pustules. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is approved to treat GPP flares in adults. Effisayil 2 (NCT04399837) evaluated the efficacy and safety of subcutaneous spesolimab in preventing GPP flares. Here, we report the effect of spesolimab versus placebo on Target Plaque Severity Score (TPSS) in patients with concomitant plaque psoriasis (PsO) in Effisayil 2.&#x0D; Materials &amp; Methods: Eligible patients with a history of GPP were randomized (1:1:1:1) to high-dose spesolimab (loading dose 600 mg, maintenance dose 300 mg every 4 weeks), medium-dose spesolimab (loading: 600 mg, maintenance: 300 mg every 12 weeks), low-dose spesolimab (loading: 300 mg, maintenance: 150 mg every 12 weeks), or placebo for 48 weeks. One PsO lesion of ≥9 cm2 with TPSS total score ≥5 and induration sub-score ≥2 was selected by the investigator at baseline for each participant. Severity of erythema, scaling, and induration (plaque thickness) of the target lesion was assessed at baseline and subsequent visits on a 5-point scale (0, none to 4, very marked), with the summation of the 3 subscores representing the TPSS total score (0-12).&#x0D; Results: TPSS was measured in the 33/123 (27%) patients with PsO in the trial (9 placebo, 10 low-dose, 7 medium-dose, 7 high-dose). Mean TPSS total score was 4.2 in placebo and 4.6 in spesolimab-treated patients at baseline. By Week 4, mean TPSS remained similar in both groups (placebo, 4.3; spesolimab, 4.6). By Week 16, mean TPSS in the placebo group increased to 4.4 and decreased to 3.6 in spesolimab-treated patients. Mean TPSS total scores at Week 48 for both groups were below baseline (placebo, 3.3; spesolimab, 3.8). The number of patients with TPSS data declined in both groups over time due to GPP flare and/or early discontinuation.&#x0D; Conclusion: Low baseline TPSS scores observed in this subpopulation of 33 GPP patients with concomitant PsO suggest that concomitant PsO plaque characteristics in GPP are generally mild to moderate. TPSS scores remained low and consistent throughout the trial in both dosing groups and decreases in TPSS score by Week 16 (spesolimab-treated) and Week 48 (both groups) compared to baseline were observed.

Effect of High-Dose Subcutaneous Spesolimab on Skin Manifestations: Results from the Pivotal Effisayil 2 Trial of Flare Prevention in Generalized Pustular Psoriasis

Introduction &amp; Objectives: Generalized pustular psoriasis (GPP) is a chronic, rare and potentially life-threatening skin disease, characterized by flares of sterile pustules. Spesolimab, an anti-interleukin-36 receptor monoclonal antibody, is an effective and approved treatment for GPP flares in adults. Effisayil 2 (NCT04399837) was a pivotal, randomized controlled trial that evaluated the efficacy and safety of subcutaneous spesolimab in preventing GPP flares. Here, we report the effect of high-dose spesolimab versus placebo on GPP lesions.&#x0D; Materials &amp; Methods: Eligible patients with a history of GPP were randomized (1:1:1:1) to receive one of three subcutaneous spesolimab regimens or placebo for 48 weeks. High-dose spesolimab regimen was loading dose 600 mg, followed by maintenance dose 300 mg every 4 weeks. GPP Physician Global Assessment (GPPGA) subscores for erythema, pustules and scaling/crusting, and total score were compared between high-dose spesolimab and placebo groups at baseline and over the treatment period (scale: 0, clear to 4, severe).&#x0D; Results: Proportion of patients with baseline score of 0 for each GPPGA subscore and total score was generally similar between treatment groups, except erythema; (high-dose spesolimab [n=30] vs placebo [n=31]: erythema, 13.3% vs 22.6%; pustules, 66.7% vs 67.7%; scaling/crusting, 23.3% vs 22.6%; total score, 10.0% vs 12.9%). By Week 4, proportion of patients with scores of 0 increased with high-dose spesolimab versus placebo, (erythema, 33.3% vs 19.4%; pustules, 80.0% vs 41.9%; scaling/crusting, 30.0% vs 19.4%; total score, 26.7% vs 16.1%), and high-dose spesolimab group had fewer flares (10.0% vs 35.5%). This trend was maintained at Week 24 (erythema, 36.7% vs 22.6%; pustules, 63.3% vs 45.2%; scaling/crusting, 36.7% vs 19.4%; total score, 33.3% vs 19.4%) and Week 48 (erythema, 36.7% vs 22.6%; pustules, 66.7% vs 45.2%; scaling/crusting, 43.3% vs 25.8%; total score, 36.7% vs 22.6%). There were no new flares after Week 4 in high-dose spesolimab group; however, flares increased with placebo (45.2% at Week 24; 51.6% at Week 48).&#x0D; Conclusion: Versus placebo, high-dose subcutaneous spesolimab resulted in a greater proportion of patients maintaining GPPGA scores of 0, a lower proportion having flares at Week 4, and no new flares after Week 4. This was sustained at Weeks 24 and 48. 

Expected Spesolimab Plasma Exposure following Intravenous and Subcutaneous Dosing in Patients with Generalized Pustular Psoriasis

Introduction: Generalized pustular psoriasis (GPP) is a chronic, potentially life-threatening inflammatory skin disease characterized by widespread flares of sterile pustules. Spesolimab is a first-in-class anti-interleukin-36 receptor monoclonal antibody approved to treat GPP flares in adults via intravenous (IV) infusion. The aim of this study was to simulate the plasma pharmacokinetics (PK) of IV versus subcutaneous (SC) doses of spesolimab to compare drug exposure profiles and support dosing strategies in patients with GPP.&#x0D;  Methods: A population PK model was developed using individual-level PK, anti-drug antibody, and covariate data from eighteen studies in which subjects were treated with IV or SC spesolimab.1 The resulting PK model was used to simulate concentration-time profiles following varying doses of IV and SC spesolimab. Peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), and area under the curve (AUC) were summarized for each dose regimen.&#x0D; Results: Simulated spesolimab exposures demonstrated that the Cmax and AUC of the single dose 900 mg IV infusion consistently exceeded that of various single doses of SC spesolimab tested. A SC dose greater than two-fold higher would be required to attain a Cmax comparable to that of spesolimab 900 mg IV. The difference in exposure between the two administration routes was most pronounced in the first 2 weeks after administration. Slow absorption is expected with SC injection, with Tmax attained at later time points after SC dosing compared to immediately following the 90-minute infusion for IV dosing. Results were the same when simulating a two-dose regimen administered one week apart.&#x0D;  Conclusions: PK simulations suggest that treatment with IV and SC spesolimab can result in differences in drug exposure in clinical practice. The immediate and high exposure of IV spesolimab compared with the lower exposure of SC spesolimab are supportive of IV dosing with spesolimab in acute GPP flare treatment vs SC dosing.

Epidemiology, characteristics of disease and unmet needs of patients with generalized pustular psoriasis: a large Italian Delphi consensus.

Generalized pustular psoriasis (GPP) is a rare and chronic, debilitating skin condition characterised, in its acute flare phase, by clinically severe and potentially life-threatening systemic manifestations. Data on GPP are still scanty, particularly in Europe and at a national level. To provide expert indications on several disease-related and patient-related aspects of GPP, with specific focus to the Italian context. We conducted an iterative eDelphi study following the recommended criteria for reporting methods and results. After a thorough bibliographic review aimed to identify unknown or controversial issues in GPP, the following areas were investigated through a few specific questions/statements for each area: 1) disease epidemiology; 2) disease characteristics, with specific interest towards GPP flares; 3) diagnosis and diagnostic delay; 4) GPP treatment; 5) GPP patient journey and use of healthcare resources in Italy; 6) unmet needs and quality of life. An Executive Board of 9 principal investigators revised and approved the topics to be examined and overviewed the whole project. A total of 35 experts from different Italian areas, including 34 board-certified Italian dermatologists and one representative of patients' associations, took part in the study. A high agreement in responses from Italian experts emerged during two eDelphi iterations on - among several other aspects - GPP prevalence and incidence in Italy, use of European Rare and Severe Psoriasis Expert Network diagnostic criteria, flare frequency and duration, best diagnostic and care pathway, and main unmet needs of Italian patients. On the other hand, a broad spectrum of treatments (of different drug classes) was reported both in the acute and chronic phases of GPP, and no consensus on the issue was thus achieved. Consensus findings from this Delphi study of GPP experts may be useful to fill gaps of knowledge and improve awareness of this rare disease, as well as to help clinical and public health management of GPP in Italy.

Targeted review of IL36RN mutations in patients with generalised pustular psoriasis.

Generalised pustular psoriasis (GPP) is a rare and chronic skin disease historically treated with therapies that were originally intended to treat plaque psoriasis (PsO). However, GPP and plaque PsO have distinct pathogeneses and clinical courses. This study aimed to further characterise the unique genetic background of GPP by summarising evidence on the frequency and type of IL36RN gene mutation, a gene that normally suppresses proinflammatory responses, in patients with GPP compared to patients with GPP and plaque PsO, and patients with plaque PsO only. A targeted literature review was conducted to identify studies reporting IL36RN mutations and/or HLA-Cw6 allele frequency in patients with GPP. Meta-analyses showed a significantly higher rate of IL36RN mutations in the GPP-only population compared to the GPP+plaque PsO population (OR 3.51; 95% CI 2.29, 5.38). Monoallelic mutations of IL36RN were found in up to 33.3%, and biallelic mutations in up to 73.2% of patients with GPP (GPP-only and GPP+plaque PsO), in contrast with mono- and biallelic frequencies of only 0%-11.9% and 0%, respectively, in patients with plaque PsO only. Mean age-of-onset ranged from 5.9 to 48.9years old, with most studies reporting a GPP age-of-onset between 20 and 40years old. Twenty-one mutations were identified in the biallelic state and three in monoallelic. The most reported mutations were c.115+6T>C (p. Arg10ArgfsX1) (18 studies); c.227C>T (p.Pro76Leu) (10 studies); and c.338C> T (p.Ser113Leu) (8 studies). Mutations varied depending on geography and ethnicity, with the most frequently reported mutation predominantly reported in East Asian studies and international studies that included Asian patients. Rates of HLA-Cw6, the risk allele most strongly associated with plaque PsO, were 0%-28.6% for patients with GPP, similar to rates in the general population (10.5%-20%). Considering the differences between GPP and plaque PsO in aetiology and disease symptoms, effective, GPP-specific treatment options are needed, and recent research suggests that blockade of IL-36 signalling may be an effective target for treatment of GPP.

Exploring the Clinical Presentation, Course, and Burden of Disease in Generalized Pustular Psoriasis [Podcast].

Generalized pustular psoriasis (GPP) is the most severe form of pustular psoriasis and affects large areas of the body. GPP is a rare disease, and has a variable presentation; thus, its diagnosis is challenging. The onset of symptoms is rapid, with the appearance of painful skin erythema, followed by the widespread eruption of sterile pustules. Acute GPP (called a flare) is often accompanied by systemic symptoms, including high fever, pain in skin lesions, malaise, and fatigue. Approximately half of GPP flares require hospitalization, with an average inpatient duration of 10-14 days. GPP prevalence estimates range from approximately 2-124 cases per million persons, with a female predominance. The most common age of onset of GPP is 40-60 years, although cases have been described in younger adults and children. GPP affects every aspect of patients' lives and has a high physical and psycho-social impact. Recent research on the interleukin-36 pathway associated with GPP led to the development of a GPP-specific treatment, spesolimab, which was approved by the US FDA in September 2022. This podcast explores the clinical presentation, disease course, and burden of disease in GPP, including differential diagnosis and common triggers of an acute flare.

Therapeutic Potential of Spesolimab-Sbzo in the Management of Generalized Pustular Psoriasis Flares in Adults: Evidence to Date.

Generalized pustular psoriasis (GPP) is a rare, chronic, and severe skin disorder characterized by the eruption of non-infectious pustules on an erythematous background often associated with systemic symptoms. It may appear in association with plaque psoriasis or occur in previously healthy individuals. It differs from psoriasis vulgaris in clinical presentation, immunopathogenesis, histology, and therapeutic strategies. Overexpression of interleukin 36 (IL-36) or a loss-of-function mutation of IL-36 receptor antagonist (IL-36RA) are thought to play a pivotal role in the pathogenesis of this disease. There are currently no globally approved guidelines for the treatment of GPP, and the therapies used so far, with variable results, have given unsatisfactory results. Spesolimab, a selective humanized antibody against the IL-36 receptor that blocks its activation, is the first biologic drug approved in Europe in December 2022 for the treatment of GPP flares. It represents a promising therapy, demonstrating efficacy in reducing disease severity and improving patient outcomes. In our review, we have analyzed the latest advancements and findings regarding the efficacy and safety of spesolimab in the context of GPP management.

Successful Treatment of Generalized Pustular Psoriasis during Pregnancy by Cyclosporin and Etanercept: Own Experience and Review of Literature

Psoriasis is a common inflammatory skin disease affecting about 2% of the population. Generalized pustular psoriasis (GPP) is a rare variant of this disease, and it can be life-threatening for a pregnant woman and fetus. Medication during pregnancy can be challenging since many drugs can cause marked adverse effects for a fetus or newborn baby. Because controlled studies are difficult to perform, the knowledge grows slowly, e.g., from case reports. Here we describe a review of past and present treatments for GPP patients with a special reference to pregnancy and our experience on two GPP cases treated with cyclosporin and etanercept during pregnancy with successful outcomes of infants.

Spesolimab treatment for the prevention of flares in people with generalized pustular psoriasis (GPP): a plain language summary of the Effisayil™ 2 study

What is this study about? Generalized pustular psoriasis (shortened to GPP) is a rare, potentially life-threatening disease in which pus-filled blisters or pustules may suddenly form all over the body. The drug spesolimab has been approved to treat worsening GPP (known as flares) in many countries. However, it was not known if spesolimab could prevent the symptoms of GPP. This summary reports the results from a clinical study called Effisayil™ 2, that was done to understand if spesolimab was a safe and effective way to prevent flares in people with GPP. In the study, 123 participants, recruited in 20 different countries, were given one of three different doses of spesolimab (low, medium, or high) or a non-active medicine (placebo) over 48 weeks. What were the results? Participants who received spesolimab had fewer GPP flares over the course of the 48-week study. Different doses of the drug were tested and compared to placebo, and a high dose of spesolimab worked better than low and medium doses. Using spesolimab also reduced the chance of developing skin symptoms, such as redness or pustules, and prevented quality of life getting worse over 48 weeks. While some participants experienced unwanted effects, they were mostly mild or moderate and most did not appear to be caused by spesolimab, or the dose at which it was given. What do the results of the study mean? The results indicate that a high dose of spesolimab works well to prevent GPP flares and stop the disease getting worse. Health authorities are looking at the results of this study to decide if spesolimab can also be prescribed for the prevention of GPP flares.

Clinical and Disease Burden of Patients with Generalized Pustular Psoriasis: A Review of Real-World Evidence.

Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening disease. There is limited understanding of patient characteristics in GPP and their correlation with disease progression or healthcare resource utilization. Our review aims to examine real-world evidence on these characteristics and the associated disease burden as related to economic and quality of life factors. Results showed that most patients with GPP experienced flares once a year, lasting from 2weeks to 3months, with > 80% of patients having residual disease post-flare, with/without treatment, indicating the long-term nature of GPP. The impact of GPP on patients' daily activities was significant, even in the absence of a flare. GPP adversely affected mental health, and anxiety and depression were reported regularly. Patients with GPP had more comorbidities, were prescribed more medication, and had more inpatient and outpatient visits than in matched plaque psoriasis or general population cohorts. Improving the education of healthcare providers in diagnosing GPP, defining disease flares, and managing the disease, as well as making globally accepted clinical guidelines for GPP treatment available, could help to reduce the burden on patients with GPP. Effective therapies that control and prevent GPP flares and manage chronic disease are needed.

Regional differences in the prevalence of generalized pustular psoriasis in Japan.

Generalized pustular psoriasis (GPP), a rare form of psoriasis, is characterized by neutrophil-rich, sterile pustules. In Japan, GPP has intractable and rare disease designation, which allows patients to access support from national and local governments for medical expenses. Previously, similar numbers of patients in Tokyo and Hokkaido have been shown to have GPP designation, despite different population sizes. Here, we determine whether there are regional differences in the proportion of patients receiving GPP designation status in Japan and aim to identify causal factors. In this descriptive, retrospective cohort study, publicly available data were collected on the number of patients with intractable and rare disease designation for GPP in each prefecture and age classification (April 2018-March 2021). Three other designated intractable and rare disease cohorts were included: pemphigus, rare skin diseases, and all diseases. The primary outcome was the standardized morbidity ratio (SMR) of patients at prefecture level (observed numbers divided by expected). Regional differences were compared with the statistical expectation for the total population and age distribution of each prefecture. Regional differences were observed in all cohorts. Overall, 1910 patients had GPP as a designated intractable and rare disease in 2020. Regional differences in SMRs for GPP were observed with high SMRs (≥1.5) in Hokkaido, Tottori, Kagawa, and Miyazaki, and low SMRs (<0.6) in Gunma and Kanagawa. Regional differences in SMRs for GPP did not correlate with the number of medical doctors or dermatologists or internal migration. The number of medical doctors or dermatologists correlated with SMRs in the rare skin diseases and total cohorts. Regional differences in Japan exist in the number of patients with GPP who have an intractable and rare disease designation. Managing rare diseases is an important public health issue, and further research is required to elucidate the factors contributing to these differences.

Characteristics and management of generalized pustular psoriasis (GPP): Experience from the Central and Eastern Europe (CEE) GPP Expert Network.

Generalized pustular psoriasis (GPP) is a rare, inflammatory skin disease characterized by widespread eruption of sterile pustules with or without systemic symptoms. This study aimed to describe the demographics of patients with GPP in Central and Eastern Europe (CEE), present the clinical characteristics of individual GPP flares and explore the current treatment landscape. Patient demographics were collected at the times of last observation and previous treatment. Characteristics of a patient's last (most recent) and most severe (from all documented episodes) flare were provided at clinician's discretion. Fifty-eight patients were recruited from 12 centres in nine CEE countries; median (range) age was 61 (16-92) years and 60.3% (35 out of 58) were female. The most common comorbidities were hypertension (43.1% [25 out of 58]) and hyperlipidaemia (32.8% [19 out of 58]). Thirty-four patients (58.6%) presented with concomitant plaque psoriasis before or during the course of GPP. Data from two separate flares were recorded in 26 individuals; in 32 patients, the most recent flare was reported as the most severe. Over 90% of patients with a flare episode classified as most severe by clinicians were hospitalized, with >75% of these individuals having a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score of 3 or 4. Systemic symptoms were more common in patients with a GPPGA score of 3 or 4 but were also manifest in individuals with a GPPGA score ≤2. A significant correlation was observed between a combined systemic disease score of clinical and laboratory features and both GPPGA total score (r = 0.385, p < 0.001) and GPPGA pustulation subscore (r = 0.305, p < 0.05). Considerable heterogeneity in the presentation of GPP flares was observed, both between patients and within-patient. All GPP flares were associated with a significant clinical burden, highlighting the unmet need for accurate and early diagnosis.