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Generalized pustular psoriasis (GPP) is a rare and highly heterogenous skin disease, characterized by flares of neutrophilic pustules and erythema. As a rare disease with few clinical studies and no standardized management approaches, there is a paucity of knowledge regarding GPP.Conduct a Delphi panel study to identify current evidence and gain advanced insights into GPP.A systematic literature review was used to identify published literature and develop statements categorized into four key domains: clinical course and flare definition; diagnosis; treatment goals; and holistic management. Statements were rated on a Likert scale by a panel of dermatologists in two rounds of online questionnaires; the threshold for consensus was agreement by ≥80%.Twenty-one panelists reached consensus on 70.9%, 61.8%, 100.0%, and 81.8% of statements in the "clinical course and flare definition", "diagnosis", "treatment goals", and "holistic management of GPP" domains, respectively. There was clear consensus on GPP being phenotypically, genetically, and immunologically distinct from plaque psoriasis. Clinical course is highly variable, with an extensive range of complications. Clinical and histologic features supporting GPP diagnosis reached high levels of agreement, and although laboratory evaluations were considered helpful for diagnosis and monitoring disease severity, there was uncertainty around the value of individual tests. All acute and long-term treatment goals reached consensus, including rapid and sustained clearance of pustules, erythema, scaling and crust, clearance of skin lesions, and prevention of new flares. Potential triggers, associated comorbidities, and differential diagnoses achieved lower rates of consensus, indicating that further evidence is needed.Global consensus between dermatologists was reached on clinically meaningful goals for GPP treatment, on key features of GPP flares, and on approaches for assessing disease severity and multidisciplinary management of patients. On this basis, we present a management algorithm for patients with GPP for use in clinical practice.

Generalized pustular psoriasis (GPP) is a rare auto-inflammatory skin disease characterised by acute episodes of sterile pustule formation. Diagnosis and treatment of the disease have historically been complicated by a lack of awareness, and no consistent global definition or clinical coding standards. Now acknowledged as a distinct clinical entity with a recognised genetic component, GPP can take a serious and life-threatening course due to systemic inflammatory complications and its association with various comorbidities. As with other rare diseases, there are significant challenges to understanding the epidemiology of GPP, notably a small patient population, non-standardised study methodologies and ethnic differences in its presentation. A clearer understanding of GPP is therefore required for clinicians to better manage patients with this rare condition. In this review article, we present an overview of the available data on GPP prevalence estimates in key demographics and report the frequency of genetic mutations associated with the disease. We detail the incidence of known comorbidities and summarise the data on mortality and assigned causes of death. Lastly, we discuss the various factors that impact the collection, interpretation and comparison of these data.

Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by flares of widespread erythema with sterile pustules, and can be relapsing with recurrent flares, or persistent with intermittent flares. Spesolimab, a humanized anti-interleukin-36 (IL-36) receptor monoclonal antibody, targets the key IL-36 pathogenetic pathway in GPP. A previous study showed that spesolimab treatment led to rapid pustular and skin clearance in patients with GPP flares, which was sustained for up to 12 weeks. This study investigates the long-term effects of spesolimab on GPP flares, for which no specific treatments are currently available. The Effisayil™ 2 study will assess whether maintenance treatment with subcutaneous spesolimab prevents the occurrence of GPP flares and determine the optimal dosing regimen to achieve this aim.Patients will have a documented history of GPP with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear) at screening and randomization. Patients will be randomized 1:1:1:1 to three groups receiving a 600-mg subcutaneous loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 or 12 weeks, or a 300-mg loading dose followed by a 150-mg maintenance dose administered every 12 weeks, and one group receiving placebo, for 48 weeks. The primary endpoint is time to first GPP flare. If a patient experiences a GPP flare during the randomized maintenance treatment period, an open-label intravenous dose of 900-mg spesolimab will be administered, with an option for a second intravenous dose after 1 week.Effisayil™ 2 is the first placebo-controlled study in patients with GPP to investigate whether maintenance treatment with spesolimab can prevent flares and provide sustained disease control. This study will provide valuable insights on the long-term management of patients with this potentially life-threatening skin disease.NCT04399837.The aim of the Effisayil™ 2 study is to see whether long-term treatment with the antibody spesolimab helps prevent skin flares in people with generalized pustular psoriasis (GPP). Patients can take part in the Effisayil™ 2 study if they have well-controlled GPP before they begin treatment in the study; that is, they will have skin that is clear or almost clear. Patients will be randomly divided into four groups, with similar numbers of patients in each group. In three of the four groups, patients will be given different doses of spesolimab for 48 weeks. In the fourth group, patients will be given a placebo for 48 weeks. The main goal of the study is to see how long it takes patients to have a GPP flare, while they are being given spesolimab or placebo. If any patient has a GPP flare during the study, they can be treated with another dose of spesolimab (and possibly a second dose 1 week later if needed), to help control the GPP flare. In this way, the Effisayil™ 2 study will help doctors and patients to learn how to manage GPP over time, so that GPP flares can be avoided.

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.

Generalized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterized by episodes of widespread sterile macroscopic pustules, with or without systemic inflammation and/or plaque psoriasis. Multiple GPP subtypes have been described, from acute GPP of von Zumbusch to milder, annular pustular psoriasis. Generalized pustular psoriasis mainly affects adults, with a female preponderance, but juvenile GPP also occurs. Flares are a hallmark of GPP and may occur de novo or be provoked by triggers, including withdrawal of systemic corticosteroids, infections, stress, pregnancy, and menstruation. Severity of flares varies widely between patients, and between flares in an individual patient. Significant flares are often accompanied by systemic symptoms, notably fever, general malaise, and extracutaneous manifestations such as arthritis, uveitis, and neutrophilic cholangitis. Common laboratory abnormalities include neutrophilia, elevated C-reactive protein levels, hypocalcemia, and abnormal liver function tests. The clinical course of GPP is highly variable; it can be a relapsing disease with recurrent flares and no pustulation between flares or a persistent disease with perpetual mild pustulation punctuated with flares of greater severity. Patients may have multiple flares per year or a flare every few years. Most flares last 2-5 weeks and approximately 50% require hospitalization. Life-threatening complications include sepsis and renal, hepatic, respiratory, and heart failure. Reported mortality rates are 2-16%.

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: 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.

Generalized pustular psoriasis is a potentially life-threatening neutrophilic skin disease characterized by recurrent flares of widespread erythema and eruption of sterile pustules. In the Effisayil™ 1 study (NCT03782792), 53 patients with a generalized pustular psoriasis flare were treated with placebo or spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, the first targeted treatment to be studied in a randomized clinical trial. Spesolimab treatment resulted in rapid pustular and skin clearance, with an acceptable safety profile. Here, we evaluate the efficacy and safety of spesolimab in 29 Asian patients in the Effisayil™ 1 study. The primary endpoint, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (no visible pustules) at Week 1, was achieved by 10 patients (62.5%) randomized to spesolimab and one patient (7.7%) randomized to placebo (risk difference 54.8, 95% confidence interval [CI] 17.3-79.8). The key secondary endpoint, a GPPGA total score of 0 or 1 (clear or almost clear skin) at Week 1, was achieved by eight (50.0%) and two (15.4%) patients, respectively (risk difference 34.6, 95% CI -3.1-64.7). This was similar to previously published data in the overall population in whom the primary and key secondary endpoints were achieved by 54% versus 6% and 43% versus 11% of patients, respectively. The percentages of Asian patients randomized to spesolimab with a GPPGA pustulation subscore of 0 and GPPGA total score of 0 or 1 were sustained above 60% for up to 12 weeks. In these patients, patient-reported outcomes also improved and markers of systemic inflammation were normalized. Eleven (68.8%) and eight (61.5%) of spesolimab- and placebo-treated patients, respectively, experienced at least one adverse event. In conclusion, spesolimab improved outcomes in Asian patients compared with placebo, supporting its use in the treatment of generalized pustular psoriasis flares.

Summary Background There are no population-based epidemiological data on psoriasis in Southeast Asia, including Malaysia. Objectives To determine the incidence and prevalence of psoriasis over 11 years in multiethnic Johor Bahru, Malaysia. Methods A population-based cohort study was made using the Teleprimary Care database between January 2010 and December 2020. Cases of psoriasis, identified by ICD-10 diagnostic codes, were validated by dermatologists. Annual prevalence and incidence were estimated and stratified by age, sex and ethnicity. Results We identified 3932 people with dermatologist-confirmed psoriasis, including 1830 incident cases, among 1 164 724 Malaysians, yielding an 11-year prevalence of 0·34% [95% confidence interval (CI) 0·33–0·35] and incidence of 34·2 per 100 000 person-years (95% CI 32·6–35·8). Rates were higher in Indian patients; the prevalences were 0·54% (0·50–0·58) in Indian, 0·38% (0·36–0·40) in Chinese and 0·29% (0·28–0·30) in Malay patients, and the respective incidences per 100 000 person-years were 52·5 (47·3–57·7), 38·0 (34·1–41·8) and 30·0 (28·2–31·8). Rates were higher in males; the prevalence was 0·39% (0·37–0·41) in males and 0·29% (0·27–0·30) in females, and the respective incidences per 100 000 person-years were 40·7 (38·2–43·2) and 28·3 (26·4–30·3). Between 2010 and 2020, annual psoriasis prevalence and incidence increased steadily from 0·27% to 0·51% and from 27·8 to 60·9 per 100 000 person-years, respectively. Annual rates were consistently higher in male and Indian patients. Overall, psoriasis was significantly more common in males than females [odds ratio (OR) 1·37, 95% CI 1·29–1·46] and in Indian and Chinese patients vs. Malay (OR 1·85, 1·71–2·01 and OR 1·30, 1·20–1·41, respectively). Prevalence increased with age, with the highest rates in the groups aged 50–59 and 60–69 years at 0·67% and 0·66%, respectively. A modest bimodal trend in age of psoriasis onset was observed, with first and second peaks at 20–29 and 50–59 years. Disease onset was significantly earlier in females than males [mean (SD) 36·8 (17·3) vs. 42·0 (17·2) years, P < 0·001] and in Malay vs. Indian and Chinese patients [mean (SD): Malay 36·4 (17·5), Indian 40·8 (15·2), Chinese 47·4 (16·9) years, P < 0·001]. Conclusions We found that psoriasis incidence and prevalence are increasing and varied by age, sex and ethnicity. Our findings should help inform healthcare planning and management for patients with psoriasis in Malaysia. What is already known about this topic? The incidence and prevalence of psoriasis are generally lower in Asian populations and children.There is a lack of agreement on sex-specific differences in psoriasis incidence and prevalence.There has been no population-based study on the incidence and prevalence of psoriasis in Southeast Asia, including Malaysia.There is no information on differences in psoriasis prevalence and incidence by sex, age and ethnicity in Malaysia. What does this study add? Psoriasis incidence and prevalence are increasing in the multiethnic population of Johor Bahru, Malaysia.Incidence and prevalence rates were higher in male than female patients and were consistently highest among Indian patients, followed by Chinese and Malay.A modest bimodality in the age of psoriasis onset was observed among the groups aged 20–29 and 50–59 years.Psoriasis onset was significantly later in male than female patients and in Chinese vs. Indian and Malay patients.

Background Co-trimoxazole, a sulfonamide antibiotic, is used to treat a variety of infections worldwide, and it remains a common first-line medicine for prophylaxis against Pneumocystis jiroveci pneumonia. However, it can cause severe cutaneous adverse reaction (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms. The pathomechanism of co-trimoxazole–induced SCAR remains unclear. Objective We aimed to investigate the genetic predisposition of co-trimoxazole–induced SCAR. Methods We conducted a multicountry case-control association study that included 151 patients with of co-trimoxazole–induced SCAR and 4631 population controls from Taiwan, Thailand, and Malaysia, as well as 138 tolerant controls from Taiwan. Whole-genome sequencing was performed for the patients and population controls from Taiwan; it further validated the results from Thailand and Malaysia. Results The whole-genome sequencing study (43 case patients vs 507 controls) discovered that the single-nucleotide polymorphism rs41554616, which is located between the HLA-B and MICA loci, had the strongest association with co-trimoxazole–induced SCAR (P = 8.2 × 10−9; odds ratio [OR] = 7.7). There were weak associations of variants in co-trimoxazole–related metabolizing enzymes (CYP2D6, GSTP1, GCLC, N-acetyltransferase [NAT2], and CYP2C8). A replication study using HLA genotyping revealed that HLA-B∗13:01 was strongly associated with co-trimoxazole–induced SCAR (the combined sample comprised 91 case patients vs 2545 controls [P = 7.2 × 10−21; OR = 8.7]). A strong HLA association was also observed in the case patients from Thailand (P = 3.2 × 10−5; OR = 3.6) and Malaysia (P = .002; OR = 12.8), respectively. A meta-analysis and phenotype stratification study further indicated a strong association between HLA-B∗13:01 and co-trimoxazole–induced drug reaction with eosinophilia and systemic symptoms (P = 4.2 × 10−23; OR = 40.1). Conclusion This study identified HLA-B∗13:01 as an important genetic factor associated with co-trimoxazole–induced SCAR in Asians.

Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares.In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity.A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

IntroductionGeneralized pustular psoriasis (GPP) is a rare, potentially life-threatening disease characterised by recurrent flares of widespread neutrophilic aseptic skin pustular eruption. Despite the availability of approved biologics for GPP in Japan, Taiwan and Thailand, associated evidence is largely based on uncontrolled studies in which acute flares were not directly assessed. Therefore, there is a high unmet need to investigate new rapid-acting effective treatments that resolve symptoms associated with acute GPP flares. A prior Phase I proof-of-concept study showed rapid improvements in skin and pustule clearance with a single intravenous dose of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients presenting with an acute GPP flare. Here, we present the design and rationale of Effisayil 1, a global, Phase II, placebo-controlled study to evaluate the efficacy, safety and tolerability of spesolimab in patients presenting with an acute GPP flare.Methods and analysisAt least 51 patients with an acute GPP flare will be randomised 2:1 to receive a single 900 mg intravenous dose of spesolimab or placebo and followed for up to 28 weeks. The primary endpoint is a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (pustule clearance) at Week 1. The key secondary endpoint is a GPPGA score of 0 or 1 (clear or almost clear) at Week 1. Safety will be assessed over the study duration by the occurrence of treatment-emergent adverse events. Blood and skin biopsies will be collected to assess biomarkers. Superiority of spesolimab over placebo in the proportion of patients achieving the primary and key secondary endpoints will be evaluated.Ethics and disseminationThe study complies with the ethical principles of the Declaration of Helsinki, the International Council for Harmonisation’s Good Clinical Practice and local regulations. Ethics committee approvals have been obtained for each centre from all participating countries and are listed in online supplementary file 1. Primary results will be published in a peer-reviewed journal.Trial registration detailsClinicalTrials.gov identifier: NCT03782792; Pre-results.

Background The multi-morbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse COVID-19 outcomes but data are limited. Objective Characterize the course of COVID-19 in psoriasis and identify factors associated with hospitalization. Methods Clinicians reported psoriasis patients with confirmed/suspected COVID-19 via an international registry, PsoProtect. Multiple logistic regression assessed the association between clinical/demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviours. Results Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% a non-biologic and 10% no systemic treatment for psoriasis. 348 (93%) fully recovered from COVID-19, 77 (21%) were hospitalized and nine (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted OR 1.59 per 10 years, 95% CI 1.19-2.13), male sex (OR 2.51, 95% CI 1.23-5.12), non-white ethnicity (OR 3.15, 95% CI 1.24-8.03) and comorbid chronic lung disease (OR 3.87, 95% CI 1.52-9.83). Hospitalization was more frequent in patients using non-biologic systemic therapy than biologics (OR 2.84, 95% CI 1.31-6.18). No significant differences were found between biologic classes. Independent patient-reported data (n=1,626 across 48 countries) suggested lower levels of social isolation in individuals receiving non-biologic systemic therapy compared to biologics (OR 0.68, 95% CI 0.50-0.94). Conclusion In this international moderate-severe psoriasis case series, biologics use was associated with lower risk of COVID-19-related hospitalization than non-biologic systemic therapies, however further investigation is warranted due to potential selection bias and unmeasured confounding. Established risk factors (being older, male, non-white ethnicity, comorbidities) were associated with higher hospitalization rates. Clinical Implications We identify risk factors for COVID-19-related hospitalization in psoriasis patients, including older age, male sex, non-white ethnicity and comorbidities. Use of biologics was associated with lower hospitalization risk than non-biologic systemic therapies., Capsule summary: In this global registry-based study, risk factors for COVID-19-related hospitalization in psoriasis patients were older age, male sex, non-white ethnicity and comorbidities. Use of biologics was associated with lower hospitalization risk than non-biologic systemic treatment.

Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. While IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extra-cutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalised pustular psoriasis (GPP), a clinical variant associated with pervasive up-regulation of IL-36 signalling. By undertaking blood and neutrophil RNA-sequencing, we demonstrated that affected individuals display a prominent Type-I IFN signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 de-regulation and Type-I IFN over-expression in patients with severe psoriasis vulgaris (PsV). We also found that the activation of Type-I IFN genes was associated with extra-cutaneous morbidity, in both GPP and PsV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells (pDCs), where it potentiates Toll-like Receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the up-regulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/Type-I IFN axis contributing to extra-cutaneous inflammation in psoriasis.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole exome sequencing of 19 unrelated cases, we identified one affected individual harbouring a homozygous splice-site mutation (c.2031-2A>C) in MPO. The same homozygous change was subsequently identified in a further subject suffering from acral pustular psoriasis, a disease phenotypically related to GPP.MPO encodes myeloperoxidase, an essential component of neutrophil azurophil granules. Of interest, the c.2031-2A>C allele was previously described as a genetic determinant of myeloperoxidase deficiency (MPOD), a condition which can causes recurrent infections. Here, a systematic literature review identified four individuals suffering from MPOD and pustular skin disease, further strengthening the link between MPO and pustular inflammation.A subsequent analysis of the UK Biobank cohort demonstrated that the c.2031-2A>C allele was associated with increased neutrophil abundance in the general population (P=5.1×10−6). The same applied to three further MPOD mutations for which genotype data was available, with two alleles generating p-values −10. Finally, treatment of healthy neutrophils with an MPO inhibitor reduced cell apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers.These findings identify MPO mutations as genetic determinants of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89–418.13; corrected P = 2.92 × 10–4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P

Background\ud\udA core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed‐upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e‐Delphi surveys. In this manuscript, we describe two in‐person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items.\ud\ud\udObjectives\ud\udTo consider which items from a long list of candidate items to exclude and which to cluster into outcome domains.\ud\ud\udMethods\ud\udThe study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey.\ud\ud\udResults\ud\udForty‐one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS‐specific quality of life, satisfaction, symptoms, pain and global assessments.\ud\ud\udConclusions\ud\udThe HISTORIC consensus meetings I and II will be followed by further e‐Delphi rounds to finalize the core domain set, building on the work of the in‐person consensus meetings.

Interleukin-36 Blockade in Pustular Psoriasis Seven patients with pustular psoriasis, three with mutations in IL36RN, were treated with a monoclonal antibody against interleukin-36 receptor and had...

Background Limited information exists regarding juvenile generalized pustular psoriasis (GPP). We aim to determine the clinical profile and outcome of Malaysians with juvenile GPP. Methods Review of hospital case notes on patients with juvenile GPP. Results Twenty-seven patients with juvenile GPP were identified. Female to male ratio was 1.4:1. The median age at onset of GPP was 6.5 years. Ten patients had prior psoriasis with a median pre-pustular duration of 2.7 years. Onset of GPP was earlier in patients without prior psoriasis (5.1 years vs. 12.0 years, P = 0.002). Precipitating factors identified included stress, upper respiratory tract infection, systemic steroid use, vaccination, and pregnancy. A positive family history of psoriasis and GPP was present in six and one patient(s), respectively. Twenty-one patients had acute, five annular, and one localized variant of GPP. Arthritis was present in 22.2%. Fever, leukocytosis, and transaminitis were mainly seen in patients with acute GPP at 80.9, 72.2, and 11.1%, respectively. Among 20 patients screened, eight carry IL36RN variants and one has CARD14 mutation. IL36RN-positive patients have more severe disease characterized by early onset, low prevalence of prior plaque psoriasis, high prevalence of systemic inflammation, and need for continuous long-term systemic therapy. Acitretin and cyclosporine were effective in aborting acute GPP in 100% of 16 and 66.7% of six patients treated, respectively. However, relapses were common. Only three of the 17 patients whose initial acute GPP was controlled with systemic agents were successfully weaned off treatment. Conclusions Juvenile GPP is a chronic recalcitrant disease. IL36RN-positive patients have more severe disease.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Phenytoin (PHT) is a common cause of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Although HLA-B*15:02 is associated with PHT-induced SJS/TEN (PHT-SJS/TEN) in Han Chinese and Thais, the genetic basis for susceptibility to PHT-induced SCARs (PHT-SCAR) in other populations remains unclear. We performed a case-control association study by genotyping the human leukocyte antigen (HLA)-B alleles of 16 Malay PHT-SCAR patients (13 SJS/TEN and 3 DRESS), 32 PHT-tolerant controls and 300 healthy ethnicity-matched controls. A novel genetic biomarker, HLA-B*15:13, showed significant association with PHT-SJS/TEN (53.8%, 7/13 cases) (odds ratio (OR) 11.28, P=0.003) and PHT-DRESS (100%, 3/3 cases) (OR 59.00, P=0.003) when compared with PHT-tolerant controls (9.4%, 3/32 controls). We also confirmed HLA-B*15:02 association with PHT-SJS/TEN (61.5%, 8/13 cases vs 21.9%, 7/32 controls; OR 5.71, P=0.016) when compared with PHT-tolerant controls. These alleles may serve as markers to predict PHT-SCAR in Malays.

Psoriasis is an immune-mediated skin disorder associated with severe systemic co-morbidities. Both chronic and acute forms of the disease are characterised by abnormal interleukin (IL)-36 signalling. While the mechanisms whereby IL-36 promotes cutaneous inflammation are well established, its systemic effects have not been investigated. To address this issue, we initially measured leukocyte gene expression in generalised pustular psoriasis, an acute disease variant caused by mutations of the IL-36 receptor antagonist. By undertaking whole-blood and neutrophil RNA-sequencing in affected individuals, we identified a Type-I IFN signature, which correlated with IL-36 signalling up-regulation. We then validated these observations in patients with chronic plaque psoriasis. Finally, we demonstrated that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates Toll-like Receptor (TLR)-9 activation and IFN-alpha production. This effect was mediated by the induction of PLSCR1, an endosomal TLR-9 transporter. These results define an IL-36/TLR-9/Type-I IFN axis that could be targeted for the treatment of psoriasis co-morbidities.

Caspase recruitment family member 14 (CARD14, also known as CARMA2), is a scaffold protein that mediates NF-κB signal transduction in skin keratinocytes. Gain-of-function CARD14 mutations have been documented in familial forms of psoriasis vulgaris (PV) and pityriasis rubra pilaris (PRP). More recent investigations have also implicated CARD14 in the pathogenesis of pustular psoriasis. Follow-up studies, however, have been limited, so that it is not clear to what extent CARD14 alleles account for the above conditions. Here, we sought to address this question by carrying out a systematic CARD14 analysis in an extended patient cohort (n=416). We observed no disease alleles in subjects with familial PV (n=159), erythrodermic psoriasis (n=23), acral pustular psoriasis (n=100), or sporadic PRP (n=29). Conversely, our analysis of 105 individuals with generalized pustular psoriasis (GPP) identified a low-frequency variant (p.Asp176His) that causes constitutive CARD14 oligomerization and shows a significant association with GPP in Asian populations (P=8.4 × 10−5; odds ratio=6.4). These data indicate that the analysis of CARD14 mutations could help stratify pustular psoriasis cohorts but would be mostly uninformative in the context of psoriasis and sporadic PRP.

Objectives: To differentiate the leprosy agents Mycobacterium leprae and Mycobacterium lepromatosis and correlate them with geographic distribution and clinicopathologic features. Methods: Species-specific polymerase chain reactions were used to detect each bacillus in archived skin biopsy specimens from patients with leprosy from Brazil (n = 52), Malaysia (n = 31), Myanmar (n = 9), and Uganda (n = 4). Findings were correlated with clinical and pathologic data. Results: Etiologic species was detected in 46 of the 52 Brazilian patients, including 36 patients with M leprae , seven with M lepromatosis , and three with both bacilli. The seven patients with sole M lepromatosis all had tuberculoid leprosy, whereas only nine of the 36 patients infected with M leprae exhibited this type, and the rest were lepromatous ( P < .001). All patients with dual infections had lepromatous leprosy. Of the nine patients from Myanmar, six were test positive: four with M leprae and two with M lepromatosis . Of the Malaysian and Ugandan patients, only M leprae was detected in 27 of the 31 Malaysians and two of the four Ugandans. Conclusions: The leprosy agents vary in geographic distribution. Finding M lepromatosis in Brazil and Myanmar suggests wide existence of this newly discovered species. The leprosy manifestations likely vary with the etiologic agents.

Background Adverse drug reactions are most commonly cutaneous in nature. Patterns of cutaneous adverse drug reactions (ADRs) and their causative drugs vary among the different populations previously studied. Objective Our aim is to determine the clinical pattern of drug eruptions and the common drugs implicated, particularly in severe cutaneous ADRs in our population. Materials and Methods This study was done by analyzing the database established for all adverse cutaneous drug reactions seen from January 2001 until December 2008. Results A total of 281 cutaneous ADRs were seen in 280 patients. The most common reaction pattern was maculopapular eruption (111 cases, 39.5%) followed by StevensJohnson Syndrome (SJS: 79 cases, 28.1%), drug reaction with eosinophilia and systemic symptoms (DRESS: 19 cases, 6.8%), toxic epidermal necrolysis (TEN: 16 cases, 5.7 %), urticaria/angioedema (15 cases, 5.3%) and fixed drug eruptions (15 cases, 5.3%). Antibiotics (38.8%) and anticonvulsants (23.8%) accounted for 62.6% of the 281 cutaneous ADRs seen. Allopurinol was implicated in 39 (13.9%), carbamazepine in 29 (10.3%), phenytoin in 27 (9.6%) and cotrimoxazole in 26 (9.3%) cases. Carbamazepine, allopurinol and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 24.0%, 18.8% and 12.5% respectively of the 96 cases seen whereas DRESS was mainly caused by allopurinol (10 cases, 52.6%) and phenytoin (3 cases, 15.8%). Discussion The reaction patterns and drugs causing cutaneous ADRs in our population are similar to those seen in other countries although we have a much higher proportion of severe cutaneous ADRs probably due to referral bias, different prescribing habit and a higher prevalence of HLA-B*1502 and HLA-B*5801 which are genetic markers for carbamazepine-induced SJS/TEN and allopurinol-induced SJS/TEN/DRESS respectively. Conclusion The most common reaction pattern seen in our study population was maculopapular eruptions. Antibiotics, anticonvulsants and NSAIDs were the most frequently implicated drug groups. Carbamazepine and allopurinol were the two main causative drugs of severe ADRs in our population.

The CARD14 (Caspase Recruitment Family Member 14) locus encodes a scaffold protein that mediates NF-kB signalling in keratinocytes and is therefore crucial to the maintenance of skin immune homeostasis. In keeping with this notion, gain-of-function CARD14 mutations have been observed in patients with plaque psoriasis and pityriasis rubra pilaris, two skin disorders mediated by abnormal T cell activation. More recently, a CARD14 missense variant has been tentatively associated with generalised pustular psoriasis (GPP), an auto-inflammatory condition characterised by acute episodes of skin pustulation and systemic upset.

Contains fulltext : 138240.pdf (Publisher’s version ) (Closed access) Adaptor protein complex 1 (AP-1) is an evolutionary conserved heterotetramer that promotes vesicular trafficking between the trans-Golgi network and the endosomes. The knockout of most murine AP-1 complex subunits is embryonically lethal, so the identification of human disease-associated alleles has the unique potential to deliver insights into gene function. Here, we report two founder mutations (c.11T>G [p.Phe4Cys] and c.97C>T [p.Arg33Trp]) in AP1S3, the gene encoding AP-1 complex subunit sigma1C, in 15 unrelated individuals with a severe autoinflammatory skin disorder known as pustular psoriasis. Because the variants are predicted to destabilize the 3D structure of the AP-1 complex, we generated AP1S3-knockdown cell lines to investigate the consequences of AP-1 deficiency in skin keratinocytes. We found that AP1S3 silencing disrupted the endosomal translocation of the innate pattern-recognition receptor TLR-3 (Toll-like receptor 3) and resulted in a marked inhibition of downstream signaling. These findings identify pustular psoriasis as an autoinflammatory phenotype caused by defects in vesicular trafficking and demonstrate a requirement of AP-1 for Toll-like receptor homeostasis.

Background Generalized pustular psoriasis (GPP) is a severe but rare variant of psoriasis. Our objective is to review the clinical profile, comorbidities, and outcome of patients with GPP. Materials and methods A retrospective note review of all patients with adult-onset GPP. Results A total of 102 patients with adult-onset GPP were diagnosed between 1989 and November 2011, with a female to male ratio of 2 : 1. The mean age at onset of GPP was 40.9 years (range: 21–81 years). Acute GPP was the most common variant seen (95 cases), followed by four localized variants of GPP and three with annular pustular psoriasis. Fever and painful skin were present in 89% of patients, arthritis in 34.7%, and leukocytosis in 78.4%. Common triggers were systemic steroids (45 cases), pregnancy (17 cases), and upper respiratory tract infections (16 cases). A positive family history of psoriasis and GPP was present in 29% and 11%, respectively. Comorbidities included obesity (42.9%), hypertension (25.7%), hyperlipidemia (25.7%), and diabetes mellitus (23.7%). The mean duration of admission and pustular flare for acute GPP was 10.3 days (range: 3–44 days) and 16 days (range: 7–60 days), respectively. Fifty-four patients responded to systemic retinoid, 21 to methotrexate, eight to cyclosporine, and one to adalimumab, but recurrences were common. Conclusions Our study confirms the poor response of GPP to currently available anti-psoriatic agents, with frequent flare-ups. There is a need for a more effective targeted therapy for this condition.

Item does not contain fulltext OBJECTIVE: To investigate the relationship of excess and central adiposity with pediatric psoriasis severity. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, cross-sectional study of 409 psoriatic children. Psoriasis was classified as mild (worst Physician's Global Assessment score /=3 with body surface area >10%). Children were enrolled from 9 countries between June 19, 2009, and December 2, 2011. MAIN OUTCOME MEASURES: Excess adiposity (body mass index percentile) and central adiposity (waist circumference percentile and waist to height ratio). RESULTS: Excess adiposity (body mass index >/=85th percentile) occurred in 37.9% of psoriatic children (n=155) vs 20.5% of controls (n=42) but did not differ significantly by severity. The odds ratio (95% CI) of obesity (body mass index >/=95th percentile) overall in psoriatic children vs controls was 4.29 (1.96-9.39) and was higher with severe (4.92; 2.20-10.99) than with mild (3.60; 1.56-8.30) psoriasis, particularly in the United States (7.60; 2.47-23.34, and 4.72; 1.43-15.56, respectively). Waist circumference above the 90th percentile occurred in 9.3% of the control (n=19), 14.0% of the mild psoriasis (n=27), and 21.2% of the of severe psoriasis (n=43) participants internationally; this incidence was highest in the United States (12.0% [n=13], 20.8% [16], and 31.1% [32], respectively). Waist to height ratio was significantly higher in psoriatic (0.48) vs control (0.46) children but was unaffected by psoriasis severity. Children with severe psoriasis at its worst, but mild at enrollment, showed no significant difference in excess or central adiposity from children whose psoriasis remained severe. CONCLUSIONS: Globally, children with psoriasis have excess adiposity and increased central adiposity regardless of psoriasis severity. The increased metabolic risks associated with excess and central adiposity warrant early monitoring and lifestyle modification. Trial Registration: clinicaltrials.gov Identifier: NCT00879944

Background: Ustekinumab is a fully human monoclonal antibody approved for the treatment of chronic moderate-to-severe plaque psoriasis in adults. However, factors including efficacy, tolerability, ease of use, and cost burden may affect ustekinumab utilization. Noncompliance may, in turn, affect treatment response. Objective: To evaluate ustekinumab utilization in the real-world setting in Asia-Pacific countries. Methods: In this phase 4 observational study conducted in Indonesia, Malaysia, Singapore, Korea, and Taiwan, adults with plaque psoriasis receiving ustekinumab were followed for up to 52 weeks. Study endpoints were the proportion of all patients using ustekinumab according to label-recommended intervals and the proportion of Korean patients who achieved a psoriasis area severity index 75 response at week 16. Safety was assessed by monitoring adverse events. Results: Overall, 169 patients received ustekinumab (Korea, n=102; other countries, n=67). Just over half (56.2%) of patients used ustekinumab with the label-recommended interval from baseline to week 40; the proportion was higher in Korea (73.5%) than in other countries (29.9%), probably because ustekinumab was provided without charge for Korean patients up to week 40. Noncompliance increased after week 40 in Korea and from week 28 in other Asia-Pacific countries, with cost cited as the most common reason. At week 16, 56.9% of Korean patients achieved a Psoriasis Area Severity Index 75 response. Safety results were in line with those seen in previous studies. Conclusion: More than half of all patients in Asia-Pacific countries used ustekinumab as per the label-recommended dose interval, but reimbursement variations between countries may have confounded overall results. (Ann Dermatol 28(2) 222∼231, 2016)