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    The Prevalence and Disease Characteristics of Generalized Pustular Psoriasis. Zheng Min,Jullien Denis,Eyerich Kilian American journal of clinical dermatology Generalized pustular psoriasis (GPP) is a rare disease that has only recently benefited from a consistent definition and clinical coding standard. A lack of disease awareness combined with clinical similarities to other types of psoriasis have historically complicated the diagnosis of GPP. It is now clear that GPP requires a differential diagnosis from psoriasis vulgaris (plaque psoriasis), and better understanding of the genetic characteristics underlying GPP may improve the accuracy of diagnoses in the future. GPP can present at any age but is most common in the fifth decade of life. There appears to be a female preponderance in GPP, although there is notable variability in prevalence by geographical region and between ethnicities. GPP is potentially life-threatening, associated with several serious complications, and may require emergency treatment, particularly for complications arising from systemic inflammation. As with many rare diseases, there are inherent challenges to understanding the epidemiology of GPP. In addition to small patient numbers, estimating the prevalence of rare diseases is further complicated by studies that use non-standardized methodologies and that are conducted in different populations. These complications in data gathering have led to marked variability in GPP case estimates by geographical region and between ethnicities. There is ongoing research into disease characteristics, and insights into regional measures of prevalence are essential to increasing our understanding of GPP. 10.1007/s40257-021-00664-x
    Clinical Course and Characteristics of Generalized Pustular Psoriasis. Choon Siew Eng,Navarini Alexander A,Pinter Andreas American journal of clinical dermatology 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%. 10.1007/s40257-021-00654-z
    Clinical Disease Measures in Generalized Pustular Psoriasis. Burden A David,Choon Siew Eng,Gottlieb Alice B,Navarini Alexander A,Warren Richard B American journal of clinical dermatology Generalized pustular psoriasis (GPP) is a rare neutrophilic skin condition characterized by episodes of widespread eruption of sterile macroscopic pustules that can be associated with systemic inflammation. The rarity of GPP and its heterogeneous cutaneous and extracutaneous symptoms pose considerable challenges to the development and adoption of comprehensive accurate disease measures for the routine clinical assessment of disease severity and the evaluation of new treatments in clinical trials. Psoriasis disease measures remain among the most commonly used methods for evaluating patients with GPP, despite their limitations owing to a lack of assessment of pustules (a hallmark of GPP), systemic inflammation, and disease symptoms. The adaptation of psoriasis disease measures and the development of assessment tools specific for GPP severity will enable more effective and accurate monitoring of patients with GPP and enhance the clinical development of new therapies. Further clinical validation of recently developed modified assessment tools, such as the Generalized Pustular Psoriasis Physician Global Assessment and the Generalized Pustular Psoriasis Area and Severity Index, and international consensus on using quantitative tools and patient-reported outcome measures in the development of new treatments are needed to advance patient care. 10.1007/s40257-021-00653-0
    Treatment Options and Goals for Patients with Generalized Pustular Psoriasis. Krueger James,Puig Lluís,Thaçi Diamant American journal of clinical dermatology Generalized pustular psoriasis (GPP) is a rare, severe neutrophilic skin disorder characterized by sudden widespread eruption of superficial sterile pustules with or without systemic inflammation. GPP flares can be life-threatening if untreated due to potential severe complications such as cardiovascular failure and serious infections. Currently, there are no GPP-specific therapies approved in the USA or Europe. Retinoids, cyclosporine, and methotrexate are the most commonly used non-biologic therapies for GPP. The evidence that supports the currently available treatment options is mainly based on case reports and small, open-label, single-arm studies. However, recent advances in our understanding of the pathogenic mechanisms of GPP and the identification of gene mutations linked to the disease have paved the way for the development of specific targeted therapies that selectively suppress the autoinflammatory and autoimmune mechanisms induced during GPP flares. Several biologic agents that target key cytokines involved in the activation of inflammatory pathways, such as tumor necrosis factor-α blockers and interleukin (IL)-17, IL-23, and IL-12 inhibitors, have emerged as potential treatments for GPP, with several being approved in Japan. The evidence supporting the efficacy of these agents is mainly derived from small, uncontrolled trials. A notable recent advance is the discovery of IL36RN mutations and the central role of IL-36 receptor ligands in the pathogenesis of GPP, which has defined key therapeutic targets for the disease. Biologic agents that target the IL-36 pathway have demonstrated promising efficacy in patients with GPP, marking the beginning of a new era of targeted therapy for GPP. 10.1007/s40257-021-00658-9
    Pathophysiology of Generalized Pustular Psoriasis. Marrakchi Slaheddine,Puig Lluis American journal of clinical dermatology Generalized pustular psoriasis (GPP) is a rare, severe form of pustular psoriasis characterized by widespread, recurrent episodes of neutrophil-rich pustule formation in the epidermis, which can be accompanied by fever and systemic inflammation. Recent clinical, histologic, and genetic evidence indicates that GPP is a distinct entity from plaque psoriasis, with different cytokine pathways predominant in the manifestation of each disease. The interleukin-36 (IL-36) signaling cascade plays a key role in regulating the innate immune system, and its dysregulation appears central to the pathogenesis of GPP. The altered expression of various IL-36 pathway constituents has been shown to cause a positive feedback loop of uncontrolled signaling and excess production of inflammatory cytokines, which in turn leads to chemokine induction and neutrophil recruitment in the epidermis. Given the potentially life-threatening nature of GPP episodes, drug interventions that rapidly achieve disease resolution are required. Early phase data indicate that treatments targeting various components of the IL-36 inflammatory cascade represent promising areas of research. However, there are currently no therapeutic agents specifically approved for GPP in the USA or Europe. Understanding the inflammatory pathways, associated risk factors, and role of neutrophils in the manifestation and perpetuation of GPP flares remains a key goal in developing effective therapeutics. In this article, we summarize the current understanding of GPP, describe novel therapeutic opportunities, and detail how the unique pathophysiology of the disease may inform future treatment strategies. 10.1007/s40257-021-00655-y
    Impact of Generalized Pustular Psoriasis from the Perspective of People Living with the Condition: Results of an Online Survey. Reisner Dale V,Johnsson Frida Dunger,Kotowsky Nirali,Brunette Steven,Valdecantos Wendell,Eyerich Kilian American journal of clinical dermatology BACKGROUND:Generalized pustular psoriasis (GPP) is a rare disease characterized by episodic worsening (flares). Knowledge of the burden of GPP and the experience of affected individuals is limited. AIMS:To conduct a survey of people living with GPP to understand how they experience GPP flares, which therapies they have received and are receiving, and how GPP impacts their activities of daily living. METHODS:The online survey consisted of 43 questions answered by individuals recruited from an opt-in market research database. The research team performed a targeted outreach to identify individuals with GPP. The survey included screening questions to determine if potential participants qualified for inclusion. Eligible individuals were US residents aged ≥ 18 years who self-reported that they had been diagnosed with GPP. Respondents provided consent to participate and received compensation (fair market value) for their time. RESULTS:Between August 4 and 14, 2020, 66 people living with GPP in the USA were surveyed. Most participants were female, aged 40-59 years, had been diagnosed ≥ 1 year previously, and had experienced ≥ 2 flares in the past year. A substantial proportion of respondents had symptoms for years, had consulted multiple healthcare professionals, and experienced misdiagnoses before receiving a diagnosis of GPP. Emotional stress was the most common cause of flares and many respondents reported a fear of flares. Respondents defined flares by the presence of itching, an increase in the size of the affected area, more crusts or pustules, and fatigue. A change in mood was the most burdensome symptom. Most respondents were receiving topical corticosteroids and only approximately one-third felt their condition was well controlled. GPP had an impact on activities of daily living even in the absence of flares and many respondents felt that their physician did not understand the level of emotional, psychological, or physical pain caused by GPP. CONCLUSIONS:GPP imposes a substantial emotional burden on patients, with wide-ranging impacts on activities of daily living beyond the physical discomfort of skin lesions. 10.1007/s40257-021-00663-y
    Candida Infection Associated with Anti-IL-17 Medication: A Systematic Analysis and Review of the Literature. American journal of clinical dermatology Anti-interleukin (IL)-17 agents have shown excellent therapeutic efficacy in patients with psoriasis and are expected to be expanded to other chronic inflammatory diseases. However, patients receiving anti-IL-17 agents are at an increased risk of developing Candida infection, with some agents reported to increase the incidence in a dose-dependent manner. Interleukin-17 is secreted by the Th17 subset of CD4+ lymphocytes, CD8+ T cells, and innate cells, including natural killer T cells, lymphoid tissue inducer cells, innate lymphoid cells, and γδ-T cells, and plays an important role in antifungal defense. Genetic defects in the IL-17-signaling pathway in both humans and animal models render susceptibility to candidiasis caused by Candida albicans. The purpose of this narrative review is to evaluate the literature on the role of IL-17 in protection against candidiasis, the prevalence of candidiasis in anti-IL-17 agent use, and to offer clinical recommendations on the diagnosis and management of anti-IL-17 medication-associated candidiasis. 10.1007/s40257-022-00686-z
    Cutaneous Manifestations of Inflammatory Bowel Disease: A Basic Overview. American journal of clinical dermatology Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal (GI) tract that is subdivided into Crohn's disease (CD) and ulcerative colitis (UC). CD is characterized by involvement of the entire GI tract, while UC mainly affects the distal GI tract. Moreover, both CD and UC can present with extraintestinal manifestations (EIMs) of the disease affecting multiple organ systems including the hepatobiliary tract, kidney, bones, eyes, joints, and skin. These complications can cause significant morbidity and negatively impact the quality of life for IBD patients. Although the pathogenesis of EIMs is not clearly elucidated, it is postulated that the diseased GI mucosa similarly stimulates excess immune responses at the extraintestinal sites. Cutaneous EIMs occur in up to 15% of patients with IBD, often predating their IBD diagnosis. They are categorized into (1) specific, (2) reactive, (3) associated, and (4) treatment-induced. Here, we review the epidemiological, clinical, diagnostic, and histologic features of the most commonly described cutaneous EIMs of IBD along with their respective treatment options. 10.1007/s40257-022-00689-w
    Time to Relapse After Discontinuing Systemic Treatment for Psoriasis: A Systematic Review. American journal of clinical dermatology BACKGROUND:The decision of when to discontinue systemic treatment after achieving remission in psoriasis is an important question. In this systematic review, we sought to evaluate time to relapse after the discontinuation of systemic treatment in psoriasis patients. METHODS:Systematic searches of PubMed, Cochrane Library, and Embase databases were performed for randomized controlled studies reporting time to relapse after discontinuation of systemic drugs in psoriasis patients. In addition, pharmaceutical companies were contacted by the authors regarding missing data from the identified publications. In each publication, the time to psoriasis relapse and the timing of drug discontinuation were carefully assessed. The level of psoriasis control at the time of drug discontinuation and the definition used for psoriasis relapse were taken into account. RESULTS:Thirty articles published before April 2021 were included in the systematic review. Four articles focused on conventional systemic treatments with methotrexate and/or cyclosporine, nine focused on tumor necrosis factor (TNF) antagonists, eight focused on interleukin-17 (IL-17) antagonists, eight focused on IL-12/23 or IL-23 antagonists, and one focused on tofacitinib and apremilast. Different definitions were used to define psoriasis treatment success at the time of drug discontinuation. Similarly, heterogeneous criteria were used to define psoriasis relapse. Comparison between drugs was performed indirectly (i.e. across studies) for most drugs. Considering time of 50% loss of maximum Psoriasis Area Severity Index (PASI) improvement, a shorter median time to psoriasis relapse was observed with traditional systemic treatment (~ 4 weeks) compared to biological agents (from 12 to ~ 34 weeks). When using stringent relapse criteria, such as loss of PASI 90, a longer time to relapse after treatment cessation was observed with IL-23 antagonists (21-42 weeks) versus IL-17 antagonists (7-24 weeks). CONCLUSION:Biological agents are associated with a longer time to relapse than oral systemic agents after drug discontinuation. Among biologicals, IL-23 antagonists are associated with the longest time to relapse. These findings may have clinical consequences for the selection of systemic agents when intermittent treatment is necessary. 10.1007/s40257-022-00679-y