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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.

ZusammenfassungDie Klinik und Poliklinik für Dermatologie und Allergologie des Klinikums der Universität München vertritt die gesamte Breite der akademischen Medizin in Patientenversorgung, Forschung und Lehre. Sie hat mit dem ersten dermatologischen Lehrstuhl im Jahr 1863 die universitäre Dermatologie Deutschlands begründet. Herausragende Münchner Ordinarien haben seitdem zum internationalen Ruf der deutschen Dermatologie beigetragen. Mit den zwei Trägerschaften aus Universität und der Stadt München (MÜK) beinhaltet sie eine große Poliklinik mit jährlich nahezu 100 000 Kontakten, ein Bettenhaus mit 104 stationären Betten, jeweils eine große stationäre und ambulante operative Abteilung, die Tagesklinik sowie verschiedene Spezialabteilungen und -sprechstunden. Sie erlauben eine vielschichtige, hochqualitative und spezialisierte Patientenversorgung. Die Forschung mit Studienzentren sowie klinisch und experimentell orientierten Forschergruppen zu verschiedenen Schwerpunkten ermöglicht eine stete Weiterentwicklung des medizinischen Standards und des pathophysiologischen Wissens und sichert den wissenschaftlichen Ruf der Klinik über die Grenzen hinaus. Ein strukturiertes Weiterbildungsprogramm für die Assistentinnen und Assistenten garantiert eine klinisch vielschichtige Facharztausbildung. Die Lehre erlaubt durch Hauptvorlesung, Seminare, Tutorials und Unterricht am Krankenbett mit über 1300 jährlich abgehaltenen Lehrstunden für die Studierenden einen strukturierten Einblick in das Fach der Dermatologie. Hinzu kommen dermatologische Vorlesungen für die Zahnmediziner sowie zur Berufsdermatologie. Hiermit ist die Klinik und Poliklinik für Dermatologie und Allergologie des Klinikums der Universität München eine der größten dermatologischen akademischen Einrichtungen ihrer Art, nicht nur in Deutschland.

Autoreactive T cells pose a constant risk for the emergence of autoimmune skin diseases in genetically predisposed individuals carrying certain HLA risk alleles. Immune tolerance mechanisms are opposed by broad HLA-presented self-immunopeptidomes, a predefined repertoire of polyspecific TCRs, the continuous generation of new antibody specificities by somatic recombination of Ig genes in B cells, and heightened proinflammatory reactivity. Increased autoantigen presentation by HLA molecules, cross-activation of pathogen-induced T cells against autologous structures, altered metabolism of self-proteins, and excessive production of proinflammatory signals may all contribute to the breakdown of immune tolerance and the development of autoimmune skin diseases.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/., The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Background: Behcet disease (BD) presents with lymphocytic and neutrophilic vasculitis of unknown aetiology. HLA-B*51, the endoplasmic reticulum aminopeptidase 1 (ERAP1), and interleukin 23 receptor (IL23R)/IL12R are genetic risk factors. IL-23 regulates IL-17A, which controls the recruitment and activation of neutrophils. Objectives: to determine pathological changes in BD skin lesions related to the complex genetic predisposition. Methods : we characterized the expression of IL-17A and IL-23A in various cell types by immunohistological double staining of sections from papulopustular skin lesions of acute attacks of BD and psoriasis vulgaris lesions, another HLA-class I-associated T-cell-mediated autoimmune disease in which excessive T-cell-derived IL-17A production promotes neutrophil activation. Results: we found that in BD lesions, as in psoriasis, actively expanding CD8(+) T cells were the predominant source of IL-17A. IL-17A(+) CD8(+) T (T(c)17) cells outnumbered infiltrating IL-17A(+) CD4(+) T cells. Unlike the epidermal localization of CD8(+) T cells in psoriasis, T(c)17 cells in BD lesions mainly infiltrated the perivascular tissue and the blood vessel walls of dermis and subcutaneous tissue. They co-localised with a marked IL-23A expression by CD11c(+) dendritic cells and CD68(+) macrophages. IL-17A expression was associated with extensive recruitment of neutrophils around blood vessels that formed neutrophil extracellular traps (NETs). Conclusions: in BD, the genetic predisposition may mediate antigen-specific activation and differentiation of a T(c)17 response, possibly targeting endothelial (auto)antigens. Neutrophils recruited by IL-17A in this process may enhance tissue damage by extensive NET formation (NETosis). Thus, the IL-23/IL-17 axis presumably controls neutrophilic inflammation in BD vasculitis in the context of a predominant antigen-specific CD8(+) T-cell response., Deutsche Forschungsgemeinschaft; Scientific and Technological Research Council of Turkey (TÜBİTAK); 2219 Postdoctoral Research Grant; L'OREAL-UNESCO for Women in Science Fellowship of Turkey; LMU–China Scholarship Council Program Full Doctoral Study-Model; Projekt DEAL

Generalized pustular psoriasis (GPP) is a rare inflammatory skin disease with a considerable clinical burden. In the EffisayilTo evaluate patient-reported outcomes (PROs) of patients with GPP who were treated with intravenous (IV) spesolimab 900 mg in the Effisayil53 patients presenting with a GPP flare were randomized (2:1) to receive a single dose of IV spesolimab 900 mg or placebo and were followed for 12 weeks. Four PROs [pain visual analog scale (pain VAS); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue); Dermatology Life Quality Index (DLQI); and Psoriasis Symptom Scale (PSS)] were assessed throughout the 12-week study. Minimal clinically important differences (MCIDs) were defined. All data are reported descriptively.In patients who received spesolimab, improvements from baseline (median [Q1, Q3]) were observed in pain VAS (-21.3 [-55.3, -3.1]), FACIT-Fatigue (7.0 [1.0, 20.0]), DLQI (-2.5 [-8.0, 1.0]), and PSS (-4.0 [-7.0, 0.0]) within 1 week of treatment. These improvements were sustained over 12 weeks and corresponded to the achievement of MCIDs at Week 1, which were also sustained over 12 weeks. Patients in the placebo arm experienced improvements in PROs and achievement of MCIDs after receipt of open-label spesolimab at Week 1.Patients with a GPP flare treated with spesolimab achieved improvements in PROs by Week 1, which were sustained for 12 weeks, and achieved MCIDs as early as Week 1.

ZusammenfassungDupilumab ist ein monoklonaler Antikörper, der an die gemeinsame α‑Kette des IL(Interleukin)-4- und IL-13-Rezeptors bindet und den Th(T-Helferzelle)2-Signalweg blockiert, der bei der Entstehung des atopischen Ekzems eine Schlüsselrolle spielt. Wir berichten über den Fall eines 40-jährigen Patienten, der nach 6 Wochen Dupilumab-Therapie eine histologisch gesicherte Psoriasis entwickelte. Das eigenmächtige, abrupte Absetzen der ungewöhnlichen, nicht leitliniengerechten oralen Steroidtherapie und die Blockade des Th2-Signalwegs durch Dupilumab dürften die entscheidenden Auslösefaktoren für die erstmalige Ausbildung der Psoriasis bei unserem Patienten gewesen sein.

Autoimmune diseases develop when autoantigens activate previously quiescent self-reactive lymphocytes. Gene–gene interaction between certain HLA class I risk alleles and variants of the endoplasmic reticulum aminopeptidase ERAP1 controls the risk for common immune-mediated diseases, including psoriasis, ankylosing spondylitis, and Behçet disease. The functional mechanisms underlying this statistical association are unknown. In psoriasis, HLA-C*06:02 mediates an autoimmune response against melanocytes by autoantigen presentation. Using various genetically modified cell lines together with an autoreactive psoriatic TCR in a TCR activation assay, we demonstrate in this study that in psoriasis, ERAP1 generates the causative melanocyte autoantigen through trimming N-terminal elongated peptide precursors to the appropriate length for presentation by HLA-C*06:02. An ERAP1 risk haplotype for psoriasis produced the autoantigen much more efficiently and increased HLA-C expression and stimulation of the psoriatic TCR by melanocytes significantly more than a protective haplotype. Compared with the overall HLA class I molecules, cell surface expression of HLA-C decreased significantly more upon ERAP1 knockout. The combined upregulation of ERAP1 and HLA-C on melanocytes in psoriasis lesions emphasizes the pathogenic relevance of their interaction in patients. We conclude that in psoriasis pathogenesis, the increased generation of an ERAP1-dependent autoantigen by an ERAP1 risk haplotype enhances the likelihood that autoantigen presentation by HLA-C*06:02 will exceed the threshold for activation of potentially autoreactive T cells, thereby triggering CD8+ T cell–mediated autoimmune disease. These data identify ERAP1 function as a central checkpoint and promising therapeutic target in psoriasis and possibly other HLA class I–associated diseases with a similar genetic predisposition.

Psoriasis is a chronic, immune‐mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL‐23)/T‐helper 17 (TH17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL‐23, a heterodimer composed of a p40 subunit also found in IL‐12 and a p19 subunit exclusive to IL‐23. IL‐23 is important for maintaining TH17 responses, and levels of IL‐23 are elevated in psoriatic skin compared with non‐lesional skin. A number of agents that specifically inhibit IL‐23p19 are currently in development for the treatment of moderate‐to‐severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL‐23/TH17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+ T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+ T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+ T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell−mediated inflammation in GPP.

Methotrexate (MTX) is an antirheumatic drug used worldwide in many indications of chronic inflammation and autoimmunity including psoriasis.1 In principle, it is safe if monitored carefully and has major cost-effective therapeutic benefits.2 Major adverse events for MTX are related to the folate antagonism and primarily affect highly proliferative tissues such as bone marrow and gastrointestinal mucosa.3 Life-threatening myelosuppression leading to sepsis with potential fatal outcome is the most serious complication of MTX treatment that may occur despite regular dose administration.4 By analyzing 3 cases of myelosuppression during low-dose MTX treatment with mucocutaneous manifestations, we find that impaired renal elimination to be the leading cause of MTX toxicity and identify the different durations of plasma and intracellular half-lives of MTX as the main reason for bone marrow suppression in spite of normal MTX trough levels.

HLA-C*06:02 is the main psoriasis risk allele. By the unbiased analysis of a Vα3S1/Vβ13S1 T-cell receptor from pathogenic psoriatic CD8 + T cells, we had recently proven that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation in psoriasis and identified ADAMTSL5 as a melanocyte autoantigen. We concluded that psoriasis is based on a melanocyte-specific immune response and that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway. Understanding this pathway, however, requires more detailed explanation. It is based on the fact that an HLA class I-restricted autoreactive CD8 + T-cell response must be directed against a particular target cell type, because HLA class I molecules present peptide antigens generated from cytoplasmic (i.e., intracellular) proteins. This review summarizes the findings on the melanocyte-specific autoimmune response in the context of the immune mechanisms related to HLA function and T-cell receptor–antigen recognition. Identifying melanocytes as target cells of the psoriatic immune response now explains psoriasis as a primary autoimmune skin disease.

Chronic immune-mediated disorders (IMDs) constitute a major health burden. Understanding IMD pathogenesis is facing two major constraints: Missing heritability explaining familial clustering, and missing autoantigens. Pinpointing IMD risk genes and autoimmune targets, however, is of fundamental importance for developing novel causal therapies. The strongest association of all IMDs is seen with human leukocyte antigen (HLA) alleles. Using psoriasis as an IMD model this article reviews the pathogenic role HLA molecules may have within the polygenic predisposition of IMDs. It concludes that disease-associated HLA alleles account for both missing heritability and autoimmune mechanisms by facilitating tissue-specific autoimmune responses through autoantigen presentation.

Psoriasis ist eine HLA-assoziierte T‑Zell-vermittelte Erkrankung der Haut. Unklar geblieben war bisher, welche Rolle das Hauptrisiko-Allel HLA-C*06:02 in der Psoriasispathogenese spielt und wodurch die pathogene T‑Zell-Antwort in der Haut der Patienten aktiviert wird. Schlussel zur Immunpathogenese der Psoriasis war die Analyse der Spezifitat der infiltrierenden lasionalen psoriatischen CD8+-T-Zellen. Die Untersuchungen der lasionalen psoriatischen T‑Zell-Reaktivitat belegen, dass Psoriasis eine Autoimmunerkrankung darstellt. Sie beruht auf einer Autoimmunantwort gegen Melanozyten, welche praferenziell von HLA-C*06:02 durch Autoantigenprasentation vermittelt wird. Die Mechanismen dieser Autoimmunreaktion werden hier im Kontext der polygenetischen Pradisposition der Psoriasis diskutiert.

Psoriasis is a chronic inflammatory disorder of the epidermis, which can be induced by systemic factors, such as streptococci infections or drugs. In addition, psoriasis can be caused by a local cutaneus trauma, known as Koebner phenomenon. Here, we describe a woman with psoriasis in remission, who developed a new psoriatic lesion due to a cutaneous infection with Borrelia burgdorferi. After causal therapy with doxycycline, the erythema migrans and psoriasis lesions disappeared.

Lichen planus (LP) classifies into different subtypes depending on morphology and localization. Localized LP of the lower limb (LPLL) manifests a great challenge due to persistent itching, therapeutic resistance and the risk to develop into SCC. We report two cases with LPLL refractory to standard topical therapy, which were successfully treated with psoralen cream plus UVA photochemotherapy (cream-PUVA). We propose cream-PUVA as an alternative therapeutic option effective for localized LP of the lower limbs.

Objective.To evaluate patients with psoriatic arthritis (PsA) receiving etanercept (ETN) monotherapy or ETN plus conventional synthetic disease-modifying antirheumatic drugs (csDMARD) to determine the proportion achieving a clinically meaningful response in arthritis, psoriasis, and quality of life simultaneously.Methods.A prospective, multicenter, 52-week observational study in patients with active PsA evaluated treatment with ETN in clinical practice (ClinicalTrials.gov:NCT00293722). This analysis assessed simultaneous achievement of 3 treatment targets: low disease activity (LDA) based on 28-joint count Disease Activity Score (DAS28); body surface area (BSA) involvement ≤ 3%; and a score > 45 on the Medical Outcomes Study Short Form-12 (SF-12) physical component summary.Results.Of 579 patients, 380 received ETN monotherapy and 199 received combination ETN plus csDMARD. At 52 weeks, data for all 3 disease domains were available for 251 patients receiving monotherapy and 151 receiving combination therapy. In the monotherapy and combination therapy groups, 61 (24.3%) and 37 (24.5%) patients, respectively, achieved all 3 treatment targets simultaneously. A significantly greater proportion of patients receiving monotherapy versus combination therapy achieved SF-12 > 45 (43.0% vs 31.8%; p < 0.05) and DAS28 LDA (72.5% vs 62.3%; p < 0.05). Conversely, BSA ≤ 3% was reached by a significantly greater proportion receiving combination therapy (75.5% vs 56.6%; p < 0.001). However, baseline BSA involvement was higher for the monotherapy group.Conclusion.While nearly half the patients achieved arthritis and psoriasis treatment targets simultaneously and one-fourth reached all 3 treatment targets, combining ETN and csDMARD did not substantially improve clinical response compared with ETN monotherapy in this real-world PsA patient population.

Background Psoriasis is a systemic immune-mediated chronic inflammatory disease. In the skin, the antimicrobial proteins koebnerisin (S100A15) and psoriasin (S100A7) are overexpressed in the epidermis of psoriatic lesions and mediate inflammation as chemoattractants for immune cells. Their role for systemic inflammation in circulating leukocytes is unknown. Objective The aim of the study was to identify circulating leukocyte populations as a source of koebnerisin and psoriasin. Further, immune-stimulatory effects of these S100A proteins on circulating leukocytes were evaluated and their role as therapeutic response markers in patients with psoriasis was analyzed upon UVB treatment. Methods The expression and production of koebnerisin and psoriasin by leukocytes were assessed by quantitative real-time PCR (qRT-PCR) and immunoblotting. The S100A protein mediated regulation of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs) was measured with qRT-PCR and cytometric bead assay. Results We identified circulating leukocytes as novel sources of koebnerisin (S100A15) and psoriasin (S100A7). Circulating leukocytes (PBMCs) of patients with psoriasis produced increased levels of koebnerisin and psoriasin compared to healthy individuals. Both S100A proteins further acted as ‘alarmins’ on PBMC to induce proinflammatory cytokines implicated in the pathogenesis of psoriasis, such as IL-1β, TNF-α, IL-6 and IL-8. Koebnerisin levels were suppressed in PBMC of psoriatic patients when effectively treated with narrow-band UVB. Conclusions Data suggest that koebnerisin and psoriasin are systemic pro-inflammatory mediators and koebnerisin acts as a therapeutic response marker in psoriasis.

The clinical efficacy of biologic agents for the treatment of moderate to severe psoriasis is well proven in clinical studies, but patients may lose response over time. Loss of response may be due to immunogenicity and the formation of anti-drug antibodies (ADA). Although data on the immunogenicity of drugs used to treat psoriasis are now emerging, more information on the impact of factors, such as dosing regimens and concomitant immunosuppressive therapy is needed. Exploring research from other disease areas where immunogenicity has long been recognised as a significant clinical issue may help in developing future strategies for using drug level and ADA measurements to help tailor biologic therapy to meet individual needs. To this end, we analyse what is known about biologics and immunogenicity in psoriasis. In order to learn from other indications, we then address the issue of immunogenicity for three different types of biologic treatments. First, factor VIII-substitution in haemophilia, where the immune system is newly exposed to a physiologic but formerly absent protein. Second, the use of biologics in inflammatory bowel disease, where similar treatment challenges apply as observed in psoriasis. Third, immunogenicity in multiple sclerosis caused by therapeutic antibodies or interferons. Immunogenicity strategies used in other disease areas will need to be tested in psoriasis before they can be widely adopted in routine clinical practice.

Arakawa et al. discovered that the autoimmune response in psoriasis is directed against melanocytes. They show that the main psoriasis risk allele HLA-C*06:02 mediates melanocyte-specific autoimmunity and identify ADAMTSL5 as a melanocyte autoantigen, which stimulates IL-17 and IFN-γ production in CD8+ T cells., Psoriasis vulgaris is a common T cell–mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8+ T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02–restricted psoriatic T cell response. We found that a Vα3S1/Vβ13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8+ T cell clone of an HLA-C*06:02–positive psoriasis patient specifically recognizes HLA-C*06:02–positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02–presented melanocytic autoantigen of the Vα3S1/Vβ13S1 TCR. Consistent with the Vα3S1/Vβ13S1-TCR reactivity, we observed numerous CD8+ T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8+ T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8+ T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14 or AP1S3 provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4

Background: Rare variants in the genes IL36RN, CARD14 and AP1S3 have been identified to cause or contribute to pustular skin diseases, primarily generalized pustular psoriasis (GPP). Objective: To better understand the disease relevance of these genes, we screened our cohorts of patients with pustular skin diseases [primarily GPP and palmoplantar pustular psoriasis (PPP)] for coding changes in these three genes. Carriers of single heterozygous IL36RN mutations were screened for a second mutation in IL36RN. Methods: Coding exons of IL36RN, CARD14 and AP1S3 were sequenced in 67 patients - 61 with GPP, two with acute generalized exanthematous pustulosis and four with acrodermatitis continua of Hallopeau. We screened IL36RN and AP1S3 for intragenic copy-number variants and 258 patients with PPP for coding changes in AP1S3. Eleven heterozygous IL36RN mutations carriers were analysed for a second noncoding IL36RN mutation. Genotype-phenotype correlations in carriers/noncarriers of IL36RN mutations were assessed within the GPP cohort. Results: The majority of patients (GPP, 64%) did not carry rare variants in any of the three genes. Biallelic and monoallelic IL36RN mutations were identified in 15 and five patients with GPP, respectively. Noncoding rare IL36RN variants were not identified in heterozygous carriers. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Additional rare CARD14 or AP1S3 variants were identified in 15% of IL36RN mutation carriers. Conclusion: sThe identification of IL36RN mutation carriers harbouring additional rare variants in CARD14 or AP1S3 indicates a more complex mode of inheritance of pustular psoriasis. Our results suggest that, in heterozygous IL36RN mutation carriers, there are additional disease-causing genetic factors outside IL36RN. What's already known about this topic? The genes IL36RN, CARD14 and AP1S3 have been implicated in pustular skin disease with IL36RN having a major role. Most studies have analysed variants in different genes separately. Significant subsets of patients with a pustular skin disease carry a single heterozygous mutation in IL36RN, leaving unanswered whether and how the variant is disease-contributing. What does this study add? Intragenic copy-number variants or noncoding mutations in carriers of single IL36RN mutations were not found. In total, 15% of patients with generalized pustular psoriasis (GPP) with IL36RN mutations carried variants in CARD14 or AP1S3, providing evidence for a complex inheritance. Lack of causal /disease-contributing variants in 64% of GPP patients suggests a role for other, not yet identified genes. Genotype-phenotype correlation did not reveal significant correlations aside from the presence of IL36RN mutations with age at onset. What is the translational message? This study of three genes provides evidence that the inheritance of GPP is more complex than previously understood. The role of known genes in GPP is rather limited, as almost two-thirds of patients do not carry a variant in any of these genes. In palmoplantar pustular psoriasis, the percentage of noncarriers is even lower. Further genetic studies will reveal the diseases' pathogenesis and provide a basis to use/develop more specific treatments. Linked Comment:Capon. Br J Dermatol 2018;178:589-590 Respond to this article

Biological drugs such as the tumour necrosis factor inhibitors have revolutionized the treatment of psoriasis, but some have the potential to induce an unwanted immune response. This immunogenicity may be associated with low trough drug levels, reduced clinical efficacy, reduced drug survival and an increased risk for adverse events. This article presents a literature review of the evidence on immunogenicity of biologics used in the treatment of psoriasis and considers the implications for therapeutic decision-making in the management of patients with moderate-to-severe psoriasis.

Secukinumab, a human monoclonal antibody that selectively targets interleukin-17A, is highly efficacious in the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favorable safety profile.Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg, or placebo self-administered by prefilled syringe at baseline, weeks 1, 2, and 3, and then every four weeks from week 4 to 48. Efficacy responses (≥ 75/90/100% improvement in Psoriasis Area and Severity Index [PASI 75/90/100] and clear/almost clear skin by Investigator's Global Assessment 2011 modified version [IGA mod 2011 0/1]) were measured to week 52. Patient-reported usability of the prefilled syringe was evaluated by the Self-Injection Assessment Questionnaire to week 48.The efficacy of secukinumab increased to week 16 and was maintained to week 52. With secukinumab 300 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 83.5%/68.0%/47.5% and 71.5% of patients when analyzed by multiple imputation, respectively, and by 75.9%/62.1%/43.1% and 63.8% of patients when analyzed by nonresponder imputation, respectively. With secukinumab 150 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 63.5%/50.3%/31.1% and 43.6% of patients when analyzed by multiple imputation, respectively, and by 61.0%/49.2%/30.5% and 42.4% of patients when analyzed by nonresponder imputation, respectively. Self-reported acceptability of the prefilled syringe was high throughout the study. The incidence of adverse events (AE) was well balanced between groups, with AEs reported in 74.4% of patients receiving secukinumab 300 mg and 77.3% of patients receiving secukinumab 150 mg. Nasopharyngitis was the most common AE across both secukinumab groups.Self-administration of secukinumab by prefilled syringe was associated with robust and sustained efficacy and a favorable safety profile up to week 52.br /br /emJ Drugs Dermatol./em2016;15(10):1226-1234.

Importance Generalized pustular psoriasis von Zumbusch type (GPP) is the most severe manifestation of psoriasis. The etiology of GPP is only partially understood, and GPP lacks approved treatments. Loss-of-function mutations in the interleukin 36 (IL-36) receptor antagonist ( IL36RN ), an inhibitor of innate immune activation in the skin, and therapeutic efficacy of IL-1 blockade in a subset of patients with GPP are viewed as evidence for an autoinflammatory pathogenesis. A pathogenic role of T cells has not been considered. Objective To test whether ustekinumab, a monoclonal antibody blocking IL-12 and IL-23, is an effective treatment modality for patients in whom GPP treatment with conventional psoriasis drugs or antagonists of tumor necrosis factor (TNF) has not been sufficiently effective, is contraindicated, or has lost efficacy. Design, Setting, and Participants We treated a series of 4 patients with GPP with ustekinumab, which was applied on an outpatient basis according to the dosing regimen approved for psoriasis vulgaris. In 3 patients it was combined with low doses of the retinoid acitretin. IL36RN mutations were determined in all 4 patients by means of targeted sequencing of genomic DNA. Main outcome measures The response to therapy was assessed by clinical examination. Results The 4 patients were female. Sequencing of IL36RN identified a homozygous mutation in case 1 (Pro76Leu). The other 3 patients carried no rare IL36RN variants. Overall GPP duration ranged from 50 to 146 months. Ustekinumab treatment is currently ongoing in all 4 patients without loss of efficacy, currently reaching treatment durations of 17 (case 1) to 44 months (case 3). Ustekinumab treatment induced sustained remissions in all 4 GPP patients. This response was independent of IL36RN mutations and consolidated by combination with low doses of the retinoid acitretin. Conclusions and Relevance Ustekinumab-induced remissions suggest that T cells play a crucial role in GPP pathogenesis based on the documented role that IL-12 and IL-23 play in autoimmune diseases through differentiating helper T cell 1 (T H 1) and maintaining T H 17 responses. Acitretin treatment may support ustekinumab efficacy, possibly by suppressing T H 17 responses through the retinoid-related orphan receptors, RORγt and RORα. Combining IL-12/IL-23 blockade and acitretin may constitute an efficient treatment modality interfering with GPP pathomechanisms.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294–300. OA hybrid

The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and "alarmins" to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as "alarmins" to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.

Lichen planus (LP) classifies into different subtypes depending on morphology and localization. Localized LP of the lower limb (LPLL) manifests a great challenge due to persistent itching, therapeutic resistance and the risk to develop into SCC. We report two cases with LPLL refractory to standard topical therapy, which were successfully treated with psoralen cream plus UVA photochemotherapy (cream-PUVA). We propose cream-PUVA as an alternative therapeutic option effective for localized LP of the lower limbs.

Background Scalp psoriasis is a difficult to treat and usually chronic manifestation of psoriasis. The CalePso study showed that CPS (Clobex® Shampoo) in maintenance therapy of scalp psoriasis (twice weekly) significantly increases the probability of keeping patient under remission during 6 months, compared with vehicle (40.3% relapses vs. 11.6% relapses, ITT). Objective The objective of the study was to assess the cost-effectiveness of a maintenance therapy with CPS vs. its vehicle in nine European countries. Methods A 24-week decision tree model was developed with 4-weekly time steps. The considered population has moderate scalp psoriasis successfully treated with a daily application of CPS up to 4 weeks. Data were taken from the CalePso study and from national experts’ recommendations for alternative treatment choices, with their probabilities of success taken from literature to develop country-specific models. Health benefits are measured in disease-free days (DFD). The economic analysis includes drug and physician costs. A probabilistic sensitivity analysis (PrSA) assesses the uncertainty of the model. Results Depending on the country, the mean total number of DFDs per patient is 21–42% higher with CPS compared with vehicle, and the mean total cost is 11–31% lower. The mean costs per DFD are 30–46% lower with CPS compared with the vehicle. The PrSA showed in 1000 simulations that CPS is more effective vs. vehicle in 100% of the cases and less expensive than its vehicle in 80–99% of the cases. Conclusion This model suggests that CPS is cost-effective in maintaining the success achieved in moderate scalp psoriasis patients.

Summary Background. Diagnostic classification of chronic hand eczema (CHE) represents a major clinical and taxonomic challenge because of its wide aetiological and clinical heterogeneity. Aim. To develop an algorithm for the diagnosis and classification of CHE. Methods. Well-defined aetiological, clinical and morphological criteria of CHE were arranged graphically in a diagnostic hierarchy, and validated in 137 German patients with hand eczema. Results. The algorithm distinguished chronic hand eczema due to contact allergy, irritant damage or a combination of the two, each either with or without atopy, and also atopic hand eczema and idiopathic hand eczema lacking obvious causative factors. Foot involvement helped to distinguish idiopathic from irritant hand eczema. Each subtype could occur either with a hyperkeratotic–rhagadiform, dyshidrotic or mixed morphology, but certain hand eczema subtypes had clear morphological preferences. Conclusions. By providing a more precise clinical definition this diagnostic algorithm could improve the classification and taxonomy of hand eczema subtypes, facilitating more rational treatment decisions and allowing better treatment outcome analysis.

Summary Background: The causal association between hepatitis virus infections and lichen planus (LP) remains a matter of controversy. Reliable figures for German patients are still lacking. Patients and Methods: We analyzed the prevalence of serum antibodies against hepatitis B and C viruses (HBV, HCV) in 265 LP patients and compared the results to 257 patients with chronic urticaria (URT) and 222 patients with malignant melanoma (MM). Additionally, we analyzed age- and sex-specific differences. Results: The prevalence of HBV (13.2 % or 14.7 %) antibodies was significantly higher in patients with LP and URT patients than in the MM control group (HBV: 5.4 %, p 0.05) than in MM patients (0.4 %). The prevalences of HBV and HCV in the MM control group were comparable to those in the general German population (HBV: 5–8 %, HCV: 0.4–0.7 %). An analysis by sub-groups showed that these differences resulted from sex- and age-dependent prevalences. HBV antibodies were significantly more common only in male LP patients (16.1 %) and in male (20.0 %) and female URT patients (15.6 %) aged 31–60 years. The greater prevalence of HCV in female LP patients older than 60 years of age was not significant. Conclusions: LP is not specifically associated with hepatitis B or C antibodies in the Caucasian population of Germany. The higher prevalences of HBV antibodies found in LP and URT patients may be a reflection of age- and sex-related factors rather than disease-specific exposure to HBV infections. The increased prevalences seen in patients with LP or URT compared to MM patients may suggest that HBV infection serves as an unspecific trigger for a specific immune reaction of another origin.