In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-α (TNFα)-associated genes specifically expressed in psoriasis, among which IL-36γ was the most outstanding marker. In subsequent immunohistological analyses, IL-36γ was confirmed to be expressed in psoriasis lesions only. IL-36γ peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFα-treatment. Furthermore, IL-36γ immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36γ as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36γ might also provide a future drug target, because of its potential amplifier role in TNFα- and IL-17 pathways in psoriatic skin inflammation.

(1) Background: Numerous vaccines are under preclinical and clinical development for prevention of severe course and lethal outcome of coronavirus disease 2019 (COVID-19). In light of high efficacy rates and satisfactory safety profiles, some agents have already reached approval and are now distributed worldwide, with varying availability. Real-world data on cutaneous adverse drug reactions (ADRs) remain limited. (2) Methods: We performed a literature research concerning cutaneous ADRs to different COVID-19 vaccines, and incorporated our own experiences. (3) Results: Injection site reactions are the most frequent side effects arising from all vaccine types. Moreover, delayed cutaneous ADRs may occur after several days, either as a primary manifestation or as a flare of a pre-existing inflammatory dermatosis. Cutaneous ADRs may be divided according to their cytokine profile, based on the preponderance of specific T-cell subsets (i.e., Th1, Th2, Th17/22, Tregs). Specific cutaneous ADRs mimic immunogenic reactions to the natural infection with SARS-CoV-2, which is associated with an abundance of type I interferons. (4) Conclusions: Further studies are required in order to determine the best suitable vaccine type for individual groups of patients, including patients suffering from chronic inflammatory dermatoses.

SummaryBackground 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). Objectives 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.

Summary Background and rationale Xerosis cutis (also referred to as xeroderma, dry skin, asteatosis) affects more than 10 million individuals in Germany. It is among the most common dermatological diagnoses and a cardinal symptom of many dermatological, internal and neurological diseases. Even though it has been established that basic skin care plays a significant role in the management of patients with xerosis cutis, there are as yet no evidence‐based algorithms for diagnosis and treatment. Objective The present position paper provides physicians across all specialties with a practical, symptom‐based approach to the prevention, diagnosis and treatment of xerosis cutis. Methods Within a structured decision‐making process, a panel of experienced dermatologists first defined questions relevant to everyday clinical practice, which were then addressed by a systematic review of the literature. Based on the evidence available as well as expert consensus, diagnostic and treatment algorithms were subsequently developed and agreed upon. Results Xerosis cutis is generally diagnosed on clinical grounds. Possible trigger factors must be avoided, and comorbidities should be adequately and specifically treated. Suitable skin care products should be chosen with a view to improving skin hydration and restoring its barrier function. They should therefore contain both rehydrating and lipid‐replenishing components. The “drier” the skin appears, the greater the lipid content should be (preferably using water‐in‐oil formulations). The choice of ingredients is based on a patient's individual symptoms, such as scaling (e.g., urea), fissures/rhagades (e.g., urea or dexpanthenol), erythema (e.g., licochalcone A) and pruritus (e.g., polidocanol). Other factors to be considered include the site affected and patient age. Ingredients or rather combinations thereof for which there is good clinical evidence should be preferentially used. The best evidence by far is available for urea, whose efficacy in the treatment of xerosis is further enhanced by combining it with other natural moisturizing components and ceramides. The “xerosimeter” is a tool developed in an effort to facilitate patient management and for training purposes. It not only includes practical tools for diagnosis and follow‐up but also a classification of ingredients and a structured treatment algorithm. Conclusion The structured symptom‐ and evidence‐based approach proposed herein contains a road map for diagnosis and treatment of xerosis cutis. It aims to raise awareness in terms of prevention and early treatment of this condition and may thus improve quality of life and prevent potential sequelae.

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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.

Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proc Natl Acad Sci USA 106: 7979-84 Davies H, Bignell GR, Cox C et al. (2002) Mutations of the BRAF gene in human cancer. Nature 417:949-54 Dhomen N, Da Rocha Dias S, Hayward R et al. (2010) Inducible expression of (V600E) Braf using tyrosinase-driven Cre recombinase results in embryonic lethality. Pigment Cell Melanoma Res 23:112-20 Groesser L, Herschberger E, Ruetten A et al. (2012) Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 44:783-7 Krishnaswami SR, Kumar S, Ordoukhanian P et al. (2014) Fate and plasticity of the epidermis in response to congenital activation of BRAF.

Dry skin is a frequent condition in the adult general population and needs special attention. Known risk factors may facilitate identifying patients at risk for deterioration.