The impact of the cardiovascular component and somatic mutations on ageing.

Mechanistic insight into ageing may empower prolonging the lifespan of humans; however, a complete understanding of this process is still lacking despite a plethora of ageing theories. In order to address this, we investigated the association of lifespan with eight phenotypic traits, that is, litter size, body mass, female and male sexual maturity, somatic mutation, heart, respiratory, and metabolic rate. In support of the somatic mutation theory, we analysed 15 mammalian species and their whole-genome sequencing deriving somatic mutation rate, which displayed the strongest negative correlation with lifespan. All remaining phenotypic traits showed almost equivalent strong associations across this mammalian cohort, however, resting heart rate explained additional variance in lifespan. Integrating somatic mutation and resting heart rate boosted the prediction of lifespan, thus highlighting that resting heart rate may either directly influence lifespan, or represents an epiphenomenon for additional lower-level mechanisms, for example, metabolic rate, that are associated with lifespan.

Histology-based classifier to distinguish early mycosis fungoides from atopic dermatitis.

BACKGROUND: Histopathological differentiation of early mycosis fungoides (MF) from benign chronic inflammatory dermatoses remains difficult and often impossible, despite the inclusion of all available diagnostic parameters. OBJECTIVE: To identify the most impactful histological criteria for a predictive diagnostic model to discriminate MF from atopic dermatitis (AD). METHODS: In this multicentre study, two cohorts of patients with either unequivocal AD or MF were evaluated by two independent dermatopathologists. Based on 32 histological attributes, a hypothesis-free prediction model was developed and validated on an independent patient's cohort. RESULTS: A reduced set of two histological features (presence of atypical lymphocytes in either epidermis or dermis) was trained. In an independent validation cohort, this model showed high predictive power (95% sensitivity and 100% specificity) to differentiate MF from AD and robustness against inter-individual investigator differences. LIMITATIONS: The study investigated a limited number of cases and the classifier is based on subjectively evaluated histological criteria. CONCLUSION: Aiming at distinguishing early MF from AD, the proposed binary classifier performed well in an independent cohort and across observers. Combining this histological classifier with immunohistochemical and/or molecular techniques (such as clonality analysis or molecular classifiers) could further promote differentiation of early MF and AD.

[Molecular diagnosis of hand eczema]. / Molekulare Diagnostik des Handekzems.

BACKGROUND: Because hand eczema is a diagnostic challenge even for experienced dermatologists, a correct diagnosis is essential to ensure success of specific therapies. OBJECTIVES: Prerequisites for successful molecular diagnostics in general and in hand eczema in particular are discussed. MATERIALS AND METHODS: Basic research and opinion statement on new developments in molecular diagnostics are considered with a special focus on hand eczema. RESULTS: The first molecular classifier to distinguish psoriasis from (hand) eczema signature has been introduced as CE-marked in vitro diagnostics (CE-IVD); many more biomarkers associated with diagnostics, theranostics, or natural course of the disease are currently being investigated. CONCLUSIONS: Diagnosis of hand eczema will be supported by molecular diagnostics in the near future; we are at the beginning of the molecular era in dermatology.

The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response.

BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.

Gene Expression-Based Molecular Test as Diagnostic Aid for the Differential Diagnosis of Psoriasis and Eczema in Formalin-Fixed and Paraffin-Embedded Tissue, Microbiopsies, and Tape Strips.

Highly effective targeted therapies are available to treat noncommunicable chronic inflammatory skin diseases. In contrast, the exact diagnosis of noncommunicable chronic inflammatory skin diseases is complicated by its complex pathogenesis and clinical and histological overlap. Particularly, the differential diagnosis of psoriasis and eczema can be challenging in some cases, and molecular diagnostic tools need to be developed to support a gold standard diagnosis. The aim of this work was to develop a real-time PCR-based molecular classifier to distinguish psoriasis from eczema in formalin-fixed and paraffin-embedded-fixed skin samples and to evaluate the use of minimally invasive microbiopsies and tape strips for molecular diagnosis. In this study, we present a formalin-fixed and paraffin-embedded-based molecular classifier that determines the probability for psoriasis with a sensitivity/specificity of 92%/100%, respectively, and an area under the curve of 0.97, delivering comparable results to our previous published RNAprotect-based molecular classifier. The psoriasis probability, as well as levels of NOS2 expression, positively correlated with the disease hallmarks of psoriasis and negatively with eczema hallmarks. Furthermore, minimally invasive tape strips and microbiopsies were effectively used to differentiate psoriasis from eczema. In summary, the molecular classifier offers broad usage in pathology laboratories as well as outpatient settings and can support the differential diagnosis of noncommunicable chronic inflammatory skin diseases on a molecular level using formalin-fixed and paraffin-embedded tissue, microbiopsies, and tape strips.

Status quo and future perspectives of molecular diagnostics in dermatology.

Molecular diagnostics (MDx) has become an indispensable pillar of diagnostics in dermatology. Modern sequencing technologies allow for identification of rare genodermatoses, analysis of somatic mutations in melanoma are prerequisite for targeted therapies, and cutaneous infectious pathogens are quickly detected by PCR and other amplification methods. However, to push innovation in molecular diagnostics and tackle so far unmet clinical needs, research activities need to be bundled and the pipeline from idea to MDx product clearly rolled out. Only then, the requirements for technical validity and clinical utility of novel biomarkers can be fulfilled and the long-term vision of personalized medicine will be realized.

Molecular diagnostics in dermatology: An online survey to study usage, obstacles and requirements in Germany.

BACKGROUND AND OBJECTIVES: Molecular diagnostics (MDx) increasingly gains importance in dermatology and its application is a prerequisite for personalized medicine. The goal of this cross-sectional study was to determine how MDx is implemented in dermatologists' offices in the three fields of oncology, inflammation and infectiology and which hurdles office-based dermatologists face in terms of MDx. METHODS: Physician members of the Association of the German Dermatologists (Berufsverband der Deutschen Dermatologen e. V.; BVDD) were surveyed via an online questionnaire on MDx. RESULTS: 39.6 % of the 192 participants reported using MDx. Of these, the vast majority used MDx for diagnosing infectious diseases (86.5 % and 44.3 % of users perform MDx for detection of funghi and sexually transmitted diseases, respectively). Only a small minority applied MDx to answer oncological or immunological questions. The major obstacles for non-users as compared to users were difficulties in implementation, lack of expertise as well as time, personnel, and technical availability. Reimbursement was a main issue in both groups. CONCLUSIONS: Despite availability of specific therapies requiring precision medicine, MDx has not yet been broadly implemented in office-based dermatology. To advance MDx, more needs to be done in terms of continuous education, availability of reliable and valid tests, and reimbursability.

T-Cell‒Mediated Autoimmunity: Mechanisms and Future Directions.

T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing autoantibodies. Technological advances have contributed to identifying autoantigens, the Holy Grail of autoimmunity, in many inflammatory disorders of the skin. Novel therapeutic approaches such as chimeric (auto)antibody receptor T cells are a milestone on the way to finding individualized, well-tolerated, targeted therapies. This review summarizes the current knowledge on pathogenesis, immune response pattern‒related ontology, diagnostic approaches, and treatment options of autoimmune skin diseases.

Immunocompromised Patients with Therapy-Refractory Chronic Skin Diseases Show Reactivation of Latent Epstein‒Barr Virus and Cytomegalovirus Infection.

Reactivation of latent Epstein‒Barr virus (EBV) and/or Cytomegalovirus (CMV) infection is a dreaded complication in immunocompromised patients receiving hematopoietic stem cell transplantation. Evidence is sparse on whether subclinical reactivation of viral infection may also be of clinical relevance in dermatological patients. We screened patients (N = 206) suffering from chronic skin diseases for subclinical reactivation of EBV and CMV infection. We found that immunocompromised patients with therapy-refractory chronic skin diseases showed higher rates of subclinical reactivation of CMV and EBV infection (6.7% vs. 0% for EBV and 16.7% vs. 5.6% for CMV) and a higher prevalence of virus-specific DNA in skin tissue (30.8% vs. 0% for EBV and 21.4% vs. 0% for CMV) than nonimmunocompromised patients with chronic skin diseases. T cells isolated from lesional skin exhibited up to 14-fold increased proliferation with production of T helper type 1 and T helper type 17 cytokines on stimulation with viral proteins, providing evidence for possible aggravation of the underlying skin diseases by viral infection. Improvement of skin lesions in patients with reactivation of CMV infection (n = 4) was observed on antiviral treatment. Our data suggest that subclinical reactivation of EBV and/or CMV infection is an under-recognized condition in the dermatological patient population with chronic skin diseases.

IFN-1s: Sentinels Shaping Distinct Immune Responses in Skin.

IFN-1s are early sentinels of potential danger in skin. Two interconnected axes exist: plasmacytoid dendritic cells (DCs) secreting IFN-α in response to single strand RNA or DNA and keratinocytes secreting IFN-κ after stimulation with double strand RNA or other IFNs. Both IFN-α and IFN-κ induce macrophages and DC subpopulations to secrete master regulators of cytotoxicity or wound healing, the latter related to psoriasis pathogenesis.

Hidradenitis Suppurativa: Where We Are and Where We Are Going.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease primarily affecting apocrine gland-rich areas of the body. It is a multifactorial disease in which genetic and environmental factors play a key role. The primary defect in HS pathophysiology involves follicular occlusion of the folliculopilosebaceous unit, followed by follicular rupture and immune responses. Innate pro-inflammatory cytokines (e.g., IL-1ß, and TNF-α); mediators of activated T helper (Th)1 and Th17 cells (e.g., IFN-γ, and IL-17); and effector mechanisms of neutrophilic granulocytes, macrophages, and plasma cells are involved. On the other hand, HS lesions contain anti-inflammatory mediators (e.g., IL-10) and show limited activity of Th22 cells. The inflammatory vicious circle finally results in pain, purulence, tissue destruction, and scarring. HS pathogenesis is still enigmatic, and a valid animal model for HS is currently not available. All these aspects represent a challenge for the development of therapeutic approaches, which are urgently needed for this debilitating disease. Available treatments are limited, mostly off-label, and surgical interventions are often required to achieve remission. In this paper, we provide an overview of the current knowledge surrounding HS, including the diagnosis, pathogenesis, treatments, and existing translational studies.

IMPROVE 1.0: Individual Monitoring of Psoriasis Activity by Regular Online App Questionnaires and Outpatient Visits.

Smartphone apps gain more and more importance in supporting management of chronic diseases. Psoriasis is a highly prevalent, lifelong chronic inflammatory skin disease with a high impact on patient's quality of life. Disease management includes regular topical and systemic treatment of skin lesions as well as co-treatment of metabolic and psychologic disorders. In this study, we investigated the potential of a new smartphone app (IMPROVE 1.0) for individual monitoring of disease activity and disease influencing factors. Twelve out of 50 psoriasis patients asked for study participation performed self-assessment of psoriasis severity, life quality, and stress scores using the app over a period of 1 year. Every 2 months, study participants were carefully examined by a dermatologist in order to control the quality of app-reported data. We found that psoriasis severity and life quality values as entered in the app closely correlate to physician's examination. Furthermore, we detected strong correlations of disease activity with life quality and psoriasis serum biomarker. Temporal relations between psoriasis aggravation and previous changes of lifestyle factors, such as increased stress levels, were observed in individual patients, indicating a high potential for preventive interventions in future psoriasis apps. The vast majority of study participants evaluated IMPROVE 1.0 app positively and wish to include the app into their daily life. Hence, we demonstrate that smartphone apps are a useful tool to raise self-awareness for the dimensions of complex diseases and fully integrate psoriasis patients into individual disease management. These data are important to develop more advanced digital tools supporting the management of chronic diseases in the future.

Predicting persistence of atopic dermatitis in children using clinical attributes and serum proteins.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin disease in children, with 30% of all those diagnosed developing chronic or relapsing disease by adolescence. Such disease persistence cannot yet be predicted. The aim of the present study was to predict the natural course of AD using clinical parameters and serum proteins. METHODS: Sera of 144 children with AD (age 0-3 years) were analyzed for IgE and 33 cytokines, chemokines, and growth factors. Patient disease course until the age of 7 years was assessed retrospectively. Unsupervised k-means clustering was performed to define disease endotypes. Identified factors associated with AD persistence at the age of 7 years were validated in children with AD in an independent cohort (LISA Munich; n = 168). Logistic regression and XGBoosting methods followed by cross-validation were applied to predict individual disease outcomes. RESULTS: Three distinct endotypes were found in infancy, characterized by a unique inflammatory signature. Factors associated with disease persistence were disease score (SCORAD), involvement of the limbs, flexural lesion distribution at the age of 3 years, allergic comorbidities, and disease exacerbation by the trigger factors stress, pollen exposure, and change in weather. Persistence was predicted with a sensitivity of 81.8% and a specificity of 82.4%. Factors with a high impact on the prediction of persistence were SCORAD at the age of 3 years, trigger factors, and low VEGF serum levels. CONCLUSION: Atopic dermatitis in infancy comprises three immunological endotypes. Disease persistence can be predicted using serum cytokines and clinical variables.

Optical features of human skin revealed by optoacoustic mesoscopy in the visible and short-wave infrared regions.

Detailed assessment of skin conditions or the efficacy of skin treatments could greatly benefit from noninvasively assessing the distribution of cutaneous and subcutaneous structures and biomolecules. We considered ultrawideband raster scan optoacoustic mesoscopy with an extended wavelength range from visible to short-wave infrared and observed previously unseen high-resolution images of lipids colocalized with water, melanin, and hemoglobin distribution in human skin. Based on this contrast, the technique resolves subcutaneous fat, the pilosebaceous unit with complete hair strand and bulb, dermal microvasculature, and epidermal structures. We further visualize melanoidins that form via the Maillard reaction in the ultrathin stratum corneum layer, analyze their absorption spectrum, and separate them from the melanin layer. The suggested method may allow novel interrogation of skin conditions, possibly impacting diagnostics and medical and cosmetic treatments.

[Molecular diagnostics of hand eczema]. / Molekulare Diagnostik des Handekzems.

BACKGROUND: Using current diagnostic tools for hand eczema, namely clinical picture and histology, differential diagnoses such as psoriasis palmaris usually cannot be ruled out. OBJECTIVES: Discussion of current diagnostic possibilities for hand eczema; presentation and critical evaluation of proposed biomarkers for molecular diagnostics and outlook how diagnostics in dermatology will change in the near future. MATERIALS AND METHODS: In this article, we discuss basic research and provide a review of the literature. RESULTS: Molecular diagnostics has the potential to substantially improve diagnosis of hand eczema; prerequisites are prospective validation of proposed markers and availability of valid and cost-effective diagnostics. CONCLUSIONS: In the near future, the diagnosis of hand eczema will be complemented by software algorithms and artificial intelligence on the one hand and simple, precise, and economic molecular diagnostic devices on the other.

Psoriasis Pathogenesis: Keratinocytes Are Back in the Spotlight.

Psoriasis is a T helper type 17-mediated immune disease. Initial triggers that lead to T helper type 17 production and inflammatory cell recruitment into skin are being delineated. Autoantigens that stimulate T helper type 17 cells are also being identified. A new and important piece of the puzzle indicates that keratinocytes not only amplify inflammation, but that they are essential for a full-blown IL-17-mediated psoriatic phenotype in mice.