Autoinflammatory Keratinization Diseases-The Concept, Pathophysiology, and Clinical Implications.

Recent advances in medical genetics elucidated the background of diseases characterized by superficial dermal and epidermal inflammation with resultant aberrant keratosis. This led to introducing the term autoinflammatory keratinization diseases encompassing entities in which monogenic mutations cause spontaneous activation of the innate immunity and subsequent disruption of the keratinization process. Originally, autoinflammatory keratinization diseases were attributed to pathogenic variants of CARD14 (generalized pustular psoriasis with concomitant psoriasis vulgaris, palmoplantar pustulosis, type V pityriasis rubra pilaris), IL36RN (generalized pustular psoriasis without concomitant psoriasis vulgaris, impetigo herpetiformis, acrodermatitis continua of Hallopeau), NLRP1 (familial forms of keratosis lichenoides chronica), and genes of the mevalonate pathway, i.e., MVK, PMVK, MVD, and FDPS (porokeratosis). Since then, endotypes underlying novel entities matching the concept of autoinflammatory keratinization diseases have been discovered (mutations of JAK1, POMP, and EGFR). This review describes the concept and pathophysiology of autoinflammatory keratinization diseases and outlines the characteristic clinical features of the associated entities. Furthermore, a novel term for NLRP1-associated autoinflammatory disease with epithelial dyskeratosis (NADED) describing the spectrum of autoinflammatory keratinization diseases secondary to NLRP1 mutations is proposed.

Differential diagnosis of red scalp. The importance of trichoscopy.

Red scalp is a common complaint which may constitute a diagnostic and therapeutic challenge in daily clinical practice. Among the numerous diseases which cause diffuse scalp erythema are psoriasis, seborrheic dermatitis, contact dermatitis, diffuse lichen planopilaris, dermatomyositis and scalp rosacea. Accurate diagnosis is crucial for optimal treatment outcomes. Histology most frequently discriminates the underlying condition, but it requires scalp biopsy. In many cases the combination of clinical examination and trichoscopy is sufficient for establishing the correct diagnosis. The main trichoscopic features of psoriasis are silver-white scaling, regular distributed dotted (glomerular) vessels or twisted red loops and punctate hemorrhages. Yellowish-white scaling and thin arborizing vessels are typical features of seborrheic dermatitis. Contact dermatitis is characterized by the presence of yellow exudate and polymorphic vessels, while perifollicular scaling and erythema with the lack of follicular openings are typical findings in lichen planopilaris. In scalp dermatomyositis, tortuous and arborizing vessels with interfollicular and perifollicular pigmentation may be detected. The most characteristic features of scalp rosacea are perifollicular scaling and arborizing vessels. This review also summarizes histologic features and therapeutic options for these conditions.

The profile of adipokines associated with fibrosis and impaired microcirculation in systemic sclerosis.

PURPOSE: Adipokines belong to a group of molecules mostly produced by adipose tissue. Abnormalities in the secretion of several adipokines have already implicated to play a pathogenic role in systemic sclerosis (SSc). However, the possible role of numerous molecules still needs to be clarified. The aim of the study was to determine whether the altered level of selected circulating adipokines might correlate with the intensity of fibrosis and vasculopathy in the course of SSc. MATERIALS AND METHODS: Serum concentrations of chemerin, adipsin, retinol-binding protein 4, apelin, visfatin, omentin-1, and vaspin were determined with ELISA in the sera of patients with SSc (n â€‹= â€‹55) and healthy controls (n â€‹= â€‹25). RESULTS: The serum concentration of adipsin (p â€‹= â€‹0.03) and visfatin (p â€‹= â€‹0.04) was significantly increased and the level of retinol-binding protein 4 (p â€‹= â€‹0.03) was decreased in diffuse compared to limited cutaneous SSc. Moreover, serum adipsin level correlated positively with the intensity of skin fibrosis measured with the modified Rodnan skin score (r â€‹= â€‹0.31, p â€‹= â€‹0.02) and was significantly higher in patients with pulmonary arterial hypertension than in those without the condition (p â€‹= â€‹0.03). The concentrations of adipsin (p â€‹= â€‹0.01) and visfatin (p â€‹= â€‹0.04) were significantly increased and the level of apelin (p â€‹= â€‹0.02) was decreased in patients with active digital ulcerations compared to individuals without this complication. CONCLUSION: Adipsin may be considered a pivotal protein in the development of both fibrosis and impaired microcirculation. Its abnormal concentration reflects the intensity of skin thickening and the presence of pulmonary arterial hypertension. Adipsin, visfatin, and apelin are adipose tissue-derived molecules associated with digital vasculopathy.

Multilocus-sequence typing reveals clonality of Staphylococcus aureus in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is exacerbated by Staphylococcus aureus, which is capable of displacing not only the physiological microbiota, but also other strains of its own species. Analyses of the molecular characteristics and relationships of S. aureus strains present in different microniches are lacking. OBJECTIVES: To determine, using multilocus sequence typing (MLST), the relationship of S. aureus isolates from the lesional and nonlesional skin and anterior nares of patients with AD, and to review the characteristics of the dominant clones. METHODS: Sixty-three individuals with active AD were enrolled. Ten patients with moderate-to-severe AD (SCoring of Atopic Dermatitis score ≥ 25) colonized by S. aureus in all analysed locations were included in the MLST analysis. RESULTS: The most prevalent sequence types were 7 (10/30 strains; 33.3%), 15 and 97 (both 5/30 strains; 16.7%) all of which were associated with the expression of adhesins and toxins promoting chronic microbial dysbiosis, skin barrier damage and inflammation. Six patients (60%) were carriers of clonal S. aureus strains at all analysed locations, three (30%) carriers in lesional and nonlesional skin, and one (10%) was a carrier in nonlesional skin and the anterior nares. CONCLUSIONS: The results imply that the identified S. aureus lineages are better adapted to dominate the microbiota in AD. Decontaminating the identified reservoirs of S. aureus (i.e. anterior nares and nonlesional skin) could reduce the severity of AD.

The Clinical Significance of Salusins in Systemic Sclerosis-A Cross-Sectional Study.

Background: Systemic sclerosis (SSc) is a connective tissue disease manifesting with progressive fibrosis of the skin and internal organs. Its pathogenesis is strictly associated with vascular disfunction and damage. Salusin-α and salusin-ß, endogenous peptides regulating secretion of pro-inflammatory cytokines and vascular smooth muscle proliferation, may potentially play a role in SSc pathogenesis. Objectives: The aim of this study was to assess the concentration of salusins in sera of patients with SSc and healthy controls and to evaluate correlations between the salusins levels and selected clinical parameters within the study group. Materials and methods: 48 patients with SSc (44 women; mean age, 56.4, standard deviation, 11.4) and 25 adult healthy volunteers (25 women; mean age, 55.2, standard deviation, 11.2) were enrolled. All patients with SSc were treated with vasodilators and twenty-seven of them (56%) also received immunosuppressive therapy. Results: Circulating salusin-α was significantly elevated in patients with SSc in comparison to healthy controls (U = 350.5, p = 0.004). Patients with SSc receiving immunosuppression had higher serum salusin-α concentrations compared with those without immunosuppressive therapy (U = 176.0, p = 0.026). No correlation was observed between salusins concentrations and skin or internal organ involvement parameters. Conclusions: Salusin-α, a bioactive peptide mitigating the endothelial disfunction, was elevated in patients with systemic sclerosis receiving vasodilators and immunosuppressants. Increased salusin-α concertation may be associated with the initiation of atheroprotective processes in patients with SSc managed pharmacologically, which requires verification in future studies.

Immunopathogenesis of Atopic Dermatitis: Focus on Interleukins as Disease Drivers and Therapeutic Targets for Novel Treatments.

Atopic dermatitis is a chronic, recurrent inflammatory skin disorder manifesting by eczematous lesions and intense pruritus. Atopic dermatitis develops primarily as a result of an epidermal barrier defect and immunological imbalance. Advances in understanding these pathogenetic hallmarks, and particularly the complex role of interleukins as atopic dermatitis drivers, resulted in achieving significant therapeutic breakthroughs. Novel medications involve monoclonal antibodies specifically blocking the function of selected interleukins and small molecules such as Janus kinase inhibitors limiting downstream signaling to reduce the expression of a wider array of proinflammatory factors. Nevertheless, a subset of patients remains refractory to those treatments, highlighting the complexity of atopic dermatitis immunopathogenesis in different populations. In this review, we address the immunological heterogeneity of atopic dermatitis endotypes and phenotypes and present novel interleukin-oriented therapies for this disease.

EGFR inhibitor-induced folliculitis decalvans: a case series and management guidelines.

Epidermal growth factor receptor (EGFR) is one of therapeutic targets in oncology for solid tumors originating from epithelial tissue, such as non-small-cell lung carcinoma (NSCLC) and breast cancer. EGFR inhibitors used in cancer treatment may cause a broad spectrum of dose-dependent cutaneous adverse events, including acneiform papulopustular rash, nail and hair disturbances, xerosis, and mucositis. The pathogenesis of the EGFR inhibitor-induced adverse reactions originates from disturbances in keratinocyte differentiation, cytokine secretion, and neutrophil chemotaxis. One of the rare, yet distressing adverse events may be folliculitis decalvans, a progressive neutrophil-driven scarring alopecia with hair tufts formation resembling doll's hair. Early diagnosis and introduction of treatment are crucial for disease prognosis since a long course of the disease leads to decreased quality of life. Here, we review the literature cases of EGFR inhibitor-induced folliculitis decalvans and provide guidance on management and prevention of this condition in oncologic patients. Furthermore, we report the first afatinib-associated folliculitis decalvans in three female patients with NSCLC.

The Accuracy of Clinical Diagnosis in 2135 Lesions on the Face. A Retrospective Analysis of Histopathological Records.

Introduction: Biopsy of facial skin lesions is an important supplement to dermatological diagnostics, especially in doubtful cases or suspected of being malignant. Objectives: The aim of the retrospective study of 2135 histopathological records of lesions on the face was to: establish the most common indications for a skin biopsy in patients with facial lesions, establish the frequency of histopathological diagnoses, evaluate how often clinically suspected inflammatory lesions are identified as tumors in histopathology, evaluate the accuracy of clinical diagnoses of the most common skin tumors and dermatoses. Methods: It was a retrospective study. Histopathological records from the lesions on the face from years 2010-2017 were analyzed. Results: The mean age of patients was 69.3 [7-98]. Fifty-eight percent of the patients were women. Among 2135 clinical diagnoses skin tumors were suspected in 1905 cases. Among 2169 obtained histopathological results (34 biopsies showed 2 diseases), we identified skin tumors in 1940 cases, with 1388 confirmed as malignant. The clinical diagnosis of a specific benign or malignant skin tumor was accurate in 1013/1634 subjects, in comparison to inflammatory lesions, which were correct in 67/148 cases, (P = 0.0001). Among all preliminary inflammatory diagnoses, 33/204 lesions were identified as skin tumors in histopathology. Conclusions: In conclusion in most cases of skin tumors the clinical diagnosis is confirmed by histopathological examination. In case of facial inflammatory lesions, the accuracy of clinical diagnosis is lower, with a significant number of facial lesions appearing inflammatory in clinical evaluation but being diagnosed as skin cancers in pathology.

Enterotoxin Gene Cluster and selX Are Associated with Atopic Dermatitis Severity-A Cross-Sectional Molecular Study of Staphylococcus aureus Superantigens.

Staphylococcus aureus superantigens (SAgs) have been reported to aggravate atopic dermatitis. However, comprehensive analyses of these molecules in multiple microniches are lacking. The present study involved 50 adult patients with active atopic dermatitis. S. aureus was isolated from the lesional skin, nonlesional skin, and anterior nares. Multiplex-PCR was performed to identify genes encoding (1) selX (core genome); (2) seg, selI, selM, selN, selO, selU (enterotoxin gene cluster, EGC); and (3) sea, seb, sec, sed, see, tstH (classic SAgs encoded on other mobile genetic elements). The results were correlated to clinical parameters of the study group. selx and EGC were the most prevalent in all microniches. The number of SAg-encoding genes correlated between the anterior nares and nonlesional skin, and between the nonlesional and lesional skin. On lesional skin, the total number of SAg genes correlated with disease severity (total and objective SCORAD, intensity, erythema, edema/papulation, lichenification and dryness). Linear regression revealed that AD severity was predicted only by selx and EGC. This study revealed that selX and EGC are associated with atopic dermatitis severity. Anterior nares and nonlesional skin could be reservoirs of SAg-positive S. aureus. Restoring the physiological microbiome could reduce the SAg burden and alleviate syndromes of atopic dermatitis.

3D skin bioprinting: future potential for skin regeneration.

Skin provides protection against external agents and plays an essential role in maintaining the body homeostasis. Bioprinting as a novel strategy involves computer-controlled deposition of cells and scaffolds into a three-dimensional (3D) construction of skin. 3D bioprinting gives an opportunity to generate multi-layered vascularized skin grafts that can overcome the limitations of current skin substitutes. The main indication is treatment of troublesome wounds, especially severe burns and non-healing chronic lesions. Bioprinted skin equivalents offer a promising approach in the field of regenerative medicine. This review presents and discusses 3D skin construct formation, its limitations and modifications, and its usefulness.

The Role of the Cutaneous Mycobiome in Atopic Dermatitis.

Atopic dermatitis is a chronic inflammatory skin disorder characterized by eczematous lesions, itch, and a significant deterioration in the quality of life. Recently, microbiome dysbiosis has been implicated in the pathogenesis of atopic dermatitis. Changes in the fungal microbiome (also termed mycobiome) appear to be an important factor influencing the clinical picture of this entity. This review summarizes the available insights into the role of the cutaneous mycobiome in atopic dermatitis and the new research possibilities in this field. The prevalence and characteristics of key fungal species, the most important pathogenesis pathways, as well as classic and emerging therapies of fungal dysbiosis and infections complicating atopic dermatitis, are presented.

Contact eczema induced by hybrid manicure. The role of acrylates as a causative factor.

Introduction: Acrylates are widespread plastic materials, known for their sensitizing properties. So far, allergy to acrylate monomers has been known as occupational eczema, mainly concerning dentists and manicurists. However, a surge of allergic contact dermatitis (ACD) cases related to acrylates among users of hybrid varnishes have recently been reported. Aim: This article reviews the pathogenesis, clinical manifestations, and dermoscopic features of contact eczema induced by hybrid manicure. Material and methods: The study was performed on a group of 8 women. Clinical and dermoscopic features were evaluated and correlated with the period of exposure to acrylates. In addition, all patients underwent mycological examination to exclude fungal co-infection. Results: Mycological examinations in all patients gave negative results, although 1 patient developed local secondary mixed supra-infection due to Pseudomonas aeruginosa and Candida spp. Distribution of clinical manifestations corresponded to the area of contact with the allergen and comprised both skin and nail changes. The severity of inflammation correlated positively with the exposure period. Subungual hyperkeratosis and onycholysis were the most common findings (8/8 patients), and eczematous finger pulp fissuring was a rarer sign (2/8 patients) but more specific clinically. Conclusions: The surge of contact dermatitis related to acrylates seen in recent years requires dermatologists' awareness. Nail changes induced by hybrid manicure can mimic onychomycosis or nail psoriasis. Therefore comprehensive patch testing should be performed in doubtful cases. Due to the lack of patch tests in our study, we can only suspect that we were dealing with allergic contact dermatitis. In case of confirmed allergy to acrylates, the patient should be aware of this and avoid them.

The Analysis of a Genome-Wide Association Study (GWAS) of Overweight and Obesity in Psoriasis.

There is evidence that the concomitance of psoriasis and obesity may originate from the interplay between multiple genetic pathways and involve gene−gene interactions. The aim of this study was to compare the genetic background related to obesity among psoriatic patients versus healthy controls by means of a Genome-Wide Association Study (GWAS). A total of 972 psoriatic patients and a total of 5878 healthy donors were enrolled in this study. DNA samples were genotyped for over 500,000 single nucleotide polymorphisms (SNPs) using Infinium CoreExome BeadChips (Illumina, San Diego, CA, USA). Statistical analysis identified eleven signals (p < 1 × 10−5) associated with BMI across the study groups and revealed a varying effect size in each sub-cohort. Seven of the alternative alleles (rs1558902 in the FTO gene, rs696574 in the CALCRL gene, as well as rs10968110, rs4551082, rs4609724, rs9320269, and rs2338833,) are associated with increased BMI among all psoriatic patients and four (rs1556519 in the ITLN2 gene, rs12972098 in the AC003006.7 gene, rs12676670 in the PAG1 gene, and rs1321529) are associated with lower BMI. The results of our study may lead to further insights into the understanding of the pathogenesis of obesity among psoriatic patients.

Raynaud's Phenomenon with Focus on Systemic Sclerosis.

Raynaud's phenomenon is a painful vascular condition in which abnormal vasoconstriction of the digital arteries causes blanching of the skin. The treatment approach can vary depending on the underlying cause of disease. Raynaud's phenomenon can present as a primary symptom, in which there is no evidence of underlying disease, or secondary to a range of medical conditions or therapies. Systemic sclerosis is one of the most frequent causes of secondary Raynaud's phenomenon; its appearance may occur long before other signs and symptoms. Timely, accurate identification of secondary Raynaud's phenomenon may accelerate a final diagnosis and positively alter prognosis. Capillaroscopy is fundamental in the diagnosis and differentiation of primary and secondary Raynaud's phenomenon. It is helpful in the very early stages of systemic sclerosis, along with its role in disease monitoring. An extensive range of pharmacotherapies with various routes of administration are available for Raynaud's phenomenon but a standardized therapeutic plan is still lacking. This review provides insight into recent advances in the understanding of Raynaud's phenomenon pathophysiology, diagnostic methods, and treatment approaches.

Chronic Plaque Psoriasis in Poland: Disease Severity, Prevalence of Comorbidities, and Quality of Life.

The epidemiology of psoriasis has not been widely assessed in Polish population so far. This study aimed to investigate psoriasis epidemiological situation by evaluating disease course and severity, management, comorbidities, environmental factors, and knowledge about this disorder among psoriatic patients in Poland. A cross-sectional cohort population-based study enrolled 1080 psoriatic patients and 1200 controls. The mean age of psoriasis onset was 27.6 years; 78.24% had type I psoriasis. Positive family history of psoriasis was reported in 44.81% of patients, whereas itch was reported in vast majority of patients (83.33%). Based on PASI score moderate psoriasis was the most common in studied group (mean 12.63 ± 9.33, range 0−67.2). The DLQI score (12.01 ± 7.41, range 0−30.0) indicated a very large effect of psoriasis on the quality of life. Hypertension was the most prevalent comorbidity (33.80%), followed by obesity (16.85%) and dyslipidemia (11.85%). Stress was the foremost cause of disease exacerbation (66.20%); however, infections (44.07%) and seasonal changes (45.09%) had also an impact on the course of psoriasis. Psoriatic patients were more often smokers (37.59%) vs. general population (27.50%; p < 0.0001). In conclusion, epidemiological studies help clinicians in better disease and patient understanding, which may translate into better management and patient compliance.

Future Treatment Options in Systemic Sclerosis-Potential Targets and Ongoing Clinical Trials.

Systemic sclerosis is an autoimmune connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. The pathogenesis of systemic sclerosis is very complex. Mediators produced by immune cells are involved in the inflammatory processes occurring in the tissues. The currently available therapeutic options are often insufficient to halt disease progress. This article presents an overview of potential therapeutic targets and the pipeline of possible future therapeutic options. It is based on research of clinical trials involving novel, unestablished methods of treatment. Increasing knowledge of the processes and mediators involved in systemic scleroderma has led to the initiation of drug trials with therapeutic targets of CD28-CD80/86, CD19, CCL24, CD20, CD30, tumor necrosis factor (TNF), transforming growth factor ß (TGF-ß), B-cell activating factor (BAFF), lysophosphatidic acid receptor 1 (LPA1 receptor), soluble guanylate cyclase (sGC), Janus kinases (JAK), interleukin 6 (IL-6), endothelin receptor, and autotaxin. Data from clinical trials on these drugs indicate a significant potential for several new therapeutic options for systemic sclerosis in the upcoming future.