Signatures of epigenetic, biological and mitotic age acceleration and telomere shortening are associated with arsenic-induced skin lesions.

Chronic arsenic exposure is a global health hazard significantly associated with the development of deleterious cutaneous changes and increased keratinocyte cancer risk. Although arsenic exposure is associated with broad-scale cellular and molecular changes, gaps exist in understanding how these changes impact the skin and facilitate malignant transformation. Recently developed epigenetic "clocks" can accurately predict chronological, biological and mitotic age, as well as telomere length, on the basis of tissue DNA methylation state. Deviations of predicted from expected age (epigenetic age dysregulation) have been associated with numerous complex diseases, increased all-cause mortality and higher cancer risk. We investigated the ability of these algorithms to detect molecular changes associated with chronic arsenic exposure in the context of associated skin lesions. To accomplish this, we utilized a multi-algorithmic approach incorporating seven "clocks" (Horvath, Skin&Blood, PhenoAge, PCPhenoAge, GrimAge, DNAmTL and epiTOC2) to analyze peripheral blood of pediatric and adult cohorts of arsenic-exposed (n = 84) and arsenic-naïve (n = 33) individuals, among whom n = 18 were affected by skin lesions. Arsenic-exposed adults with skin lesions exhibited accelerated epigenetic (Skin&Blood: + 7.0 years [95% CI 3.7; 10.2], q = 6.8 × 10-4), biological (PhenoAge: + 5.8 years [95% CI 0.7; 11.0], q = 7.4 × 10-2, p = 2.8 × 10-2) and mitotic age (epiTOC2: + 19.7 annual cell divisions [95% CI 1.8; 37.7], q = 7.4 × 10-2, p = 3.2 × 10-2) compared to healthy arsenic-naïve individuals; and accelerated epigenetic age (Skin&Blood: + 2.8 years [95% CI 0.2; 5.3], q = 2.4 × 10-1, p = 3.4 × 10-2) compared to lesion-free arsenic-exposed individuals. Moreover, lesion-free exposed adults exhibited accelerated Skin&Blood age (+ 4.2 [95% CI 1.3; 7.1], q = 3.8 × 10-2) compared to their arsenic-naïve counterparts. Compared to the pediatric group, arsenic-exposed adults exhibited accelerated epigenetic (+ 3.1 to 4.4 years (95% CI 1.2; 6.4], q = 2.4 × 10-4-3.1 × 10-3), biological (+ 7.4 to 7.8 years [95% CI 3.0; 12.1] q = 1.6 × 10-3-2.8 × 10-3) and mitotic age (+ 50.0 annual cell divisions [95% CI 15.6; 84.5], q = 7.8 × 10-3), as well as shortened telomere length (- 0.23 kilobases [95% CI - 0.13; - 0.33], q = 2.4 × 10-4), across all seven algorithms. We demonstrate that lifetime arsenic exposure and presence of arsenic-associated skin lesions are associated with accelerated epigenetic, biological and mitotic age, and shortened telomere length, reflecting altered immune signaling and genomic regulation. Our findings highlight the usefulness of DNA methylation-based algorithms in identifying deleterious molecular changes associated with chronic exposure to the heavy metal, serving as potential prognosticators of arsenic-induced cutaneous malignancy.

Editor's Highlights - May 2024.

Dermatological research and education have predominantly focused on lighter skin types in the past, leading to a significant gap in knowledge and understanding of conditions in darker skin types. This has contributed to disparities in the diagnosis and treatment of diseases in patients with skin of color. In the current issue of the Journal, we highlight four papers on the epidemiology and clinics of skin of color patients but also emphasize the importance of education and research in the dermatopathology of SOC patients.

The role of thymic stromal lymphopoietin in cutaneous disorders.

Thymic Stromal Lymphopoietin (TSLP) is an important cytokine that invokes early immune responses. TSLP, an IL-7-like cytokine encoded by the TSLP gene, activates JAK1 and JAK2 signaling pathways, stimulating dendritic cells to induce inflammatory Th2 cells. This cytokine is associated with pruritus in various cutaneous disorders, particularly atopic dermatitis. Varying levels of the cytokine TSLP have been demonstrated in studies of different cutaneous disorders. Pharmacological treatment targeting TSLP has been explored recently, particularly in the realm of atopic dermatitis.This review explores the relation of TSLP to cutaneous diseases, highlighting its potential as a biomarker for monitoring disease progression in discoid lupus erythematosus (DLE). The pharmacological therapy involving TSLP is discussed, along with the potential role of TSLP promotion in the treatment of alopecia areata. This overview examines the background, structure, and functions of TSLP, with a focus on its association with cutaneous disorders and a special focus on the impact of the atopic march.

Lymphoplasmocytic plaque in children: A report of an atypical location.

Lymphoplasmocytic plaque in children (LPC) is a rare and distinctive skin disorder primarily affecting the pediatric population. Characterized by its unique histopathological features, the condition manifests as well-defined plaques with a predominance of lymphocytes and plasma cells infiltrating the dermis. Despite its limited prevalence, recognizing this entity is crucial for accurate diagnosis and appropriate management of affected patients. We report the case of a 10-year-old male presenting with LPC in the extensor surface of the upper arm, a rarely reported location, treated with both topical and intralesional corticosteroids resulting in partial improvement.

Punch Biopsy Extraction With Fingers.

Punch biopsies are commonly used in dermatology for diagnosing skin diseases. Traditional methods involve the use of forceps, skin hooks, and scissors, which add to health care costs. The technique described here offers a cost-effective and efficient alternative for obtaining specimens.

Dermoscopy to differentiate clinically similar inflammatory and neoplastic skin lesions.

INTRODUCTION: Over the few last decades, dermoscopy has become an invaluable and popular imaging technique that complements the diagnostic armamentarium of dermatologists, being employed for both tumors and inflammatory diseases. Whereas distinction between neoplastic and inflammatory lesions is often straightforward based on clinical data, there are some scenarios that may be troublesome, e.g., solitary inflammatory lesions or tumors superimposed to a widespread inflammatory condition that may share macroscopic morphological findings. EVIDENCE ACQUISITION: We reviewed the literature to identify dermoscopic clues to support the differential diagnosis of clinically similar inflammatory and neoplastic skin lesions, also providing the histological background of such dermoscopic points of differentiation. EVIDENCE SYNTHESIS: Dermoscopic differentiating features were identified for 12 relatively common challenging scenarios, including Bowen's disease and basal cell carcinoma vs. psoriasis and dermatitis, erythroplasia of Queyrat vs. inflammatory balanitis, mammary and extramammary Paget's disease vs. inflammatory mimickers, actinic keratoses vs. discoid lupus erythematosus, squamous cell carcinoma vs. hypertrophic lichen planus and lichen simplex chronicus, actinic cheilitis vs. inflammatory cheilitis, keratoacanthomas vs. prurigo nodularis, nodular lymphomas vs. pseudolymphomas and inflammatory mimickers, mycosis fungoides vs. parapsoriasis and inflammatory mimickers, angiosarcoma vs granuloma faciale, and Kaposi sarcoma vs pseudo-Kaposi. CONCLUSIONS: Dermoscopy may be of aid in differentiating clinically similar inflammatory and neoplastic skin lesions.

Microblading reaction as a manifestation of systemic sarcoidosis: two case reports and a review of the literature.

BACKGROUND: Sarcoidosis is a multisystemic disease characterized by granulomatous inflammation. Sarcoidosis often poses a diagnostic challenge owing to its nonspecific or mild clinical features. In 20-35% of cases, sarcoidosis initially presents on skin. However, skin lesions commonly mimic dermatological conditions. Therefore, it is important to not underestimate the skin manifestations and perform histopathological examinations to make a timely diagnosis. CASE PRESENTATION: We present two cases of 33-year-old Caucasian female patients with orange-red macules and plaques that developed in the eyebrow area 1 and 6 years after microblading, respectively. Histopathological examination confirmed a diagnosis of sarcoidosis. The lymph nodes and lungs were also affected in both patients. CONCLUSION: Our two reports suggest that an esthetic procedure involving dermal or subcutaneous injection of foreign materials can trigger the development of cutaneous and systemic sarcoidosis. However, this relationship has not been described yet. Physicians should, therefore, be aware of this complication to properly evaluate and treat such patients in a timely manner.

[Research advances on the role of aerobic glycolysis in skin fibrosis diseases].

Skin fibrosis diseases mainly include hypertrophic scar, keloid, and systemic sclerosis, etc. The main pathological features are excessive activation of fibroblasts and abnormal deposition of extracellular matrix. In recent years, studies have shown that aerobic glycolysis is closely related to the occurrence and development of skin fibrosis diseases. Drugs targeting aerobic glycolysis has provided new ideas for skin anti-fibrosis treatment. This article reviews the role of enzymes and products related to aerobic glycolysis in the occurrence and development of skin fibrosis diseases and the drugs targeting aerobic glycolysis for the treatment of skin fibrosis diseases.

[Research progresses on acute skin failure in children].

Acute skin failure (ASF) is an inevitable damage to the skin and subcutaneous tissue caused by hemodynamic instability and/or low perfusion. At present, there are some understandings and reports about adult ASF at home and abroad, but there are few reports about children's ASF. This article reviewed the definition, pathophysiological changes, risk factors, clinical manifestations, and management of children's ASF, and put forward suggestions in order to provide ideas for clinical diagnosis and treatment of children's ASF, and promote the further study of children's ASF.

A Protocol for the Automated Assessment of Cutaneous Pathology in a Mouse Model of Hemichannel Dysfunction.

In this chapter, we provide detailed instructions to perform quantitative reflectance imaging in a mouse model of a rare epidermal disorder caused by hyperactive connexin 26 hemichannels. Reflectance imaging is a versatile and powerful tool in dermatology, offering noninvasive, high-resolution insights into skin pathology, which is essential for both clinical practice and research. This approach offers several advantages and applications. Unlike traditional biopsy, reflectance imaging is noninvasive, allowing for real-time, in vivo examination of the skin. This is particularly valuable for monitoring chronic conditions or assessing the efficacy of treatments over time, enabling the detailed examination of skin morphology. This is crucial for identifying features of skin diseases such as cancers, inflammatory conditions, and infections. In therapeutic applications, reflectance imaging can be used to monitor the response of skin lesions to treatments. It can help in identifying the most representative area of a lesion for biopsy, thereby increasing the diagnostic accuracy. Reflectance imaging can also be used to diagnose and monitor inflammatory skin diseases, like psoriasis and eczema, by visualizing changes in skin structure and cellular infiltration. As the technology becomes more accessible, it has potential in telemedicine, allowing for remote diagnosis and monitoring of skin conditions. In academic settings, reflectance imaging can be a powerful research tool, enabling the study of skin pathology and the effects of novel treatments, including the development of monoclonal antibodies for therapeutic applications.

Facial cutaneous Rosai-Dorfman disease: a case report.

BACKGROUND: Rosai-Dorfman disease (RDD) is a form of non-Langerhans cell histiocytosis in which the activated histiocytes of the lymph nodes and other organs begin to accumulate following excessive production. Bilateral, massive, and painless lymphadenopathy are classic presentations. Systemic RDD is already known to be a rare condition, but isolated cutaneous RDD is extremely rare. We presented a rare and unusual presentations of a disease. CASE PRESENTATION: A 35-year-old Thai female with a 6-month history of a small acne-like lesion that rapidly progressed to 5 cm tumor-like lesions on the face within 3 months. Tissue histology showed a dense dermal infiltration of histiocytes with emperipolesis phenomenon. Immunohistochemistry was positive for S100 protein and CD68 and negative for CD1a. Oral prednisolone (50 mg/day) was initiated with a favorable outcome at the one-month follow-up. However, prednisolone yielded a partial response at 2-month follow-up, leading to application of another modality. CONCLUSION: Although cutaneous Rosai-Dorfman disease is considered benign and well medical responded disease, patients with atypical presentation and rapid growing lesion may necessitate aggressive multimodal treatment.

Resolution of painful trichodysplasia spinulosa with topical cidofovir: case report.

Purpose: Trichodysplasia spinulosa (TS) is a rare, disfiguring skin condition which presents with widespread asymptomatic or pruritic, skin-colored papules with white protruding keratin spiculations in immunocompromised individuals. Due to its rarity, there is little data to guide treatment decisions. The purpose of this article is to report a case of TS that completely resolved after treatment with topical cidofovir.Materials and methods: A 19-year-old immunosuppressed female presented with widespread painful, itchy bumps on the nose and face. Upon examination, there were erythematous papules with hyperkeratinized spicules affecting the central face. Biopsy of the lesions was consistent with TS which was confirmed via PCR analysis. The tenderness of this patient's eruption was highly atypical for TS. Once daily topical application of compounded 1% cidofovir cream was prescribed.Results: The patient's symptoms resolved completely after 4 weeks of therapy with topical cidofovir 1% cream, without reduction of immunosuppression.Conclusions: Topical cidofovir 1% cream may be a valuable treatment for this rare disease.

Comparison of organ involvement clusters in Black and White American sarcoidosis patients from a prospectively collected patient registry.

BACKGROUND: Due to the heterogeneity of sarcoidosis, there is a need to define clinical phenotypes to allow for tailoring of clinical care and identification of more homogenous populations to facilitate research. METHODS: We utilized data from a prospectively collected registry of sarcoidosis patients seen at a single quaternary referral center between January 2019 and February 2021. We used multiple correspondence analysis (MCA) and k-means clustering to investigate if the clusters previously identified in the GenPhenReSa study were reproducible in a US population. We also investigated if these clusters were stable when the population was stratified by race. RESULTS: We replicated 3 of the 5 clusters seen in the GenPhenReSa study in our cohort. We likewise identified similar clusters between White and Black patients with sarcoidosis. Differences in organ manifestations associations between White and Black patients were seen primarily in relation to cardiac, neurologic, and ocular involvement. CONCLUSIONS: The organ clusters of liver-spleen, isolated pulmonary, and musculoskeletal-skin were reproducible in a US cohort, and in both Black and White patients.

Features of tattoo-associated cutaneous lymphoid hyperplasia on reflectance confocal microscopy and line-field confocal optical coherence tomography.

The popularity of tattoos has led to an increase in associated skin reactions, including complications such as infection, allergic reactions and rare conditions such as tattoo-induced cutaneous lymphoid hyperplasia (CLH). CLH is a benign lymphoproliferative reaction with clinical features resembling malignant cutaneous lymphomas. Non-invasive diagnostic tools like reflectance confocal microscopy (RCM) and the new line-field confocal optical coherence tomography (LC-OCT) are being studied in dermatology better to understand the morphological patterns of many dermatological diseases. Between September 2021 and May 2023, patients with suspicious lesions for tattoo-related CLH were analysed using RCM and LC-OCT before confirming the diagnosis of CLH through skin biopsy and histopathological examination. The study included five cases of CLH. It focused on the analysis of high-quality LC-OCT images/videos and RCM images to investigate the features of CLH in tattooed individuals. Most (80%) cases exhibited a mixed T and B lymphocyte infiltration subtype, while 20% showed a predominant T infiltration subtype. RCM and LC-OCT revealed characteristic features, including architectural disarray, fibrosis, lymphoid infiltrates, and pigment deposits in the epidermis and dermis. Non-invasive tools such as RCM and LC-OCT are valuable in diagnosing tattoo-related CLH. While skin biopsy remains the current standard for diagnosis, RCM and LC-OCT can serve as helpful adjuncts in identifying the most representative area for biopsy. They may potentially become alternative diagnostic options in the future, offering benefits in terms of cost, diagnostic efficiency, aesthetics and patient satisfaction as the prevalence of tattoo-related adverse reactions continues to rise.

A case report of multicentric reticulohistiocytosis with atypical cutaneous presentation.

Multicentric reticulohistiocytosis (MRH) is a rare systemic disorder characterized by histiocytic hyperplasia that mainly involves the skin, mucous membranes, and joints. The typical clinical features include papules, nodules, and arthritis. MRH lesions are relatively extensive but small and scattered. Joint inflammation is characterized by diffuse symmetric polyarthritis as the first symptom, which can be severe and disabling due to destructive joint changes. MRH is easily misdiagnosed in clinical practice. Here, we report the case of an elderly male patient who presented with polyarticular pain in the hip and interphalangeal joints as the first manifestation, followed by the development of large, isolated, bulging skin nodules, which are atypical MRH lesions. This is rare in all MRH case reports, and we made the correct diagnosis by combining skin histopathology, immunohistochemistry, and other clinical examinations. We performed surgical treatment on the local skin lesions of this patient. This case suggests that clinicians should actively correlate the condition and accurately diagnose MRH when encountering atypical skin changes or other diseases as the first symptom and explore the mechanisms of MRH and other clinical manifestations.

Skin and lung fibrosis induced by bleomycin in mice: a systematic review.

OBJECTIVE: Scleroderma, or systemic sclerosis (SSc), is a chronic autoimmune connective disease with an unknown etiology and poorly understood pathogenesis. The striking array of autoimmune, vascular, and fibrotic changes that develop in almost all patients makes SSc unique among connective tissue diseases. Although no animal model developed for SSc to date fully represents all features of human disease, some animal models that demonstrate features of SSc may help to better understand the pathogenesis of the disease and to develop new therapeutic options. In this review, we aimed to evaluate skin fibrosis and lung involvement in a bleomycin (BLM)-induced mouse model and to evaluate the differences between studies. METHODS: A systematic literature review (PRISMA guideline) on PubMed and EMBASE (until May 2023, without limits) was performed. A primary literature search was conducted using the PubMed and EMBASE databases for all articles published from 1990 to May 2023. Review articles, human studies, and non-dermatological studies were excluded. Of the 38 non-duplicated studies, 20 articles were included. RESULTS: Among inducible animal models, the BLM-induced SSc is still the most widely used. In recent years, the measurement of tissue thickness between the epidermal-dermal junction and the dermal-adipose tissue junction (dermal layer) has become more widely accepted. CONCLUSIONS: In animal studies, it is important to simultaneously evaluate lung tissues in addition to skin fibrosis induced in mice by subcutaneous BLM application, following the 3R (replacement, reduction, and refinement) principle to avoid cruelty to animals.

Adenosine A2B receptor agonist improves epidermal barrier integrity in a murine model of epidermal hyperplasia.

Adenosine regulates multiple physiological processes through the activation of four receptor subtypes, of which the A2B adenosine receptor (A2BAR) has the lowest affinity for adenosine. Being the adenosine receptor subtype most prominently expressed in epidermis, we recently described the antiproliferative and anti-inflammatory effect of the selective A2BAR agonist BAY60-6583 (BAY) in human keratinocytes stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA), so we sought to establish the effect of topical application of BAY in a model of murine epidermal hyperplasia. Topical application of BAY (1 or 10 µg/site) prevented the inflammatory reaction and skin lesions induced by TPA, minimizing hyperproliferation and acanthosis, as well as the expression of specific markers of proliferative keratinocytes. On the other hand, pre-treatment with the selective A2BAR antagonist, PSB-1115 (PSB, 5 or 50 µg/site) reversed these beneficial effects. Additionally, BAY application normalized the expression of epidermal barrier proteins, whose integrity is altered in inflammatory skin diseases, while treatment with the antagonist alone worsened it. Our results, besides confirming the anti-inflammatory and antiproliferative effects of the A2BAR agonist, further demonstrate a role of A2BAR activation to preserve the epidermal barrier. Therefore, the activation of A2BAR may constitute a possible new pharmacological target for the treatment of skin inflammatory diseases such as psoriasis.

Melatonin restores DNFB-induced dysbiosis of skin microbiota in a mouse model of atopic dermatitis.

BACKGROUND: The epidermic microbiota plays crucial roles in the pathogenesis of atopic dermatitis (AD), a common inflammatory skin disease. Melatonin (MLT) has been shown to ameliorate skin damage in AD patients, yet the underlying mechanism is unclear. METHODS: Using 2,4-dinitrofluorobenzene (DNFB) to induce an AD model, MLT intervention was applied for 14 days to observe its pharmaceutical effect. Skin lesions were observed using HE staining, toluidine blue staining and electron microscopy. Dermal proinflammatory factor (IL-4 and IL-13) and intestinal barrier indices (ZO1 and Occludin) were assessed by immunohistochemistry and RT-qPCR, respectively. The dysbiotic microbiota was analyzed using 16S rRNA sequencing. RESULTS: MLT significantly improved skin lesion size; inflammatory status (mast cells, IgE, IL-4, and IL-13); and the imbalance of the epidermal microbiota in AD mice. Notably, Staphylococcus aureus is the key bacterium associated with dysbiosis of the epidermal microbiota and may be involved in the fine modulation of mast cells, IL-4, IL-13 and IgE. Correlation analysis between AD and the gut revealed that intestinal dysbiosis occurred earlier than that of the pathological structure in the gut. CONCLUSION: Melatonin reverses DNFB-induced skin damage and epidermal dysbiosis, especially in S. aureus.