[Multilocular pyoderma gangrenosum : Association with primary manifestation of primary biliary cholangitis]. / Multilokuläres Pyoderma gangraenosum : Assoziation mit der Erstmanifestation einer primär biliären Cholangitis.

A 16-year-old female patient with previously diagnosed acne vulgaris was transferred to our clinic in reduced general condition with rapidly progressive and extremely painful ulcerations. In the laboratory exam, inflammatory parameters were highly elevated, but she was normothermic. Based on the findings, we diagnosed multilocular pyoderma gangrenosum. Further investigations established the diagnosis of primary biliary cholangitis as the underlying condition. Treatment with systemic corticosteroids was initiated and we started therapy with ursodeoxycholic acid. This led to improvement within a few days. PAPA-syndrome (pyogenic arthritis, pyoderma gangrenosum and acne vulgaris) could be ruled out by genetic analysis.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions.

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

Indurated erythema of abdominal skin: An unusual presentation of metastatic endometrial carcinoma-Case report with literature review.

Carcinoma erysipelatoides (CE) is a rare clinical manifestation of cutaneous metastasis, which mimics inflammatory conditions such as erysipelas. Depending on the site of the originating tumour, unusual manifestations involving different sites of the body may occur. We herein report a case of a 60-year-old female patient with metastatic endometrial carcinoma presenting as CE of the abdominal skin and the inguinal folds. Even though the diagnosis of advanced malignancy had been established before and she was currently receiving chemotherapy (carboplatin and paclitaxel), the clinical appearance closely resembled fungal (candidal intertrigo) and consecutively bacterial (erysipelas) infection, which resulted in treatment with antimycotics and antibiotics at first. Dermatohistopathological examination of skin biopsies revealed a diffuse and nodular infiltrate of pleomorphic atypical tumour cells with strong expression of cytokeratin 7 and PAX8, also detectable within lymphatic vessels. Therapy comprised antiseptic ointments to prevent superinfection, palliative electron beam radiation and supportive care. Since there were no targetable KRAS-, NRAS- and BRAF-gene mutations, systemic therapy was switched to checkpoint inhibition (pembrolizumab) in combination with lenvatinib. The overall prognosis of cutaneous metastasis of endometrial carcinoma is dismal with most patients succumbing to disease within few months. Similarly, our patient died after 3 months due to sepsis in the course of malignant pleural effusion. We aim to highlight the possibility of unusual sites of CE and the risk of respective clinical misdiagnoses.

Degree of Actinic Elastosis Is a Surrogate of Exposure to Chronic Ultraviolet Radiation and Correlates More Strongly with Cutaneous Squamous Cell Carcinoma than Basal Cell Carcinoma.

(1) Background: Keratinocyte cancer (KC) is associated with exposure to ultraviolet (UV) radiation. However, data are controversial as to whether chronic UV exposure or high intermittent UV exposure are key drivers of carcinogenesis in cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC). Prolonged sun exposure of the skin causes photo-aging, which is associated with actinic elastosis, a condition characterized by the degeneration of elastin in the upper dermis, which is assessable via conventional histology. In this study, we aimed to compare the degree of actinic elastosis in different types of KC with regard to various patient characteristics. (2) Methods: We defined a semiquantitative score for the degree of actinic elastosis ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration). The extent was measured histometrically by two independent dermatohistopathologists in the immediate vicinity of 353 KC. The scores were merged and matched with tumor types (cSCC and BCC with subtypes), and clinical variables such as body site, sex and age. (3) Results: As expected, the degree of actinic elastosis correlated with age. However, it was significantly higher in cSCC compared to BCC irrespective of age, sex, body site and tumor subtypes. (4): Conclusions: Lifetime sun exposure may be estimated via routine histology using this scoring technique for actinic elastosis as a surrogate marker. cSCCs are more strongly associated with chronic UV exposure than BCCs, even in sun-exposed localizations such as the face.

Sustainability of dermatological offices and clinics: challenges and potential solutions.

Ongoing high consumption of resources results in exceeding the planetary boundaries. Modern healthcare systems contribute to this problem. To address this issue, this article provides an overview of various aspects of sustainable actions in medical offices and clinics that can also be applied to dermatology. Specific fields of action include energy consumption, structural measures, traffic and mobility, organization including digitalization as well as personnel and evaluation. Moreover, we discuss specific topics such as hygiene and cleansing, dermatosurgery and prescription practices. External treatments and cosmetics are discussed separately as dermatological peculiarities. Finally, we provide information on established initiatives for more sustainable health care in Germany. We aim to encourage critical reappraisal of currently established practices and to stimulate the implementation of sustainable measures.

[Aspects of sustainability of topical therapy]. / Aspekte der Nachhaltigkeit in der topischen Therapie.

BACKGROUND: Topical compounds are an important treatment option in dermatology. Many ingredients and packaging do not yet sufficiently fulfill sustainable criteria. OBJECTIVES: This article aims to provide a compact overview of sustainability criteria of topical compounds and packaging. MATERIALS AND METHODS: Based on a selective literature search and personal experience, common ingredients and packaging of topical preparations are summarized. RESULTS: Topical preparations often contain mineral oils, acrylates, silicones and polyethylene glycols (PEG), which show poor biodegradability and may accumulate in the environment. As an alternative to these non-renewable substances, plant-based fats, oils, and waxes can be used. Biopolymers such as plant-based gum, agar-agar, pectin, and biologically produced hyaluronic acid are an alternative to plastic polymers. The environmental footprint of glass as packaging material is overestimated. Currently, plastics and aluminum may be preferable when recycled correctly. CONCLUSION: The production of topical formulations without using mineral oils, silicones, acrylates, and PEGs is technically challenging. A sustainable packaging material that fulfills all relevant functionalities is not yet available. Packaging should meet high requirements regarding ecological, economic, and social factors. Better performance with respect to new opportunities in recycling and waste management should be incorporated. Overall, the legislative authorities should provide relevant incentives for more sustainable topical compounds and packaging.

[Microplastic and dermatological care]. / Mikroplastik und dermatologische Versorgung.

BACKGROUND: Synthetic polymers (plastics) from fossil resources are produced in large quantities and reach the environment as microplastics due to improper disposal and via various entry routes. This may lead to implications on flora, fauna, and humans. OBJECTIVES: This article aims to provide a concise overview for dermatologists about this complex topic and how it relates to daily medical practice. MATERIALS AND METHODS: We performed a selective literature review regarding microplastics and sustainability in dermatology in liaison with the collaborative research center on microplastics at the University of Bayreuth. RESULTS: Primary and secondary microplastics are released into the environment on a large scale and accumulate in aquatic and terrestrial ecosystems. This may lead to their disruption and bears potential to create ecological niches for human pathogenic species. Humans and animals inhale and ingest microplastics, and the health consequences have not been sufficiently investigated. This is mainly because microplastics are not a homogenous group of substances, and potential effects depend on various properties (e.g., type of polymer, size, shape, additivation, surface charge). Dermatological care is resource intensive and contributes in various ways to this matter. CONCLUSION: Plastics are currently indispensable in many fields. Nevertheless, physicians have the responsibility to prevent negative consequences for the health of society (precautionary principle). Extensive efforts are thus necessary for better sustainability; this includes medical care.

[Sustainable transformation of practices and outpatient clinics]. / Nachhaltige Transformation von Praxen und Ambulanzen.

BACKGROUND: Climate change as a consequence of anthropogenic greenhouse gas emissions (CO2e) favors weather extremes. This challenges the healthcare system to cope with negative consequences and to remain functional at the same time. Despite rising costs and shortage of staff, sick people in an aging society must be increasingly cared for in a resource-efficient and climate-neutral manner without compromising the quality of care. AIM: This article summarizes current challenges for practices and outpatient clinics due to climate change and societal transformation. In addition, steps to implement transformative interventions are discussed. MATERIALS AND METHODS: Selective literature review in PubMed database was conducted on the impact of climate change on the healthcare system, crisis resilience, climate management, overprescription, and co-benefits. RESULTS: Crisis-resilient practices are attuned to challenges resulting from climate change. Communicating co-benefits in the physician-patient conversation can accelerate the transformation to a sustainable society. CONCLUSION: Rapidly changing environmental conditions require adaptation on the part of the healthcare system. Education and prevention are key to meet this challenge. Transformation to sustainable practices is an ongoing process and it represents a holistic concept that encompasses social, environmental, and economic aspects, which are interdependent and cannot be considered separately.

Subtypes of Melanomas Associated with Different Degrees of Actinic Elastosis in Conventional Histology, Irrespective of Age and Body Site, Suggesting Chronic Ultraviolet Light Exposure as Driver for Lentigo Maligna Melanoma and Nodular Melanoma.

(1) Background: Ultraviolet (UV) radiation and sunburns are associated with an increased incidence of acquired nevi and melanomas. However, the data are controversial as to whether chronic UV exposure or high intermittent UV exposure is the major carcinogenic factor in melanocytic tumors. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure in nevi and different clinical melanoma subtypes (i.e., superficial spreading melanoma (SSM), nodular malignant melanoma (NMM), acral lentiginous melanoma (ALM), and lentigo maligna melanoma (LMM)) with respect to clinical variables (age, sex, and body site). (2) Methods: We defined a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 595 melanocytic lesions from 559 patients with their clinical variables. (3) Results: The TEG was correlated with age and UV-exposed body sites. Furthermore, the TEG was significantly higher in LMM than in all other types of melanomas and the TEG in NMM was higher than in SSM, irrespective of patient age and tumor site. (4) Conclusions: High cumulative UV exposure is more strongly associated with LMM and NMM than with other melanoma subtypes.

Characterization of B cells in lupus erythematosus skin biopsies in the context of different immune cell infiltration patterns.

Cutaneous lesions in lupus erythematosus (LE) subtypes are heterogenous. In line with the heterogeneity of the clinical presentation, the underlying lesional inflammation in LE skin samples is defined by different immune cell infiltrates. Pathophysiologically, lesional inflammation is driven by autoreactive cytotoxic T cells, targeting keratinocytes; plasmacytoid dendritic cells (pDCs), producing large amounts of interferon (IFN); and B cells, whose function in cutaneous LE is still unclear. This study aims to (a) classify inflammatory patterns with regard to the dominating cell type or cytokine expression and (b) investigating the specific role of B cells in LE skin lesions. Therefore, the immunohistological expression of inflammatory surrogates (CD20, CD123, MXA) in skin samples of n = 119 LE (subtypes: subacute cutaneous LE, chronic discoid LE, chilblain LE, LE tumidus, other LE) and n = 17 patients with inflammatory skin diseases (atopic dermatitis, psoriasis) were assessed. Samples were classified with regard to inflammatory groups. In addition multiplex-immunohistochemical analyses of n = 17 LE skin samples focusing on lesional B cells were conducted. In this study, we show that cutaneous lesions present with eight different inflammatory groups dominated by B cells, pDCs, a strong IFN expression, or overlapping patterns. Altogether, LE subtypes show heterogenous infiltration regardless of LE subtype, certain subtypes display a preference for infiltration groups. Furthermore, lesional B cells either form diffuse infiltrates or pseudofollicular structures, wherein they show antigen-presenting and T cell-activating properties. Altogether, in the light of emerging targeted therapeutic options, we suggest histological assessment in regard to B-cell or pDC preponderance to allow tailored treatment decisions.

DNA methylation regulates TIGIT expression within the melanoma microenvironment, is prognostic for overall survival, and predicts progression-free survival in patients treated with anti-PD-1 immunotherapy.

BACKGROUND: TIGIT is an immune checkpoint under investigation as therapeutic target. Understanding the regulation of TIGIT on an epigenetic level might support the development of companion biomarkers. METHODS: We correlated TIGIT DNA methylation of single CpG sites with gene expression, signatures of immune infiltrates and interferon-γ, and survival in melanoma. We further analyzed methylation levels in immune cell subsets, melanocyte and melanoma cell lines. TIGIT expression patterns within components of the melanoma microenvironment were analyzed by single cell sequencing. We used quantitative methylation-specific PCR, flow cytometry, and immunohistochemistry for correlations between expression and methylation and to assess the effect of pharmacological demethylation of melanoma cells treated with 5-aza-2-deoxycytidine (decitabine). Finally, we investigated the association of patients' survival with TIGIT mRNA and methylation. RESULTS: Depending on the sequence context of the analyzed CpG site, we found a cell type-specific TIGIT gene locus methylation pattern and significant correlations of TIGIT methylation with mRNA expression, an interferon γ signature, and distinct immune cell infiltrates, including TIGIT+ lymphocytes. We detected a melanoma cell-intrinsic TIGIT protein expression. Pharmacological demethylation of the A375 melanoma cell line led to a constitutive TIGIT expression. Low promoter flank methylation and high mRNA expression was associated with patients' prognosis and predicted progression-free survival in patients treated with anti-PD-1 immunotherapy. A high TIGIT+ lymphocyte score was associated with better progression-free survival under anti-PD-1 immunotherapy. CONCLUSIONS: Our data demonstrate an epigenetic regulation of TIGIT expression via DNA methylation within the melanoma microenvironment. TIGIT DNA methylation and expression may serve as predictive biomarkers in the context of immunotherapies in melanoma.

Bullous Pemphigoid in Patients Receiving Immune-Checkpoint Inhibitors and Psoriatic Patients-Focus on Clinical and Histopathological Variation.

BACKGROUND: The most common autoimmune blistering disease, bullous pemphigoid (BP), shows an increased prevalence in psoriatic patients and oncologic patients undergoing immune-checkpoint blockade (ICB). Even though the same autoantigens (BP180/BP230) are detectable, it remains obscure whether clinical or histopathological differences exist between these different groups of BP patients. In this study, we strived to analyze this matter based on own data and previously published reports. METHODS: We performed an institutional chart review from 2010-2020 to identify BP patients with psoriasis (n = 6) or underlying ICB (n = 4) and matched them with idiopathic cases of BP (n = 33). We compared clinical characteristics, subtypes, and dermatopathological determinants (e.g., tissue eosinophilia/neutrophilia, papillary edema, lymphocytic infiltration) among the groups. RESULTS: ICB-associated BP affects men more often and might show mucosal involvement more frequently. We found no statistically significant dermatopathological differences among the groups. CONCLUSIONS: Clinicians should be aware of an increased risk of BP in patients with psoriasis and oncologic patients receiving ICB; atypical pruritic skin lesions should prompt a workup including a skin biopsy for histopathology and direct immunofluorescence in these patients. Larger studies might be necessary to detect slight dermatopathological variation.

Annular plaques mimicking Rowell's syndrome in the course of coronavirus disease 2019 mRNA vaccines: An overlooked phenomenon?

Effective vaccines for prevention of severe course and lethal outcome of coronavirus disease 2019 have been developed and approved in regulatory rolling and fast-track procedures; they are now widely distributed worldwide. Data about cutaneous side-effects of the new mRNA-type vaccines is scant, however. We herein report two similar cases of cutaneous adverse drug reactions (ADR) mimicking Rowell's syndrome that occurred after the first dose of BNT162b2 and mRNA-1273, respectively. Both patients achieved prompt clinical improvement with a short pulse of oral prednisolone and non-steroidal inflammatory drugs. We suspect this phenomenon to occur in a timeframe of 7-14 days after vaccination due to an interferon-γ-driven shift towards type I immunity in susceptible individuals. As rheumatic patients were excluded from phase III clinical trials and as most countries prioritized the elderly population to receive the vaccinations first, cutaneous ADR might become more frequent once the younger part of the population is vaccinated over the course of 2021. Atypical cutaneous ADR might be misinterpreted or overlooked by non-dermatologists. Further studies are required to determine the best suitable vaccine types for individual groups of patients.

Targeted Therapies in Autoimmune Skin Diseases.

Unlike the established anti-inflammatory drugs with a broad range, new-targeted therapeutic approaches have emerged in the management of autoimmune skin diseases to increase efficacy and decrease adverse reactions on the basis of an improved molecular understanding of pathogenesis. Most inflammatory dermatoses are driven by misled immune responses physiologically directed at exogenous pathogens, that is, type 1 immunity against viral pathogens, type 2 immunity against parasites, and type 3 immunity against fungi and bacteria. Pathogenic hallmarks of these major immune reaction patterns are characterized within this article, and a comprehensive overview of current clinical trials evaluating targeted therapeutics for respective dermatoses is outlined.

The Initial Stage of Neutrophilic Dermatosis of the Dorsal Hands: A Case Report and Discussion of Differential Diagnoses.

Neutrophilic dermatosis of the dorsal hands (NDDH) is considered a localized variant of acute febrile neutrophilic dermatosis. It is a rare condition and presents with erythematous tender nodules and plaques on the extensor sides of the hands. Forty percent of NDDH cases occur in association with an underlying disease, with hematologic disorders being the most frequent type. Here, we describe the case of a 77-year-old male patient who presented with acute tumid, erythematous lesions of the fingers. As part of this report, we discuss possible differential diagnoses of NDDH and seek to raise awareness of this rare condition, as misdiagnoses often lead to a delay in adequate treatment and thus more dramatic disease courses.

Single-Center Clinico-Pathological Case Study of 19 Patients with Cutaneous Adverse Reactions Following COVID-19 Vaccines.

(1) Background: Coronavirus disease 2019 (COVID-19) vaccines are currently employed on a population-wide scale in most countries worldwide. Data about unusual cutaneous adverse drug reactions (ADR) are scant, though. (2) Methods: We retrospectively analyzed moderate to severe vaccine-related ADR in the Department of Dermatology and Allergy of the University Hospital Bonn between May to June 2021 and analyzed related skin biopsies. (3) Results: As a specialized dermatological academic center, we encountered a total of n = 19 clinically and pathologically heterogeneous cutaneous ADR with a female predominance. Delayed cutaneous ADR occurred as late as 30 days after vaccination. The majority of ADR were mild, though a few patients required systemic treatment (antihistamines, glucocorticosteroids). (4) Conclusions: The clinico-pathological spectrum of cutaneous side effects with COVID-19 vaccines is wide; however, the benefits outweigh the risks by far. More dermatopathological studies on cutaneous ADR not limited to COVID-19 vaccines are desirable to enable a better understanding of underlying pathophysiological mechanisms.