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Introduction: Dupilumab has emerged as a promising treatment option for bullous pemphigoid (BP). Rapid identification of responders could avoid the need for additional immunosuppressive treatments that are associated with increased morbidity and mortality. Methods: To investigate the course of itch as an early indicator of treatment response, data of 12 BP patients treated with dupilumab at the University Hospital of Zurich were retrospectively evaluated. Disease severity was assessed by bullous pemphigoid disease area index (BPDAI) and pruritus by a numeric rating scale (NRS, 0–10) at baseline; days 1, 3, 14; months 1, 2; and the last follow-up. Results: A total of 8/12 patients (67%) had complete response, and 4/12 patients (33%) had partial response during dupilumab treatment. Notably, a highly significant reduction of pruritus (p < 0.0001) was observed already on day 1 with further improvement at later time points. Moreover, fast relief of itch could predict treatment response with a significant correlation to clinical response on day 14 (Spearman correlation R 0.70, p value 0.025), with a positive but non-significant trend on day 3 (R 0.63, p value 0.091). Additionally, 92% (11/12 patients) were on dupilumab monotherapy at the last follow-up without any concomitant systemic or topical treatment for BP. Conclusions: The rapid and significant decline in BP-associated pruritus observed with dupilumab correlated significantly with disease remission. Early evaluation of pruritus response could change how BP is treated in the future and avoid additional immunosuppressive treatment in BP. Plain Language Summary: Bullous pemphigoid is a rare autoimmune skin disease causing bullae and severe itch with a mortality rate of about 20% within the first year. Immunosuppressive medications, such as corticosteroids, are commonly used to treat bullous pemphigoid, but these treatments are associated with many side effects and increased mortality, especially in long-term applications. Dupilumab is an antibody that selectively targets specific immunological drivers of bullous pemphigoid. Recent research poses dupilumab as an emerging non-immunosuppressive option to effectively treat bullous pemphigoid. However, the improvement of itch in relation to the treatment period was not yet thoroughly analyzed. Thus, we aimed to investigate the course of itch. In this study, we assessed changes in itch and disease severity in 12 patients with bullous pemphigoid treated with dupilumab, by using health records collected at the University Hospital of Zurich in Switzerland between June 2022 and April 2023. We found that itch significantly improved on average with a reduction of 47.6% already on day 1, 73.3% on day 3, 71.2% on day 14, 85.1% on day 28, and 89.1% on day 56, as well as 95.6% on the last follow-up. Notably, after 2 months, 67% of patients reported over 90% improvement in itch, compared with itch before dupilumab was started, along with significant improvement in disease severity. In conclusion, our findings indicate that itch reduction is an early indicator of how patients respond to the dupilumab treatment and helps stop concomitant immunosuppressive medications in advance. [ABSTRACT FROM AUTHOR]

Lichen planus (LP) is a highly prevalent inflammatory skin disease. While various clinical subtypes have been defined, detailed comparisons of these variants are lacking. This study aimed to elucidate differences in gene expression and cellular composition across LP subtypes. Lesional skin biopsies from 28 LP patients (classical, oral, genital, and lichen planopilaris) and seven non-diseased skin controls (NDC) were analyzed. Gene expression profiling of 730 inflammation-related genes was conducted using NanoString. Immune cell compositions were assessed by multiplex immunohistochemistry. Gene expression profiles revealed unique inflammatory signatures for each LP subtype. Lichen planopilaris exhibited the most divergence, with downregulated gene expression and upregulation of complement pathway genes (C5-7), along with elevated M2 macrophages. Oral and genital LP demonstrated similar profiles with strong upregulation of TNF-related and Toll-like receptor-associated genes. Oral LP showed the highest upregulation of cytotoxicity-associated genes, as well as high numbers of CD8+ IL-17A+ (Tc17) cells (8.02%). Interferon gene signatures were strongly upregulated in oral and classical LP. The study highlights distinct differences in inflammatory gene expression and cell composition across LP subtypes, emphasizing the need for tailored therapeutic approaches. [ABSTRACT FROM AUTHOR]

Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors in its development, the precise pathogenesis of Martorell HYTILU remains elusive. To reach a better understanding of Martorell HYTILU, transcriptomic analysis was conducted through RNA sequencing and immunohistochemical comparison of Martorell HYTILU (n = 17) with chronic venous ulcers (n = 4) and healthy skin (n = 4). Gene expression analysis showed a marked activation of immune-related pathways in both Martorell HYTILU and chronic venous ulcers compared with healthy skin. Notably, neutrophil activity was substantially higher in Martorell HYTILU. While pathway analysis revealed a mild downregulation of several immune pathways in Martorell HYTILU compared with chronic venous ulcers, keratinization, cornification, and epidermis development were significantly upregulated in Martorell HYTILU. Additionally, STAC2, a gene encoding for a protein promoting the expression of the calcium channel Cav1.1, was significantly upregulated in Martorell HYTILU and was detected perivascularly in situ (Martorell HYTILU n = 24; chronic venous ulcers n = 9, healthy skin n = 11). The high expression of STAC2 in Martorell HYTILU suggests that increased calcium influx plays an important role in the pathogenesis of the disease. Consequently, calcium channel antagonists could be a promising treatment avenue for Martorell HYTILU. [ABSTRACT FROM AUTHOR]

Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life‐threatening cutaneous adverse reactions. There is still no consensus on adjuvant treatments, and little is known about their effects on systemic inflammation in SJS/TEN. Our aim was to characterize the systemic and cutaneous immune profiles of SJS/TEN patients and to investigate whether/how intravenous immunoglobulins (IVIG), cyclosporine A (CSA), and best supportive care only (BSCO) affected the systemic immune signature and clinical outcome (6 week‐mortality, complications, hospitalization stay). Methods: We included 16 patients with SJS/TEN, treated with high‐dose IVIG (n = 8), CSA (n = 4) or BSCO (n = 4). Serial serum samples were obtained prior‐, 5–7 days, and 21 days after treatment onset. Serum levels of inflammation−/immune response‐associated proteins were measured by high‐throughput proteomics assay (OLINK) and cytotoxic molecules by ELISA. RNA extracted from skin biopsies collected prior treatment was analyzed by Nanostring. Results: Serum inflammatory profiles in SJS/TEN patients were notably characterized by massive upregulation of type 1 immune response and proinflammatory markers. Surprisingly, there was limited overlap between cutaneous and serum immune profiles. Serial serological measurements of immune response markers showed very diverse dynamics between the different treatment groups. IVIG‐treated patients showed completely different dynamics and most significant proteomic changes in an early phase (Day 5–7). In all treatment groups, type 1−/inflammatory response markers were dampened at day 21. Clinically, there were no outcome differences. Conclusion: Our study demonstrates that BSCO, CSA, and IVIG have very diverse biological effects on the systemic inflammatory response in SJS/TEN, which may not correlate with clinical outcome differences. [ABSTRACT FROM AUTHOR]

Clinical differential diagnosis of arteriolosclerotic ulcers of Martorell is challenging due to the lack of clearly affirmative instrument-based diagnostic criteria. The aim of this study was to develop vascular histomorphological diagnostic criteria differentiating Martorell ulcers from other types of leg ulcers. The histomorphology of patients diagnosed with arteriolosclerotic ulcers of Martorell (n = 67) was compared with that of patients with venous leg ulcers, necrotizing leukocytoclastic vasculitis, pyoderma gangrenosum, and non-ulcerative controls (n = 15 each). In a multivariable logistic regression model, the rates of arteriolar calcification (odds ratio (OR) 42.71, 95% confidence interval (CI) 7.43-443.96, p < 0.001) and subendothelial hyalinosis (OR 29.28, 95% CI 4.88-278.21, p <0.001) were significantly higher in arteriolosclerotic ulcers of Martorell. Arteriolar cellularity was significantly lower in Martorell ulcers than in controls (OR 0.003, 95 CI < 0.001-0.97, p = 0.05). However, the wall-to-lumen ratio was similar in all ulcers (OR 0.975, 95% CI 0.598-2.04, p =0.929). Based on the Youden index, a wall cellularity of < 0.24 cells/100 µm2 was determined as the optimum cut-off point (sensitivity 0.955, specificity 0.944). Thus, arteriolar calcification, subendothelial hyalinosis, and arteriolar cellularity revealed high discriminatory power for arteriolosclerotic ulcers of Martorell. [ABSTRACT FROM AUTHOR]

Autoinflammatory syndromes are a steadily growing group of inflammatory diseases caused by abnormal regulations of the innate immune system. The clinical presentation is multifaceted, but recurrent fever, skin involvement, joint inflammation and other systemic symptoms of inflammation are characteristic. In contrast to classic autoimmune diseases, autoantibodies or specific T cells are not involved in the pathogenesis. In fact, innate immunity plays the most important role in autoinflammation. While activation of the innate immune system is usually self-limiting in healthy individuals, mutations and dysregulation can lead to chronic and excessive activation of innate immune responses and to the development of autoinflammatory diseases., (© 2021 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Dermatofibrosarcoma protuberans (DFSP) is a rare, infiltrative, soft tissue tumor. It has a propensity for deep invasion but a low risk for distant metastasis. The classic presentation is a slowly progressive, painless, and erythematous to purpuric patch on the trunk or arms. A deep, subcutaneous punch biopsy or incisional biopsy should be performed for diagnosis in all suspected cases; wide undermining of the skin is to be avoided for minimizing the risk of tumor seeding and for retaining the feasibility of histopathologic examination of re-excisions. Histopathologic distinction of DFSP from dermatofibroma requires immunohistochemical assessment for CD34, factor XIIIa, nestin, apolipoprotein D, and cathepsin K. Management of this cutaneous sarcoma involves a multidisciplinary oncologic approach. Surgical excision is usually the first step in management. DFSP has a high propensity for local recurrence, even when surgical margins are negative; therefore, radiation therapy or rarely systemic therapy is recommended, especially for locally advanced or metastatic cases. The indolent nature of DFSP requires lifelong surveillance for recurrence; however, most recurrences occur within 3 years of the primary excision. The median time for the development of a local recurrence is estimated to be 32 months. An emerging theragnostic transmembrane receptor target, folate hydrolase-1 (FOLH1; prostate-specific membrane antigen), has been expressed in benign dermatofibromas and in high-grade sarcomatous phenotypes. These findings suggest that DFSP may also express FOLH1, which could allow for surveillance with FOLH1 PET/CT and antibody-mediated brachytherapy.