Darier disease is a rare autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene encoding for sarcoendoplasmic reticulum Ca²⁺ ATPase isoform 2. The skin disease is characterized by a chronic relapsing course with recurrent reddish‐brown keratotic papules and plaques located mainly in seborrhoeic areas. Due to chronic inflammation and epidermal barrier defects of the skin, patients often develop severe bacterial and viral superinfections. Therapeutic options are limited, mainly symptomatic and in most cases unsatisfactory in the long term. Patients are advised to avoid aggravating factors such as high temperature, high humidity, UV radiation and mechanical irritation. To prevent superinfection, antiseptics and periodic use of topical corticosteroids are fundamental in treatment. In case of bacterial and viral superinfection, systemic anti‐infective therapy is often necessary. Currently, the most effective treatment option for extensive and persistent skin lesions is systemic retinoids, which are thought to mainly target the epidermal compartment (e.g. by reducing hyperkeratosis). One hallmark of Darier disease patients is chronic skin inflammation. We and others have previously reported Th17 cells in the dermal infiltrate of inflamed Darier disease skin. Counteracting inflammation by blocking the IL‐23/IL‐17 axis improved skin manifestations in a small cohort of previously therapy‐resistant patients over 1 year. Furthermore, several other topical treatment options for mild disease as well as various ablative therapies and surgical excision have been proposed to be effective in some patients with hypertrophic skin lesions. This article aims to outline the pathogenesis, clinical features, diagnosis/differential diagnosis and available treatment modalities of Darier disease.

Darier disease (DD) is a rare, inherited multi-organ disorder associated with mutations in the ATP2A2 gene. DD patients often have skin involvement characterized by malodorous, inflamed skin and recurrent, severe infections. Therapeutic options are limited and inadequate for the long-term management of this chronic disease. The aim of this study was to characterize the cutaneous immune infiltrate in DD skin lesions in detail and to identify new therapeutic targets. Using gene and protein expression profiling assays including scRNA sequencing, we demonstrate enhanced expression of Th17-related genes and cytokines and increased numbers of Th17 cells in six DD patients. We provide evidence that targeting the IL-17/IL-23 axis in a case series of three DD patients with monoclonal antibodies is efficacious with significant clinical improvement. As DD is a chronic, relapsing disease, our findings might pave the way toward additional options for the long-term management of skin inflammation in patients with DD.

Dupilumab is the first biological treatment approved for moderate-to-severe atopic dermatitis (AD). Efficacy and safety have been demonstrated in clinical trials, but real-life data is still limited. The objective of this study was to retrospectively evaluate Dupilumab treatment in AD patients in a real-life clinical setting. Effectiveness and safety outcomes were collected at baseline and after 2, 6, 10, 24, 39, and 52 weeks by using clinical scores for disease activity, as well as serological markers. Ninety-four patients from five dermatological hospitals were included. After 24 weeks of treatment, the median Investigator Global Assessment (IGA) and Eczema Area and Severity Index (EASI) showed a significant reduction compared to baseline (3.9 ± 0.7 vs. 1.4 ± 0.8 and 26.5 ± 12.5 vs. 6.4 ± 6.5). Interestingly, we observed rosacea-like folliculitis as an unexpected side effect in 6.4% of patients. Dupilumab proves to be an effective and well-tolerated treatment under real-life conditions. The occurrence of rosacea-like folliculitis warrants further mechanistic investigation.

Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32β–major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients’ skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.