Interleukin-4 and -13 Gene Expression Profiles in Immune-Related Bullous Pemphigoid Indicate Efficacy of IL-4/IL-13 Inhibitors

Simple Summary Immune checkpoint inhibitor therapies are effective in treating different types of cancer. However, they also induceimmune-related adverse events, such as immune-related bullous pemphigoid (irBP), a cutaneous autoimmune disease that leads to blistering. To identify the best treatment option for irBP, this multicenter study analyzed gene expression in skin biopsies from patients with irBP to understand the underlying pathomechanism. We found that, similar to the spontaneous form of bullous pemphigoid (BP), interleukin-4 (IL-4) and interleukin-13 (IL-13) were upregulated. Thus, for patients who develop irBP as a side effect of cancer immunotherapy, IL-4 and IL-13 inhibitors such as dupilumab, so far approved to treat atopic dermatitis and prurigo nodularis, appear to be a promising new treatment option.Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70–90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.This research was funded by BMBF Grant MelAutim ‘Systems medicine of melanoma and autoimmunity in the context of immunotherapy’ (01ZX1905E and 01ZX2205E).BMBF Grant MelAutim ‘Systems medicine of melanoma and autoimmunity in the context of immunotherapy

A phase 2b basket trial approach to treat multiple rare and fibrotic skin diseases

Fibrotic skin diseases are rare, chronic, and often debilitating conditions characterized by excessive extracellular matrix deposition, leading to tissue scarring and functional impairment. Despite their severity, diseases—such as lichen sclerosus et atrophicus (LSA), frontal fibrosing alopecia (FFA), radiation-induced skin fibrosis (RISF), eosinophilic fasciitis (EF), pansclerotic disabling morphea (PDM), and linear circumscript sclerodermia (LCS)—lack approved therapies and are underrepresented in clinical research. This phase 2b multicenter basket trial proposes a novel approach to evaluate a common antifibrotic therapy across these diverse but pathophysiologically related conditions. The trial employs a two-stage Simon design to address the statistical challenges posed by small patient populations, allowing the inclusion of ultra-rare diseases while maintaining analytical rigor. LSA and FFA serve as primary study groups due to higher prevalence, while EF, RISF, PDM, and LCS are included as exploratory arms. The study aims to assess the efficacy, safety, and tolerability of the selected therapy, while also providing mechanistic insights into fibrosis through molecular analyses. The primary endpoint is a ≥ 1-point improvement in the Investigator Global Assessment (IGA) at 24 weeks. Secondary endpoints at 52 weeks encompass quality of life (Dermatological Life Quality Index (DLQI), EuroQol Group Quality of Life Questionnaire (EuroQol five dimensions (EQ-5D))), symptom relief (itch and pain Numeric Rating Scale (NRS)), and disease-specific clinical scores. The trial excludes a placebo arm due to ethical considerations in progressive, untreated diseases but allows rescue therapies for disease progression. This design not only facilitates access to treatment for underserved populations but also leverages shared clinical and molecular features to enhance statistical power. By integrating disease-specific and global outcome measures, the study aims to generate robust evidence for repurposing existing therapies. If successful, this trial could serve as a model for future research in rare fibrotic diseases, accelerating drug development and improving patient outcomes

Congenital deficiency reveals critical role of ISG15 in skin homeostasis.

Ulcerating skin lesions are manifestations of human ISG15 deficiency, a type I interferonopathy. However, chronic inflammation may not be their exclusive cause. We describe two siblings with recurrent skin ulcers that healed with scar formation upon corticosteroid treatment. Both had a homozygous nonsense mutation in the ISG15 gene, leading to unstable ISG15 protein lacking the functional domain. We characterized ISG15-/- dermal fibroblasts, HaCaT keratinocytes, and human induced pluripotent stem cell-derived vascular endothelial cells. ISG15-deficient cells exhibited the expected hyperinflammatory phenotype, but also dysregulated expression of molecules critical for connective tissue and epidermis integrity, including reduced collagens and adhesion molecules, but increased matrix metalloproteases. ISG15-/- fibroblasts exhibited elevated ROS levels and reduced ROS scavenger expression. As opposed to hyperinflammation, defective collagen and integrin synthesis was not rescued by conjugation-deficient ISG15. Cell migration was retarded in ISG15-/- fibroblasts and HaCaT keratinocytes, but normalized under ruxolitinib treatment. Desmosome density was reduced in an ISG15-/- 3D epidermis model. Additionally, there were loose architecture and reduced collagen and desmoglein expression, which could be reversed by treatment with ruxolitinib/doxycycline/TGF-β1. These results reveal critical roles of ISG15 in maintaining cell migration and epidermis and connective tissue homeostasis, whereby the latter likely requires its conjugation to yet unidentified targets

Transcriptomic analysis of aggressive meningiomas identifies PTTG1 and LEPR as prognostic biomarkers independent of WHO grade

Meningiomas are frequent central nervous system tumors. Although most meningiomas are benign (WHO grade I) and curable by surgery, WHO grade II and III tumors remain therapeutically challenging due to frequent recurrence. Interestingly, relapse also occurs in some WHO grade I meningiomas. Hence, we investigated the transcriptional features defining aggressive (recurrent, malignantly progressing or WHO grade III) meningiomas in 144 cases. Meningiomas were categorized into non-recurrent (NR), recurrent (R), and tumors undergoing malignant progression (M) in addition to their WHO grade. Unsupervised transcriptomic analysis in 62 meningiomas revealed transcriptional profiles lining up according to WHO grade and clinical subgroup. Notably aggressive subgroups (R+M tumors and WHO grade III) shared a large set of differentially expressed genes (n = 332; p 1.25). In an independent multicenter validation set (n = 82), differential expression of 10 genes between WHO grades was confirmed. Additionally, among WHO grade I tumors differential expression between NR and aggressive R+M tumors was affirmed for PTTG1, AURKB, ECT2, UBE2C and PRC1, while MN1 and LEPR discriminated between NR and R+M WHO grade II tumors. Univariate survival analysis revealed a significant association with progression-free survival for PTTG1, LEPR, MN1, ECT2, PRC1, COX10, UBE2C expression, while multivariate analysis identified a prediction for PTTG1 and LEPR mRNA expression independent of gender, WHO grade and extent of resection. Finally, stainings of PTTG1 and LEPR confirmed malignancy-associated protein expression changes. In conclusion, based on the so far largest study sample of WHO grade III and recurrent meningiomas we report a comprehensive transcriptional landscape and two prognostic markers