Inflammatory signatures in bullous pemphigoid‐approaching precision medicine?

Bullous pemphigoid (BP), an autoimmune subepidermal blistering disease of primarily the elderly, exhibits a number of different clinical presentations ranging from erythematous eczema-like to tense blistering due to autoantibody binding at the dermal-epidermal junction. Treatment is mainly based on super-potent topical steroids or immunosuppressive treatment exhibiting a number of partially severe side effects in this fragile population.1 The current understanding of BP pathogenesis includes a predominant Th2 inflammation. In this issue, Calabrese et al.2 present their work on proteome-based clustering of BP patients based on their inflammatory pattern through analysis of paired skin and serum samples. This approach allows insights in both systemic as well as local inflammatory profiles and increases the understanding of the complex mechanisms contributing to disease. The authors identified chemokine C-C-motif ligand (CCL)13, not only to correlate with disease severity and serum autoantibody titres but also to function as a segregation marker within BP patients with regard to their inflammatory profile. This included a prominent expression of IL-13 over IL-4 and IL-5, with IL-13 levels correlating with anti-BP180 and anti-BP230 autoantibody titres but not with disease activity. Their work supplements recent findings, which highlight the IL-13/IL-13RA1 interactions as a significant player in lesional skin of BP. The Th2 cells are reported as the main source of IL-13, their interplay with fibroblasts as well as dendritic cells expressing IL-13 RA leading to amplification of the Th2 inflammatory cascade including CCL17 upregulation in myeloid cells.3 The latter were found to correlate with anti-BP180 NC16A autoantibody levels and Bullous Pemphigoid Disease Area Index. Inhibition of the IL-13/IL-4 axis with dupilumab has been proposed as a therapeutic option in BP, as several case series showed promising results and recent data from the LIBERTY-BP ADEPT phase 2/3 study find dupilumab efficient in reaching sustained remission in 18.3% of patients at 36 weeks, as presented at the 2025 American Academy of Dermatology Annual Meeting (Florida), which recently led to its licensing for the treatment of BP by the US Food and Drug Administration, highlighting the importance of Th2-driven pathogenesis in BP. On the other hand, IL-17 signalling has been proposed as a mode of action in BP development as IL-17 positive cells are upregulated in BP skin and IL-17 levels are upregulated in serum of BP patients. In line, this study found CCL20 as one of the Th17-associated chemokines elevated in BP skin as confirmed by publicly available scRNA seq data. This may argue for a contributor's role of the IL-17 pathway. Accordingly, anti-IL-17 treatments have shown some benefit in BP, but overall reports remain inconclusive and warrant further investigations.4, 5 The results of this study include the identification of two independent clusters of patients, one showing a decreased, the other a higher inflammatory proteome constellation with enriched Th2 signature and eosinophil/neutrophil-related markers. The more inflammatory cluster showed significantly higher anti-BP180 autoantibody titres. Disentanglement of distinct subtypes of BP by either clinical presentation, autoantibody profile and cytokine milieu is challenging. The presented findings add another piece to the puzzle in the understanding of the complex interplay between cell types as well as chemo- and cytokines in the pathogenesis of BP. Combining the findings of recent studies into a comprehensive profiling of the inflammatory signature will contribute to the classification of BP endotypes. Patient inflammatory profiles may enter routine diagnostics, shaping an environment for guided treatment decisions, preventive matters and more precise prognosis in the future, directing clinical practice a step closer towards precision medicine. NvB has received honoraria from Fresenius medical care, support for attending meetings and/or travel from Euroimmun and she is an inventor in a patent of the University of Lübeck together with Euroimmun. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.