A clinically actionable stratification of bullous pemphigoid using a disease activity score reveals a targetable inflammatory endotype

BACKGROUND: Bullous pemphigoid (BP) exhibits significant clinical heterogeneity. The molecular drivers underlying these distinct phenotypes remain poorly understood, hindering the development of precision medicine approaches. OBJECTIVES: To correlate clinical phenotypes, defined by the Bullous Pemphigoid Disease Area Index (BPDAI), with molecular endotypes using serum proteomic profiling. METHODS: This cohort study enrolled 143 hospitalized patients with BP at a tertiary centre between January 2024 and June 2025. Patients were stratified into inflammatory BP (I-BP; BPDAI urticaria/erythema subscore ≥5) and pauci-inflammatory BP (PI-BP; subscore <5) based on the first quartile of the subscore. Clinical features, laboratory parameters, and treatment outcomes were compared. Serum proteomic profiling (Olink Target 96 Inflammation) was performed in a representative subset (n=37). RESULTS: Among 143 patients (mean age 73.9 years; 58.7% male), 108 (75.5%) were classified as I-BP and 35 (24.5%) as PI-BP. Compared to PI-BP, I-BP patients were younger, had more severe pruritus, and exhibited significantly elevated peripheral eosinophil counts (0.6 vs 0.2 ×109/L; P=0.001) and serum IL-5 levels (52.5 vs 3.9 pg/mL; P=0.007). Despite receiving more intensive therapy, I-BP patients required a longer median hospital stay (8 vs 7 days; P=0.029). Proteomic analysis identified eight differentially expressed proteins. IL-13, thymic stromal lymphopoietin (TSLP), oncostatin M (OSM), and MCP-4 were upregulated in I-BP and showed positive correlation with the urticaria/erythema subscore (P<0.05) but not with the erosions/blisters subscore. IL-13 demonstrated the highest diagnostic accuracy for the I-BP endotype (AUC=0.87). Functional enrichment analysis confirmed differential activation of type 2 inflammation and the JAK-STAT signaling pathway in the I-BP group. CONCLUSIONS: The BPDAI urticaria/erythema subscore serves as a reliable clinical surrogate for a Th2-driven molecular endotype in BP. The identification of a specific Th2-ligand/JAK-STAT-signaling circuit in the inflammatory phenotype supports a stratified treatment approach, suggesting that patients with a high inflammatory burden may benefit from targeted type 2 immunotherapies or JAK inhibitors, which warrants further prospective validation.