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

Abstract

Bullous pemphigoid (BP) exhibits significant clinical heterogeneity. The molecular drivers underlying these distinct phenotypes remain poorly understood, hindering the development of precision medicine approaches. To correlate clinical phenotypes, defined by the Bullous Pemphigoid Disease Area Index (BPDAI), with molecular endotypes using serum proteomic profiling. This cohort study enrolled 143 patients with BP hospitalized at a tertiary centre between January 2024 and June 2025. Patients were stratified as having inflammatory BP (I-BP; BPDAI urticaria/erythema subscore ≥ 5) and pauci-inflammatory BP (PI-BP; BPDAI urticaria/erythema 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). Of the 143 enrolled patients [mean (SD) age 73.9 (11.2) years; 84 (58.7%) men], 108 (75.5%) were classified as having I-BP and 35 (24.5%) as having PI-BP. Compared with those with PI-BP, patients with I-BP were younger, had more severe pruritus and had significantly elevated peripheral eosinophil counts (0.6 vs. 0.2 × 109 cells L-1; P = 0.001) and serum interleukin (IL)-5 levels (19.8 vs. 3.9 pg mL-1; P = 0.007). Despite receiving more intensive therapy, patients with I-BP required a longer median hospital stay (8 vs. 7 days; P = 0.03). Proteomic analysis identified eight differentially expressed proteins. IL-13, thymic stromal lymphopoietin, oncostatin M and monocyte chemoattractant protein-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 (area under the curve = 0.87). Functional enrichment analysis confirmed differential activation of type 2 inflammation and the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signalling pathway in the I-BP group. The BPDAI urticaria/erythema subscore serves as a reliable clinical surrogate for a T helper 2 (Th2)-driven molecular endotype in BP. The identification of a specific Th2 ligand-JAK/STAT signalling 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.