Linagliptin is a risk factor for bullous pemphigoid associated with BP180-NC16A/BP230 seronegativity and milder severity: Evidence from a prospective case-control study supporting ECD-BP180 enzyme-linked immunosorbent assay in reducing diagnostic delay.

Abstract

Despite the established association between gliptins and bullous pemphigoid (BP), knowledge of BP risk and its clinical and immunological phenotypes among individual gliptins remains fragmentary. To estimate BP risk among different gliptins, compare the demographic, clinical, and immunological profiles of idiopathic and patients with bullous pemphigoid and gliptin-treated type 2 diabetes (BPT2D-G), and evaluate the diagnostic performance of a BP180-ectodomain enzyme-linked immunosorbent assay. Patients with BP and/or type 2 diabetes who visited 2 Italian hospitals during 2019 to 2023 were prospectively enrolled and clinically/immunologically characterized in a case-control study using in-house enzyme-linked immunosorbent assays detecting reactivity to BP180 extracellular epitopes. Overall, gliptin exposure demonstrated a strong association with BP, whereas sitagliptin did not exhibit a comparable effect. BPT2D-G showed a distinctive humoral profile, with high reactivity to other epitopes beyond BP180-noncollagenous 16A domain. A subset of patients, mainly exposed to linagliptin and BP180-noncollagenous 16A domain/BP230 negative, presented milder, often noninflammatory disease: a BP180-ectodomain assay improved diagnostic performances in these patients. Potential residual confounding; limited generalizability; limited data on gliptin exposure duration. The observational design precludes causal inference. Different BP risks among gliptins may inform therapeutic choices, favoring sitagliptin in elderly patients. Personalized management of patients with BP180-noncollagenous 16A domain/BP230-negative BPT2D-G may reduce unnecessary use of high-potency topical and systemic corticosteroids. BP180-ectodomain-based diagnostic assays may facilitate BPT2D-G diagnosis.