SummaryBackgroundBullous pemphigoid (BP) is an autoimmune disease characterized by tense blisters that are usually preceded by urticarial eruptions. Affected patients exhibit IgG and/or IgE autoantibodies against BP180 and/or BP230. Their relative importance in disease pathogenesis has not been fully elucidated.ObjectivesThe aim of this study was to provide a better characterization of the circulating and tissue‐resident IgE in patients with BP at the serological, structural and functional levels.MethodsSera (n = 19) and skin (n = 33) from patients with BP were analysed via enzyme‐linked immunosorbent assay (ELISA) and immunofluorescence, respectively.ResultsThe results obtained show that many patients with BP exhibit elevated IgE levels in the serum and in the skin. In the skin, it is very rarely and only sparsely found along the basement membrane zone, but is prominently present on mast cells and eosinophils. At least a portion of these IgE antibodies are BP‐specific, as evidenced by serum ELISA and by the colocalization of BP180 and FcεRI‐bound IgE on mast cells and/or eosinophils. An important role of these immune reactants can be inferred from our additional finding that cross‐linking of IgE, derived from BP sera, on FcεRI‐expressing rat basophils with BP180 results in robust degranulation of these cells.ConclusionsWe propose the existence of a disease pathway alternative to IgG and complement that may well be responsible for some of the clinical features of this autoimmune disease.

Deposition of autoantibodies (a-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population.