The immunophenotype of immune checkpoint-induced bullous pemphigoid: a cohort study

Immune checkpoint inhibitors (ICIs) are increasingly used in cancer therapy and have been linked to adverse dermatologic effects, including bullous pemphigoid (BP), which may necessitate treatment interruption. This study aims to characterize the immunologic profile of ICI-induced BP (BPICI) and identify associated autoantibodies. We conducted a retrospective cohort study (2015-2022) at Rambam Health Care Campus, including patients aged ≥ 18 years who received anti-PD-1/PD-L1 therapy and developed BP. Controls included (1) patients with non-BP cutaneous adverse events (NBPICI), (2) ICI-treated patients without cutaneous immune-related adverse events (irAEs) (NirAEICI), and (3) BP patients not treated with ICIs (BPNICI). Sera were analyzed via ELISA for BP180NC16A, BP230, Dsg1, Dsg3, and collagen VII autoantibodies. Of 242 patients with cutaneous irAEs, 16 patients were diagnosed with BP (BPICI group), and 11 patients had sera available for analysis. ELISA detected BP180NC16A antibodies in 81.8% of BPICI cases, while other autoantibodies were negative in all but one case. BPICI patients were significantly older (p < 0.05), more often male (p = 0.0066), and predominantly had cutaneous squamous cell carcinoma (SCC, 43.8%). Patients with SCC had a significantly increased hazard ratio (HR 9.41, 95% confidence interval (CI) 3.43-25.77) for BP development. BP onset occurred later in BPICI (mean 61.3 weeks) than in other irAEs (mean 32.2 weeks), but latency did not differ according to cancer type. BPICI patients required higher average daily prednisone doses per kilogram body weight during the first six months compared to BPNICI (p < 0.05). Most patients (66.6%) permanently discontinued ICI therapy due to BP. Our findings suggest that ICI-induced BP shares a similar immunologic profile with classic BP, without evidence of antigen spreading, and that SCC patients are at greater risk.