Risk Factors for the Development of Bullous Pemphigoid in US Patients Receiving Immune Checkpoint Inhibitors

Question  What risk factors are associated with development of bullous pemphigoid (BP) in patients receiving immune checkpoint inhibitors (ICIs)?

Finding  In this cohort study of 2955 patients treated with ICIs, age 70 years or older or having melanoma or nonmelanoma skin cancer was associated with elevated risk for developing ICI-induced BP.

Meaning  Patients with risk factors for BP development should be counseled and monitored throughout ICI treatment.

Importance  De novo bullous pemphigoid (BP) is a rare immune-mediated adverse event from immune checkpoint inhibitors (ICIs) that can necessitate permanent discontinuation of the anticancer therapy, but the risk factors for developing this toxic effect are unknown.

Objective  To compare potential risk factors for BP in patients treated with ICIs who did and did not develop BP.

Design, Setting, and Participants  This cohort and nested propensity score–matched case-control study was conducted at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Massachusetts General Hospital. All patients at these facilities with de novo BP after ICI treatment were compared with all patients on the cancer registry who were treated with ICIs between October 1, 2014, and December 31, 2020. Patients with incomplete or blinded data regarding the ICI agent or total cycles were excluded.

Exposures  In the cohort, assessed potential risk factors included age at ICI introduction, sex, ICI molecular target, and cancer type, which were then used as matching variables. In the propensity score–matched case-control analysis, risk factors assessed included sex, race and ethnicity, cancer stage, metastasis sites, idiopathic BP comorbidities, pre–ICI vaccination, radiation history, body mass index, and derived neutrophil-to-lymphocyte ratio.

Main Outcomes and Measures  Diagnosis of BP at any point after ICI treatment, confirmed by direct immunofluorescence, indirect immunofluorescence, autoantibody serologies, or diagnostic consensus among study board-certified dermatologists. Odds ratios (ORs) and 95% CIs were calculated for all risk factors. In the secondary analysis, best overall responses to ICIs between cases and controls were compared by Fisher exact test.

Results  Among 5636 patients treated with ICIs at Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Massachusetts General Hospital during the study period, 35 (0.6%; median [IQR] age, 72.8 [13.4] years; 71.4% [25] male patients) developed BP. In a multivariate logistic regression model that assessed 2955 patients with complete data in the cancer registry, age 70 years or older (OR, 2.32; 95% CI, 1.19-4.59; P = .01), having melanoma (OR, 3.21; 95% CI, 1.51-6.58; P < .003), and having nonmelanoma skin cancer (OR, 8.32; 95% CI, 2.81-21.13; P < .001) were significantly associated with developing BP. In the nested 1:2 case-control comparison of all 35 cases to 70 propensity score–matched controls, a complete or partial response on initial restaging imaging was a risk factor for BP development (OR, 3.37; 95% CI, 1.35-9.30; P = .01). Bullous pemphigoid cases also more frequently exhibited overall tumor response to ICIs than matched controls (29 of 35 [82.9%] vs 43 of 70 [61.4%]; P = .03).

Conclusions and Relevance  In this cohort study, age 70 years or older and skin cancer were associated with increased risk of developing ICI-associated BP. Given the association of BP with improved initial and best overall tumor responses, early identification and toxic effect–directed treatment should be prioritized, especially in individuals at risk for developing de novo BP.