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

Abstract

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 PARTICIPANTSThis 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. EXPOSURESIn 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 MEASURESDiagnosis 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 RELEVANCEIn 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 treat...

Cutaneous immune‐related adverse events from immune checkpoint inhibitor therapy: Moving beyond “maculopapular rash”

“…The association of BP with response was confirmed on a larger cohort of 35 patients, where risk factors for disease development were also studied using a multivariate logistic regression model. 16 Risk factors for the development of ICI-BP included age > 70 (OR, 2.32; 95% CI, 1.19-4.59, p = 0.01); skin cancer, specifically nonmelanoma skin cancer (OR, 8.32; 95% CI, 2.81-21.13, p < 0.01) and melanoma (OR, 3.21; 95% CI, 1.51-6.58, p < 0.01), and initial response to ICI on first imaging (OR, 3.37; 95% CI, 1.35-9.30, p = 0.01).…”

Hemidesmosomal Reactivity and Treatment Recommendations in Immune Checkpoint Inhibitor-Induced Bullous Pemphigoid—A Retrospective, Monocentric Study

“…In some cases, irAEs mimic features of classic autoimmune disorders (11). ICI-induced bullous pemphigoid (ICI-BP), which seems to be immunopathologically indistinguishable from sporadic BP, was found in around 0.6% of 5,636 patients treated for nonmelanoma skin cancer (NMSC) or melanoma (12) and in up to 3.8% of 358 patients, who had cutaneous irAE during ICI treatment for melanoma (in total 2,459 patients) (13). Risk factors for BP were age above 70 years and early anti-tumour response (12).…”

“…ICI-induced bullous pemphigoid (ICI-BP), which seems to be immunopathologically indistinguishable from sporadic BP, was found in around 0.6% of 5,636 patients treated for nonmelanoma skin cancer (NMSC) or melanoma (12) and in up to 3.8% of 358 patients, who had cutaneous irAE during ICI treatment for melanoma (in total 2,459 patients) (13). Risk factors for BP were age above 70 years and early anti-tumour response (12). Depending on the disease severity of ICI-BP, sometimes there is the necessity for discontinuation of cancer treatment and additional systemic immunosuppression (14).…”

A 72-year-old man with nonhealing facial erosions and bullae

“…Based on a recent propensity score-matched case-control study, age greater than 70 years at the time of receiving first immune checkpoint inhibitor cycle, history of melanoma, and history of nonmelanoma skin cancers are all associated with increased risk of developing BP among a cohort of patients treated with ICIs. 2 Radiotherapy is also an independent risk factor for BP. 3 While the underlying pathophysiology is unknown, it has been hypothesized that radiotherapy causes tissue damage, leading to increased antigen exposure and increased autoantibody production.…”

“…All of the above listed answer choices are risk factors for BP. Based on a recent propensity score-matched case-control study, age greater than 70 years at the time of receiving first immune checkpoint inhibitor cycle, history of melanoma, and history of nonmelanoma skin cancers are all associated with increased risk of developing BP among a cohort of patients treated with ICIs 2.…”