Retrospective Analysis of Checkpoint Inhibitor Therapy-Associated Cases of Bullous Pemphigoid From Six German Dermatology Centers

Abstract

Immune-related adverse events (irAEs) are a class-effect of checkpoint inhibitors (CIs). The development of a Bullous pemphigoid (BP)-like blistering disease, driven by autoantibodies against the hemidesmosomal protein BP180, is a potentially serious irAE whose incidence seems to be increasing. We therefore set out to characterize the clinical and (immuno)histopathological features and treatment responses of cases of BP which developed during or after CI therapy collated in six German tertiary referral centers between 2014 and 2018. We identified twelve cases of BP which emerged during and/or after CI therapy. The time interval between the initiation of CI therapy and the diagnosis of BP was 3-74 weeks (median: 23 weeks). Age at the time of diagnosis of BP varied between 62 and 80 years (median: 76 years). The clinical presentation of the patients was diverse but the severity was relatively mild when compared to that seen in most cases of spontaneous BP. Only four patients met all of the immunopathological criteria recommended in the European guidelines for the diagnosis of BP. Topical corticosteroid treatment was sufficient to achieve disease control in most patients. CI therapy could be continued in 8 out of 12 patients. In summary, our study indicates that cases of BP during or after CI therapy bear several peculiarities distinguishing them from spontaneous BP. Given the diversity of the clinical presentation of CI-induced BP the application of existing diagnostic algorithms developed for spontaneous BP can be utilized to uncover the frequency and features of CI-induced BP and to develop and optimize management algorithms.

Keywords: PD-1 - PD-L1 axis; autoantibodies; autoimmunity; checkpoint inhibitors; ipilimumab; nivolumab; pembrolizumab; pemphigoid disease.

Figure 1

Distribution of age and latency after the initiation of CI therapy to the diagnosis of bullous pemphigoid (BP). (A) Age of patients at the diagnosis of BP. (B) Time interval in weeks between the initiation of CI therapy and the diagnosis of BP. Results are presented as violin plot. Each dot represents one patient (n = 12). The red dashed line represents the median, the red dotted lines the 25 and 75% percentiles.

Figure 2

Examples of clinical manifestations of cases diagnosed as bullous pemphigoid (BP) under CI therapy. (A) Patient presenting with erythematous urticaria and tense blisters and erosions scattered over larger areas of the body, typical for classical BP. Patients presenting with (B) a single blister and (C) a single blister and erythematous urticaria. (D) Eczematous skin changes. (E) Oral mucosal erosions.