Autoimmune Bullous Disorders Associated With Immune Checkpoint Inhibitors

BACKGROUNDImmune checkpoint inhibitors (ICIs) directed against PD-1, PD-L1, and CTLA-4 augment antitumor immune responses but may also induce unintended immune activation, resulting in immune-related adverse events (irAEs). Cutaneous manifestations of irAEs are among the most common, ranging from mild eruptions to severe autoimmune blistering disorders (AIBDs). Although bullous pemphigoid (BP) is the most reported ICI-related autoimmune bullous disorder (irAIBD), data on the spectrum, and management of other ICI-associated AIBDs remain limited. Understanding these reactions is crucial to managing treatment interruptions and influencing oncologic outcomes.

OBJECTIVEThis study aims to comprehensively characterize ICI-associated irAIBDs by examining demographics, clinical presentation, disease severity, therapeutic approaches, treatment responses, clinical outcomes, and mortality.

METHODSA single-institution retrospective chart review was conducted, using a text-based database search from 2011-2023. Adult patients (≥18 years) with biopsy-confirmed AIBDs attributed to ICIs were included. Demographic, oncologic, and immunotherapy details, as well as clinical, histopathologic, and immunofluorescence characteristics of AIBDs, were reviewed. Treatment approaches, outcomes, and mortality data were analyzed.

RESULTSForty-four patients with irAIBDs were identified, predominantly representing males (29, 65.9%) with a mean age of 70.4 years (range: 62-80 years). Lung carcinoma (12, 27.2%) and melanoma (9, 20.4%) were the most frequent underlying malignancies, and pembrolizumab (25, 56.8%) was the most common agent. Bullous pemphigoid (BP) accounted for most cases (36, 81.8%), followed by lichen planus pemphigoides (LPP) (6, 13.6%), with one case each of mucous membrane pemphigoid (MMP) and linear IgA bullous dermatosis (LABD). Pruritus was reported in most (42, 9%) patients, and upper (36, 81.8%), lower (32, 72.2%) extremities and the chest (34, 77.2%) were most often involved. Eosinophilic infiltration was present in most (23, 81.8%) of BP cases, and linear IgG and C3 deposition were the predominant immunofluorescence patterns in BP. Most patients received topical (34, 77.2%) and/or systemic corticosteroids (32, 72.7%), while 16 required at least temporary ICI discontinuation. Four BP (4, 9.1%) patients were treated with dupilumab. Other systemic agents used included doxycycline (22, 50%), intravenous immunoglobulin (IVIG) (5, 11.3%), rituximab (6, 13.6%), dapsone (1, 2.2%), mycophenolate mofetil (1, 2.2%), methotrexate (1, 2.2%), and colchicine (1, 2.2%). Three cases with Grade 3 severity necessitated permanent ICI discontinuation. Clinical stabilization (24, 54.5%) or remission of the irAIBD (16, 36.3%) was achieved in most cases. One death (2.2%) was attributed to sepsis in a patient with severe irAIBD.

CONCLUSIONICI-associated AIBDs are uncommon but clinically significant complications. Most patients in our cohort continued ICI therapy during management of their irAIBD, while others required temporary or permanent interruption. These findings highlight the importance of prompt recognition and multidisciplinary management of these uncommon toxicities.

Abstract from PubMed