Autoimmune bullous dermatoses in cancer patients treated by immunotherapy: a literature review and Italian multicentric experience

Abstract

Cutaneous immune-related adverse events are frequently associated with immune checkpoint inhibitors (ICIs) administration in cancer patients. In fact, these monoclonal antibodies bind the cytotoxic T-lymphocyte antigen-4 and programmed cell death-1/ligand 1 leading to a non-specific activation of the immune system against both tumoral cells and self-antigens. The skin is the most frequently affected organ system appearing involved especially by inflammatory manifestations such as maculopapular, lichenoid, psoriatic, and eczematous eruptions. Although less common, ICI-induced autoimmune blistering diseases have also been reported, with an estimated overall incidence of less than 5%. Bullous pemphigoid-like eruption is the predominant phenotype, while lichen planus pemphigoides, pemphigus vulgaris, and mucous membrane pemphigoid have been described anecdotally. Overall, they have a wide range of clinical presentations and often overlap with each other leading to a delayed diagnosis. Achieving adequate control of skin toxicity in these cases often requires immunosuppressive systemic therapies and/or interruption of ICI treatment, presenting a therapeutic challenge in the context of cancer management. In this study, we present a case series from Italy based on a multicenter, retrospective, observational study, which included 45 patients treated with ICIs who developed ICI-induced bullous pemphigoid. In addition, we performed a comprehensive review to identify the cases reported in the literature on ICI-induced autoimmune bullous diseases. Several theories seeking their underlying pathogenesis have been reported and this work aims to better understand what is known so far on this issue.

Keywords: anti PD-1; anti PD-L1; bullous pemphigoid; cutaneous irAE; immunotherapy; lichen planus pemphigoides; mucous membrane pemphigoid; pemphigus.

Figure 1

Demographic and clinical characteristics of the 373 ICI-induced BP cases identified among published articles. These pie charts report overall patient demographic [sex and age] and tumor characteristics [tumor type and immunotherapy]. *Other tumor type: urothelial cancer [n = 14], Merkel cell carcinoma [n = 4], colorectal cancer [n = 3], endometrial carcinoma [n = 2], breast cancer [n = 2], esophageal/gastric cancer [n = 2], mesothelioma [n = 2], prostate cancer [n = 2], thymoma [n = 1], hepatocellular carcinoma [n = 1], intrahepatic cholangiocarcinoma [n = 1], brain pinoblastoma [n = 1], glottic cancer [n = 1], salivary gland cancer [n = 1], peripheral T-cell lymphoma [n = 1], cervical cancer [n = 1], anaplastic thyroid carcinoma [n = 1]. **Other immunotherapy: cemiplimab [n = 7], durvalumab [n = 5], atezolizumab [n = 5], ipilimumab [n = 3], bintrafusp alfa [n = 4], tislelizumab [n = 1], avelumab [n = 1]. ICI, immune checkpoint inhibitor; BP, bullous pemphigoid; NR, not reported; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; NMSC, non-melanoma skin cancer; HNSCC, head and neck squamous cell carcinoma.