Phenotype/Immunologic Profiling in ircAEs—Response
Authors: Elena Goleva, Mario E. Lacouture, Andrea P. Moy, Jeffrey A. Kern, Donald Y.M. Leung
Journal: Clinical Cancer Research (2024)

We appreciate a thoughtful letter by Drs. Damodaran and Lehman regarding our study (1). The identification of pemphigoid-like features within various clinical morphologies emphasizes the complexity of immune-related cutaneous adverse events (ircAE) classification and underscores the necessity for a more nuanced approach in categorizing these events. The observations by our colleagues about the potential presence of pemphigoid diseases in our dataset provide a valuable perspective that complements our findings. The point with regard to the presence of basement membrane zone deposition of IgG and/or complement C3 is well taken. Incorporating direct immunofluorescence (DIF) testing and additional diagnostic tools, such as indirect immunofluorescence with salt-split skin, esophageal substrates, and ELISA for pemphigoid-specific biomarkers into the diagnostic workflow, as suggested, could refine ircAE classification criteria.Indeed, in our study, serum samples from ircAE patients and a comparison cohort were tested for autoantibodies associated with blistering skin diseases, including antibodies to bullous pemphigoid 180 and bullous pemphigoid 230 antigens and anti–desmoglein-1 and anti–desmoglein-3 antibodies. All samples were tested by a reference clinical laboratory at Mayo Clinic. These antibodies were found at low titers in a small subset of patients from the ircAE cohort and some patients from cohort 2 (no rash). Skin biopsy specimens for DIF to IgG, IgA, and IgM antibodies, complement C3, and fibrinogen deposition were analyzed (Beutner Laboratories). Although antibody and C3 deposition were seen at the dermoepidermal junction in a subset of skin biopsies from ircAE patients, identification of the epidermal proteins targeted by these antibodies requires additional evaluation. Furthermore, several nonbullous dermatitis ircAE cases showed serum antibody positivity to the common blistering disease epidermal antigens, but these cases were not associated with the corresponding characteristic DIF findings.Furthermore, Drs. Damodaran's and Lehman's observation with regard to the variable lag time between lichenoid lesions and blister formation is noteworthy. We agree that extended longitudinal follow-up could provide additional insights into the evolution of these lesions and aid in more accurate clinical and pathologic classification. To date, however, our 12-month follow-up assessment of ircAE patients with nonbullous dermatitis showed that autoantibodies and/or linear deposition of immunoglobulins and complement that were detected, were not associated with the development of clinical bullous dermatitis in these patients. At this time, the diagnostic value of these autoantibody findings is unclear, and these relationships require further investigation.We will consider these recommendations in future research and clinical applications to improve the accuracy and utility of autoantibody and DIF findings in the context of ircAE management.E. Goleva reports grants from Sanofi/Genzyme outside the submitted work. M.E. Lacouture reports grants from NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Grant (U01 AR077511) during the conduct of the study, as well as grants and personal fees from AstraZeneca, OnQuality Pharmaceuticals, Novartis, Kintara, and Marengo outside the submitted work. A.P. Moy reports grants from NIH/NIAMS during the conduct of the study. J.A. Kern reports grants from NIAMS during the conduct of the study (U01 AR077511). D.Y.M. Leung reports grants from NIH/National Institute of Arthritis and Musculoskeletal and Skin Disorders (NIAMS) Grant (U01 AR077511) and NIH/NCI Cancer Center Support Grant (P30 CA008748) during the conduct of this study, as well as grants from Sanofi/Genzyme outside of submitted work.This project was supported by an NIH/NIAMS Grant U01 AR077511.