Background Immune-related cutaneous adverse events (ircAE) occur frequently and present with various phenotypes, suggesting distinct immunologic pathways underlying their development. Currently, ircAE treatment is empiric. Comprehensive immunologic endotype profiling is needed to understand the mechanisms driving the development of ircAEs and provide a rational basis for treatment with therapies that target specific endotypes.
Methods Patients on CPIs were recruited from Memorial Sloan Kettering Cancer Center (MSK) (New York, New York), National Jewish Health (Denver, Colorado), and The Melanoma and Skin Cancer Institute (Denver, Colorado) from 9/2020 to 12/2022. Patients with ircAEs ≥ grade 2 were enrolled into cohort 1 and patients without ircAE were enrolled into cohort 2 (controls). At the initial visit, patients in both cohorts underwent detailed phenotyping, biospecimen collection, and patient-reported outcome (PRO) questionnaires.
Results Demographics of enrolled patients are depicted in (table 1). Clinical evaluation yielded 8 distinct ircAE phenotypes (figure 1). Patients with all ircAE phenotypes except vitiligo reported reduced quality of life (p<0.01). Complete blood counts (CBC) of patients with ircAEs did not differ from those of control patients, except for decreased lymphocytes in pruritus and lichenoid ircAEs (p<0.05). Patients with pruritus had significant elevations (all values shown as median log10 fold change compared to controls) in IL-4 (0.41) and IL - 12p70 (0.22) in the skin and IL-4 (0.31), IL-5 (0.16), and IL-17A (0.19) in the plasma. Those with maculopapular ircAEs had elevations of all measured Th1, Th2, Th17/22, and regulatory cytokines in the skin (p<0.05-p<0.001) and IP-10, IL-4, IL-17a, and IL-10 (p<0.05-p<0.001) in the plasma. Psoriasiform, lichenoid, bullous pemphigoid, and vitiligo-like ircAEs were associated with significant upregulation of IP-10 (1.61, 1.06, 0.67, 0.66, respectively) in the skin. Finally, eczema and urticaria ircAEs had increased levels of IL-5 (0.32, 0.49, respectively) and IL-31 in the plasma (0.16, 0.31, respectively), with eczema also demonstrating a significant increase in the production of IP-10 (0.86). Compared to controls, histopathologic analysis of biopsies from lesional skin of all clinical phenotypes showed an increased density of lymphocytes (p<0.0001) and eosinophils (p<0.05-p<0.0001) ; increased neutrophilic infiltrate was also detected in psoriasiform (p<0.0001) and urticarial ircAEs (p<0.001).
Conclusions A distinct endotype has been identified for clinical phenotypes of ircAEs. This identification of upregulated immune pathways will allow individualized management through rational selection of targeted treatments. These endotypes are not detected with CBCs, suggesting that expanded cytokine analysis of skin and plasma is needed to understand mechanisms of ircAE development and guide therapy.
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