Skin and systemic interplay in immune checkpoint inhibitor therapy: Evidence of global immune activation

Background: Immune-related adverse events (irAEs) from immune checkpoint inhibitor therapies (ICI; PD-1/L1, CTLA-4, and/or LAG3) are non-trivial. Cutaneous irAEs (cirAEs) are some of the earliest to occur, but their implication as markers of broader systemic immune activation remains unclear. Objective: To evaluate the association between cirAEs and systemic irAEs in melanoma patients receiving ICI. Methods: We performed a retrospective cohort study of 18,886 (aged 18 or older) primary melanoma patients (C43) using the TrinetX network. We performed 1:1 propensity score matching (PSM) between patients who developed cirAEs within 6 months of ICI initiation (cirAE group) and those that did not (non-cirAE group). Time-to-event analyses for 13 organ-systems (cardiac, endocrine, renal, pulmonary, neurologic, hepatic, hematologic, musculoskeletal, ocular, gastrointestinal (GI), rheumatologic, and electrolyte abnormalities) involving 54 distinct irAE categories were performed using Kaplan-Meier curves and Cox models. To approximate temporal ordering, we applied a dual index-date framework: a primary analysis anchoring both cohorts at ICI initiation, and a secondary analysis re-anchoring the cirAE cohort at the onset of cirAE. For each outcome, equality of hazard ratios (HRs) across anchors was tested using a Wald chi-square test with a false discovery rate correction to evaluate for coherence between the frameworks. Results: In the matched cohort, the cox model showed significantly higher hazards in patients who developed cirAEs in the first year post-ICI. 32 distinct conditions were significantly associated with cirAEs. HRs ranged from 1.4 to nearly 5-fold higher vs. the matched non-cirAE cohort. The strongest signals were in GI (mucosal and secretory disorders; HR=5.06[3.54-7.23]), joint disorders (musculoskeletal conditions including pain, stiffness, and bursopathy, HR=2.67[2.08-3.42]), and esophagitis (HR=2.64[1.41-4.97]). Nine out of the 32 conditions including hypo-osmolality and hyponatremia and acute kidney injury showed non-coherence, marked by attenuated HRs and loss of significance in the cirAE-anchored analysis compared to the primary. As expected, the cirAE group showed improved survival (HR=0.61[0.54-0.70]) in the cirAE cohort (86%) compared to 79% in the non-cirAE group at the end of the 1-year time window, corresponding to approximately 171 additional survivors in the cirAE cohort. Conclusions: cirAEs are associated with increased 1-year risk of numerous systemic irAEs across multiple organ systems, whereas others show reduced effect sizes in the secondary analysis, suggesting that their risk is concentrated pre-cirAE. The robustness of associations across temporal anchors suggests that cirAEs may serve as early markers of broader immune activation, warranting enhanced monitoring and multidisciplinary management.