Metabolic syndrome and immune-related adverse events

BACKGROUND: Years into the immune checkpoint inhibitor (ICI) era, immune-related adverse events (irAE) remain largely unpredictable. Prior studies have examined irAE associations with weight and metabolic diseases, yielding mixed findings. We therefore analyzed these and other variables potentially associated with heightened inflammation and irAE development. METHODS: For ICI-treated individuals enrolled in a prospective institutional clinical and biospecimen registry, we collected demographic, clinical, laboratory, and residence data, pre-ICI serum cytokine levels, and irAE details. We calculated metabolic syndrome (MetS) and area deprivation index (ADI, a measure of neighborhood socioeconomic status), both of which have been associated with heightened inflammation. Patients were categorized as having MetS if they had ≥ 3 of 5 criteria at ICI initiation: hypertension, obesity, elevated HbA1c, low HDL, elevated triglycerides. Baseline serum cytokine/chemokine levels were determined using a multiplex platform. We analyzed associations across variables using logistic regression, Mann-Whitney U, and Cochran Armitage tests, accounting for multiple comparisons. RESULTS: Overall, 178 ICI-treated patients were included in the analysis, of whom 99 (56%) were classified as having MetS. In multivariable analysis, patients with MetS had greater odds of both grade ≥ 2 irAE (OR 2.82; 95% CI, 1.35-6.14; P = 0.007) and grade ≥ 3 irAE (OR 3.53; 95% CI 1.27-11.68; P = 0.02). However, MetS was not associated with pre-treatment cytokine levels. In contrast, ADI was associated with multiple inflammatory cytokines but not with MetS or irAE. CONCLUSIONS: MetS is associated with increased likelihood of moderate and severe irAE. The mechanism and mitigation of this risk merit further investigation.