Clinical characteristics and therapies of multi-organ immune related adverse events

Immune checkpoint inhibitors (ICIs) activate the immune system by blocking PD-1, CTLA-4, and PD-L1, thereby inducing autoimmune-mediated adverse reactions known as immune-related adverse events (irAEs). When two or more organs are involved, this condition is defined as multi-organ immune-related adverse events (multi-organ irAEs). Patients with multi-organ irAEs account for approximately 20%-30% of all irAE cases; however, clinical research focusing on this subset remains limited. The purpose of this study is to analyze the clinical characteristics, optimal therapeutic approaches, and mortality-related risk factors of multi-organ irAEs. We searched all case reports of irAEs associated with ICIs in the PubMed, Web of Science, Cochrane Library, and Embase databases from their inception to January 2022. Search terms included "Immune Checkpoint Inhibitors", "Checkpoint Inhibitors, Immune", "Immune Checkpoint Blockers", "PD-L1", "CTLA-4 Inhibitor", "PD-1", and "Case report". After removing duplicate literature and applying strict inclusion/exclusion criteria, a total of 2,740 articles were included, encompassing 2,964 patients (782 with multi-organ irAEs and 2,182 with single-organ irAEs). Patients were stratified by the number of affected organs to compare clinical characteristics between multi-organ and single-organ irAE groups. For patients with multi-organ irAEs, subgroup analyzes were performed based on glucocorticoid dosage to identify optimal treatment strategies, and further stratified by survival status to explore potential mortality risk factors. No statistically significant differences in age or sex were observed between patients with multi-organ irAEs and those with single-organ irAEs (P > 0.05). However, the multi-organ irAE group exhibited significantly higher proportions of cardiovascular toxicity, thyroid toxicity, skin toxicity, and severe adverse reactions (P < 0.05), as well as a significantly elevated mortality rate (P < 0.05). Among patients with severe multi-organ irAEs, there were no significant differences in sex or age between high-dose and low-dose glucocorticoid subgroups (P > 0.05); notably, the high-dose glucocorticoid group had a significantly higher mortality rate (P < 0.05). For patients with non-severe multi-organ irAEs, no statistically significant differences in sex, age, mortality, or prognosis were detected between high-dose and low-dose glucocorticoid groups (P > 0.05). Multivariate logistic regression analysis revealed that cardiovascular toxicity, pulmonary toxicity, hepatotoxicity, and myositis were positively correlated with mortality in patients with multi-organ irAEs (OR > 1, P < 0.05). The most common organ combinations in multi-organ irAEs are "cardiac + neurological, cardiac + pulmonary, thyroid + pituitary, cardiac + hepatic, and gastrointestinal + skin". Multi-organ irAEs are generally more severe and associated with poorer outcomes compared to single-organ irAEs. High-dose glucocorticoids did not demonstrate superior prognostic outcomes and may be associated with an increased mortality risk in severe irAEs.clinical decisions regarding glucocorticoid dosing should be individualized based on the severity of irAEs and the specific organs involved.Cardiovascular toxicity, pulmonary toxicity, hepatotoxicity, and myositis are potential mortality risk factors for multi-organ irAEs induced by ICIs.