Immune checkpoint inhibitors and adrenal insufficiency: a large-sample case series study.

Background: Adrenal insufficiency (AI) represents a rare, yet potentially life-threatening immune checkpoint inhibitor (ICI)-related adverse event. The clinical characteristics of ICI-induced AI are still poorly defined due to its low incidence but need to be comprehensively understood. Methods: We systematically retrieved and screened the PubMed/Medline, Embase, Web of Science, and Cochrane Library databases for all articles published on AI related to anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death protein-1 (PD-1) receptor or its ligand (PD-L1), or combination ICI therapy. The retrieved articles were reviewed and selected in accordance with the exclusion criteria. The detailed data of individual cases were then collected and analyzed. Results: We identified 206 ICI-induced AI patients, comprising 11 (5.3%) primary AI patients, 191 (92.7%) secondary AI patients, and 4 (1.9%) mixed-type AI patients. The subclassification of the secondary AI patients, comprising 108 isolated adrenocorticotropic hormone (ACTH) insufficiency (IAD) and 83 multiple pituitary hormone deficiency (MPHD) patients, revealed that 56.5% of secondary AIs were related to IAD. Fatigue, anorexia/loss of appetite, headache, and nausea/vomiting were the most prevalent symptoms, and MPHD patients had a significantly higher rate of headache than primary AI patients and IAD patients (67.2% Discussion: The ICI-induced AI events could be primary, secondary, or mixed-type, and IAD was the most common reason for such events. The symptoms were usually unspecific and could be complex. AI should be excluded in a timely manner, and the patients should be followed-up with and receive extra attention for AI events even after the discontinuation of ICI treatment. Additionally, the discrepancy in relation to clinical characteristics between anti-PD-1- and anti-CTLA4-induced AI events warrants further exploration.