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

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.

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.

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% vs. 9.1% vs. 10.2%; P=0.000). Further, anti-PD-1-induced AI patients showed more complex and poorer clinical manifestations than anti-CTLA-4-induced patients, including a higher rate of emergency admission (28.7% vs. 4.9%; P=0.003), tachycardia (30.4% vs. 0; P=0.014), hypotension (50.0% vs. 8.6%; P=0.000), hypoglycemia (19.5% vs. 2.6%; P=0.014), hyponatremia (64.2% vs. 33.3%; P=0.002), and a prolonged median duration from ICI initiation to symptom onset (26 vs. 9 weeks; P=0.000).

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.