Fluctuations in serum adrenocorticotropic hormone concentration may predict the onset of immune checkpoint inhibitor-related hypophysitis

Immune checkpoint inhibitor (ICI)-related hypophysitis (RH) is a common immune-related adverse event. The early detection of ICI-RH prevents life-threatening adrenal insufficiency. However, good predictors of secondary adrenal insufficiency in ICI-RH have not yet been reported. We hypothesized that fluctuations in serum adrenocorticotropic hormone (ACTH) and cortisol levels occur similarly to those in thyroid-stimulating hormone and thyroid hormone (thyroxine and triiodothyronine) levels in ICI-related thyroiditis. Here, we sought to test this hypothesis. Patients who used ICI and had a history of measurement of serum ACTH and cortisol concentrations were retrieved from electronic medical records, and those with a history of glucocorticoid use were excluded from the analysis. We evaluated fluctuations in serum ACTH and cortisol concentrations and the development of ICI-RH. For patients with ICI-RH, data at three points (before ICI administration (pre), maximum ACTH concentration (peak), and onset of ICI-RH) were analyzed to evaluate hormone fluctuations. A total of 202 patients were retrieved from the medical record. Forty-three patients were diagnosed with ICI-RH. Twenty-six out of 43 patients had sufficient data to evaluate fluctuations in serum ACTH and cortisol concentrations and no history of glucocorticoid use. ACTH concentrations changed from 37.4 (29.9-48.3) (pre) to 64.4 (46.5-106.2) (peak) pg/mL (1.72-fold increase, p=0.0026) in the patients with ICI-RH before the onset. There were no differences in cortisol concentrations between the pre and peak values in patients with ICI-RH. We also evaluated the fluctuations in serum ACTH and cortisol levels in patients who did not receive ICI-RH (62 cases). However, elevation of serum ACTH levels was not observed in patients without ICI-RH, suggesting that transient elevation of serum ACTH levels is a unique phenomenon in patients with ICI-RH. In conclusion, serum ACTH levels were transiently elevated in some patients with ICI-RH before the onset of secondary adrenal insufficiency. Monitoring the ACTH levels and their fluctuations may help predict the onset of ICI-RH.