Concurrent Pituitary and Thyroid Immune-Related Adverse Events after Immune Checkpoint Inhibitors Associated with HLA-DR15–Related Haplotypes

Some patients undergoing immune checkpoint blockade treatment develop immune-related adverse events (irAE) affecting multiple organs, but whether pituitary and thyroid dysfunction is prone to co-occur is unclear. A total of 1,014 patients treated at Nagoya University Hospital were prospectively assessed for pituitary and thyroid function, and human leukocyte antigens (HLA) were analyzed in patients with pituitary and/or thyroid irAEs. Pituitary irAE and thyroid irAE developed in 68 and 128 patients, respectively. The incidence of thyroid irAE was significantly higher in patients who developed pituitary irAE compared with those who did not [21/68 (30.9%) vs. 107/946 (11.3%), P < 0.001], and the difference remained significant with tumor type and therapeutic agents used as stratified factors (Cochran-Mantel-Haenszel test, P = 0.001). The frequencies of HLA-DRB1*15:01 (12.5% vs. 7.6%, P = 0.049) and DRB1*15:02 (16.9% vs. 10.6%, P = 0.025) were significantly higher in patients with pituitary irAE compared with those in a database containing Japanese subjects. The frequency of the DRB1*15:01-associated haplotype (DRB1*15:01-DQB1*06:02-DPB1*02:01) was significantly higher in patients who developed both pituitary and thyroid irAEs compared with the control (14.3% vs. 3.1%, P = 0.002), and the DRB1*15:02-associated haplotype (DRB1*15:02-DQB1*06:01-DPB1*09:01) frequency was significantly higher in patients who developed pituitary irAE but not thyroid irAE compared with the control (18.1% vs. 8.9%, P = 0.006); both findings were confirmed in the validation cohort comprising 92 patients with pituitary irAE from seven hospitals. In conclusion, pituitary and thyroid irAEs are prone to co-occur, and HLA-DR15-associated haplotypes are related to this co-occurrence.