Increased Risk of Thyroid Dysfunction by PD-1 and CTLA-4 Blockade in Patients Without Thyroid Autoantibodies at Baseline

Abstract

Background Previous studies showed that although the risk of thyroid dysfunction (thyroid immune-related adverse events [irAEs]) induced by anti-programmed cell death-1 antibodies (PD-1-Ab) was as low as 2–7% in patients negative for anti-thyroid-antibodies (ATAs) at baseline, it was much higher (30–50%) in patients positive for ATAs. However, whether a similar increase occurs with combination therapy using PD-1-Ab plus anti-cytotoxic T-lymphocyte antigen-4 antibody (CTLA-4-Ab) is unknown. Methods A total of 451 patients with malignancies treated with PD-1-Ab, CTLA-4-Ab, or a combination of PD-1-Ab plus CTLA-4-Ab (PD-1/CTLA-4-Abs) were evaluated for ATAs at baseline and for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the last clinical visit. Results Of the 451 patients, 51 developed thyroid-irAEs after immunotherapy [41 of 416 (9.9%) treated with PD-1-Ab, 0 of 8 (0%) with CTLA-4-Ab, and 10 of 27 (37.0%) with PD-1/CTLA-4-Abs]. The cumulative incidence of thyroid-irAEs was significantly higher in patients who were positive versus negative for ATAs at baseline after both PD-1-Ab [28/87 (32.2%) vs. 13/329 (4.0%), p < 0.001] and PD-1/CTLA-4-Abs [6/10 (60.0%) vs. 4/17 (23.5%), p < 0.05] treatments. The risk of thyroid-irAEs induced by PD-1/CTLA-4Abs, which was significantly higher than that induced by PD-1-Ab, in patients negative for ATAs at baseline was not statistically different from that induced by PD-1-Ab in patients positive for ATAs at baseline. Conclusions This study showed that the incidence of thyroid-irAEs was high and not negligible after PD-1/CTLA-4-Abs treatment even in patients negative for ATAs at baseline.

Clinical biomarkers for thyroid immune-related adverse events in patients with stage III and IV gastrointestinal tumors

“…Additionally, higher eosinophil count (>0.20 × 10 9 /L), higher level of TSH (>2.205mIU/L) and positivie TPOAb were identified as baseline factors for thyroid irAEs association in gastrointestinal tumors, which was also consistent with previous findings in solid tumors (26)(27)(28).…”

Changes in TgAb and TPOAb titers are greater in thyrotoxicosis than isolated hypothyroidism induced by PD-1 blockade

“…The patient characteristics are shown in Table 1. We have previously reported the nivolumab and pembrolizumab treatment regimens [9,12]. Nivolumab or pembrolizumab treatments were continued until disease progression, death, occurrence of unacceptable severe adverse events, or if the patient withdrew consent for treatment.…”

Combined use of tyrosine kinase inhibitors with PD-(L)1 blockade increased the risk of thyroid dysfunction in PD-(L)1 blockade: a prospective study

“…Although thyroid dysfunction can be induced by any class of ICIs, they occur more often following anti-programmed cell death-1 antibody (PD-1-Ab) or anti-programmed cell death-1 ligand-1 antibody (PD-L1-Ab) therapy compared with cytotoxic T-lymphocyte antigen-4 antibody monotherapy [ 7 , 8 ]. Previously, we reported that thyroid dysfunction was observed in 9.9% (41/416) of patients treated with PD-1-Ab [ 9 ] and 10.1% (15/148) of patients treated with PD-L1-Ab [ 10 ]. Thyroid dysfunction is classified as thyrotoxicosis and hypothyroidism, and most cases of thyrotoxicosis are destructive thyroiditis (DT).…”

“…Thyroid dysfunction is classified as thyrotoxicosis and hypothyroidism, and most cases of thyrotoxicosis are destructive thyroiditis (DT). In our previous prospective studies, the incidences of DT and hypothyroidism were 6.7 and 3.1% during PD-1-Ab therapy [ 9 ] and 5.4 and 4.7% during PD-L1-Ab therapy [ 10 ], respectively.…”