Immune Checkpoint Inhibitor-related New-onset Thyroid Dysfunction: A Retrospective Analysis Using the US FDA Adverse Event Reporting System

Abstract

Objectives The study aimed to investigate the prevalence and demographic characteristics of an immune checkpoint inhibitor (ICI)-related thyroid dysfunction (ICI-TD), and to explore risk factors of poor clinical outcome using data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods This is a retrospective study. All cases, aged over 18-year olds, of new-onset or new-diagnosed thyroid dysfunction related to FDA-approved ICIs from January 1, 2011 to December 31, 2020 were identified using FAERS. Data of age, gender, other combined endocrinopathies related to ICIs besides ICI-TDs, and the prognosis was analyzed. Results In total, 2.60% (2971/114 121) cases of ICI-TDs were identified. Among them, 1842 (62.0%) developed hypothyroidism, 675 (22.7%) were hyperthyroidism, and 454 (15.3%) presented in thyroiditis without the mention of thyroid function. Patients on anti- programmed cell death protein-1 (PD-1) therapy displayed higher risk of hypothyroidism compared with other 3 regimens, respectively (P < .01 for all). The likelihood of other immune-related endocrinopathies in patients on the combination therapy of anti-cytotoxic T-cell-associated protein-4 (CTLA-4) and anti-PD-1 was significantly elevated than anti-PD-1 (odds ratio [OR] 2.362, 95% confidence interval [CI] [1.925-2.898], P < .001) and anti-programmed death-ligand 1 (PD-L1) regimens (OR 4.857, 95%CI [3.228-7.308], P < .001). The risk of severe cases was positively related to hypothyroidism in individuals on anti-PD-1 therapy (OR 1.587, 95%CI [1.146-2.197], P = .005) and those on anti-CTLA-4 therapy (OR 3.616, 95%CI [1.285-10.171], P = .015). The risk of severe cases was positively associated with the comorbidity with other endocrinopathies (anti-PD-1 group, OR 0.285, 95%CI [0.200-0.467], P < .001; anti-PD-1+anti-CTLA-4 group, OR 0.574, 95%CI [0.371-0.890], P = .013). Conclusions Regular monitor of thyroid function is indispensable, since ICI-TDs manifested as hypothyroidism or hyperthyroidism, especially those on the combination therapy. Awareness among health care professionals is critical when hypothyroidism occurs, which might indicate poor clinical outcomes.

Severe thyrotoxicosis induced by tislelizumab: a case report and literature review

“…In our data set, there was a rare incidence of Grade 3 hypothyroidism and of hyperthyroidism events (0.2%). A retrospective analysis of the US Food and Drug Administration adverse event reporting system reported that 9.3% (171/1842) of patients presented with hyperthyroidism before hypothyroidism ( 29 ). Lee et al.…”

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

“…Liothyronine, being classically used to treat hypothyroidism, could be useful to reduce the risk of irAEs of the thyroid caused by anti-PD-1 mAbs. Nevertheless, the potential use of liothyronine in combination with an ICI would require careful and regular monitoring of thyroid functions, as is already the case for different immune checkpoint inhibitor therapies [ 45 ].…”

Immune checkpoint inhibitor-related endocrinopathies

“…The incidence and manifestations of each ICI-related endocrinopathy are listed in Table 2 . [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ] ICI-induced APS is even rare. In our previous study, the likelihood of APS in patients on combination therapy of anti-CTLA-4 and anti-PD-1 increased onefold than in patients on PD-1 inhibitors and fourfold than in those on PD-L1 inhibitors.…”

“…In our previous study, the likelihood of APS in patients on combination therapy of anti-CTLA-4 and anti-PD-1 increased onefold than in patients on PD-1 inhibitors and fourfold than in those on PD-L1 inhibitors. [ 32 ]…”

“…In patients on ICI therapy with adverse events, the immune-related endocrinopathies, including ICI-TDs and other accompanying endocrinopathies, were positively associated with the risk of severe clinical outcomes comprising hospitalization, disabled or life-threatening situations, while they were negatively related to the risk of death. [ 32 ] Therefore, irAEs of endocrine organs are critical clues for clinicians to pay attention to. Once the endocrine function alters and endocrinologic irAEs happen, oncologists or endocrinologists ought to start administering replacement therapy or other management in time to avoid serious clinical outcomes.…”