Thyroid Toxicity Following Immune Checkpoint Inhibitor Treatment in Advanced Cancer

Abstract

Background: Inhibitory antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) have antitumor efficacy and are now standard of care in the management of multiple cancer subtypes. However, the use is complicated by the development of autoimmunity, which can occur in multiple organ systems. Thyroiditis is the most common immune-related adverse event. Summary: Immune checkpoint inhibitor (ICI)-associated thyroiditis affects over 10% of treated patients. PD-1 inhibitors are associated with greater risk of thyroid dysfunction relative to CTLA-4 inhibitors, although the highest risk occurs with combined anti-CTLA-4 and anti-PD-1 treatment. Onset is typically rapid, within weeks to months and both hyperthyroidism and hypothyroidism can occur. The most frequent pattern of thyroid dysfunction is transient hyperthyroidism with evolution to hypothyroidism over four to six weeks. Most cases are asymptomatic and resolve without dedicated treatment. There is no sex or age predominance, and predictive risk factors have not been reliably identified. Thyroid autoantibodies are variably present and are not clearly related to the risk or progression of thyroid dysfunction following treatment with an ICI. Observational data suggest that development of ICI-associated thyroiditis may predict improved survival. Conclusions: ICI-associated thyroiditis is a distinct clinical entity. Mechanisms underlying etiology remain largely unknown. Awareness among health professionals is important to limit morbidity and avoid unnecessary periods of untreated hypothyroidism.

Keywords: cytotoxic T lymphocyte antigen-4; immune checkpoint; immune-related adverse event; programmed cell death-1; thyroiditis.