PD-1 Immunotherapies Induce Painless Thyroiditis in Patients With Metastatic Malignancies

Paul G. Walfish, CM, OOnt

Treatment with programmed cell death 1 (PD-1) immunotherapy across various oncology clinical trials has been associated with the induction of painless thyroiditis, characterized by transient thyrotoxicosis and hypothyroidism, in patients with metastatic malignancies, according to a presentation by Paul G. Walfish, CM, OOnt, of the Department of Endocrinology at Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases at Mount Sinai Hospital in Toronto, Canada, during the 84th Annual Meeting of the American Thyroid Association. With the evolving use of PD-1, it is important for clinicians to monitor patients for the clinical and biochemical signs of thyroid dysfunction and treat potential adverse consequences.

Walfish and colleagues identified a subgroup of 10 patients with documented metastatic malignancies who received immunotherapy with PD-1 receptor antibodies as part of a clinical trial. In the subgroup, 7 patients had malignant melanoma and 3 patients had non-small cell lung cancer. These clinical trial participants had abnormal thyroid function tests and were referred to a tertiary thyroidology clinic for diagnosis and management.

Overall, 60% of patients were female, and the average patient age was 55 years. Sixty percent of patients displayed transient thyrotoxicosis and negative thyrotropin binding inhibitory immunoglobulins and required treatment with beta blockers. Anti-thyroid antibodies, including both anti-thyroglobulin and anti-thyroid peroxidase, were identified in 4 patients (67%). After approximately 4 weeks, thyroidotoxicosis spontaneously resolved, but patients required thyroid hormone replacement therapy with levothyroxine to treat their hypothyroidism. The remaining 4 patients presented with hypothyroidism that was not preceded by a thyrotoxic phase. These patients displayed serological evidence of anti-thyroid antibodies an average of 6 to 8 weeks following initial PD-1 drug exposure. No relationship was consistently seen between the occurrence of painless thyroiditis syndrome and a patient's oncological response to immunotherapy.

Novel immunotherapies that have recently been investigated for the treatment of several malignancies have now been recognized to have selective immunotoxic effects on the thyroid gland and several other endocrine organs. Since these effects do not occur in all patients exposed to such therapy, it is likely that affected individuals have an immunogenetic susceptibility to such adverse consequences.

Previously, Walfish's group and other researchers have demonstrated that polymorphic variations of the cytotoxic T lymphocyte antigen-4 (CTLA-4) receptor gene can predispose individuals to a variety of autoimmune endocrine disorder such as Grave's disease, Addison's disease, Hashimoto's thyroiditis, and type 1 diabetes mellitus. In this case, a similar mechanism (polymorphic variants of the PD-1 receptor gene) may account for the occurrence of painless thyroiditis in a subgroup of patients treated with anti-PD-1 monoclonal antibodies (mAbs). Perhaps similar alterations in immune checkpoints may account for cases of sporadic or postpartum thyroiditis.

Like CTLA-4, PD-1 is a negative immune regulator that prevents T-cell proliferation, activation, and cytokine release in response to foreign antigens. Negative regulation is mediated by the PD-1 receptor and its PD-L1 or PD-L2 ligands. Both CTLA-4 and PD-1 receptors are important checkpoint inhibitors, and mAb blockade of these targets is a promising novel immunotherapy for the treatment of several metastatic malignancies.

Upregulation of PD-1 ligands occurs in some tumors and can contribute to the inhibition of active T-cell immune surveillance. Binding of PD-1 ligands to PD-1 receptors found on T cells inhibits T-cell proliferation and cytokine production to prevent tumor attack. Anti-PD-1 receptor mAbs release the blockade and permit an anti-tumor immune response to metastases. Although adverse endocrinopathies, including thyroid dysfunction, have recently been described secondary to treatment with anti-CTLA-4 mAb therapy, the potential for similar effects on thyroid dysfunction following anti-PD‑1 mAb immunotherapy have not been well characterized.

Some cases of painless thyroiditis have occurred sporadically or in the postpartum period, while other cases have been reported in response to other endogenous stimuli such as Grave's disease, Addison's disease before treatment, and Cushing's disease after remission. Additionally, a number of medications, including treatment with interferon-alfa and ribavirin, kinase inhibitors, interleukin-2, amiodarone, lithium, and iodine, have been associated with the development of painless thyroiditis. Walfish also noted that some patients develop painless thyroiditis after radiation treatment or following a surgical procedure in which the thyroid has been too vigorously palpated.

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