Association of antithyroglobulin antibodies with the development of thyroid dysfunction induced by nivolumab

Abstract

Thyroid dysfunction (TD) induced by immune checkpoint inhibitors is not sufficiently understood. The purpose of this retrospective observational study was to identify risk factors and the clinical course of TD induced by nivolumab. Patients with advanced solid tumors who were treated with nivolumab from March 2009 through to March 2016 at the National Cancer Center Hospital (Tokyo, Japan) were included. Thyroid function and antithyroid Abs from serum samples among all patients were evaluated at baseline and during nivolumab treatment. Overt hypothyroidism was defined as low serum‐free T4 together with elevated thyroid‐stimulating hormone (TSH) >10 μIU/mL. Thyrotoxicosis was defined as low TSH with elevated free T4 and/or free T3. We defined thyroid autoimmunity as the presence of antithyroid Abs at baseline, including antithyroid peroxidase Abs and antithyroglobulin Abs (TgAb). Twenty‐three (14%) of a total of 168 patients developed TD, including 17 cases of hypothyroidism and 20 of thyrotoxicosis. Thyrotoxicosis followed by hypothyroidism occurred in 14 cases. Fourteen of 35 patients (40%) with thyroid autoimmunity developed TD vs 9 of 133 (7%) without (odds ratio 9.19; 95% confidence interval [CI], 3.53‐23.9). In multivariate analysis, elevated TSH and TgAb at baseline were significantly associated with the development of TD, with odds ratio of 7.36 (95% CI, 1.66‐32.7) and 26.5 (95% CI, 8.18‐85.8), respectively. Association between TD and elevated antithyroid peroxidase Abs at baseline was not significant. These results suggest that patients with pre‐existing TgAb and elevated TSH at baseline are at high risk of TD.

Three‐year follow‐up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non‐small cell lung cancer: Pooled analysis of ONO‐4538‐05 and ONO‐4538‐06 studies

“…The frequency of irAEs has previously been shown to increase in patients with a history of autoimmune disease who were administered with an immune checkpoint inhibitor. Furthermore, the frequency of anti‐PD‐1 antibody‐induced thyroid dysfunction appears to increase in the presence of baseline thyroid‐related autoantibody positivity . A relationship between antinuclear antibodies and immune checkpoint inhibitors with respect to safety has not been reported to date, and the present data indicate that these factors are not correlated.…”

“…Furthermore, the frequency of anti-PD-1 antibody-induced thyroid dysfunction appears to increase in the presence of baseline thyroid-related autoantibody positivity. 20,21 A relationship between antinuclear antibodies and immune checkpoint inhibitors with respect to safety has not been reported to date, and the present data indicate that these factors are not correlated. A substantial proportion of patients were found to express PD-L1 in the present study, and previous data have suggested that these patients might be at increased risk of a poorer prognosis.…”

Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society

“…It is possible that activation of pre-existing autoimmunity against thyroid glands is involved in the pathogenesis of thyroid dysfunction induced by ICIs. For example, the incidence of thyroid dysfunction is reportedly higher in patients who have anti-thyroglobulin antibodies (TgAb) and/or anti-thyroid peroxidase antibodies (TPOAb) prior to the initiation of the treatment with nivolumab than in patients without these antibodies [22,23]. In most cases of thyroid dysfunction induced by ICIs, thyroid ultrasonography shows diffuse enlargement of the thyroid gland accompanied by decreased internal blood flow and low internal echogenicity, while thyroid scintigraphy shows decreased uptake of isotope, suggestive of destructive thyroiditis.…”

“…In clinical practice, it would be beneficial to identify, in advance, which patients are at greatest risk of developing an endocrine irAEs induced by an ICI. It has been reported that the presence of TgAb and/or TPOAb in serum may be potential biomarkers of thyroid dysfunction induced by the anti-PD-1 antibody [22,23]. On the other hand, there are no reports to date that have shown predictive biomarkers for endocrine irAEs other than thyroid dysfunction.…”

Thyroid disorders in programmed death 1 inhibitor‐treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor?

“…ICI‐related TAEs have been variously described as hyperthyroidism and/or hypothyroidism (both overt and subclinical) and/or as a destructive thyroiditis with an initial phase of thyrotoxicosis, which may evolve to transient or permanent hypothyroidism . According to previous studies, 12% of patients had the typical course of destructive thyroiditis. Lee et al describe the evolution of thyroiditis in 20% of patients treated with anti‐PD‐1 monotherapy.…”