BACKGROUND
Immune checkpoint inhibitor (ICI) drugs are an extremely valuable new class of drugs for the treatment of many types of cancers. As such, they are being used a lot currently with excellent results. The ICI drugs work by turning on the immune system to attack and destroy the cancer cells. Occasionally, this results in turning on the immune system to attack normal cells and this often includes the thyroid. This is known as ICI–associated thyroiditis, which causes a destructive inflammation in the thyroid. The most common result of this is ICI-associated hypothyroidism. When it occurs, most patients end up requiring thyroid hormone replacement.

Older patients who develop ICI-associated hypothyroidism are prone to worsening of osteoporosis and developing heart issues because of thyroid hormone overtreatment or to lower quality of life because of thyroid hormone undertreatment. Hence, finding the best levothyroxine dose would be beneficial in improving this population’s medical care, especially given their advanced cancer and the potential other adverse effects of ICI drugs. This study evaluates the dose of thyroid hormone replacement required to achieve stable normal thyroid function in patients with ICI-associated hypothyroidism, as compared with those with Hashimoto’s thyroiditis and those without a thyroid.

THE FULL ARTICLE TITLE
Mosaferi T et al 2022 Optimal thyroid hormone replacement dose in immune checkpoint inhibitorassociated hypothyroidism is distinct from Hashimoto’s thyroiditis. Thyroid. Epub 2022 Feb 24. PMID: 35199588.

SUMMARY OF THE STUDY
This study of adults was conducted at an academic medical center from January 1, 2015, through August 24, 2020. Cases included adults with ICI-associated thyroiditis who presented with high thyroid levels followed by either: (i) hypothyroidism (TSH >4.7 mIU/L) requiring thyroid hormone replacement or (ii) resolution to normal thyroid status (consecutive normal TSH levels not requiring thyroid hormone replacement). Controls included adults with Hashimoto’s thyroiditis or absent thyroid gland requiring levothyroxine replacement. A stable normal thyroid state was defined as two consecutive normal TSH levels (0.3–4.7 mIU/L) at least 6 weeks apart.

Of 103 adults with ICI-associated thyroiditis (average age ~65 years; 57.6% female), 66 (64.1%) achieved a stable normal thyroid state while 37 (36%) developed ICI-associated hypothyroidism. The most common cancers in this group were lung and skin cancers, and the most common ICI was PD-1 (programmed cell death-1) monotherapy (71.2%). The average time to thyrotoxicosis was 6 weeks (longer for monotherapy and shorter for combination therapy). Patients with ICI-associated hypothyroidism were more frequently likely to have coronary artery disease or osteoporosis and to use medications that interfere with thyroid hormone requirements (magnesium, PPIs, TKIs, and glucocorticoids) than in the controls with Hashimoto’s thyroiditis and no thyroid gland.

The average levothyroxine dose needed to achieve a stable normal thyroid state in patients with ICI-associated hypothyroidism (~1.45 mcg/kg/day) was higher than that of the average dose in the Hashimoto’s thyroiditis controls (1.25 mcg/kg/day). The dose was not different from that for patients without a thyroid (1.54 mcg/kg/day). Age and use of interfering medications were not predictive of the differences in dosing and there was no difference according to sex.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Thyroid hormone dose requirements for patients with ICI-associated hypothyroidism were similar to those in patients without a thyroid gland but higher than for those with Hashimoto’s thyroiditis. The authors recommend that in patients with ICI-associated hypothyroidism, levothyroxine therapy should be started at an initial weightbased dose of 1.45 μg/kg/day once serum free thyroxine levels fall below the reference range.

— Alan P. Farwell, MD

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