Division of Endocrinology, Diabetes, and Metabolism, Los Angeles, California, USA.
Department of Medicine, Los Angeles, California, USA.
Thyroid. 2022 May;32(5):496-504. doi: 10.1089/thy.2021.0685. Epub 2022 Mar 31.
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant ( = 0.0093). Dosing differences were not explained by age or use of interfering medications. ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.
免疫检查点抑制剂（ICI）已彻底改变了许多晚期癌症的治疗方法，但已被确认为会引起治疗受限的免疫相关不良事件（IrAE）。ICI 相关性甲状腺炎是最常见的内分泌 IrAE，通常会发展为永久性甲状腺功能减退症。这些患者的最佳甲状腺激素替代治疗仍不清楚。我们报告了 ICI 相关性甲状腺炎引起的甲状腺功能减退症患者达到稳定甲状腺功能正常状态所需的左甲状腺素（LT4）剂量，并与桥本甲状腺炎（HT）和甲状腺功能减退症患者进行了比较。我们对在学术医疗中心接受 LT4 治疗的 ICI 相关性甲状腺功能减退症成人进行了回顾性研究。从电子病历中收集患者数据。病例有 ICI 暴露，随后首先出现甲状腺功能亢进，然后出现甲状腺功能减退。对照组为 HT（阳性甲状腺自身抗体，需要 LT4）和甲状腺功能减退症（甲状腺全部切除术或放射性碘消融术，需要 LT4）患者。排除了中枢性甲状腺功能减退症、甲状腺癌、妊娠、胃肠道间质瘤和使用 L-三碘甲状腺原氨酸的患者。我们的主要结果通过线性回归模型比较了 ICI 相关性甲状腺功能减退症、HT 和甲状腺功能减退症患者达到甲状腺功能正常状态（6 周以上连续血清促甲状腺素 0.3-4.7 mIU/L）所需的 LT4 剂量，同时考虑了年龄和可能的干扰药物的影响。次要分析考虑了内分泌专科治疗对达到甲状腺功能正常状态时间的影响。确定了 103 例 ICI 相关性甲状腺炎患者。103 例患者中有 66 例达到甲状腺功能正常；2 例为甲状腺固有功能恢复，64 例为 LT4。在 ICI 相关性甲状腺功能减退症患者中，达到稳定甲状腺功能正常状态所需的 LT4 剂量平均为 1.45±0.47 mcg/[kg·天]，在 HT 患者中为 1.25±0.49 mcg/[kg·天]，在甲状腺功能减退症患者中为 1.54±0.38 mcg/[kg·天]，使用实际体重。ICI 相关性甲状腺功能减退症与 HT 之间的剂量差异具有统计学意义（=0.0093）。年龄或使用干扰药物并不能解释剂量差异。ICI 相关性甲状腺炎是甲状腺功能减退症的一个越来越被认识的原因。我们的研究表明，与 HT 患者相比，ICI 相关性甲状腺功能减退症患者的甲状腺激素给药需求不同。基于我们的发现和之前的报告，我们建议在 ICI 相关性甲状腺炎患者中，一旦血清游离甲状腺素水平低于参考范围，就应以 1.45 mcg/[kg·天]的初始基于体重的剂量开始 LT4 治疗。
