1 Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine; The University of Texas MD Anderson Cancer Center , Houston, Texas.
2 Department of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine , Houston, Texas.
Thyroid. 2018 Oct;28(10):1243-1251. doi: 10.1089/thy.2018.0116.
Although immune-related thyroiditis (irT) with immune checkpoint inhibitors (ICI) is a common consequence, its natural course and management recommendations are not well characterized in existing guidelines. This study sought to investigate the evolution of irT and describe its course and sequelae.
This was a retrospective study of cancer patients treated with ICI between November 2014 and July 2016 at MD Anderson Cancer Center and referred for endocrinology evaluation for suspected irT. Patients included had normal baseline thyroid function tests prior to starting ICI and developed thyrotoxicosis due to irT.
Of 657 patients treated with ICI during the study period, 43(6.5%) met the inclusion criteria. ICI included: ipilimumab + nivolumab (40%), nivolumab (33%), pembrolizumab (21%), and other (7%). Cancer diagnoses observed were melanoma (23%), renal-cell carcinoma (21%), lung cancer (19%), bladder cancer (12%), colon cancer (9%), and other cancers (15%). Median time from ICI start to thyrotoxicosis was 5.3 weeks (range 0.6-19.6 weeks). Clinically, patients presented with painless thyroiditis, and 67% were asymptomatic during the thyrotoxicosis phase. Thyrotoxicosis lasted a median of six weeks (range 2.6-39.7 weeks). Hypothyroidism developed in 37 (84%) patients at a median of 10.4 weeks (range 3.4-48.7 weeks) after starting ICI. These patients remained on levothyroxine and ICI at a median follow-up of 57.4 weeks (range 1-156.7 weeks) from hypothyroidism onset. Four patients recovered without initiating levothyroxine and remained euthyroid at a median follow-up of 11.35 months (range 4.43-14.43 months). Subgroup analysis of ipilimumab + nivolumab versus nivolumab alone showed a median time to thyrotoxicosis of two weeks [confidence interval (CI) 3.5-8.4] versus six weeks ([CI 1.2-2.8]; p = 0.26) and time to hypothyroidism of 10 weeks [CI 8.1-11.9] versus 17 weeks ([CI 8.8-25.2]; p = 0.029) after starting ICI. Thyroid peroxidase and thyroglobulin antibodies were present in 45% and 33% at the time of irT diagnosis.
IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.
尽管免疫相关甲状腺炎（irT）与免疫检查点抑制剂（ICI）有关，但在现有指南中，其自然病程和管理建议尚不清楚。本研究旨在探讨 irT 的演变，并描述其病程和后遗症。
这是一项回顾性研究，纳入了 2014 年 11 月至 2016 年 7 月期间在 MD 安德森癌症中心接受 ICI 治疗并因疑似 irT 转至内分泌科评估的癌症患者。患者在开始 ICI 前甲状腺功能检查正常，随后因 irT 出现甲状腺毒症。
在研究期间接受 ICI 治疗的 657 例患者中，有 43 例（6.5%）符合纳入标准。ICI 包括：ipilimumab + nivolumab（40%）、nivolumab（33%）、pembrolizumab（21%）和其他（7%）。观察到的癌症诊断包括黑色素瘤（23%）、肾细胞癌（21%）、肺癌（19%）、膀胱癌（12%）、结肠癌（9%）和其他癌症（15%）。从开始 ICI 到出现甲状腺毒症的中位时间为 5.3 周（范围 0.6-19.6 周）。临床上，患者表现为无痛性甲状腺炎，67%的患者在甲状腺毒症期无症状。甲状腺毒症持续中位时间为 6 周（范围 2.6-39.7 周）。开始 ICI 后，37 例（84%）患者出现甲状腺功能减退，中位时间为 10.4 周（范围 3.4-48.7 周）。这些患者在开始 ICI 后中位随访 57.4 周（范围 1-156.7 周）时仍在服用左甲状腺素和 ICI。4 例患者在未开始左甲状腺素治疗的情况下恢复，中位随访 11.35 个月（范围 4.43-14.43 个月）时仍处于甲状腺功能正常状态。ipilimumab + nivolumab 与 nivolumab 单独治疗的亚组分析显示，甲状腺毒症的中位时间分别为 2 周（95%置信区间 [CI]：3.5-8.4）和 6 周（95%CI：1.2-2.8）（p=0.26），甲状腺功能减退的中位时间分别为 10 周（95%CI：8.1-11.9）和 17 周（95%CI：8.8-25.2）（p=0.029）。irT 诊断时，甲状腺过氧化物酶和甲状腺球蛋白抗体的阳性率分别为 45%和 33%。
irT 表现为早期出现甲状腺毒症，主要为无症状，随后迅速过渡至需要长期左甲状腺素替代治疗的甲状腺功能减退。联合 ICI 治疗时 irT 的演变更快。在 ICI 期间应频繁监测甲状腺功能检查。未来的指南需要认识到这一实体，并纳入其管理。
