1 Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine , Kyoto, Japan .
2 Preemptive Medicine and Lifestyle Disease Research Center, Kyoto University Hospital , Kyoto, Japan .
Thyroid. 2017 Jul;27(7):894-901. doi: 10.1089/thy.2016.0562. Epub 2017 Jun 21.
The programmed cell death-1 (PD-1) pathway is a novel therapeutic target in immune checkpoint therapy for cancer. It consists of the PD-1 receptor and its two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Nivolumab is an anti-PD-1 monoclonal antibody approved for malignant melanoma, advanced non-small cell lung cancer, and advanced renal cell carcinoma in Japan. Thyrotoxicosis and hypothyroidism have both been reported in international Phase 3 studies and national post-marketing surveillance of nivolumab in Japan.
This study analyzed five consecutive cases with thyroid dysfunction associated with nivolumab therapy. Second, it examined the mRNA and protein expressions of PD-L1 and PD-L2 by reverse transcription polymerase chain reaction and Western blotting.
All patients were diagnosed with painless thyroiditis. Thyrotoxicosis developed within four weeks from the first administration of nivolumab and normalized within four weeks of onset in three of the five patients. Hypothyroidism after transient thyrotoxicosis developed in two patients, and preexisting hypothyroidism persisted in one patient. The other two patients were treated with glucocorticoids and discontinued nivolumab therapy for comorbid adverse events. One did not develop hypothyroidism, and the other developed mild, transient hypothyroidism. In addition, it was verified that normal thyroid tissue expresses PD-L1 and PD-L2 mRNA and those proteins.
In the present cases, nivolumab-induced thyrotoxicosis seemed to be associated with painless thyroiditis, while no patient with Graves' disease was observed. A transient and rapid course with subsequent hypothyroidism was observed in nivolumab-induced thyroiditis. In addition, it was verified that PD-L1 and PD-L2 are expressed in normal thyroid tissue. This suggests that nivolumab therapy reduces immune tolerance, even in normal thyroid tissue, and leads to the development of thyroiditis. Treating thyrotoxicosis with only supportive care and considering levothyroxine replacement therapy once subsequent hypothyroidism occurs is proposed. Further investigations are required to confirm whether glucocorticoid therapy and discontinuation of nivolumab therapy prevent subsequent hypothyroidism.
程序性细胞死亡蛋白 1（PD-1）通路是癌症免疫检查点治疗的一个新的治疗靶点。它由 PD-1 受体及其两个配体，程序性死亡配体 1（PD-L1）和程序性死亡配体 2（PD-L2）组成。纳武单抗是一种抗 PD-1 单克隆抗体，在日本被批准用于治疗恶性黑色素瘤、晚期非小细胞肺癌和晚期肾细胞癌。在国际 3 期研究和日本纳武单抗的国家上市后监测中，均报告了甲状腺功能亢进和甲状腺功能减退。
本研究分析了 5 例与纳武单抗治疗相关的甲状腺功能障碍病例。其次，通过逆转录聚合酶链反应和 Western blot 检测 PD-L1 和 PD-L2 的 mRNA 和蛋白表达。
所有患者均被诊断为无痛性甲状腺炎。5 例患者中有 3 例在纳武单抗首次给药后 4 周内出现甲状腺功能亢进，且在发病后 4 周内恢复正常。2 例在短暂性甲状腺功能亢进后出现甲状腺功能减退，1 例原有甲状腺功能减退持续存在。另外 2 例患者因合并不良反应而接受糖皮质激素治疗并停用纳武单抗。其中 1 例未出现甲状腺功能减退，另 1 例出现轻度、短暂性甲状腺功能减退。此外，证实正常甲状腺组织表达 PD-L1 和 PD-L2 的 mRNA 和蛋白。
在本病例中，纳武单抗诱导的甲状腺功能亢进似乎与无痛性甲状腺炎有关，而未观察到格雷夫斯病患者。纳武单抗诱导的甲状腺炎表现为短暂而迅速的病程，随后出现甲状腺功能减退。此外，证实 PD-L1 和 PD-L2 在正常甲状腺组织中表达。这表明，纳武单抗治疗降低了免疫耐受，即使在正常甲状腺组织中也是如此，从而导致甲状腺炎的发生。建议仅采用支持治疗治疗甲状腺功能亢进，并在随后发生甲状腺功能减退时考虑给予左甲状腺素替代治疗。需要进一步研究来确认糖皮质激素治疗和停用纳武单抗是否可以预防随后发生的甲状腺功能减退。
