Department of Surgery, Division of Ophthalmology, Cedars Sinai Medical Center, Los Angeles, California, USA.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Am J Ophthalmol. 2019 Dec;208:281-288. doi: 10.1016/j.ajo.2019.07.021. Epub 2019 Aug 1.
Improved understanding of thyroid eye disease (TED) pathogenesis has facilitated identification of a targeted molecular approach for TED treatment offering the potential to halt or slow disease progression in a nonsurgical manner. Herein, we provide a summary of the current knowledge of TED management, followed by discussion of a novel insulin-like growth factor-1 receptor (IGF-1R) antagonist antibody and its potential to change the course of the disease.
Perspective.
Review of the literature and authors' experience.
Many publications demonstrate IGF-1R overexpression in TED, and its activation as an autoantigen as a critical factor in TED pathogenesis. Several in vitro studies demonstrate that IGF-1R inhibition attenuates downstream molecular events including cytokine and hyaluronan production, and cellular differentiation. These observations led to the hypothesis that blocking IGF-1R may abrogate the clinical progression of TED. The recent completion of phase 2 and 3 randomized, placebo-controlled trials demonstrate the efficacy and safety of teprotumumab, a fully human monoclonal IGF-1R antagonist antibody, in patients with moderate-to-severe, active TED. Both the phase 2 and the recent phase 3 study results demonstrate that more patients with active TED receiving teprotumumab experienced a meaningful improvement in proptosis.
Current TED treatment strategies target inflammation and symptoms, but do not modify the disease course. Therefore, proptosis as well as strabismus and its resulting diplopia often remain, impacting patient well-being and quality of life over the long term. Targeted molecular therapy using teprotumumab demonstrates disease-modifying benefits with the potential to shift the paradigm for TED treatment.
对甲状腺眼病（TED）发病机制的深入了解促进了针对 TED 治疗的靶向分子方法的确定，这种方法有可能以非手术的方式阻止或减缓疾病的进展。本文总结了 TED 管理的现有知识，随后讨论了一种新型胰岛素样生长因子-1 受体（IGF-1R）拮抗剂抗体及其改变疾病进程的潜力。
观点。
文献回顾和作者经验。
许多出版物表明 IGF-1R 在 TED 中过度表达，其作为自身抗原的激活是 TED 发病机制中的关键因素。几项体外研究表明，IGF-1R 抑制可减弱下游分子事件，包括细胞因子和透明质酸的产生以及细胞分化。这些观察结果导致了这样一种假设，即阻断 IGF-1R 可能会阻止 TED 的临床进展。最近完成的 2 期和 3 期随机、安慰剂对照试验表明，teprotumumab（一种完全人源单克隆 IGF-1R 拮抗剂抗体）在中重度、活动性 TED 患者中的疗效和安全性。2 期和最近的 3 期研究结果均表明，接受 teprotumumab 治疗的活动性 TED 患者中，更多患者的眼球突出度有显著改善。
目前的 TED 治疗策略针对炎症和症状，但不会改变疾病进程。因此，眼球突出以及斜视及其导致的复视往往仍然存在，长期影响患者的生活质量和生活质量。使用 teprotumumab 的靶向分子治疗具有疾病修饰益处，有可能改变 TED 治疗的范式。
