Ciarmatori Nicolò, Quaranta Leoni Flavia, Quaranta Leoni Francesco M
Department of Translational Medicine, University of Ferrara, 44121 Ferrara, Italy.
Department of Ophthalmology, Ospedali Privati Forlì "Villa Igea", 47122 Forlì, Italy.
J Clin Med. 2025 Aug 6;14(15):5528. doi: 10.3390/jcm14155528.
Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves' disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life.
甲状腺眼病（TED）是一种罕见的自身免疫性眼眶疾病，主要与格雷夫斯病相关。其特征为眼眶炎症、组织重塑以及潜在的视觉功能损害。传统疗法，尤其是全身使用糖皮质激素，仅能提供部分症状缓解，无法逆转如眼球突出和复视等慢性结构改变，且伴有大量不良反应。本综述旨在综合近期对TED发病机制的认识进展，并批判性地评估新兴治疗策略。使用MEDLINE、Embase和国际临床试验注册库进行了系统的文献综述，重点关注针对TED核心分子途径的关键临床试验和研究性疗法。目前的证据表明，TED发病机制主要由眼眶成纤维细胞（OFs）通过促甲状腺激素受体（TSH-R）和胰岛素样生长因子-1受体（IGF-1R）信号通路的自身免疫激活所驱动。替普罗单抗是一种单克隆IGF-1R抑制剂，也是美国食品药品监督管理局批准用于TED的首个疗法，已显示出显著的临床益处，包括眼球突出、复视和生活质量的改善。然而，对于复发率和治疗相关不良事件，尤其是听力损害，仍存在担忧。包括下一代IGF-1R抑制剂、小分子拮抗剂、TSH-R抑制剂、新生儿Fc受体（FcRn）阻滞剂、细胞因子靶向药物和基于基因的干预措施等研究性疗法正在研发中。这些新方法旨在解决TED的炎症和纤维化成分。替普罗单抗改变了TED的治疗方式，但持续控制和降低毒性仍然是挑战。未来的治疗应侧重于靶向、基于机制的个性化方法，以改善长期疗效和患者生活质量。
