Department of Translational Research of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Front Endocrinol (Lausanne). 2021 Apr 16;12:654473. doi: 10.3389/fendo.2021.654473. eCollection 2021.
Graves' disease (GD) is an organ-specific autoimmune disorder of the thyroid, which is characterized by circulating TSH-receptor (TSH-R) stimulating antibodies (TSAb), leading to hyperthyroidism. Graves' ophthalmopathy (GO) is one of GD extra-thyroidal manifestations associated with the presence of TSAb, and insulin-like growth factor-1 receptor (IGF-1R) autoantibodies, that interact with orbital fibroblasts. Cytokines are elevated in autoimmune (i.e., IL-18, IL-6) and non-autoimmune hyperthyroidism (i.e., TNF-α, IL-8, IL-6), and this could be associated with the chronic effects of thyroid hormone increase. A prevalent Th1-immune response (not related to the hyperthyroidism , but to the autoimmune process) is reported in the immune-pathogenesis of GD and GO; Th1-chemokines (CXCL9, CXCL10, CXCL11) and the (C-X-C)R3 receptor are crucial in this process. In patients with active GO, corticosteroids, or intravenous immunoglobulins, decrease inflammation and orbital congestion, and are considered first-line therapies. The more deepened understanding of GO pathophysiology has led to different immune-modulant treatments. Cytokines, TSH-R, and IGF-1R (on the surface of B and T lymphocytes, and fibroblasts), and chemokines implicated in the autoimmune process, are possible targets of novel therapies. Drugs that target cytokines (etanercept, tocilizumab, infliximab, adalimumab) have been tested in GO, with encouraging results. The chimeric monoclonal antibody directed against CD20, RTX, reduces B lymphocytes, cytokines and the released autoantibodies. A multicenter, randomized, placebo-controlled, double-masked trial has investigated the human monoclonal blocking antibody directed against IGF-1R, teprotumumab, reporting its effectiveness in GO. In conclusion, large, controlled and randomized studies are needed to evaluate new possible targeted therapies for GO.
格雷夫斯病（GD）是一种甲状腺特异性自身免疫性疾病，其特征是循环 TSH 受体（TSH-R）刺激抗体（TSAb），导致甲状腺功能亢进。格雷夫斯眼病（GO）是 GD 的甲状腺外表现之一，与 TSAb 和胰岛素样生长因子-1 受体（IGF-1R）自身抗体有关，这些自身抗体与眼眶成纤维细胞相互作用。细胞因子在自身免疫性（即 IL-18、IL-6）和非自身免疫性甲状腺功能亢进症（即 TNF-α、IL-8、IL-6）中升高，这可能与甲状腺激素持续升高的慢性影响有关。在 GD 和 GO 的免疫发病机制中，报道了普遍存在的 Th1 免疫反应（与甲状腺功能亢进无关，但与自身免疫过程有关）；Th1-趋化因子（CXCL9、CXCL10、CXCL11）和（C-X-C）R3 受体在这一过程中至关重要。在活动期 GO 患者中，皮质类固醇或静脉注射免疫球蛋白可减少炎症和眼眶充血，被认为是一线治疗方法。对 GO 病理生理学的更深入了解导致了不同的免疫调节剂治疗。细胞因子、TSH-R 和 IGF-1R（在 B 和 T 淋巴细胞和成纤维细胞表面）以及参与自身免疫过程的趋化因子，可能是新疗法的靶点。针对细胞因子（依那西普、托珠单抗、英夫利昔单抗、阿达木单抗）的药物已在 GO 中进行了测试，结果令人鼓舞。针对 CD20 的嵌合单克隆抗体 RTX 可减少 B 淋巴细胞、细胞因子和释放的自身抗体。一项多中心、随机、安慰剂对照、双盲试验研究了针对 IGF-1R 的人源单克隆阻断抗体 teprotumumab，报告了其在 GO 中的有效性。总之，需要进行大型、对照和随机研究，以评估 GO 的新可能靶向治疗方法。
