Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

Abstract

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 per se, 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.

The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

“…Tocilizumab, a humanized recombinant IL-6R monoclonal antibody, can improve disease activity and severity in corticosteroid-resistant GO patients ( Perez-Moreiras et al., 2018 ; Sánchez-Bilbao et al., 2020 ). Infliximab, an antitumor necrosis factor (TNF)-α antibody, has been successfully used to treat sight-threatening GO ( Durrani et al., 2005 ; Komorowski et al., 2007 ; Fallahi et al., 2021 ). Both IL-6 and TNF-α are monocyte-derived key proinflammation cytokines.…”

Future Projections in Thyroid Eye Disease

“…A number of immune cells and cytokines are thought to be involved in the pathogenesis of TED ( 43 , 44 ). Several monoclonal antibodies able to interfere with cytokine signalling are available for treatment of moderate-to-severe TED, but only a few of these immunosuppressants have been tested in randomized clinical trials.…”

Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes

“…Zheng et al 10.3389/fimmu.2022.952954 be hypothesized that cell-mediated (Th1-type) immune responses predominate in the early phases of GO, whereas humoral immunity (Th2-type) plays a larger role in the latter stages.Th1 cells produce cytokines including interferon (IFN)-g, interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)-a, which cause OFs to create and release significant amounts of glycosaminoglycans like hydrophilic hyaluronan, resulting in swelling of orbital tissues (especially the extraocular muscles) (8). Among others, it has also been shown that IL-1b is associated with adipogenesis in GO (9).…”