Etanercept in the treatment of Graves’ ophthalmopathy with primary hypothyroidism and rheumatoid arthritis

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.

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“…OF have an increased expression of TSH-R, and a strong upregulation of TNF-a and IL-6, in the pathogenesis of GO (88).…”

Section: Drugs Targeting Cytokines In Gd and Gomentioning

confidence: 99%

“…After 3 years, she showed symptoms and signs of GO. Then, the patient received etanercept for RA, and after 4 months, the ocular symptoms ameliorated and exophthalmos decreased, showing that RA and GO can share similar pathogenic characteristics (88).…”

Section: Drugs Targeting Cytokines In Gd and Gomentioning

confidence: 99%

Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

et al. 2021

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“…Another paper reported a case of a patient with RA and GO. She was treated with etanercept for RA achieving also a clinical improvement of GO symptoms (Boskovic et al, 2019). Additional researches are needed in order to evaluate the effectiveness of TNF-α inhibitors, and to compare its side effects with the current medical treatment.…”

Section: Etanercept and Tocilizumabmentioning

confidence: 99%

Precision Medicine in Graves’ Disease and Ophthalmopathy

et al. 2021

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Graves’ disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves’ ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

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“…Summary of Clinical Trials and Therapeutic Applications. The efficacy of selected anti-TNFα agents in GO was described in several case reports [56][57][58]. A prospective nonrandomized trial reported the use of etanercept (25 mg twice weekly for 12 weeks) in 10 patients with active GO [59].…”

Section: Anti-tumor Necrosis Factor Alpha Therapymentioning

confidence: 99%

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Lee¹,

Kahaly²

2020

Eur Thyroid J

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Background: Both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders. Summary: Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy. Key Messages: Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.

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Etanercept in the treatment of Graves’ ophthalmopathy with primary hypothyroidism and rheumatoid arthritis

Cited by 13 publications

References 7 publications

Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

Cytokines as Targets of Novel Therapies for Graves’ Ophthalmopathy

Precision Medicine in Graves’ Disease and Ophthalmopathy

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

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