Tocilizumab for Management of Graves Orbitopathy

Article initiated by:

Jorge Meira

All authors and contributors:

Vitor Leal, Fernando Falcão-Reis, Luís Figueira, Nagham Al-Zubidi, MD, Jorge Meira, Gangadhara Sundar, MD, Michael T Yen, MD

Assigned editor:

Danah Albreiki, MBBS FRCSC, Gangadhara Sundar, MD

Review:

Assigned status Update Pending

 by Gangadhara Sundar, MD on September 24, 2022.

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Disease Entity

Graves' ophthalmopathy, otherwise termed Thyroid Eye Disease, is one of the challenging immunological orbital disorders often related to autoimmune thyroid dysfunction. An autoimmune disease that predominantly occurs in association with Graves' hyperthyroidism, it is caused by antibodies with affinity for the thyroid stimulating hormone (TSH) receptor initially produced by thyroid lymphocytes. Although the pathophysiological process is only partially misunderstood, the role of B lymphocytes is well established. Self-reactive B cells recognize an autoantigen, the TSH receptor, present in the orbit and thyroid follicular cells, and secrete cytokines (such as interleukin-6) that stimulate fibroblasts to produce glycosaminoglycans, which in turn attract fluid and result in muscle and periorbital edema

Diagnosis

Signs and symptoms of Graves' ophthalmopathy include extraocular muscle edema, peri-orbital fat and connective tissue expansion, eyelid and conjunctival swelling and erythema, exophthalmia, diplopia and, in severe cases, corneal ulceration and decreased visual acuity.

Management

For the inflammatory state of ophthalmopathy, the most commonly used initial pharmacological treatment is oral or intravenous corticotherapy. Although suppression of inflammatory activity can often be achieved, the effect of corticosteroids is pleiotropic and involves transcriptional activation and suppression of a wide range of genes resulting in significant morbidity, including worsening diabetes mellitus, osteoporosis, insomnia, psychosis, and hepatic injury. In addition, 20-25% of patients do not respond to corticosteroid therapy. Steroid-sparing agents, such as methotrexate and cyclosporine, have been reported as successful second-line agents.

Tocilizumab (TCZ) (RoActemra, Hoffmann-La Roche Ltd., Basel, Switzerland) is a recombinant humanized IgG1 anti-IL-6 monoclonal antibody. It specifically binds to both soluble and membrane bound IL-6 receptors (IL-6RS and IL-6 RM). TCZ has been approved by the EMEA (European Medicines Agency) and FDA (Food and Drug Administration) for the treatment of moderate to severe rheumatoid arthritis that does not respond to standard treatments. It is administered intravenously at a dose of 4 to 8 mg / kg every 4 weeks.

Recent studies have shown that IL-6 increases TSH receptor expression in fibroblasts. Tocilizumab's action resides in the blockage of IL-6 receptors and the resulting inflammatory process. Elevated levels of IL-6 produced by differentiated adipocytes and fibroblasts stimulate B lymphocytes to produce thyroid stimulating immunoglobulin (IST). Fibroblasts present in the orbit, when activated by TSI and TGF-β, can differentiate into myofibroblasts or adipocytes, producing glycosaminoglycans, adipogenesis and inflammation or fibrosis. Reducing the effect of IL-6 by blocking its receptors may play a role in reducing serum IST levels and improving proptosis and extraocular mobility. Tocilizumab is therefore a viable alternative to corticosteroid therapy in situations of intolerance to the adverse effects and in situations where corticosteroids are ineffective in the inflammatory control of the orbitopathy Subcutaneous administration of tocilizumab has also been reported to be efficacious in thyroid eye disease.