Tocilizumab for management of Graves Orbitopathy

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Disease Entity

Graves' ophthalmopathy is one of the remaining puzzles in thyroidology. It is an autoimmune disease that predominantly occurs in patients with Graves' hyperthyroidism, caused by antibodies with affinity for the thyroid stimulating hormone (TSH) receptor initially produced by thyroid lymphocytes. Although the pathophysiological process is still 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 (1)

Clinical

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. (2)

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. (1) Steroid-sparing agents, such as methotrexate and cyclosporine, have been reported as successful second-line agents. (3.4)

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. (1) Tocilizumab is therefore a viable alternative to corticosteroid therapy in situations of intolerance to the adverse effects (4) and in situations where corticosteroids are ineffective in the inflammatory control of the orbitopathy (1)


References

1. Pérez-Moreiras JV, Álvarez-López A, Gómez EC. Treatment of Active Corticosteroid-Resistant Graves’ Orbitopathy: Ophthal Plast Reconstr Surg. 2014;30(2):162–7.

2. Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol. Fevereiro de 2017;5(2):134–42.

3. Maldiney T, Deschasse C, Bielefeld P. Tocilizumab for the Management of Corticosteroid-Resistant Mild to Severe Graves’ Ophthalmopathy, a Report of Three Cases. Ocul Immunol Inflamm. 20 de Novembro de 2018;1–4.

4. Russell DJ, Wagner LH, Seiff SR. Tocilizumab as a steroid sparing agent for the treatment of Graves’ orbitopathy. Am J Ophthalmol Case Rep. Setembro de 2017;7:146–8.