Tocilizumab for Management of Graves Orbitopathy
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Disease Entity
Graves' ophthalmopathy(GO), otherwise termed Thyroid Eye Disease(TED), is one of the challenging immunologic orbital disorders often related to autoimmune thyroid dysfunction. Predominantly associated with Graves' hyperthyroidism, it is thought to be caused by antibodies with affinity for the thyroid stimulating hormone receptor(TSH-R) present on the thyroid epithelial cells. Although the pathophysiologic 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 orbital adipocytes and fibroblasts in addition to the 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]. Targeted therapy has been making inroads in various orbital disorders - inflammations, neoplasms, and systemic disorders as well.
Diagnosis
Signs and symptoms of Graves' ophthalmopathy are consequential to secondary effects on the orbital and peri orbital tissues. These arise from extraocular muscle edema and infiltration with peri-orbital fat and connective tissue expansion. Secondary manifestations include eyelid and conjunctival swelling and erythema, exophthalmos, diplopia and, in severe cases, corneal ulceration from severe exposure keratopathy and compression of the optic nerve at the orbital apex with decreased visual acuity. [2]
Management
Graves Ophthalmopathy, although mostly self limiting in the majority often warrants management owing to the degree of morbidity, symptomatology and significant reduction in quality of life. For the early Active Inflammatory state, the most commonly used initial pharmacological treatment is either oral or preferably intravenous pulsed corticosteroid therapy. 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. Unmonitored, potential side effects include worsening diabetes mellitus, osteoporosis, insomnia, psychosis, and hepatic injury. In addition, 20-25% of patients do not respond to standard recommended doses of corticosteroid therapy. [1] Steroid-sparing agents, such as azathioprine, methotrexate or cyclosporine, have been reported as successful second-line agents but have variable effects with their respective toxicities. [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][5] Subcutaneous administration of tocilizumab has also been reported to be efficacious in thyroid eye disease.[6][7]
In summary, Tocilizumab, an IL-6 agent may be an alternative following inadequate or failed response to conventional and other evidence based second line therapeutic options for persistent/refractory severe Graves ophthalmopathy, including Dysthyroid optic Neuropathy prior to considering urgent orbital decompression.
References
- ↑ 1.0 1.1 1.2 1.3 Pérez-Moreiras JV, Álvarez-López A, Gómez EC. Treatment of Active Corticosteroid-Resistant Graves’ Orbitopathy: Ophthal Plast Reconstr Surg. 2014;30(2):162–7.
- ↑ Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves’ ophthalmopathy. Lancet Diabetes Endocrinol. Fevereiro de 2017;5(2):134–42.
- ↑ 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.
- ↑ 4.0 4.1 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.
- ↑ Sy A, Eliasieh K, Silkiss RZ. Clinical Response to Tocilizumab in Severe Thyroid Eye Disease. Ophthalmic Plast Reconstr Surg. 2017 May/Jun;33(3):e55-e57. doi: 10.1097/IOP.0000000000000730. PMID: 27281483.
- ↑ Copperman T, Idowu OO, Kersten RC, Vagefi MR. Subcutaneous Tocilizumab for Thyroid Eye Disease: Simplified Dosing and Delivery. Ophthalmic Plast Reconstr Surg. 2019 May/Jun;35(3):e64-e66. doi: 10.1097/IOP.0000000000001346. PMID: 30865069.
- ↑ Silkiss RZ, Paap MK, Roelofs KA, Agi J, Weis E. Treatment of corticosteroid-resistant thyroid eye disease with subcutaneous tocilizumab. Can J Ophthalmol. 2021 Feb;56(1):66-70. doi: 10.1016/j.jcjo.2020.07.020. Epub 2020 Sep 10. PMID: 32919997.
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