Tocilizumab for Management of Graves Orbitopathy
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Disease Entity
Graves orbitopathy(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 understood, 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 orbitopathy are consequential to secondary effects on the orbital and peri orbital tissues. Early manifestations arise from fibroblasts within extraocular muscles and infiltration with periorbital 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 Orbitopathy, 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 of the disease, corticosteroids administered intravenously as pulsed doses is most commonly administered in most parts of the world 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 which may be minimzed with serial clinical and laboratory monitoring. In addition, 20-25% of patients do not respond to standard recommended doses of corticosteroid therapy and may benefit from higher doses with toxicity being looked out for. [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 anti-interleukin-6 receptor (IL-6R) 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 may be administered intravenously at a dose of 4 to 8 mg / kg every 4 weeks or subcutaneously at doses of 162 mg weekly. Duration of therapy is based on sustainability of clinical response with relapse rates of 8.2%.
Most evidence is in the form of isolated or small case series although there is only one randomized controlled clinical trial to date.
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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