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How suitable is intravenous tocilizumab for the treatment of Graves’ ophthalmopathy?

Graves’ ophthalmopathy (GO), also known as thyroidassociated orbitopathy, is the main extrathyroidal manifestation of Graves’ disease. The symptoms of GO range from sore, gritty, and red eyes to double vision, reduced vision, and loss of vision. Lid retraction and proptosis are common. Inflammation and fibrosis of the elevator and Muller’s muscle can cause upper eyelid retraction, which is seen in up to 90% of affected individuals. Proptosis is caused by expansion of orbital fat (type 1 orbitopathy), extraocular muscles (type 2 orbitopathy), or both [1]. All these symptoms significantly affect the quality of life of patients with Graves’ disease. Most of the signs and symptoms of GO can be explained by the expansion of the orbital contents. The orbital fibroblasts are the target of a spectrum of autoimmune responses that collectively induce proliferation, excess adipogenesis, and overproduction of the extracellular matrix [2]. The clinical manifestations of GO can be assessed using different scales, such as the Clinical Activity Score (CAS). A high CAS helps to select and follow patients who can benefit from immunosuppressive treatment. In mild forms of the disease (95% of the patients), treatment consists of local therapy or systemic corticosteroids. However, GO may be severe and constitute a real medical emergency (sight-threatening GO due to dysthyroid optic neuropathy and/or corneal breakdown). Since it can lead to permanent visual loss, immediate intervention is necessary. The first step in the treatment of thyroid-associated orbitopathy is appropriate control of thyroid function through antithyroid drugs, radioactive iodine, and/or thyroidectomy. Selection of therapy should take into account the clinical history, disease activity, the severity of GO, and previous therapies. Recommendations were very recently updated by the European Group on Grave’s Orbitopathy (EUGOGO). Based on current evidence, efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after informed counseling, the guideline now recommends iv methylprednisolone plus mycophenolate sodium as first-line treatment for patients with active GO [3]. Disappointing results have been reported in up to 20% to 30% of cases treated with corticosteroids. Second-line therapies for moderate-to-severe and active Graves’ ophthalmopathy refractory to iv methylprednisolone are under evaluation. According to the EUGOGO guidelines [3], second-line therapies for moderate-to-severe and active GO refractory to iv methylprednisolone can include a second course of iv methylprednisolone, oral GC combined with either cyclosporine or azathioprine, and various biological therapies. Improved understanding of the pathophysiological mechanisms leading to this inflammatory autoimmune complication has enabled the use of various immunomodulatory agents that are currently under evaluation and whose place in the therapeutic strategy remains to be determined [4]. The main processes involved in the pathogenesis of GO are cytokine production, inflammation, synthesis of hyaluronic acid, adipogenesis, and myofibrillogenesis. The orbital tissues are infiltrated by activated mononuclear cells, predominately T cells, but also by plasmacytes, macrophages, and mast cells. Cytokines produced by leukocytes lead to the synthesis of glycosaminoglycans, causing extraocular muscle edema. Orbital fibroblasts are also more susceptible to inflammatory stimuli than fibroblasts at other sites. Orbital fibroblasts are activated via inflammatory mediators and direct cellular interaction – before proliferating and differentiating into adipocytes and myofibroblasts – and play a key role in the production of the extracellular matrix. Excessive orbital fibroblast activity contributes to expansion, remodeling, and fibrosis of the orbital tissues. Orbital fibroblasts also have the ability to secrete IL-6 and other cytokines, with subsequent orbital infiltration by activated T helper-1 cells (Th-1). IL-6 has been shown to increase expression of the TSH receptor in fibroblasts, leading to increased stimulation of the fibroblast by autoantibodies against the TSH receptor, which is observed in patients with Graves’ disease [2,5]. Monoclonal antibodies have been used in the treatment of active and refractory GO and include the following: tocilizumab (intravenous and subcutaneous), which is an antiinterleukin 6 (IL6) receptor; teprotumumab, an anti–insulin-