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

KEYWORDS:

• Graves’ ophthalmopathy
• therapy
• glucocorticoids
• tocilizumab
• immunotherapy

Graves’ ophthalmopathy (GO), also known as thyroid-associated 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 anti-interleukin 6 (IL6) receptor; teprotumumab, an anti–insulin-like growth factor 1 receptor; rituximab, which targets CD20; and infliximab, etanercept, and adalimumab, which are TNF antagonists [6].

The present Editorial focuses on tocilizumab, a humanized recombinant monoclonal antibody, because no conflictive results have been published in the literature and tocilizumab is widely available. It is used in GO owing to the significant increase in IL-6 levels in the active phase of the disease [7].

Tocilizumab has been used off-label in GO and in other autoimmune and inflammatory diseases, although it is approved for clinical use in rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome in patients treated with chimeric antigen receptor for T cell-induced severe or life-threatening cytokine release syndrome. A potential role for this monoclonal antibody has also been suggested in selected cases of severe COVID19 infection in combination with corticosteroids.

To date, tocilizumab has been evaluated in around 175 patients with active cortico-resistant GO, including single-center case reports and case series [8], an observational multicenter study [9], case control studies [10], and one randomized clinical trial [11]. On average, the CAS improved in as many as 95% of these reported patients. In most patients, proptosis and inflammation have been shown to improve.

The only available randomized clinical trial in which tocilizumab has been used as a treatment for GO corresponds is that of Perez-Moreiras et al [11], who used tocilizumab in active cortico-resistant GO and disclosed satisfactory results for activity and severity, with reduced proptosis and improved extraocular mobility. This result was subsequently confirmed in a multicenter study by Sánchez-Bilbao et al [9] and a recent observational retrospective study by Pérez-Moreiras et al [8]. There was also a decrease in the titers of anti-TSH receptor antibodies. No severe adverse effects were recorded. All the patients in this cohort had previously received methylprednisolone, which did not prove to be efficacious.

Very few published studies to date (including case reports and case series) compare the efficacy of tocilizumab with that of other therapies in GO. A randomized controlled trial comparing tocilizumab with mycophenolate in cortico-resistant GO is warranted. Tocilizumab might compare favorably with other monoclonal antibodies, e.g., rituximab, which causes less collateral damage.

Although evidence from larger-scale randomized trials and meta-analyses is needed before recommending tocilizumab as therapy in GO, preliminary studies on the proposed mechanism of action of tocilizumab have revealed new insights into the role of inflammatory cytokines in pathogenesis [2,12]. Tocilizumab may have a role in moderate-to-severe cases that are refractory to corticosteroids and in cases where corticosteroids are contraindicated. Well-designed, multicenter randomized controlled trials with large numbers of patients are warranted to further support this therapeutic option in GO. Of particular interest, clinical trials should focus on the comparison between tocilizumab as monotherapy with corticosteroids and other biologic agents in order to determine whether tocilizumab has a role in patients with active GO or whether its role is only as a therapy in those whose disease does not respond to other options.

Regarding safety, cytopenia and elevation of transaminases have been described in patients using tocilizumab. Close monitoring of these parameters is recommended [13]. In a long-term follow-up performed in a real-life study by Sanchez-Bilbao et al [9], no severe tocilizumab-related adverse reactions were reported after a mean of 16 ± 2 months of therapy with tocilizumab.

Tocilizumab supplies are now dwindling because of the COVID-19 pandemic [14]. Meanwhile, several studies have reported on the use of subcutaneous tocilizumab in GO [15,16]. The potential role of other monoclonal antibodies should be considered. A randomized controlled trial comparing teprotumumab with placebo in active GO, once every 3 weeks for 21 weeks, showed improvement in the CAS and quality of life in patients who received teprotumumab. Teprotumumab is approved by the United States Food and Drug Administration, is generally well tolerated, and has not been associated with increased serum aminotransferase values [17,18]. However, the advantages of tocilizumab over teprotumumab are the duration of treatment (shorter with tocilizumab) and its lower cost.

In GO, immunotherapy is offering an opportunity to prevent unfavorable outcomes that lead to disfigurement, impairment of vision, and severely decreased quality of life. In summary, data suggest that tocilizumab can safely and rapidly resolve inflammatory signs in cortico-resistant, moderate-to-severe, and active GO. Immunotherapy could prove to be a suitable therapeutic option. Well-designed multicenter randomized controlled trials with large samples are warranted to further support the use of this therapy in GO, in terms of both dose and duration [17].

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors acknowledge Thomas O´Boyle for revision of English.

Funding

This paper was not funded.