Description of the condition

Thyroid eye disease (TED) is an autoimmune disorder that constitutes a major clinical and therapeutic challenge. TED occurs in up to 50% of individuals with Graves' disease; however, it may also occur without current or prior hyperthyroidism, or in people who are hypothyroid due to chronic autoimmune (Hashimoto’s) thyroiditis (Bartalena 2008). Graves' disease affects approximately 1% to 2% of the adult population (Weetman 2000), and approximately 20% to 25% of those with Graves' hyperthyroidism have clinically apparent TED at the time of diagnosis (Burch 1993; Minakaran 2013). Reported incidence rates are 16/100,000 for women and 2.9/100,000 for men, and calculated prevalence is 0.25% (Bartley 1995).

The pathophysiology of TED is still not completely understood. Stimulation of inflammatory cytokines causes proliferation of the orbital fibroblasts, which in turn produce collagen and glycosaminoglycans in the extracellular matrix (Prabhakar 2003; Wiersinga 2001). The polyanionic charge and the high osmotic pressure of this matrix substance cause swelling of the extraocular muscles (Wiersinga 2001). In addition, a subgroup of orbital fibroblasts can differentiate into new mature fat cells (adipogenesis), which cause increased orbital tissue volume (Sorisky 1996). There is also a role for the humoral‐mediated immune response (Han 2006) in which thyrotropin receptor autoantibodies and immunoglobulins targeting insulin‐like growth factor‐1 receptors contribute to fibroblast activation and glycosaminoglycan secretion (Eckstein 2009; Ezra 2012).

The symptoms of TED may range from sore, gritty and red eyes to double vision, or reduced or loss of vision. The common clinical signs of TED include lid retraction and proptosis. Levator and Muller muscle inflammation and fibrosis can cause upper eyelid retraction, which is seen in up to 90% of affected individuals (Bahn 2010). Proptosis is caused by the expansion of orbital fat (type 1 orbitopathy), muscles (type 2 orbitopathy), or both (Hiromatsu 2000). TED even in its mild form has a deleterious effect on quality of life (Wickwar 2015), and in its severe form can lead to visual loss in 3% to 7% of affected individuals secondary to compressive optic neuropathy or exposure keratopathy (Bahn 2010; Barrio‐Barrio 2015; Kahaly 2005).

The clinical manifestation of TED can be assessed using several classification systems. The NO SPECS (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement, and Sight loss (due to optic nerve involvement) classification was first reported by Werner in 1969 (Werner 1969). Later, Werner published the modified NO SPECS classification and this has been widely used since (Werner 1977). The NO SPECS classification does not differentiate between inflammatory progressive and non‐inflammatory status, but grades clinical severity. Mourits and colleagues later described the Clinical Activity Score (CAS) classification, which differentiates between the active and quiescent stages of the disease and is based on the classic signs of acute inflammation (pain, swelling, redness and impaired function) (Mourits 1989). It was modified in 1997, which included 10‐points that requires two consecutive clinical examinations as three of these items are scored based on the change in clinical signs (Mourits 1997). Active ophthalmopathy is defined as the score greater than or equal to 3/7 at the first examination, or greater than or equal to 4/10 in successive examination. Later in 2006, European Group On Graves' Orbitopathy (EUGOGO) proposed a modification of this classification in which the clinical score can be obtained after a single clinical examination. This modified system has a total score of 7 and does not include an evaluation of change in visual acuity, diplopia or proptosis (EUGOGO 2006). Currently, the VISA (Vision, Inflammation, Strabismus, and Appearance) classification is widely used in the USA and North America, whereas the (EUGOGO) classification is used in Europe (Barrio‐Barrio 2015). Both these classifications assess the signs of activity and the degree of severity of the disease. As with the classification systems available, the treatment options vary: EUGOGO guidelines emphasise the use of intravenous corticosteroid (IV CS) as the superior treatment (Bartalena 2016), whereas the American Thyroid Association (2011) recommend treating the hyperthyroidism rather than the TED itself (Bahn 2011).

Smoking and unstable thyroid function levels are risk factors for TED. Smoking, even the history of smoking, is an independent risk factor associated with an impaired response to TED treatments such as IV CS (Xing 2015). In addition, radioiodine therapy is a significant risk factor for the development or worsening of TED; worsening of the condition can be prevented by use of prophylactic glucocorticoids in individuals with pre‐existing TED (Li 2016).

Individuals with TED usually receive advice on lifestyle modification, such as smoking cessation (Thornton 2007), together with a variety of medical and surgical treatment modalities ranging from immunosuppression with glucocorticoids (Kahaly 2005) to focal radiotherapy (Bartalena 2002) to surgical decompression (Kingdom 2015). Somatostatin analogues and immunomodulators, such as cyclosporine, have been trialled with limited success (Yang 2011). Oral glucocorticoid therapy tapered over 10 to 24 weeks is used frequently, although parenteral steroid administration appears to be superior in efficacy with improved quality of life (Stan 2012). A systematic review of the effectiveness of orbital irradiation found that treatment with a combination of radiotherapy and steroids is superior to steroid monotherapy (Rajendram 2008). Surgical interventions include orbital decompression, strabismus surgery and eyelid surgery. Surgical decompression is usually reserved for individuals with significant proptosis and sight‐threatening compressive optic neuropathy. Several surgical techniques have been used for orbital decompression and the endonasal approach appears to have a low complication rate (Boboridis 2015).

Description of the intervention

Tocilizumab is a recombinant humanised antihuman monoclonal antibody of the immunoglobulin G1 subclass directed against the interleukin (IL)‐6 receptor, produced by recombinant DNA technology (Perez‐Moreiras 2014). Tocilizumab specifically binds to the receptors of IL‐6 (IL‐6R), both the soluble and membrane‐bound forms (IL‐6RM). IL‐6 has been shown to inhibit both IL‐6RM and IL‐6‐mediated trans‐signalling through IL‐6R. Tocilizumab is sold under trade names such as Actemra and RoActemra and is approved by the European Medicines Agency and US Food and Drug Administration for the treatment of individuals with active moderate‐to‐severe rheumatoid arthritis that is unresponsive to standard therapies (Firestein 2003; Rose‐John 2007; Smolen 2003). It is administered intravenously at a dose of 4 to 8 mg/kg every four weeks. Many large‐scale global studies have demonstrated the efficacy and safety of tocilizumab for the treatment of individuals with rheumatoid arthritis, and in April 2008 the drug was first approved in Japan for this indication (Kaneko 2013).

How the intervention might work

There are a number of proposed theories as to how tocilizumab may work in TED. IL‐6 is a proinflammatory cytokine produced by various cell types, including T and B lymphocytes, monocytes and fibroblasts (Jyonouchi 2001; Lehmann 2008). IL‐6 is involved in various physiological processes, such as T‐cell activation, induction of immunoglobulin secretion, induction of the hepatic synthesis of acute‐phase proteins and the stimulation of haemotopoiesis. IL‐6 is present in high concentrations in individuals with TED and plays an important role in the pathogenesis of the disease, as previous in vitro and ex vivo experiments have shown (Anvari 2010; Hiromatsu 2000; Slowik 2012). Immune cells such as B and T lymphocytes play an important role in the early stages of TED. Further disease progression is postulated to involve the recruitment of T cells into the orbit to engage in reciprocal immune activation and amplify B‐cell responses, resulting in inflammatory processes such as the production of cytokines (including IL‐6) and prostaglandins that lead to the tissue expansion and remodelling that is characteristic of the orbital soft tissue expansion seen in TED (Lehmann 2008).

However, in addition to an immunomodulatory function, there is evidence that IL‐6 targeting may also affect mesenchymal cells, which could alter extracellular matrix remodelling. Recent studies have shown that IL‐6 increases the expression of the thyrotropin receptor in orbital preadipocytes (Jyonouchi 2001). Furthermore, high levels of IL‐6 produced by differentiated adipocytes and fibroblasts stimulate B lymphocytes and produce thyroid‐stimulating immunoglobulin (TSI). Fibroblasts present in the orbit, when activated by TSI and tumour growth factor‐beta, may differentiate into myofibroblasts or adipocytes, leading to glycosaminoglycan production, adipogenesis and inflammation or fibrosis (Prabhakar 2003; Smith 1997). Reducing the effect of IL‐6 by blocking its receptors may play a role in lowering TSI blood levels, and in improving proptosis and extraocular motility.

Given the role in TED of IL‐6 expression in adipocytes (Jyonouchi 2001), fibroblasts and macrophages, and the existing experience of the use of different biological therapies, the proposed theory is that inhibition of IL‐6 may be an effective treatment in TED by directly reducing the inflammatory response and fibroblast activity, and hence altering extracellular matrix remodelling.

Why it is important to do this review

TED is the most common extrathyroidal manifestation of Graves' disease and, in its severe form, it can cause visual loss. Current treatment options for moderate‐to‐severe TED include immunotherapy (mainly glucocorticosteroids), orbital radiotherapy (Rajendram 2012) and decompression surgery (Boboridis 2011). Limited drugs of proven efficacy are available for the treatment of individuals with TED. The side‐effect profiles of the currently available treatments are undesirable, especially those of the most commonly used first‐line agents ‐ glucocorticosteroids ‐ which are associated with adverse effects such as diabetes mellitus, hypertension, acute heart failure, weight gain, osteoporosis and acute liver failure.

In addition, there is an unmet need for a new treatment that can modify the natural course of the disease and reduce the incidence of late complications that can occur as a result of fibrosis following inflammation. Tocilizumab is a biological agent that has been used successfully in other autoimmune conditions including rheumatoid arthritis. Some recent studies have demonstrated the efficacy of tocilizumab in the treatment of individuals with active moderate‐to‐severe TED, but there are no clear guidelines regarding its use. It is therefore important to systematically review all the current evidence in order to draw conclusions on the use of tocilizumab in the management of TED.