Ocular treatment of thyroid eye disease

Abstract

Thyroid eye disease is an autoimmune disease affecting ocular and orbital tissues. The inflammation may or may not parallel systemic thyroid conditions such as Graves’ disease. Disease manifestations result from tissue remodeling within the orbit. The abnormal stimulation of immune cells and orbital fibroblasts is probably involved. Our current understanding of the pathophysiology of the disease is limited and few rational therapies have been designed that target the underlying disease process. Treatment strategies vary depending on disease severity and activity. Recent small-scale studies have shown some promise with B-cell-depleting drugs such as rituximab, but this therapy requires further evaluation. The testing of new treatments is hindered by the lack of a reliable animal model of thyroid eye disease.

Keywords::

• autoantibodies
• B-cell depletion
• clinical activity score
• dysthyroid optic neuropathy
• Graves’ disease
• orbital decompression
• orbital fibroblasts
• rituximab
• thyroid eye disease

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Learning Objectives

Upon completion of this activity, participants should be able to:

• • Describe clinical features and the most common presentations of TED

• • Assess risk factors associated with TED progression and describe classification systems for severity of TED

• • Review treatment options for different severity and disease activity of TED

Financial & competing interests disclosure

Editor

Elisa Manzotti, Editorial Director, Future Science Group, London, UK.Disclosure:Elisa Manzotti has disclosed no relevant financial relationships.

CME Author

Désirée Lie, MD, MSEdClinical Professor, Family Medicine, University of California, Irvine, Orange, CA, USA; Director of Research and Patient Development, Family Medicine, University of California, Irvine, Medical Center, Rossmoor, CA, USA.

Disclosure:Désirée Lie has disclosed the following relevant financial relationship: she has served as a nonproduct speaker for ‘Topics in Health’ for Merck Speaker Services.

Authors and Credentials

Knut Eichhorn, MD, PhDDepartment of Ophthalmology, University of Minnesota, Minneapolis, MN, USA.

Disclosure:Knut Eichhorn has disclosed no relevant financial relationships.

Andrew R Harrison, MDDepartment of Ophthalmology; Department of Otolaryngology, University of Minnesota, Minneapolis, MN, USA.

Disclosure:Andrew R Harrison has disclosed no relevant financial relationships.

Erick D Bothun, MDDepartment of Ophthalmology; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.

Disclosure:Erick D Bothun has disclosed no relevant financial relationships.

Linda K McLoon, PhDDepartment of Ophthalmology; Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.

Disclosure:Linda K McLoon has disclosed no relevant financial relationships.

Michael S Lee, MDDepartment of Ophthalmology; Department of Neurosurgery; Department of Neurology, University of Minnesota, Minneapolis, MN, USA.

Disclosure:Michael S Lee has disclosed no relevant financial relationships.

Figure 1. Algorithm for the management of patients with thyroid eye disease.

CAS: Clinical activity score.

Graves’ disease is an autoimmune disease characterized by the enlargement of thyroid follicles, as well as the dysregulated stimulation of thyroid hormone synthesis. The increase in the circulating thyroid hormones tri-iodothyronine (T3) and thyroxine (T4) leads to the clinical symptoms and signs of hyperthyroidism, including weight loss, heat intolerance, tremor, insomnia, tachycardia, hyper-reflexia and warm, moist skin (for a recent review on Graves’ disease, see [1]).

One of the underlying disease mechanisms of Graves’ disease is the presence of circulating antibodies directed against the thyrotropin receptor. Thyrotropin, or thyroid-stimulating hormone (TSH), is a peptide hormone secreted by the pituitary gland. TSH binds to a surface receptor on follicular cells within the thyroid gland and stimulates the synthesis and secretion of thyroid hormones. The autoantibodies present in the serum of patients with Graves’ disease are thought to bind to and activate the same receptor. Hyperthyroid Graves’ disease can be treated with multiple modalities, including medical treatments such as anti-thyroid drugs (methimazole) or radioactive iodine, and surgical treatments such as thyroidectomy [2].

In addition to the systemic symptoms and signs described earlier, many patients with Graves’ hyperthyroidism present along with characteristic ocular and orbital manifestations. It is believed that the thyroid gland and ocular adnexa share one or more antigens that are the target of autoreactive T and B lymphocytes and antibodies. The ocular disease manifestations are referred to as thyroid eye disease (TED; also referred to as Graves’, or thyroid-associated, ophthalmopathy or orbitopathy).

Epidemiology of thyroid eye disease

Graves’ disease is a relatively common autoimmune disease. The prevalence of the disease is estimated at between 0.5 and 2% [3]. Approximately 50% of patients with Graves’ disease develop clinically apparent TED. However, when patients without overt ocular involvement are investigated with orbital imaging, pathologic changes, such as enlargement of the extraocular muscles, are detected in an additional two thirds of patients [4].

The majority of patients with TED also have underlying hyperthyroid Graves’ disease. However, based on blood levels of T3, T4 and TSH, approximately 10% of patients are clinically defined as euthyroid or hypothyroid. In this minority group, thyroid-specific autoantibodies can be detected in approximately 75% of individuals, which is helpful in making the diagnosis in these atypical patients. Patients with eu- or hypothyroid eye disease are also more likely to develop asymmetric eye involvement [5].

The onset of ocular disease may coincide with, precede or follow the systemic disease manifestations, usually within 6 months before or after the onset of hyperthyroidism [6]. Systemic Graves’ disease and TED can therefore be considered two entities that probably share certain underlying disease mechanisms, but that may present and progress independently from one another. What causes the differential expression of these two entities is currently not well understood.

Women are affected more frequently by TED than men. The female-to-male ratio has been estimated at 5.5 [7]. There are two peaks in the incidence of age of onset, one in the fifth decade and another in the seventh decade [7], with women being slightly younger on average than men. In older patients, disease tends to be more severe. Ocular manifestations present as bilateral disease in 85–95% of patients [8]. In patients with bilateral disease, orbital changes may present asymmetrically, especially in those with eu- or hypothyroid disease [5].

Disease manifestations & natural history

Characteristic signs and symptoms of TED that were described in a cohort of 120 patients consisted of eyelid retraction (80%), exophthalmos (62%), extraocular muscle dysfunction with or without diplopia (43%), and pain (30%). Other common complaints include excessive tearing, foreign body sensation, redness of the eyes and eyelids, blurred vision and photophobia [9]. Severe disease with visual loss from a compressive optic neuropathy was infrequent and was seen in only 6% of the cohort described earlier. With the currently accepted course of treatment, visual loss was permanent in less than 2%, and was relatively mild (final acuity of 20/30 in one patient and 20/60 in another patient of the cohort).

The morbidity of TED resulting from ocular irritation and discomfort, tearing, double vision and cosmetic disfigurement is high. Sickness impact questionnaires demonstrate that mild-to-moderately severe TED has a significant negative influence on the quality of life of patients [10]. Compared with a reference cohort, patients scored significantly lower when asked about physical, role and social functioning, mental health, health perceptions, and bodily pain.

The natural history of TED is not completely understood. It has an incidence of 16 (female) and 2.9 (male) cases per 100,000 individuals [7]. Typically, the ophthalmopathy undergoes an initial, active phase of progressive exacerbation, followed by a subsequent partial regression and eventually an inactive phase in which the residual manifestations of the disease are unlikely to show any further substantial change [11]. The time from initial symptoms to inactivity is usually 2–5 years in most patients [7].

Pathogenesis

The characteristic clinical findings of TED of redness and swelling of the periorbital tissues (including the eyelids, conjunctiva and caruncle) are likely related to an increase in inflammatory mediators. An increase in the size and number of fat cells and fibroblasts, in conjunction with the secretion of glycosaminoglycans, leads to an expansion of the orbital volume and results in congestion of orbital structures and proptosis. Inflammation of the extraocular muscles initially causes swelling and eventually leads to fibrosis and scarring, resulting in restrictive strabismus. Optic neuropathy may result from compression of the optic nerve by enlarged muscles, especially when this occurs at the orbital apex. Eyelid retraction is a complex change and may be caused by enlargement and fibrosis of the levator palpebrae superioris muscle [12], sympathetic overstimulation [13], fixation duress due to inferior rectus restriction, and possibly orbicularis oculi weakness due to muscle loss [14]. This contributes to lagophthalmos and exposure keratopathy.

It is believed that the pathological changes outlined previously are initiated by autoreactive T lymphocytes that migrate into the fat, extraocular muscles and other soft tissues of the orbit, and become activated by reacting to autoantigens present in these tissues [15]. The activated T lymphocytes then trigger an inflammatory reaction that involves the release of cytokines, which in turn stimulates the proliferation of fibroblasts, secretion of glycosaminoglycans, expansion of fat cells and inflammation of the extraocular muscles.

The TSH receptor has been identified as a possible autoantigen that is present both in the thyroid gland and in orbital tissues, and which may trigger and sustain the autoimmune response [16]. Disease is associated with antibodies to the TSH receptor [17]. Other postulated autoantigens include the IGF receptor [18], extraocular muscle proteins [19] and thyroglobulin [15]. Although TSH receptor antibodies, especially the stimulating TSH receptor antibodies that activate the receptor on the follicular cells in the thyroid gland, conceptually explain the hyperthyroidism in systemic Graves’ disease, other factors appear to be involved in the pathogenesis of TED. In animal models, the induction of TSH receptor autoantibodies alone reproduces hyperthyroidism but does not cause TED.

Immunohistochemical analysis of the retrobulbar tissue from patients with TED shows infiltration with T lymphocytes, and to a lesser extent B lymphocytes and macrophages [20]. Patients in the early inflammatory stage of disease show a significantly more prominent T-cell infiltration than patients in the late fibrotic stage [21]. The communication between orbital fibroblasts and activated T cells may occur via CD40–CD40 ligand (CD40L) signaling. CD40 is a surface receptor expressed by B cells, some other antigen-presenting cells and orbital fibroblasts. CD40 interacts with CD40L, which is expressed on activated T cells. The expression of CD40 on orbital fibroblasts is upregulated tenfold by stimulation with IFN-γ [22]. Upon stimulation with CD40L-expressing T cells in vitro, fibroblasts expressed the proinflammatory cytokines IL-6 and -8. These studies suggest fibroblasts may be a viable target for therapy.

Orbital fibroblasts are key cellular components in tissue remodeling in the orbits of patients with TED. They not only participate in the recruitment of cells of the immune system, but are also involved in remodeling of the connective and adipose tissue, and of the extraocular muscles [15]. Smith and coworkers showed that there are two subpopulations of orbital fibroblasts that differ in their expression of the surface glycoprotein Thy-1 (CD90) [23,24]. The perimysium is a sheath of connective tissue surrounding muscle fibers and grouping them into bundles. Fibroblasts within the perimysium of extraocular muscles represent a different subpopulation from those found in the connective and adipose tissue of the orbit. The perimysial fibroblasts are Thy-1-positive. When stimulated in vitro with rosiglitazone, an agonist shown to trigger adipogenesis, they do not differentiate into adipocytes. The fibroblasts in the connective and adipose tissue of the orbit, on the other hand, contain a subpopulation of cells that are Thy-1 negative. These cells show a very dramatic response to rosiglitazone in vitro and differentiate into fat cells. It has therefore been suggested that Thy-1-negative fibroblasts are pre-adipocytes [23]. These intrinsic differences between fibroblasts within orbital tissues again suggest that they may play a role in the etiology or progression of autoimmune diseases [25].

Orbital fibroblasts incubated in vitro with cytokines such as IFN-γ or leukoregulin can also be stimulated to synthesize increased levels of extracellular matrix glycosaminoglycans such as hyaluronin [26]. This is probably one of the mechanisms of volume expansion in the orbit seen in TED. Orbital fibroblasts not only respond to cytokines secreted by lymphocytes, but they also secrete many different proinflammatory cytokines [27]. Orbital fibroblasts therefore are not only targets of proinflammatory signals, but are also amplifiers and contributors of the same. Therefore, they appear to represent a key player in the autoimmune response in TED and may be a potential target for therapy development.

Risk factors for developing disease

There appear to be both genetic and environmental factors that determine the expression of autoimmune thyroid disease. Approximately 50% of patients with Graves’ disease have a positive family history [28]. Twin studies show that disease concordance is significantly higher in monozygotic twins than in dizygotic twins, with rates of 35 and 3%, respectively [29].

There are approximately 50 genes that confer some increased susceptibility to TED [15]. Candidates include certain genes that modulate the immune response and those that are involved in thyroid hormone metabolism. Examples of genes modulating the immune response are those that encode the following proteins: HLA-DR3, CTLA-4, CD40, PTPN22 and IL-23R. Candidate genes involved in thyroid hormone metabolism include those for thyroglobulin and the TSH receptor. However, it is not a single gene but a combination of specific mutated alleles of various genes that likely confers susceptibility. The involvement of many genes may explain distinct phenotypes, variations in symptomatology, severity of disease course and treatment responses.

Furthermore, the interaction of environmental factors and an individual’s genotype contribute to the expression and severity of TED. The most significant modifiable environmental risk factor for TED is smoking [30]. Individuals with Graves’ disease who smoke are at a higher risk of developing TED, have a more severe form of disease and respond less favorably to treatment than nonsmokers in a dose-dependent fashion. Graves’ patients who currently smoke develop TED between two and ten times as often as nonsmokers. Smokers who quit reduce their risk of TED to rates similar to those who have never smoked [30–32]. Smoking also changes the response of patients to treatment with corticosteroids. One study found that nonsmokers experienced improvement in lid fissure width, proptosis and intraocular pressure, whereas smokers experienced a worsening in all three in a dose-dependent fashion [33]. Other studies have confirmed that smoking decreases the efficacy of orbital radiotherapy and systemic steroid administration, and increases the risk for progression of disease after radioactive iodine treatment [34,35].

Animal models

Thyroid eye disease occurs spontaneously only in humans. Currently, there is no reproducible animal model that simulates the disease satisfactorily to study either the pathogenesis of the disease or to test potential new treatments [36]. Hyperthyroid Graves’ disease, on the other hand, has been reproduced in various mouse models, in which TSH receptor autoantibodies are produced in response to the abnormal in vivo expression of the receptor. This has been done by injecting animals with fibroblasts [37] or B-cell lymphoma cells [38] that have been transfected to express the receptor, or by vaccinating animals with TSH receptor DNA in a eukaryotic expression system, such as adenoviral DNA vectors [39]. It has also been possible to create animal models of Graves’ disease by the passive transfer of monoclonal antibodies against the TSH receptor [40]. To varying degrees, these mouse models mimic the pathophysiology of Graves’ disease, and reproduce hyperthyroidism and thyroid gland inflammation [36].

It has been more difficult, however, to create a reproducible mouse model that simulates the extrathyroidal manifestations, in particular those that characterize TED [36]. This observation strongly suggests that autoantibodies against the TSH receptor alone are not sufficient to cause TED, and that the molecular pathophysiology of the disease is more complex, with additional factors involved.

Several studies have looked at the role that B cells play in the pathogenesis of hyperthyroid Graves’ disease by depleting B-cell survival factors such as B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) in animal models of the disease. By targeting these factors, both the rise in TSH receptor antibody levels, as well as hyperthyroidism, could be suppressed [41,42]. Once an adequate experimental model for the disease has been developed, the effect of inhibiting B-cell survival factors such as BAFF or APRIL on the severity of TED can be tested by similar methods. This will help to determine whether B-cell targeting may be a viable therapeutic strategy for TED in humans.

Other studies have looked at the effect of hyperthyroidism on the orbicularis oculi and extraocular muscles in rabbits, and noted significant loss of muscle mass [14,43]. These studies, while not replicating TED, can help to give us insight into the effects of the elevated thyroid hormone levels on orbital tissues. It may be that with an accelerated turnover of extraocular muscle fibers, cellular antigens such as calsequestrin may have an increased opportunity to be exposed to T and B lymphocytes [19]. Future studies are needed to examine this hypothesis.

Treatment of TED

It is challenging for the ophthalmologist to determine exactly where along the natural history of TED a patient may be after a single visit. A detailed history and clinical examination may differentiate between the active inflammatory phase and the inactive fibrotic phase. However, for a patient with active disease, it is not possible after a single visit to determine whether the disease is still progressing, or whether it has already peaked and may be regressing. Approximately two thirds of TED patients spontaneously enjoy mild-to-moderate improvement without medical intervention [44]. Therefore, interventional treatment decisions, except in the rare cases of sight-threatening disease, are typically not begun until after a period of observation. Medical or surgical intervention in a patient who is on the path of spontaneous improvement may cause more harm than good. In the absence of sight-threatening disease, surgical interventions should be delayed until a state of disease inactivity, and of stability of clinical signs and symptoms, has been achieved.

In the following sections, we outline in detail the treatment algorithm we use in the Center for Thyroid Eye Disease at the University of Minnesota Department of Ophthalmology (Figure 1). The algorithm is in large part based on recommendations made by the European Group on Graves’ Orbitopathy (EUGOGO), a multidisciplinary consortium of clinicians from various European centers with expertise in the management of TED [45]. As large-scale randomized clinical trials have not been conducted for most questions in the management of the disease, these recommendations were meant to be considered as a consensus statement, rather than evidence-based practice.

Two important concepts in the evaluation of patients are their disease severity and activity, which will be further elaborated on in the following two sections.

Disease severity

In 1969, a classification scheme of the eye changes in TED was introduced by the American Thyroid Association [46]. This system was subsequently modified in 1977 and has since been used to rate the severity of TED, separating patients into seven classes of disease (class 0–6) [47]. Based on the first letter of the defining characteristic of each class, the classification is known as: ‘no signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea; sight loss’ (NOSPECS) (Table 1). Furthermore, the severity of each clinical parameter in a class can be further described by a grading system of o (absent), a (minimal), b (moderate) and c (maximal).

The European Group on Graves’ Orbitopathy has recommended a different classification system for severity that stratifies patients to one of three classes (Table 2)[45].

Disease activity

Disease activity can be assessed using the clinical assessment score (CAS). This set of clinical criteria was initially described in 1989 [48] and has been widely used in assessing patients with TED and in planning their treatment. The criteria include seven clinical parameters of inflammation easily determined in the clinic. Furthermore, they include changes in three functional parameters over a period of 1–2 months (Box 1).

For each criterion met by the patient, one point is assigned, with a total CAS of 10. Patients with a low score (<3) respond poorly to immunosuppressive therapy, indicating that they have passed the disease stage of active inflammation [48]. Other studies have confirmed the clinical value of the CAS in determining disease activity and the likelihood of a response to immunosuppressive therapy. One study found that a CAS of 4 or more has a positive predictive value for a treatment response with corticosteroids of 80% [49].

The use of severity & activity measures to determine treatment

Although similar clinical parameters are used in describing disease activity and severity (such as soft tissue involvement, proptosis, extraocular motility disturbance and visual acuity), the two are not interchangeable and do not necessarily have a linear relationship, as emphasized by the following two examples.

A patient who presents with ocular pain, swelling and redness of the eyelids, caruncle and conjunctiva, but without any disturbance in vision, extraocular motility or significant proptosis, would be considered to have active disease with a high clinical activity score (CAS) of 7. This patient is most likely in the early inflammatory phase. The patient’s severity is mild according to the EUGOGO scheme and low in severity according to the NOSPECS scheme (class 2).

On the other hand, a patient without any signs of active inflammation (no pain, redness or swelling of the soft tissues), but with severe visual disability from proptosis, restriction of extraocular motility, eyelid retraction and a compressive optic neuropathy, would be considered to have inactive disease with a low CAS, most likely in the late, fibrotic, noninflammatory phase. This patient’s severity would be rated as sight threatening according to the EUGOGO scheme and very severe according to the NOSPECS scheme (class 6).

The two outlined examples demonstrate the importance of distinguishing between disease activity and severity, and this distinction has important implications for treatment, as further described in the following sections.

Sight-threatening disease

Thyroid eye disease may become sight threatening in the context of either dysthyroid optic neuropathy, a compressive optic neuropathy usually due to volume expansion in the orbital apex, or in the context of corneal ulceration from severe exposure due to lagophthalmos in a patient with a poor Bell’s phenomenon. Dysthyroid optic neuropathy is uncommon. In a long-term study, 6% of patients experienced optic nerve dysfunction at some point during their disease course [9]. However, only 2% were left with mild persistent visual loss that did not recover despite treatment [50]. Other possible mechanisms of visual loss include globe subluxation, choroidal folds and postural visual obscurations, but these are even less frequent than dysthyroid optic neuropathy. The long-term risk of permanent severe visual loss from TED is therefore low if treated adequately. However, any form of vision loss must be recognized promptly and treated aggressively to bring about reversal and to prevent deterioration that may become permanent.

Dysthyroid optic neuropathy can be treated with high-dose systemic steroids with or without orbital decompression surgery to relieve the pressure on the optic nerve. A small study showed that immediate surgical decompression as first-line therapy does not result in a better outcome than the use of intravenous steroids followed by decompression in those patients that do not respond [51]. As some patients respond adequately to high-dose steroid treatment alone and decompression surgery carries the risk of side effects such as postoperative diplopia, surgery should not be the first-line treatment [45,51]. High-dose intravenous steroids given in pulses are more efficacious than oral steroids and have a lower side effect profile [33,52]. Orbital radiotherapy alone is not recommended by EUGOGO in the treatment of dysthyroid optic neuropathy unless it is supplemented by other proven therapies [45].

For patients who are at risk of vision loss secondary to corneal breakdown, aggressive topical lubrication is recommended, but this alone may not be sufficient. As temporizing measures, a moisture chamber can be applied [53] or the eyelids can be closed over the corneal surface with a tarsorrhaphy until the cornea has healed. If there is no adequate response, patients may benefit from systemic steroids and orbital decompression [45].

Medical treatment for moderate-to-severe disease

Those patients without evidence of sight-threatening disease can be further classified into those with moderate-to-severe disease and those with mild disease, based on the consensus statement of EUGOGO [45]. The severity is determined using clinical parameters such as eyelid retraction, proptosis, corneal exposure, diplopia and soft tissue involvement as detailed in Table 2. For patients with moderate-to-severe disease, treatment options include systemic corticosteroids, orbital radiotherapy and surgery. The specific treatment modality is determined after an assessment of disease activity has been completed using the CAS outlined in Box 1.

Only patients in the active, inflammatory phase will respond to treatments that are targeted to suppress the immune response, such as systemic corticosteroids or orbital radiation. These treatments have no benefit for patients who have passed the inflammatory phase and in whom disease manifestations are the consequence of fibrotic changes in the orbital tissues. The CAS has been shown to be a useful tool in stratifying patients and in avoiding immunosuppressive therapy in those with a low activity score [48]. EUGOGO recommends a CAS of 3 or more out of 7 (the first seven clinical parameters as described in Box 1) as a threshold for active disease.

Those with active disease can be treated with local (e.g., by retrobulbar or subconjunctival injection), oral or intravenous corticosteroids. Local steroids have the lowest efficacy, and intravenous steroids the highest [33,54]. The response rate of intravenous steroids is approximately 80%, whereas it is approximately 50% for oral steroids [33]. Intravenous administration of steroids in pulses compared with oral administration is associated with fewer side effects and therefore better tolerability, a lower risk of relapse and a shorter treatment course [33]. In extremely high cumulative doses (≥8 g of methylprednisolone), intravenous administration has been reported to result in acute liver damage and a risk of life-threatening liver failure [55,56]. Lower cumulative doses that are routinely used in the treatment of patients with TED appear safe [33]. It is nevertheless recommended that patients be tested for liver dysfunction during treatment [45].

Long-term and high-dose administration of systemic corticosteroids carries a risk of osteoporosis, which may be decreased with the use of bisphosphonates [33]. Bisphosphonates are therefore recommended as concomitant therapy [45].

Orbital radiotherapy may also be used to treat moderate-to-severe active disease and has been shown to have a response rate of approximately 60% [57]. Low-dose radiation is used with a cumulative dose of 20 Gray in either ten or 20 fractions over a 2–4 week period. Orbital radiation appears to be especially efficacious in improving diplopia and extraocular motility [58]. Radiation has been shown to result in decreased extraocular muscle size, presumably due to a decrease in muscle remodeling, which may explain the effect on ocular motility [59].

Overall, radiation treatment appears relatively safe, but potential side effects include cataract, radiation retinopathy and orbital neoplasia [60]. Radiation should therefore be used cautiously in younger patients. Owing to the risk of inducing a microvascular radiation retinopathy, radiation should be avoided in those patients with a pre-existing risk of developing a microvascular retinopathy due to underlying diseases, such as diabetes or hypertension [57,60].

Surgical treatment for moderate-to-severe disease

Various surgical procedures for moderate-to-severe TED are used for the rehabilitation of those patients who are in the inactive, stable and fibrotic stage of the disease. Procedures performed include orbital decompression for disfiguring proptosis and orbital discomfort; strabismus surgery for symptomatic ocular motility restriction; eyelid recession for eyelid retraction causing lagophthalmos, exposure keratitis and disfigurement; and blepharoplasty for excessive soft-tissue prominence of the eyelids [61].

Before offering surgery, it is therefore recommended that patients show evidence of disease quiescence (i.e., a low CAS and stability of clinical signs over a period of at least 6 months) [45].

Orbital decompression is effective in reducing proptosis and orbital discomfort. Although relatively safe, inherent risks include diplopia, sensory dysfunction of the infraorbital nerve and vision loss from damage to the optic nerve. Various techniques are available, including decompression of the orbital floor, lateral orbital wall and medial orbital wall, either through open surgery or through an endoscopic approach. Endoscopic medial wall decompression, combined with an external lateral wall approach, provides effective decompression and compares favorably to a traditional three-wall technique [62]. A two-wall decompression of the medial wall and orbital floor may carry a high risk of postoperative diplopia in primary gaze, especially in those patients with some pre-existing motility restriction [63]. Decompression of the deep lateral wall may have the lowest incidence of postoperative diplopia in primary gaze, with reported rates as low as 2.6% [64]. Orbital decompression can also be achieved by removing orbital fat alone or in combination with the removal of bone [65].

Owing to the risk of inducing or worsening preoperative diplopia, orbital decompression surgery should precede extraocular muscle surgery. Owing to the risk of causing eyelid retraction while performing strabismus surgery, especially in the lower eyelid, eyelid recession surgery is often preceded by strabismus surgery [61].

Treatment of mild disease

For mild disease, the risks of medical or surgical treatments often outweigh the benefits. Supportive measures, such as frequent topical lubrication, are usually sufficient to control symptoms. Small degrees of relatively comitant diplopia may be correctable with prisms.

In some patients, however, what may be considered mild disfigurement by the physician (e.g., minor eyelid retraction of <2 mm or proptosis of <3 mm) may be experienced by the patient as sufficiently severe to justify the risks of treatment if it has a detrimental impact on the patient’s psychosocial functioning and quality of life [66,67]. Quality-of-life questionnaires can be used to assess the impact of the disease on a patient.

Supportive measures

Several measures must be considered for all patients with TED, regardless of their disease severity or activity. The one risk factor that patients have control over is the cessation of smoking. The benefits of giving up tobacco use have been shown for reducing disease severity and improving the response to treatment. This has been discussed in detail earlier in this article.

Dysthyroidism is associated with more severe TED [68]. It is therefore recommended that both hyper- and hypothyroidism be corrected in patients with TED. After treatment of hyperthyroidism with radioactive iodine, it is recommended that post-treatment hypothyroidism be corrected early, as this reduces the risk of onset or deterioration of pre-existing ophthalmopathy [69].

Radioactive iodine is one of the modalities for treating hyperthyroidism in Graves’ disease, and it is frequently used in the USA. Pre-existing TED may worsen after radioactive iodine treatment in up to 15% of patients [70]. This deterioration is transient in the majority of those affected, but is persistent in one third. The risk can be reduced if patients are treated with a short course of oral steroids at the same time [70,71]. Patients without any evidence of TED at the time of radioactive iodine treatment do not appear to be at risk.

Expert commentary

Thyroid eye disease is an autoimmune disease that in most patients is associated with hyperthyroid Graves’ disease. The disease causes significant functional limitations and cosmetic disfigurement, and in the relatively infrequent cases of severe disease may even result in permanent visual loss. Our current understanding of the pathophysiology of the disease is limited. The immune response is inappropriately activated and targeted against orbital tissues with the involvement of autoantibodies and autoreactive B and T lymphocytes. Some of the mediators that maintain and propagate this response, such as specific cytokines and surface receptors on cells of the immune system, have been identified. The orbital fibroblast represents a key cellular component that is activated by the immune system and causes some of the tissue remodeling responsible for characteristic disease manifestations.

This is where our current understanding has reached its limits. The treatments we can currently offer our patients are very non-specific and are in essence limited to suppressing the immune system as a whole for those with severe active disease. The remainder receive reassurance and supportive therapy until the inflammation has subsided. At that point they may benefit from rehabilitative surgery to correct functional and cosmetic deformities. This frustrating process may take years.

The initial events that trigger the remodeling of orbital tissues are unclear. Once these early events have been better elucidated by future research, the dysregulated molecular processes could be addressed in a more targeted manner, rather than by unnecessarily suppressing the immune system as a whole. Treating patients in the future during the initial stages of disease may arrest the abnormal remodeling processes in the orbit before they result in clinical manifestations. Our current understanding supports a potential role for the specific inhibition of the subset of B and T lymphocytes that are directed against self-antigens in the orbit; the application of local treatments to the orbit that interfere with the action of cytokines and other mediators of inflammation; and the silencing of the abnormal fibroblast response that leads to adipogenesis, deposition of extracellular matrix proteins and fibrosis of the extraocular muscles.

Some advances have recently been made by evaluating the response to drugs designed for other autoimmune diseases. One such drug is rituximab, a chimeric monoclonal antibody approved by the US FDA for the treatment of rheumatoid arthritis that is refractory to other therapies such as TNF-α inhibitors. Rituximab targets CD20, a surface antigen on B cells. Binding of the drug leads to a cytotoxic reaction and the depletion of B cells [72]. Rituximab has been used in a small cohort of patients with hyperthyroid Graves’ disease and TED [73]. The results have been promising, but also surprising, and have emphasized how little we truly understand about the pathophysiology of the disease.

The rationale for the use of rituximab in those studies was that autoantibodies are thought to be involved in causing TED, that B cells secrete antibodies, and therefore that a drug that depletes B cells should be beneficial in TED. Nine patients with hyperthyroid Graves’ disease were treated with rituximab. Seven of them had active TED, while the remaining two only had mild eyelid signs. As a control, 20 subsequent patients were treated with systemic corticosteroids alone. All of the patients treated with rituximab experienced B-cell depletion after two cycles of therapy. They also experienced a significant and sustained improvement in various disease parameters, including a decrease in proptosis as well as in their CAS. Furthermore, in contrast to the control group, none of the rituximab-treated patients had a relapse, even after rituximab therapy was stopped and their peripheral B cells returned to normal.

Surprisingly, the levels of serum autoantibodies, the presumed culprits of TED, did not decrease in response to rituximab. Furthermore, the patients’ hyperthyroidism, another manifestation of presumably the same autoimmune response, did not resolve with rituximab. All patients continued to require methimazole to control their abnormally elevated thyroid function. It appears that rituximab may be effective in TED, but we do not understand exactly why or how this occurs.

Another group evaluated the response to rituximab in patients with hyperthyroid Graves’ disease in a prospective study [74]. Ten patients were treated with rituximab plus methimazole, and a control group of ten patients was treated with methimazole alone. This study also showed that autoantibody levels were unaffected by rituximab. Rituximab did induce lasting remission (i.e., euthyroidism) in approximately 40% of patients (compared with none in the control group), but only those patients with low TSH receptor antibody levels at the start of the study showed a response. Patients with high antibody levels had no lasting response. The authors concluded that given the high cost, low efficacy and potential side effects, the use of rituximab cannot be recommended for uncomplicated hyperthyroid Graves’ disease. Two of the patients in the rituximab group also had TED, and both of them showed improvement in their symptoms [75]. Subsequently, the same group reported that even though the serum levels of TSH receptor antibodies did not decrease in response to rituximab, the stimulatory capacity of these antibodies was markedly reduced in a functional bioassay [76]. A third group also reported that rituximab can induce a lasting remission in some patients with hyperthyroid Graves’ disease, with a decrease in T4 and an increase in TSH levels [77].

To date, all reports are from small cohorts of patients, and a potential role for rituximab in the treatment of TED should be further investigated in a larger prospective and randomized study. The potential benefits of rituximab also need to be carefully weighed against the high cost of the drug. Although it is fairly well tolerated overall, reported side effects can be clinically significant, as they include infusion reactions, serum sickness, agranulocytosis and fatal infections [72].

A plethora of new molecular targets have potential for the development of new treatments, including targets other than CD20 that lead to B-cell depletion, such as CD22 and CD19 [72]. Furthermore, therapies that block the CD40–CD40L interaction [22], and those that interfere with B-cell activators such as BAFF and APRIL [41,42], could be tested for an effect in TED.

A completely novel therapy that has not yet been tested in human trials could center around the orbital fibroblast and its role in tissue remodeling in TED. Since the CD40 antigen is present on fibroblasts, blocking its interaction with CD40L present on activated T cells may also be beneficial in inhibiting fibroblast activation [22]. Blocking other fibroblast agonists that stimulate differentiation into adipocytes (e.g., rosiglitazone) or the synthesis of extracellular matrix proteins (e.g., IFN-γ or leukoregulin) may also have beneficial effects [23,26]. Targeting orbital fibroblasts may even be possible by retrobulbar delivery of drugs, thereby reducing systemic side effects.

Five-year view

Over the next 5 years, it can be expected that multidisciplinary groups, such as EUGOGO and the newly formed International Thyroid Eye Disease Study Group, will continue to promote the exchange and sharing of clinical information regarding the best management for patients with TED. These groups will also help in orchestrating much needed prospective clinical studies in order to derive evidence-based therapies. Multicenter studies will allow larger numbers of patients to be recruited. Results from such studies will provide valuable clinical information on the efficacy of various treatments.

The success of multispecialty thyroid eye clinics will hopefully continue to spread and give more patients access to coordinated care by physicians with expertise in TED.

Finally, future research into the molecular mechanisms of TED will provide greater insight into the pathogenesis of the disease, ultimately leading to therapies that address the underlying etiology. Whereas it is doubtful that we will get to define a ‘silver bullet’ for TED within the next 5 years, each new discovery from the laboratory holds the promise of getting us closer to this goal, one step at a time.

Table 1. NOSPECS classification of severity of thyroid eye disease.

Class	Definition
0	No physical signs or symptoms
1	Only signs, no symptoms (signs limited to upper lid retraction, stare, lid lag and proptosis up to 22 mm)
2	Soft tissue involvement (symptoms and signs)
3	Proptosis
4	Extraocular muscle involvement
5	Corneal involvement
6	Sight loss (optic nerve involvement)

NOSPECS: No signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea; sight loss.

Table 2. European Group on Graves’ Orbitopathy classification of severity of thyroid eye disease.

Severity score	Definition
1	Sight-threatening disease: patients with dysthyroid optic neuropathy and/or corneal breakdown
2	Moderate-to-severe disease: patients without sight-threatening disease, whose disease has sufficient impact on daily life to justify the risks of treatment (≥one of the following: lid retraction of ≥2 mm; moderate or severe soft tissue involvement; exophthalmos of ≥3 mm above normal for race and gender; inconstant or constant diplopia)
3	Mild disease: patients whose disease has only a minor impact on daily life that is insufficient to justify the risks of treatment (signs less severe than those listed under 2; corneal exposure responsive to lubrication)

Box 1. Determining the clinical activity score.

For each sign or symptom listed, one point is assigned. Points are added to determine the total clinical activity score:

• • Ocular pain at rest

• • Ocular pain on attempted up, side or down gaze

• • Redness of the eyelids

• • Swelling of the eyelids

• • Redness of the conjunctiva

• • Chemosis of the conjunctiva

• • Chemosis of the caruncle

• • Increase in proptosis by ≥2 mm

• • Decrease in eye movement in any direction by ≥5 degrees

• • Decrease in pinhole visual acuity by ≥one line on the Snellen chart

Key issues

• • Thyroid eye disease (also referred to as Graves’ orbitopathy) is an autoimmune disease affecting ocular and orbital structures.

• • Characteristic signs and symptoms include eyelid retraction, exophthalmos, extraocular muscle dysfunction, pain, redness of the ocular surface and eyelids, ocular surface irritation, blurred vision, and photophobia.

• • Visual loss is relatively uncommon but may result from a compressive optic neuropathy or corneal breakdown in severe disease.

• • The majority of patients with thyroid eye disease also have hyperthyroid Graves’ disease; however, some patients are eu- or even hypothyroid.

• • Orbital fibroblasts play a key role in the disease.

• • Treatment approaches are guided by disease activity and severity.

• • Treatment strategies include observation, lubrication, systemic corticosteroids, orbital radiation and surgery (such as orbital decompression, strabismus surgery and eyelid recession).

• • Smoking should be discouraged as it has been shown to negatively affect the disease course.

• • Experimental treatments that are currently being investigated focus on manipulating the immune function.

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Ocular treatment of thyroid eye disease

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Mrs Smith is a 65-year-old woman who was diagnosed with thyroid disease 3 months ago; she presents with complaints of bilateral diplopia, pain, tearing, and redness of her eyes. Though thyroid eye disease (TED) is suspected, which of the following features would make that diagnosis less likely?

• □ A Symptoms occurring only 3 months after the onset of systemic thyroid disease

• □ B Female sex

• □ C Onset in the sixth decade of life

• □ D Bilateral disease

2. In examining Mrs. Smith, which of the following features would confirm your suspicion of TED?

• □ A Anisocoria

• □ B Eyelid retraction and exophthalmos

• □ C Nystagmus

• □ D Visual loss

3. A 45-year-old woman has TED with lid retraction of 3 mm and severe soft tissue involvement with constant diplopia. According to the EUGOGO classification, which level of severity of TED does she represent?

• □ A Sight-threatening disease

• □ B Class 5 disease

• □ C Moderate to severe disease

• □ D Class 4 disease

4. A 58-year-old man with Graves’ disease is also a smoker of 20 cigarettes daily for the last 10 years. Which of the following best describes the association between smoking and TED?

• □ A Smokers have a higher risk of developing TED than nonsmokers

• □ B Quitting smoking will reduce the risk for TED

• □ C There is a dose-dependent association between smoking and TED treatment response

• □ D All of the above

5. A patient with TED has no pain, redness, or tissue swelling but has severe visual disability from restriction of extraocular motility and compressive optic neuropathy. Which of the following best describes his clinical activity severity score and the most appropriate next step?

• □ A Low score, treat with local corticosteroids

• □ B High score, treat with ocular surgery

• □ C Low score, treat with high-dose systemic steroids

• □ D Medium score, treat with orbital radiotherapy