Graves disease is a multisystem autoimmune disease targeting the thyroid, orbit and skin. Clinically detectable thyroid-associated ophthalmopathy (TAO) occurs in approximately 10 to 45 percent of patients with Graves disease1 with manifestations ranging from mild ocular surface disease to severe proptosis and optic neuropathy. In this article, we will review the current medical treatments available for TAO in addition to new immunomodulatory agents that target specific mediators in the pathogenesis of the disease.
TAO refers to the orbital and periorbital manifestations of Graves disease. TAO can be categorized as active or inactive based upon inflammatory signs and symptoms. The initial active phase of TAO is marked by inflammation of the extraocular muscles, orbital fat and periorbital soft tissue. Typically, patients with TAO have a self-limited course, becoming quiescent within three to five years of onset.
The inflammatory infiltrate primarily consists of CD4+ T lymphocytes, mast cells and macrophages.2 B lymphocytes also play a role in the development of TAO, functioning as immunoglobulin-secreting cells, as well as antigen presenters and potent producers of cytokines, including IL-6, lymphotoxin, TNF-α and IL-10.3 In addition, activated fibroblasts secrete hyaluronic acid, increasing the water content and clinically manifesting as orbital expansion, congestion and edema. The subsequent inactive chronic phase is characterized by fibrosis, with an increase in collagen and extracellular matrix deposition.
Patients diagnosed with TAO may have hyperthyroidism, euthyroidism or hypothyroidism. Thyroid stimulating hormone (TSH) levels are typically monitored in TAO patients in conjunction with an endocrinologist. TSH levels provide the most sensitive tool for tracking endocrinologic status.
Medical treatment is focused upon the early active inflammatory phase of TAO. Various immunosuppressive therapies have been used to treat TAO patients, including glucocorticoids, radiotherapy and immunosuppressive agents. Current research is examining specific therapies for the prevention and treatment of the inflammatory active phase of TAO. Nonspecific supportive therapy, including lubricants and punctal plugs for ocular surface disease, is beneficial. In addition, smoking cessation is critical since smokers tend to have more severe ophthalmopathy and respond poorly to treatment.4 Once the disease reaches the stable phase, medical therapy is ineffective and staged surgical rehabilitation is performed if required.
Glucocorticoids have been a mainstay for treating TAO because of their rapid anti-inflammatory effects and the paucity of alternatives. Administration is by periorbital injection or oral or intravenous routes.
Glucocorticoids can effectively reduce inflammatory signs during the active phase of the disease in more than half of patients and are indicated in select patients with moderate to severe active orbitopathy. They can reduce optic neuropathy but appear largely ineffective at preventing or reducing muscle restriction.5 In addition, there is little evidence that steroids effectively alter the natural history of the disease or diminish the eventual muscle and orbital disease manifestations. Typically steroids are used as a bridge until the stable phase is reached.
Most clinicians use both oral and intravenous steroids depending upon the severity of disease. A randomized, clinical control study showed that intravenous glucocorticoids were more effective and better tolerated than oral glucocorticoids in patients with active severe TAO.6 However, liver enzyme levels and risk factors for liver toxicity must be closely monitored since acute liver damage and death have been reported from this type of treatment.7 In addition, glucocorticoids have significant side effects with long-term use and therefore are typically discontinued after three to five months. Recurrences of inflammation are common while tapering steroids.
Orbital Radiotherapy Treatment
Orbital radiotherapy has been used for several years to treat TAO. This is an attractive modality since treatment can be done locally without the systemic side effects of glucocorticoids or immunomodulatory agents. Recently, however, the efficacy of orbital irradiation has been questioned and a review of current data, including randomized controlled clinical trials, has been performed.8 The studies available indicate that orbital radiotherapy does not seem to produce significant improvements in proptosis, eyelid retraction or soft tissue symptoms, although there may be beneficial effects on motility.9
Orbital radiotherapy should be restricted to patients with active disease. Many clinicians will opt for orbital radiation only if there is significant improvement with a short course of steroids. Side effects of orbital radiotherapy are generally mild and include ocular irritation. More serious complications include the development of cataracts and radiation retinopathy.10 Orbital radiation is typically contraindicated in patients with diabetes, as they may be at risk for retinal neovascularization.
The full potential of orbital radiotherapy still needs to be examined, as current studies are heterogeneous and include active and inactive patients and exclude those with compressive optic neuropathy. Further study of the orbital radiation regimen and coadministration of immunomodulatory agents is needed.
Various immunomodulatory agents have been used to treat TAO. Cyclosporin A, azathioprin and cyclophosphamide have all had beneficial effects in TAO patients but also have unfavorable benefit-risk relationships.11
Agents with fewer side effects are more desirable. Some that are effective at treating other autoimmune diseases are being used in TAO patients. One such agent is rituximab, an anti-CD20 monoclonal antibody that blocks activation and differentiation of B cells. A nonrandomized trial was conducted in nine patients with Graves Disease, of which seven manifested clinically active TAO.12 These patients were treated with rituximab and compared with 20 patients who received intravenous glucocorticoids. Rituximab was not effective at treating hyperthyroidism, but clinical activity scores and levels of orbital disease improved to a greater degree in patients treated with rituximab compared with those treated with intravenous glucocorticoids. The orbital disease improvements seen in patients with rituximab therapy occurred without a significant reduction in the levels of TSH receptor autoantibodies (TRAb).
The use of rituximab was also investigated in a controlled pilot study in 20 patients with Graves disease, 16 of whom were newly diagnosed.13 Four of 10 patients treated with rituximab were euthyroidic compared with no patients in the control group one year after discontinuing methimazole treatment. This study suggests that rituximab may induce Graves disease remission in a subset of patients, primarily those with low TSH receptor autoantibody (TRAb) levels.
However, the studies that have been conducted on rituximab therapy have limitations, including small sample sizes and heterogenous and relatively mild orbital disease severity among subjects. Given the costs and side effects of immunomodulatory therapy, its use in patients with uncomplicated Graves disease hyperthyroidism or mild TAO is unattractive. However, rituximab may be quite attractive as a steroid-sparing agent for treating moderate to severe orbitopathy, and its use requires further investigation.
Our current understanding of TAO's pathogenesis is incomplete, and our medical therapies are directed at suppressing the immune response. While our main medical armamentarium remains glucocorticoids, immunomodulatory agents are increasingly being used with some success. Before these new immunomodulatory agents are more widely used, they need to be studied in a more controlled manner. One key goal is to find agents that target the mechanisms behind Graves disease and prevent TAO before it becomes clinically significant.
- Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. Long-term follow-up of Graves ophthalmopathy in an incidence cohort. Ophthalmology. 1996;103(6):958-962.
- Heufelder AE, Bahn RS. Elevated expression in situ of selectin and immunoglobulin superfamily type adhesion molecules in retroocular connective tissues from patients with Graves' ophthalmopathy. Clin Exp Immunol. 1993;91(3):381-389.
- Paul W, ed. Fundamental Immunology. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.
- Eckstein A, Quadbeck B, Mueller G, et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol. 2003;87(6):773-776.
- Krassas GE, Boboridis K. Recent developments in the medical treatment of thyroid eye disease. Orbit. 2006;25(2):117-122.
- Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves' orbitopathy. J Clin Endocrinol Metab. 2005;90(9):5234-5240.
- Marino M, Morabito E, Brunetto MR, Bartalena L, Pinchera A, Marocci C. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy. Thyroid. 2004;14(5):403-406.
- Bradley EA, Gower EW, Bradley DJ, et al. Orbital radiation for graves ophthalmopathy: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(2):398-409.
- Prummel MF, Terwee CB, Gerding MN, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab. 2004;89(1):15-20.
- Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology. 2004;111(8):1557-1562.
- Krassas GE, Heufelder AE. Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts. Eur J Endocrinol. 2001;144(4):311-318.
- Salvi M, Vannucchi G, Campi I, et al. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrino. 2007;156(1):33-40.
- El Fassi D, Nielsen CH, Bonnema SJ, Hasselbalch HC, Hegedüs L. B lymphocyte depletion with the monoclonal antibody rituximab in Graves' disease: a controlled pilot study. J Clin Endocrinol Metab. 2007;92(5):1769-1772.
Drs. Hwang and Douglas state that they have no financial relationship with the manufacturer of any product discussed in this article or with the manufacturer of any competing product.