Until recently, there was no pharmaceutical agent approved by the US Food and Drug Administration (FDA) specifically for the treatment of thyroid eye disease (TED), a rare autoimmune disorder with an annual incidence of 1.9 cases for every 10,000 people.1,2 Also known as Graves orbitopathy and thyroid-associated ophthalmopathy, TED develops in approximately 25% to 40% of people with Graves disease and affects more women than men.1-3 Ocular manifestations typically occur within 2 years of onset of the autoimmune disease; its natural history is an initial active phase with escalation of orbital inflammation, followed by quiescence after approximately 12 to 18 months.2 Graves disease and TED develop at about the same time in approximately 80% of cases, although some studies have shown that patients present late with TED and that it can take months from onset of ocular symptoms to a proper diagnosis of TED.4,5

During the active phase of TED, some patients present with mild symptoms (soft tissue involvement and lid retraction) and others with more serious ocular complications, such as proptosis (exophthalmos), ocular motility restriction, and, in approximately 3.5% to 6% cases, dysthyroid optic neuropathy. During quiescence, some patients see improvement of proptosis or ocular motility, but the eye does not return to normal. A natural history study found that 22% of patients improved substantially over 12 months, 64% showed minor or no improvement, and 14% showed progressive deterioration.6 

Patient Awareness

Graves disease is characterized by abnormal enlargement of the thyroid and increased secretion of thyroid hormones. TED most often occurs in conjunction with Graves disease but can occur in people without Graves disease who have had hyperthyroidism, hypothyroidism, or other thyroid conditions.7
As a result, signs and symptoms vary widely, with ocular manifestations ranging from mild to severe. Initial symptoms include eye redness, irritation and discomfort of the eye and eyelids, blurred vision, diplopia, strabismus, photophobia, swelling near the eyelids, and difficulty moving the eye. Dry eye and pain when moving the eye are also fairly common. The hallmark of TED is proptosis. If TED is left untreated, symptoms can progress and result in loss of vision.
In the active phase of TED, the disorder is life altering and, potentially, sight threatening. Management likely involves a multidisciplinary effort by specialists in endocrinology, psychology, and ophthalmology. Psychosocial support might be warranted.7 Treating Graves disease is primarily aimed at reversing hyperthyroidism, but that will not alleviate symptoms of TED. Mild TED can be treated with something as simple as dark sunglasses, ointments, artificial tears, or even prisms that attach to eyeglasses to correct diplopia.
A recent study found that although almost all patients with either TED or Graves disease know that TED involved inflammation of orbital tissue, most did not know that TED could develop in the absence of hyperthyroidism, and approximately 30% were unaware that severe TED was associated with smoking.1 That study also found a lack of knowledge of surgical management of TED: patients overestimated the effectiveness of thyroidectomy in treating TED. They also overestimated the tendency of radioiodine to exacerbate TED and generally demonstrated poor knowledge of the role of orbital radiotherapy and orbital decompression.1

Physicians are sometimes equally misinformed; in the United Kingdom, for example, time from presentation with ocular symptoms to a confirmed diagnosis of TED was longer than 9 months.8

“A common belief is that once a patient progresses to the chronic phase of the disease, symptoms diminish and the impact on quality of life improves,” said Kimberly Cockerham, MD, of Stanford University School of Medicine. However, in a new survey of 100 patients with chronic TED at various levels of severity, the Graves’ Ophthalmopathy Quality of Life Questionnaire instrument found otherwise.9 (Dr Cockerham was the primary author of the study that fielded the survey.)

Dr Cockerham said that this survey confirms that “the quality of life of patients with chronic thyroid eye disease was reported to be significantly impaired and nearly identical to scores seen in clinical trials of patients with acute, moderate-to-severe disease.”9

Beyond Traditional Topical Therapies

Traditional treatment of TED had been limited to intravenous (IV) corticosteroids, which are recommended based on their ability to effectively and rapidly reduce orbital swelling in most patients with TED. Over the past few decades, treatment preferences have shifted from oral prednisolone to IV methylprednisolone because the latter has shown equal efficacy and reduced adverse effects (AEs).2 Regrettably, not all patients respond to treatment; AEs of long-term corticosteroid use are well documented and, perhaps most discouraging, more than 10% of patients with TED experience relapse after corticosteroid treatment is stopped.2 Corticosteroid injection of the orbital and subconjunctival fornices has been investigated, but those studies had small numbers of cases and were uncontrolled, “making recommendation of its routine use unjustified,” wrote Khong and McNab in a review article.2 

Other treatments have included glucocorticoids, with or without radiotherapy, but these only minimally affect proptosis and can also cause dose-limiting AEs. Rituximab, a chimeric human and mouse monoclonal antibody, was shown to reduce the clinical activity score (CAS) in all cases; however, some treated patients developed severe AEs, including progression to dysthyroid optic neuropathy, and contradictory results of various studies necessitate further evaluation of rituximab in larger clinical trials, Khong and McNab noted.2 The same review noted that tocilizumab, a humanized monoclonal antibody against interleukin-6 receptor, might have a role in treating severe, active, corticosteroid-resistant TED, although more studies are warranted to assess its ability to treat dysthyroid optic neuropathy.2
Other medical therapies for TED had been lacking, partly because pathogenesis is not yet completely understood. Studies of Graves disease have found specific immunoglobulins that can activate insulin-like growth factor I (IGF-1) receptor signaling, and IGF-1 can enhance the actions of thyrotropin. That receptor is particularly active in Graves disease and is targeted by pathogenic autoantibodies called thyroid-stimulating immunoglobulins.10 People with Graves disease have these autoantibodies, even when they lack ophthalmopathy. Therefore, immunotherapies might be a feasible option for treating TED. 

First FDA-Approved Treatment Specifically for TED

In January 2020, the FDA approved the first of these immunotherapies, teprotumumab-trbw (Tepezza™), a fully human IGF-1 receptor-inhibitory monoclonal antibody, for the treatment of TED. In fact, teprotumumab-trbw is the first pharmaceutical agent of any class approved for TED. 

Teprotumumab-trbw AEs
AEs commonly reported include muscle spasm, nausea, alopecia, diarrhea, fatigue, hyperglycemia, hearing impairment, dry skin, dysgeusia, and headache.

At the time of the approval of teprotumumab-trbw, Wiley Chambers, MD, deputy director of the Division of Transplant and Ophthalmology Products at the FDA, said, in a press release, that treatment “has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, nonsurgical treatment option.”12
In clinical studies, teprotumumab-trbw reduced proptosis by at least 2 mm in 83% of patients compared with 10% in the placebo group in one study and by 71% compared with 20% in the placebo group in another study.11,12 Overall, more than one-half (53%) of patients who responded at Week 24 maintained an at least 2-mm reduction in proptosis from baseline at Week 72 (approximately 1 year post-treatment). 
Approval in the United States of teprotumumab-trbw for the treatment of TED was granted based on results of 2 randomized, double-blind, placebo-controlled studies that evaluated the drug in 171 patients with moderate to severe TED. In both studies, patients were given an IV infusion every 3 weeks for a total of 8 infusions (at a dose of 10 mg/kg of body weight for the first infusion and 20 mg/kg for the 7 subsequent infusions).

In the first of these studies (ClinicalTrials.gov Identifier: NCT01868997), the primary outcome was the number of participants classified as a responder or nonresponder at Week 24. Responders were defined as participants with (1) a reduction in CAS of at least 2 points, (2) a reduction in proptosis (ie, degree of protrusion of the eye from the orbital rim) of at least 2 mm in the study eye, and (3) no deterioration (ie, no increase in CAS of ≥2 points or no increase in proptosis of ≥2 mm) in the nonstudy eye. 

In the second study (OPTIC3; ClinicalTrials.gov Identifier: NCT03298867), 88 patients were randomly assigned in a 1:1 ratio and stratified by tobacco-use status. At the end of the double-blind period (Week 24), proptosis nonresponders were eligible to enter an open-label extension study, in which they receive 8 infusions of teprotumumab-trbw. Follow-up without treatment was scheduled for Weeks 28, 36, 48, 60, and 72. Patients in the open-label extension study who completed the Week 72 visit were contacted 6 to 12 weeks later to determine if additional treatment for TED had been necessary since the Week 72 visit.

Combining these 2 studies (ClinicalTrials.gov Identifiers: NCT01868997 and NCT03298867),11 a total of 84 patients were randomly assigned to teprotumumab-trbw and 87 patients were randomly assigned to placebo. Median age was 52 years (range, 20 to 79); 86% were White, 9% Black or African American, 4% Asian, and 1% identified as “other.” Seventy-three percent were women. At baseline, 27% of patients were smokers.

In Study 2, improvement in proptosis, measured by mean change from baseline, was observed as early as Week 6 and continued to improve through Week 24. Similar results were seen in Study 1.11

The phase 3 OPTIC study3 confirmed the results of the first 2 studies: At Week 24, the percentage of patients with a proptosis response was higher with teprotumumab-trbw than with placebo (83% [34 patients] vs 10% [4 patients], respectively; (P <.001), with a mean change in proptosis of −2.82 mm in the teprotumumab-trbw group compared with −0.54 mm in the placebo group. Both the reduction in diplopia and improvement in QOL score were significantly higher in the teprotumumab-trbw group (P ≤.001).


1. Edmunds MR, Boelaert K. Knowledge of thyroid eye disease in Graves’ disease patients with and without orbitopathy. Thyroid. 2019;29(4):557-562. doi:10.1089/thy.2018.0665
2. Khong JJ, McNab A. Medical treatment in thyroid eye disease in 2020. Br J Ophthalmol. 2021;105(3):299-305. doi:10.1136/bjophthalmol-2020-316051
3. Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med. 2020;382(4):341-352. doi:10.1056/NEJMoa1910434
4. Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves’ ophthalmopathy and onset of thyroidal Graves‘ disease. J Endocrinol Invest. 1988;11(8):615-619. doi:10.1007/BF03350193
5. Perros P, Žarković M, Azzolini C, et al. PREGO (presentation of Graves’ orbitopathy) study: changes in referral patterns to European Group On Graves’ Orbitopathy (EUGOGO) centres over the period from 2000 to 2012. Br J Ophthalmol. 2015;99(11):1531-1535. doi:10.1136/bjophthalmol-2015-306733
6. Perros P, Crombie AL, Kendall-Taylor P. Natural history of thyroid associated ophthalmopathy. Clin Endocrinol (Oxf). 1995;42(1):45-50. doi:10.1111/j.1365-2265.1995.tb02597.x
7. Thyroid eye disease. Rare Disease Database. National Organization for Rare Disorders Web site. Updated April 20, 2020. Accessed March 23, 2021. https://rarediseases.org/rare-diseases/thyroid-eye-disease
8. Mellington FE, Dayan CM, Dickinson AJ, et al; Thyroid Eye Disease Amsterdam Declaration Implementation Group (TEAMeD). Management of thyroid eye disease in the United Kingdom: a multi-centre thyroid eye disease audit. Orbit. 2017;36(3):159-169. doi:10.1080/01676830.2017.1280057
9. New survey assessment finds debilitating impact of thyroid eye disease (TED) on quality of life continues well beyond acute disease into chronic phase. Press release. Horizon Therapeutics. February 22, 2021. Accessed March 23, 2021. https://ir.horizontherapeutics.com/news-releases/news-release-details/new-survey-assessment-finds-debilitating-impact-thyroid-eye 
10. Smith TJ, Kahaly GJ, Ezra DG, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. 2017;376(18):1748-1761. doi:10.1056/NEJMoa1614949
11. Tepezza. Prescribing information. Horizon Therapeutics Ireland DAC; revised January 2020. Accessed March 23, 2021. https://www.hzndocs.com/TEPEZZA-Prescribing-Information.pdf
12. FDA approves first treatment for thyroid eye disease. Press release. US Food and Drug Administration. January 21, 2020. Accessed March 23, 2021. www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-thyroid-eye-disease#:~:text=Today%2C%20the%20U.S.%20Food%20and,and%20bulge%20outwards%20(proptosis) 

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had no role in this content’s preparation. 

Reviewed March 2021