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Ophthalmic Professional

Article

Update on thyroid eye disease

The latest in our understanding of how to diagnose and treat TED

By: SHAKTHI KANAGALINGAM, MD
Ophthalmic Professional May 1, 2022 Vol 11, Issue May/June 2022 Page(s): 26, 28

The emergence of novel monoclonal antibodies is changing our management of complex ophthalmic conditions. One example is thyroid eye disease (TED).

It is important to recognize if a patient has TED to elicit a focused, detailed clinical history and determine the appropriate diagnostic testing required. This includes carefully checking for a relative afferent pupillary defect, assessing motility, stereopsis, and obtaining a static visual field.

Here, I discuss the latest in our understanding of how to diagnose and treat TED.

Overview

TED is the most common cause of proptosis and eyelid retraction in adults. It affects approximately 25% to 40% of patients with thyroid dysfunction.1,2 Each year, approximately 1 million Americans are diagnosed with TED. These patients suffer from significant facial disfigurement and visual disability, which inadvertently affects nearly every aspect of their lives. TED patients have nearly double the rates of anxiety and depression as compared to the general population. Studies assessing quality of life in this group have consistently found an overall negative impact on daily quality of life, their social and occupational lives.3,4 This is particularly so for patients who suffer from diplopia. There is both temporary and permanent occupational disability associated with this condition.

The activation of orbital fibroblasts by autoantibodies in TED patients results in the production and release of chemical signals and biological materials, which trigger swelling and congestion in the orbit. In the initial stages, TED causes eyelid changes that include retraction, lateral flare, periorbital edema, and incomplete eyelid closure (lagophthalmos), which can give rise to ocular dryness and significant discomfort. Patients can also experience a more debilitating form of TED where there is significant enlargement of extraocular muscles and orbital fat leading to proptosis and diplopia. In extreme causes, the enlargement of the extraocular muscles at the apex is significant enough to cause optic nerve compromise resulting in permanent visual loss.

Women are five to six times more likely to develop TED.1 Cigarette smokers are at significantly increased risk of developing TED, often having a more severe and prolonged activity course that threatens vision.

 

Figure 1. Active TED with worsening proptosis, lower eyelid retraction, inferior scleral show, and restrictive strabismus causing diplopia. This patient had undergone orbital decompression and eyelid surgery to correct eyelid retraction several years prior before experiencing a recurrence of active TED.Image courtesy Shakthi Kanagalingam, MD.
Figure 1. Active TED with worsening proptosis, lower eyelid retraction, inferior scleral show, and restrictive strabismus causing diplopia. This patient had undergone orbital decompression and eyelid surgery to correct eyelid retraction several years prior before experiencing a recurrence of active TED.Image courtesy Shakthi Kanagalingam, MD.

 

Diagnosis and imaging

TED has an active phase that involves acute exacerbation of inflammation and worsening ocular signs that can last from 6-36 months. A chronic inactive phase follows, in which scar tissue and fibrosis of tissues occur. The Clinical Activity Score (CAS, Figure 2) can be useful in this regard, with a CAS above 3 at the initial assessment and CAS above 4 on subsequent visits being considered active disease.


 

Figure 2. Clinical Activity Score. Image courtesy Shakthi Kanagalingam, MD.
Figure 2. Clinical Activity Score. Image courtesy Shakthi Kanagalingam, MD.

 

Due to its widespread availability and rapid image acquisition, computed topography (CT) of the orbits is an ideal choice for imaging. Bilateral enlargement of the extraocular muscle bellies with sparing of the tendinous insertions is characteristically seen. The extraocular muscles affected by TED in decreasing order of frequency is captured by the mnemonic I’M SLOw (Inferior rectus, Medial rectus, Superior rectus, Lateral rectus and Oblique muscles).

Figure 3A. Axial CT image demonstrating enlargement of the medial rectus muscle in each orbit. Image courtesy Shakthi Kanagalingam, MD.
Figure 3A. Axial CT image demonstrating enlargement of the medial rectus muscle in each orbit. Image courtesy Shakthi Kanagalingam, MD.

 


 

Figure 3B. Coronal view CT image demonstrating bilateral enlargement of the inferior, medial and superior rectus muscles in the orbits. The optic nerve is seen centrally. Image courtesy Shakthi Kanagalingam, MD.
Figure 3B. Coronal view CT image demonstrating bilateral enlargement of the inferior, medial and superior rectus muscles in the orbits. The optic nerve is seen centrally. Image courtesy Shakthi Kanagalingam, MD.

 

Therapy

Conventional therapy for active TED has included weekly methylprednisolone (Solu-MEDROL, Pfizer) intravenous infusions for a 12-week duration and/or orbital radiation, both of which are associated with substantial risks. Steroids can lead to worsening diabetes, cardiovascular disease, glaucoma, increased risk of osteoporosis, development of avascular hip necrosis, weight gain, mood changes, and lowered resistance to infections. Orbital radiation has been known to cause premature development of cataracts, radiation retinopathy, and the theoretical concern for tumorigenesis.

Orbital decompression is a primary treatment of proptosis. This surgical procedure enlarges the existing space in the orbits by partially removing the bony walls of the orbit (typically the orbital floor, medial and lateral walls). To correct large-angle diplopia, strabismus surgery is considered following the orbital decompression and after the muscle alignment is stable for months. Eyelid retraction surgery and tarsorrhaphy is done as a final stage to address persisting eyelid issues or resolve exposure keratitis. This lengthy process involves multiple staged procedures and requires patients to be out of the workforce for extensive periods of time, negatively impacting their employment. It also contributes to increases in health-care utilization.

TEPEZZA

A newer option for treatment is teprotumumab (TEPEZZA, Horizon Therapeutics), the first FDA-approved drug for TED.

TEPEZZA is a human monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR). In a multicenter randomized clinical trial for active thyroid-associated ophthalmopathy, teprotumumab was found to be more effective than placebo5 and subsequently received FDA approval for treatment of moderate-to-severe active TED. Patients treated with teprotumumab demonstrated improvement in their measured proptosis and Clinical Activity Score, which measures symptoms such as pain, swelling, and inflammation. Subjective diplopia and quality of life were reported as significantly better in clinical trials.6 TEPEZZA exhibited an overall favorable safety profile. Most common adverse events were mild to moderate, with none leading to discontinuation. These included hyperglycemia, muscle cramps, and transient auditory side effects.


 

Figure 4. Top: A patient with active TED. Bottom: Patient shown again after receiving teprotumumab infusions (TEPEZZA, Horizon Therapeutics). IMAGES COURTESY HORIZON THERAPEUTICS.
Figure 4. Top: A patient with active TED. Bottom: Patient shown again after receiving teprotumumab infusions (TEPEZZA, Horizon Therapeutics). IMAGES COURTESY HORIZON THERAPEUTICS.

 

Patients undergo a TEPEZZA infusion every 3 weeks (doses begin at 10mg/kg and go up to 20mg/kg) for a total of eight infusions. The first two doses are administered over 90 minutes, and subsequent doses are given over 60 minutes. Also, it’s important to note that insurance coverage for TEPEZZA can sometimes take up to 75 days to process.

Regardless of this, TEPEZZA appears to have promising outcomes for active TED, providing results that would have generally taken months or years to achieve with conventional therapies, if at all. Few studies have started to explore its efficacy in treating chronic TED. This would undoubtedly change our outlook for what has long been a disfiguring and disabling condition.

Conclusion

While long-term data and safety profile is needed for TEPEZZA, the clinical studies thus far have shown promising outcomes. The availability and advances in monoclonal antibodies are changing the way in which we manage TED patients for the better. OP

REFERENCES:

  1. Bartley GB, Fatourechi V, Kadramas EF, et al. Clinical features of Graves’ ophthalmopathy in an incidence cohort. AM J Ophthalmol. 1996;121 (3):284-290.
  2. Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol. 2011;22(5):385-390.
  3. Estcourt S, Quinn A, Vaidya B. Quality of life in thyroid eye disease: impact of quality of care. Eur J Endocrinol. 2011; 164(5):649-655.
  4. Cockerham KP, Padnick-Silver L, Stuertz N, et al. Quality of life in patients with chronic thyroid eye disease in the United States. Ophthalmol Ther Dec 2021;10(4):975-987.
  5. Smith TJ, Kahaly GJ, Fleming JC, et al. Teprotumumab for thyroid-associated ophthalmopathy. N Engl J Med. May 2017: 376 (18): 1748-1761.
  6. Douglas RS, Kahaly GJ, Ugradar S, et al. Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment: OPTIC-X Study. Ophthalmology. 2022;129(4):438-449.

 

Shakthi Kanagalingam, MD, is an assistant professor of surgery, ophthalmology at the Dartmouth-Hitchcock Medical Center in Lebanon, NH. She achieved her medical degree with honors at the University of Liverpool in the United Kingdom before completing her ophthalmology residency at the Vanderbilt Eye Institute in Tennessee and her neuro-ophthalmology fellowship at the Johns Hopkins Hospital in Maryland.
Shakthi Kanagalingam, MD, is an assistant professor of surgery, ophthalmology at the Dartmouth-Hitchcock Medical Center in Lebanon, NH. She achieved her medical degree with honors at the University of Liverpool in the United Kingdom before completing her ophthalmology residency at the Vanderbilt Eye Institute in Tennessee and her neuro-ophthalmology fellowship at the Johns Hopkins Hospital in Maryland.

 

Dr. Kanagalingam reported no financial disclosures.

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