The arrival of teprotumumab has been hailed as a game-changer in the treatment of thyroid eye disease (TED).

This monoclonal antibody to the insulin-like growth factor-1 receptor is the first Food and Drug Administration (FDA)-approved treatment for TED. Integrating any new therapy into the management of a disease requires an understanding of its efficacy, side effects, and costs relative to other available treatment options.

Thyroid eye disease is an autoimmune disease classically characterized by an acute inflammatory phase, lasting approximately 12 to 18 months, followed by a chronic noninflammatory phase.

Traditional treatment of TED has centered on modifying known risk factors that exacerbate the disease, medical treatment of the acute inflammatory phase of the disease, and possible surgical treatment for the postinflammatory sequelae in the chronic phase of the disease.

Surgical intervention during the acute inflammatory phase of the disease is usually reserved for sight-threatening situations (e.g., compressive optic neuropathy, exposure keratopathy).

Modifiable risk factors for TED include thyroid status, smoking, selenium deficiency, and immune dysfunction. Thyroid function should be normalized. This often involves the attention of an endocrinologist. Hyperthyroidism is present in 90% of patients with TED, hypothyroidism in 5% of patients, and a euthyroid state in approximately 5% of patients. Normalization of thyroid status can be achieved through medications, radioactive iodine, and thyroidectomy. Many endocrinologists, especially in Europe and Asia, prefer thionamide thyroid suppression as the first line of treatment, reserving thyroidectomy and radioactive iodine for persistent hyperthyroidism or recurrence after medical therapy.

There is growing evidence showing that patients with active TED and thyroid dysfunction may benefit more from thyroidectomy than from radioactive iodine ablation.

This is thought to be secondary to the removal of contributing offending antigens with surgery compared to liberation of the antigens with radioactive iodine ablation. American Thyroid Association treatment guidelines give preference to surgical thyroidectomy in moderate/severe TED.

In addition, postsurgical and postablation patients should be treated promptly with thyroid replacement to prevent hypothyroidism, which has been demonstrated to exacerbate TED.

All patients with TED who smoke should be counseled to stop smoking.

Smoking has been shown to worsen the active phase of the disease in patients with TED.

The mechanism for this is not known.

Because TED is an autoimmune disease, medical treatment has centered on modifying the immune response in patients. Design of studies to evaluate the effectiveness of treatments to alter the inflammatory phase of the disease has been difficult because of the heterogeneity of the disease and the fact that many patients will improve without treatment.

The disease tends to behave differently between male and female patients. Although more common in female patients, when male patients are affected, they tend to have a more severe course.

The disease also behaves differently in adults and children. Pediatric patients with TED rarely develop strabismus or compressive optic neuropathy.

Radiographically, 2 types of TED have been described: type I with mostly fat proliferation and type II with more myopathy.

There is a large spectrum of clinical findings within patient populations, with some patients being mildly affected, others moderately affected, and some severely affected. Well-designed studies should ideally subtype patients into homogeneous groups to determine treatment efficacy.

With finite healthcare resources, it is our responsibility to practice cost-effective, evidence-based medicine.

Corticosteroids have been a mainstay in the treatment of TED.

Oral glucocorticosteroids can rapidly reduce the inflammatory soft tissue findings of TED, but significant side effects and difficulty in tapering the treatment without rebound of inflammation are distinct disadvantages of treatment.

A landmark study showing the effectiveness of intravenous (IV) methylprednisolone versus oral prednisone changed the recommended treatment of the active phase of the disease.

This study, sponsored by the European Group on Graves Orbitopathy, demonstrated a superior response and fewer side effects of IV methylprednisolone versus oral prednisone. Serious adverse effects of high-dose corticosteroids include hyperglycemia, hepatic injury, and mental health effects. The European Group on Graves Orbitopathy protocol involves a 12-week course of IV methylprednisolone: 500 mg once weekly for 6 weeks followed by 250 mg once weekly for 6 weeks. This study changed the standard of care in the treatment of patients in the inflammatory phase of the disease.

In 2011, a randomized controlled trial showed that treatment of patients with mild TED in the inflammatory phase of their disease with oral selenium demonstrated an improvement in the inflammatory signs of the disease.

A criticism of this study was that the study subjects came from a geographic area that has a high prevalence of selenium deficiency. It is unclear if the treatment is only effective if patients are selenium deficient. Because selenium is an inexpensive, over-the-counter supplement with few adverse effects, many clinicians include selenium (100 μg twice daily for 6 months) in the treatment of patients with active TED. Some experts recommend checking selenium levels before supplementation.

Orbital radiotherapy is a controversial topic in the treatment of TED. An early randomized clinical trial questioning the effectiveness of radiation showed no beneficial effect for orbits treated with external beam radiation compared with the untreated orbits of study subjects.

Criticisms of this study included the relatively long duration of disease in study subjects, indicating that patients in the chronic phase of the disease may have been included. Other studies demonstrated effectiveness of orbital radiation in patients with significant myopathy. Many experts use radiation regularly in the treatment of active TED.

Additional studies have supported the combined use of radiation and corticosteroids.

Radiation generally should be avoided in patients with diabetes, those who are pregnant, and those aged less than 35 years.

Steroid-sparing agents include methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil, among others. Studies of these agents in the treatment of TED have shown mixed results, and therefore these agents have not been widely embraced in the treatment of active TED.

However, further study of these agents is likely warranted because these agents have a long history of use in other autoimmune diseases and have well-defined side-effect profiles.

The treatment of rheumatologic and oncologic disease underwent a paradigm shift with the introduction of molecularly targeted agents, many of which have been used in orbital disease.

Monoclonal antibodies to circulating factors and to receptors on cells involved in immune function have shown effectiveness in treating rheumatologic diseases that traditionally had a poor prognosis or required long-term treatment with nonspecific anti-inflammatory medications with significant side effects. Monoclonal antibodies investigated in the treatment of TED include rituximab, tocilizumab, and teprotumumab.

Rituximab, a monoclonal antibody to CD20 that is expressed on B-cells, was one of the first biologic agents investigated in the treatment of TED.

Two small randomized clinical trials, one placebo-controlled and the other comparing rituximab with IV methylprednisolone, yielded conflicting results regarding the effectiveness of rituximab for TED.

Tocilizumab, a monoclonal antibody to the interleukin-6 receptor, improved the inflammatory signs of all patients in a case series of 18 patients with active TED refractory to corticosteroids.

A randomized, placebo-controlled study in 32 subjects confirmed the reduction in inflammatory signs in steroid-refractive patients.

Additionally, improvement in 2 severe cases refractory to corticosteroids and orbital decompression has been reported.

Teprotumumab is currently the only FDA-approved treatment for TED.

The studies of teprotumumab, both of which were industry-sponsored, placebo-controlled randomized studies, showed efficacy of the agent versus placebo in proptosis reduction, reduction of the inflammatory score (clinical activity score), and reduction of diplopia.

Patients enrolled were in the inflammatory phase of the disease (<9 months of disease duration) and had moderate-to-severe disease with a clinical activity score of 4 or more.

Although the clinical trials of teprotumumab were limited to patients with clinically active disease, the FDA label approves teprotumumab for “TED,” without reference to disease severity or clinical activity. This has led some clinicians to use teprotumumab in the chronic, noninflammatory phase of the disease.

Whether the drug is beneficial in this group of patients is unclear. Although technically “on-label,” the efficacy of the medication in patients with chronic phase orbitopathy has not been established. There has also been discussion regarding the use of teprotumumab in mild disease. Expanding the therapeutic indications without rigorous clinical trial evidence to support the efficacy and safety of this approach is not recommended at this point.

The cost of teprotumumab is considerable. A single 500 mg vial of teprotumumab costs $14 900 (USD), and 23 vials ($343 000 cost) are required to complete a 24-week treatment course for a 70-kg (150 lbs) patient.

Because teprotumumab is dosed on the basis of total body weight, not lean body mass, a treatment course in an obese patient can approach $500 000. Use of this very expensive drug should be evidence based and reserved for the patient populations in which effectiveness is well established, such as patients with moderate-severe clinically active disease.

There are still questions regarding the durability of treatment. Relapse rates at 72 weeks after cessation of teprotumumab are as high as 40%.

Payors have requested some physicians to consider corticosteroids first, rather than teprotumumab (similar to step therapy). Careful consideration of use and cost is understandable, because the cost of teprotumumab is substantial. In addition, teprotumumab has not been directly compared with IV methylprednisolone in a superiority or noninferiority clinical trial.

Teprotumumab has several side effects that should be discussed with patients when considering its use. The most common side effects reported in the 2 randomized clinical trials of teprotumumab versus placebo were muscle spasms, affecting 25% of subjects in the teprotumumab group, and nausea, affecting 17% subjects in the teprotumumab group.

Common serious side effects included hyperglycemia and hearing impairment, which were both observed in 10% of teprotumumab subjects. The majority of patients who experienced hyperglycemia had preexisting glucose intolerance. Close monitoring of blood glucose is required in these patients. Although both hyperglycemia and hearing impairment appeared to reverse with drug withdrawal, whether some patients will develop long-term adverse sequelae from teprotumumab requires further investigation. Additionally, having been associated with exacerbation of inflammatory bowel disease causing severe diarrhea in 1 subject, teprotumumab should be used with caution in patients with inflammatory bowel disease. Because FDA approval of teprotumumab was based on a small population of 84 TED subjects who received the study drug, postmarketing surveillance will be critical to understanding the extent and severity of other side effects that may not have been encountered in the clinical trials. An important resource for postmarketing surveillance is the FDA Adverse Event Reporting System, the public website to which healthcare providers, consumers, and drug manufacturer can submit adverse event reports.

A total of 463 reports of adverse events associated with teprotumumab were reported in 2020, of which 78 were classified as serious.

The future treatment of TED is promising. The concept of using molecularly targeted agents to treat the specific pathologic pathways in the development of TED is attractive. Physicians now have an FDA-approved medication for TED. On-label use of the medication should be followed, and physicians should monitor the evolving evidence in the literature regarding the appropriate patient selection. With finite healthcare resources, it is our responsibility to practice cost-effective, evidence-based medicine. The design and implementation of additional studies to evaluate the current best treatment of TED may be difficult, but not impossible. Ideally, randomized trials comparing treatment of patients with various subtypes and clinical manifestations with available monoclonal antibodies, IV methylprednisolone, radiation, and steroid-sparing agents will help guide the optimal customized treatment of patients with this challenging disease.

https://www.aaojournal.org/article/S0161-6420(21)00167-6/fulltext