Issue: June 10, 2021
Source: Healio Interviews
Disclosures: Allen reports he was previously a consultant for Horizon Therapeutics (agreement ended in July 2020). Dosiou reports she previously served on two advisory boards for Horizon Therapeutics. Douglas reports he is a consultant for Horizon Therapeutics, Immunovant and Veridian. Granet reports no relevant financial disclosures. Leung reports no relevant financial disclosures. Stan reports he serves as a consultant for clinical trials for Horizon Therapeutics and Immunovant, with the fees paid to Mayo Clinic research funds.
June 01, 2021
12 min read
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Thyroid eye disease managed jointly by ophthalmologists and endocrinologists

Issue: June 10, 2021
Source: Healio Interviews
Disclosures: Allen reports he was previously a consultant for Horizon Therapeutics (agreement ended in July 2020). Dosiou reports she previously served on two advisory boards for Horizon Therapeutics. Douglas reports he is a consultant for Horizon Therapeutics, Immunovant and Veridian. Granet reports no relevant financial disclosures. Leung reports no relevant financial disclosures. Stan reports he serves as a consultant for clinical trials for Horizon Therapeutics and Immunovant, with the fees paid to Mayo Clinic research funds.
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Not everyone can agree on what to call thyroid eye disease.

For some, it is thyroid-associated ophthalmopathy; for others, it is thyroid-related immune orbitopathy.

Richard C. Allen, MD, PhD
When Richard C. Allen, MD, PhD, first sees a patient, he wants to know whether they have the correct diagnosis and that any thyroid abnormality has been controlled by the endocrinologist.

Source: Richard C. Allen, MD, PhD

“We published an article a bunch of years ago and missed a reference because we searched the literature using several different of these terms, and we missed an article on a similar topic of thyroid eye disease,” David B. Granet, MD, of the University of California, San Diego, said. “But someone else had done a similar study that we just didn’t find. They didn’t use ‘thyroid eye disease.’ They used something like Graves’ ophthalmopathy.”

One thing that physicians can agree on is how this disease affects patients and their lives. Thyroid eye disease (TED) is triggered by an immune response to the thyroid gland that cross-reacts with tissues around the eye.

“The immune cells attack the fat and the fibroblasts in the extraocular muscles surrounding the eye, even around the eyelids, and cause the increase in expansion of the fat and the muscle size, pushing the eye forward, causing proptosis,” Raymond Douglas, MD, PhD, director of the orbital and thyroid eye disease program at Cedars-Sinai Medical Center, said. “They will also attack the tissues around the eyes, causing eyelid retraction and inflammation, or just some very significant facial changes.”

The expansion of orbital muscles can also stretch and compress the optic nerve.

Raymond Douglas, MD, PhD
Raymond Douglas

“The patient ends up with double vision and a decrease in function, and at the same time, because the eye is pushed forward and the lids won’t close properly over the eyelid, the eyes can get dry,” Granet said. “It’s like when I have too much stuff in my garage. It all spills forward because there’s nowhere else to go.”

The change in appearance that comes with proptosis can be difficult for patients. Some even experience psychological effects and mood disturbances that are similar to what patients with cancer or HIV might face, Granet said.

Co-management with endocrinology

TED has two distinct phases, an active phase and a chronic phase. Before oculoplastic surgeons can consider surgical management of the physical manifestations associated with the disease, the underlying thyroid problems must be reined in.

“When I first see a patient, one of the first things I want to know is if they have the correct diagnosis,” Richard C. Allen, MD, PhD, of Baylor College of Medicine, said. “If they have a thyroid abnormality, it is really important to make sure that abnormality has been controlled by the endocrinologist.”

In a majority of patients, TED is linked with Graves’ disease, a condition associated with hyperthyroidism. However, according to Allen, about 5% of patients with TED have hypothyroidism, and a further 5% have no sign for thyroid disease at all.

Ophthalmologists often work hand in hand with endocrinologists who help control the thyroid function and even assist in the treatment of TED, including some of the adverse events that come along with medications used for the disease.

Endocrinology guidance for the treatment of TED has been limited, especially in the United States. The American Thyroid Association has not published guidelines specifically for TED but did address it in its 2016 guidelines on the treatment and management of hyperthyroidism.

“The ATA 2016 guidelines for the management of hyperthyroidism recommend that thyroid dysfunction should be corrected, patients should be advised to stop cigarette smoking, starting glucocorticoids should be considered, and use of radioactive iodine therapy should be cautioned against if the thyroid eye disease is active and moderate to severe, all in order to decrease the risk of developing thyroid eye disease,” Angela M. Leung, MD, MSc, an associate professor of medicine at UCLA David Geffen School of Medicine, said.

In 2016, the European Thyroid Association and the European Group on Graves’ Orbitopathy (EUGOGO) published guidelines with detailed steps for how endocrinologists should proceed with treatment of TED. The guidelines call for providers to have a patient-focused comprehensive plan for treatment centered around improving the patient’s quality of life and psychosocial well-being.

The first step an endocrinologist should take with TED is normalizing thyroid levels, according to Chrysoula Dosiou, MD, MS, a clinical professor in the division of endocrinology and medical director of the thyroid eye clinic at Stanford University School of Medicine. Both hypothyroidism and hyperthyroidism are risk factors for the disease, and failure to treat thyroid dysfunction could result in the disease worsening.

Chrysoula Dosiou, MD, MS
Chrysoula Dosiou

After restoring thyroid levels and addressing risk factors, providers should explore therapy options. Marius N. Stan, MD, a consultant in endocrinology at Mayo Clinic in Rochester, Minnesota, said endocrinologists should collaborate with ophthalmologists when considering which therapy to prescribe.

“This is a joint evaluation and decision-making between endocrinology and ophthalmology, particularly when it comes to medical treatments,” Stan said. “When it comes to surgical therapy, obviously we defer to our colleagues in ophthalmology, but medications are best handled in a joint fashion. Is this the right time? Is this the right medication? Are the side effects justified in view of potential benefits?”

Granet and his team have taken steps to further engage their endocrinology colleagues.

David B. Granet
David B. Granet

“Endocrinologists are well aware of the eye findings, but it’s just not what they do,” he said. “They don’t have all the equipment that we have, and they don’t see it as much as we do. We often have the endocrine fellows spend some time with us, and I think it’s a great experience for them. In one day of our thyroid clinic, they’ll see the full breadth of diseases that patients can present with.”

Surgical interventions

Surgical treatment of TED is a multistep process that begins with the resolution of the disease’s inflammatory phase.

“We try not to do surgery on patients in the active phase of their disease because they’re still changing,” Allen said. “If you do surgery on a patient in their active phase, you’re working on a moving target.”

Although there is no absolute definition of when a patient is ready to start moving toward surgery, Granet said he typically waits until they have at least 6 months of stability and often waits even longer. As far as sequencing of surgery, he generally begins with orbital decompression and then strabismus surgery before addressing the eyelids.

From start to finish, the process of surgery can take 9 months or longer.

“You generally want to wait 4 to 6 months after each of these surgeries to get stability,” Allen said. “You want to make sure they are completely healed before you continue. If there is a patient who has orbital issues as well as strabismus and eyelid involvement, you are potentially looking at over a year of rehabilitation.”

Consequently, surgery is not an option for every patient, and the risks and benefits need to be weighed individually for each patient, Douglas said.

“Many patients are afraid of surgery because of the complications, and it doesn’t always fix things completely,” he said.

Pharmacologic interventions

There are a few options for patients with TED, but first, Allen said, it is important to gauge the phase and severity of disease. Using a clinical activity score of 1 to 7, ranging from mild to very severe, clinicians can judge which patients will need aggressive treatment and which may only need supportive care.

“In a lot of patients with mild disease, meaning a clinical activity score of less than 3, many of them will end up getting better on their own and may not need pharmacological intervention other than just supportive care,” Allen said. “A lot of that supportive care revolves around making sure that the eyes don’t get too dry.”

In addition to artificial tears, Allen generally likes to put patients with mild TED on selenium, which demonstrated improvements in quality of life, reduced ocular involvement and slowed progression of the disease in a randomized controlled trial.

When the clinical activity score starts to creep up to 3 or 4 or more, that is when symptoms can start having a significant impact on patients’ lives. Allen said these patients may not be experiencing vision loss or double vision, but they are generally uncomfortable.

“In this situation, we try to alter the immune response,” Allen said. Like other autoimmune conditions, treatment of TED has long included the use of corticosteroids.

Research by the EUGOGO has shown that intravenous methylprednisolone is effective in the active phase of TED with fewer side effects compared with oral prednisone. Current EUGOGO protocols call for a 12-week course of methylprednisolone, including 500 mg once weekly for 6 weeks and 250 mg once weekly for a subsequent 6 weeks.

Due to the adverse effects associated with high-dose steroids, steroid-sparing agents, such as methotrexate, cyclosporine, azathioprine and mycophenolate mofetil, have been considered for the treatment of TED. However, Allen said studies of these agents have returned mixed results and have not achieved widespread use.

According to Allen, ophthalmologists have started to borrow from their rheumatologic colleagues in the exploration of monoclonal antibodies as a treatment for TED.

“The idea is that you’re actually using a targeted agent rather than something like a steroid, which is very nonspecific,” Allen said. “Monoclonal antibodies are very specific in their action.”

Research in this area has focused on three agents. The first is Rituxan (rituximab, Genentech), which targets CD20 expressed on B cells. Research on rituximab in patients with TED has yielded conflicting results. In one study published in the Journal of Endocrinology and Metabolism, researchers found it had no benefit over placebo and came with “non-negligible” adverse effects. Conversely, a study published in the same journal in 2015 found that patients treated with rituximab had better therapeutic outcomes, including clinical activity score, compared with patients treated with intravenous methylprednisolone.

“Some really promising results sort of petered out,” Allen said. “People found that maybe it’s not the wonder drug that we thought it was going to be.”

The second agent is Actemra (tocilizumab, Genentech), a monoclonal antibody to the IL-6 receptor. Studies have shown that the drug may be effective in patients with active TED who are refractory to corticosteroid therapy.

“My friends in Europe and the Middle East, they love it. They think it works really well,” Allen said. “There’s been a lot of chatter about tocilizumab and its efficacy in patients with thyroid eye disease.”

‘Game changer’

The final monoclonal antibody is also the first to receive FDA approval for the treatment of TED, Tepezza (teprotumumab, Horizon Therapeutics). Granet said the drug has been a “game changer” since its approval a little more than a year ago.

“You can get 3 mm to 4 mm of proptosis reversal,” he said. “I know that 3 mm doesn’t sound like a lot, but when you take your eye and push it forward 3 mm, it’s a lot. There are people who essentially have resolution of symptoms. It’s pretty amazing to see that without surgical intervention.”

“[Teprotumumab] is changing the landscape of treatment significantly,” Dosiou said. “There’s still a lot we need to learn about it. We need to refine dosing, determine who are the best patients to get it and exactly what stages of disease might benefit the most, understand the risks better, make it more available, decrease its costs. But still, it’s a very promising agent in TED patients, especially those with significant proptosis and diplopia.”

Douglas, one of the lead researchers on several studies of teprotumumab, said it is a human monoclonal antibody inhibitor of insulin-like growth factor-1 receptor (IGF-1R), which is expressed highly in cells, particularly fibroblasts, throughout the course of TED.

“It’s believed that blocking the IGF-1R receptor stops the downstream production of inflammatory molecules and of extracellular matrix molecules that caused these fibroblasts to proliferate and to get large and to kind of expand to the orbit,” Douglas said. “It blocks both mechanisms and appears to be highly effective.”

In a randomized, double-masked, placebo-controlled trial, Douglas and colleagues analyzed data from 83 adults with active TED assigned in a 1:1 ratio to IV infusions of teprotumumab in which 41 patients received 10 mg/kg body weight for first infusion (20 mg/kg body weight for subsequent infusions) or placebo (42 patients) once every 3 weeks for 21 weeks. The primary outcome was a reduction in proptosis of at least 2 mm at week 24.

At 24 weeks, more people in the teprotumumab group experienced a reduction in proptosis vs. placebo (83% vs. 10%; P < .001), with a number needed to treat of 1.36.

Despite these promising results, some take a more cautious approach to using teprotumumab.

“Much of what we’re trying to figure out now, as oculoplastic surgeons, is if this is the wonder drug that we think it is and is it worth the risk with regard to side effects,” Allen said. “It’s also an expensive medication, costing about $350,000 for the 24-week course.”

Allen’s chief concern is that most research is focused on the active inflammatory phase of the disease, but the phase is not specified in the FDA approval.

“We need to wait for the evidence, and there are studies that are ongoing,” Allen said. “We need to see those results before we start putting a lot of these patients on teprotumumab.”

Stan said teprotumumab also increases the risk for new-onset diabetes or worsening diabetes in patients who already have it. He said these side effects, usually reversible after completion of therapy, are why it is important for endocrinologists and ophthalmologists to communicate during treatment.

“One needs to know the risk of a patient progressing toward diabetes,” Stan said. “Has there been a history of prediabetes? Has there been a history of diabetes in pregnancy? I think that’s another reason why endocrinologists should stay very close to this field that sometimes has been considered the field of ophthalmology.”

In an extension study, Douglas and colleagues found that teprotumumab was also effective for the treatment of TED in the longer term, as well as for different disease severities. In the OPTIC-X extension study, researchers evaluated patients during the treatment-off period and found that the 56% of patients who were 24-week responders maintained the response at week 72. Patients who experienced disease flare during the treatment-off period received a second course of the drug. Among those individuals, 63% responded to treatment. Additionally, no new safety concerns were observed, including in patients who received an additional course of the drug.

“It appears to be able to work in both the active and chronic phase of the disease because the IGF-1R is overexpressed throughout the disease course,” Douglas said. “That seems to be the unifying concept here.”

Even with more research pending, Granet sees the introduction of teprotumumab as an important tool for the treatment of TED.

“There will be outliers, but it’s very exciting to be able to offer people a new option,” Granet said. “Teprotumumab has transformed our thought process about the disease and the way that patients process what they’re going through.”

He added, “We still have unanswered questions about strabismus, like when to operate and the impact of teprotumumab on the response of the extraocular muscles to surgery.”

Douglas said the research “has uncovered a significant paradigm shift in the mechanism of thyroid eye disease and potentially other autoimmune diseases. It’s a really exciting breakthrough and the first breakthrough we’ve had in the last 50 years of treating this disease.”

Better understanding of the biological pathways involved in TED will lead to more targeted therapies.

“Our knowledge regarding the pathophysiology of the disease is evolving rapidly. Understanding all the key players that are involved in the changes that happen in the orbital fibroblast environment and other tissues in the orbit with TED is fascinating and will lead to more therapeutic options going forward,” Dosiou said.

While he agrees that teprotumumab is an important addition to the armamentarium, Allen is taking things a bit slower.

“Just because we have this new hammer doesn’t mean that we need to treat every patient as a nail,” he said. “I expect more medications to come out, and I expect more data to come out with regard to use of these medications. However, we’re not at the end of the story when it comes to thyroid eye disease.”

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