Severe Thyroid Eye Disease Trials Show Hit-and-Miss Results

Nancy A Melville

February 23, 2018

Efforts to better address the ongoing clinical challenge of treating moderate-to-severe Graves' orbitopathy show some potential benefits from the addition of mycophenolate mofetil to the standard of care, methylprednisolone, no benefit from the addition of radiotherapy to oral steroids, and inconclusive results with the addition of azathioprine to oral steroids.

These latest findings are from two clinical trials published online January 30 in The Lancet Diabetes & Endocrinology.

"Based on the results ... radiotherapy should not be considered as first-line treatment of moderate-to-severe Graves' orbitopathy, while the addition of widely available, low-dose mycophenolate mofetil to the standard treatment regimen of high-dose intravenous glucocorticoids could improve treatment outcome with limited side effects," Robin Peeters, MD, PhD, of the Department of Internal Medicine, Erasmus MC Academic Center for Thyroid Diseases, Erasmus University Medical Center, Rotterdam, the Netherlands, told Medscape Medical News.

"This is an important finding because mycophenolate mofetil is affordable and easily available in most countries, and hardly has any side effects," said Peeters, coauthor of an accompanying editorial.

The first of the two randomized trials showed that the addition of the immunosuppressant mycophenolate mofetil to the current first-line treatment of methylprednisolone for Graves' orbitopathy had improved efficacy over IV methylprednisolone alone at 24 weeks; however, the study failed to meet the primary outcomes of response at 12 weeks and relapse at 24 and 36 weeks.

And in the second study, no benefits from the addition of radiotherapy to oral prednisolone were seen, while there were inconclusive results when azathioprine treatment was added to oral steroids, with some signs of a beneficial effect, but high numbers of dropouts in the study.

The two studies underscore the need for better treatment options for active moderate-to-severe Graves' orbitopathy, or thyroid eye disease, which occurs in 5% to 10% of people with Graves' disease.

Intravenous glucocorticoids, particularly methylprednisolone, are the standard of care, with the aim of suppressing orbital inflammation and preventing tissue remodeling in extraocular muscles and orbital fat.

But with concerns of cumulative toxic effects, the drugs are typically withdrawn after just 24 weeks, and subsequent recurrence at the time of withdrawal is common, with active disease commonly lasting 1 to 2 years.

Trial Misses Endpoints, But Post-Hoc Analysis Shows Clues of Efficacy

For the MINGO trial, the first of two studies exploring possible solutions, the authors theorized that the combination of mycophenolate mofetil, an immunosuppressant, could improve responses when combined with the anti-inflammatory effects of the first-line treatment methylprednisolone.

The study was authored by George J Kahaly, MD, PhD, Endocrine Outpatient Clinic at the Gutenberg University Medical Center in Mainz, Germany, and colleagues representing the European Group On Graves' Orbitopathy (EUGOGO).

In their multicenter study, 164 patients with active moderate-to-severe Graves' orbitopathy at two centers in Germany and two in Italy were randomly assigned in observer-masked fashion to treatment with IV methylprednisolone alone (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks; n = 81) or the addition of mycophenolate (one 360-mg tablet twice per day for 24 weeks; n = 83).

In terms of response rate at 12 weeks, a primary outcome, there was no significant difference in the intent-to-treat population between the monotherapy (36 of 73 patients; 49%) and combination groups (48 of 76; 63%) (OR 1.76, P = .08).

And at 24 weeks, 38 of 72 (53%) of patients remaining in the monotherapy group and 53 of 75 (71%) in the combination group had responded to treatment (OR 2.16; P = .02).

For the primary outcomes of relapse rates at 24 and 36 weeks, there were no significant differences in the monotherapy and combination groups (P = .72 and P = .61, respectively).

However, significantly more patients in the combination group at week 36 had a sustained response (49 of 73; 67%) compared with the monotherapy group (31 of 68; 46%) (P = .01), the authors note.

There were no significant differences in rates of serious adverse events, with 11 events in 10 patients in the combination group and 13 events in 13 patients in the monotherapy group.

Rates of mild and moderate (grade 1–2) drug-related adverse events were also similar in the monotherapy (20%) and combination (25%) groups (P = .48).

"To our knowledge, this study is the first to investigate the efficacy and safety of add-on mycophenolate to methylprednisolone for moderate-to-severe Graves' orbitopathy," Kahaly and colleagues say.

Although there were no significant differences in the primary outcome measures, the differences seen in the post hoc analyses suggest that combination therapy "significantly enhances the efficacy of the intravenous steroid therapy after 24 weeks, without increasing the frequency of treatment-associated adverse effects," they add.

"Therefore, in patients with active and severe Graves' orbitopathy and no contraindications for mycophenolate ... combination therapy with this drug could be considered."

Radiotherapy, Azathioprine Results Lackluster

For the second study, a 2 x 2 factorial double-blind trial dubbed the CIRTED trial, first author Rathie Rajendram, MD, of Moorfields Eye Hospital NHS Foundation Trust, London, UK, and colleagues evaluated the noncorticosteroid immunosuppressant drug azathioprine or orbital radiotherapy as additions to oral prednisolone, which is still commonly used around the world and is more convenient in many settings than intravenous corticosteroids, although not as effective.

In the study, 126 patients with active moderate-to-severe thyroid eye disease associated with proptosis or ocular motility restriction were all initially treated with a 24-week course of oral prednisolone (80 mg/day, reduced to 20 mg/day by 6 weeks, 10 mg/day by 15 weeks, and 5 mg/day by 21 weeks) and randomly assigned in the double-blind study to radiotherapy plus azathioprine (n = 31), sham radiotherapy plus azathioprine (n = 31), radiotherapy and placebo (n = 32), or sham radiotherapy and placebo (n = 32).

The radiotherapy dose was 20 Gy administered to the retrobulbar orbit in 10 to 12 fractions over 2 to 3 weeks, while azathioprine was administered for 48 weeks at doses of 100–200 mg/day (dispensed as 50-mg tablets), with adjustments for bodyweight (100 mg for < 50 kg, 150 mg for 50–79 kg, 200 mg for ≥ 80 kg).

The authors note that dropout rates were high. Treatment was discontinued by 20 patients in the radiotherapy plus azathioprine group, 21 in the sham radiotherapy plus azathioprine group, 16 in the radiotherapy plus placebo group, and 12 in the sham radiotherapy plus placebo group.

Early withdrawals (prior to 24 weeks) attributed to disease deterioration occurred as the steroid dose was reduced and were not mitigated by orbital radiotherapy, Rajendram and colleagues note.

The results showed no added benefit of radiotherapy to oral prednisone treatment of 24 weeks, and no interaction between azathioprine and radiotherapy (P interaction = .86).

After adjustments, the odds ratio for improvement in the binary clinical composite outcome score was 2.56 (P = .05) for azathioprine and 0.89 (P = .80) for radiotherapy.

A post hoc analysis of patients who completed their allocated therapy showed adjusted odds ratios for improvement of 6.83 (P = .008) for azathioprine and 1.32 (P = .67) for radiotherapy.

No significant differences were observed in measures of ophthalmopathy, clinical activity, or adverse events.

"These results do not support the use of additional radiotherapy in patients with thyroid eye disease who are treated with systemic corticosteroids," the authors say.

"Although a significant difference between placebo and azathioprine was not seen in the intention-to-treat analysis, post hoc analysis of patients who completed treatment suggest a benefit of antiproliferative immunosuppressive agents, such as azathioprine, beyond the period of corticosteroid therapy to improve long-term clinical outcomes."

Individualized Patient-Specific, Personalized Care Is Best

Although the majority of patients respond to treatment with high-dose glucocorticoids, many progress or relapse after treatment recession, with an array of troubling symptoms, Peeters said.

"In these patients, the ongoing inflammation causes enlargement of the extraocular muscles and an increase in orbital fat," he explained.

"The result of this may be proptosis, diplopia, eyelid swelling and retraction, and a feeling of pressure or pain, [and] vision may be threatened by exposure keratopathy or dysthyroid optic neuropathy.

"Moreover, prolonged and/or high-dose corticosteroid treatment, the current strategy, is frequently associated with serious side effects, including diabetes, osteoporosis, hepatic complications, and hypertension."

In the editorial, Peeters and colleagues say the radiotherapy findings have important implications, suggesting that "if radiotherapy adds little to clinical outcomes when combined with oral glucocorticoids, it is perhaps even less likely to be valuable when added to the more potent therapy, such as IV glucocorticoids."

They add that the studies' results underscore that, ultimately, individualized care is necessary to best address specific needs.

"The conflicting results in some clinical studies and the diversity of pathogenic processes that might play a part in each patient with Graves' orbitopathy mean that a personalized, patient-specific, pathway-targeting treatment is required that is tailored to the stage of disease to improve therapeutic efficacy."

The MINGO trial was funded in part by Novartis, Germany. The CIRTED trial received funding from the National Eye Research Centre, Above and Beyond, and Moorfields Eye Charity. The editorialists have reported no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online January 30, 2018. MINGO trial, CIRTED trial, Editorial

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