Matching steroid therapy, thyroid eye disease severity key to response

Take-home message: When deciding which steroid option may be best for treating patients with thyroid eye disease, first identify the severity and activity of the condition.

By Nancy Groves; Reviewed by Timothy J. Sullivan, MBBS

Brisbane, Australia-Steroids have an important role in moderately severe and sight-threatening thyroid eye disease, according to Timothy J. Sullivan, MBBS.

The majority of patients with thyroid eye disease will be managed by endocrinologists rather than ophthalmologists, noted Dr. Sullivan, MBBS, professor of ophthalmology, University of Queensland and Royal Brisbane and Women’s Hospital, Brisbane, Australia.

If their disease is mild, they probably won’t need treatment, particularly with steroids. Instead, they can often be managed with supportive measures, he noted.

“However, if we want to decide based on good guidelines about who might need treatment, we need to have grading for both severity and activity, which is quite difficult to do,” Dr. Sullivan added.

Generally, cases are classified as mild, moderate, or severe. Activity measurements can be derived from the EUGOGO system (European Group on Graves’ Orbitopathy, www.eugogo.eu) or the VISA classification system from the International Thyroid Eye Disease Society (www.thyroideyedisease.org).

Steroids are recommended for some patients because of the potential beneficial effects of their anti-inflammatory and immunosuppressive properties.

According to Dr. Sullivan, they decrease both T and B cell function and globally reduce the recruitment of neutrophils, monocytes, and macrophages, which serves to inhibit the function of many normal immunocompetent cells and to alter and modulate the release of inflammatory mediators, predominantly cytokines. This then leads to a reduction in the production of hyaluronin and secretion by orbital fibroblasts and adipocytes.

Oral therapy

Glucocorticoids are usually given orally at a relatively high dose, such as 60 to 100 mg/day of prednisone, for a prolonged period, then tapered.

“This leads to a cumulative dose of somewhere between 2 to 6 g, and this has not only significant systemic side effects but also a relatively high rate of relapse,” Dr. Sullivan said. “This led to people looking for better ways of delivering this care.”

Intravenous routes

In the 1950s, some physicians tried intravenous routes. Following several early reports, the Medical Research Council of the United Kingdom conducted a study of 28 patients; 5 received 37.5 to 100 mg/d adrenocorticotrophic hormone for 15 to 21 days, and 23 received 1-200 mg/d of cortisone. Only 3 patients had a good response, 5 achieved a temporary response, and 20 had no response.

Interestingly, all patients who responded to treatment had early onset Graves’ orbitopathy.

With limited efficacy demonstrated in this and other studies, intravenous administration was largely forgotten until the mid-1980s when active investigation resumed. More recently, in a study by Kahaly et al. published in 2005, 70 euthyroid patients were randomized to weekly IV methylprednisolone or oral prednisolone. The results showed that 77% of patients receiving IV steroids improved versus 51% of those taking oral medication (p < 0.01).

Improvement in visual acuity, quality of life, and TSH-receptor antibody levels was also statistically significant, and IV side effects were lower (p<0.001).

However, side effects occurred in both groups, affecting 51% of those in the oral steroid group and 17% in the IV group (p < 0.005).

A separate study found that serious side effects, such as acute liver failure or death, could occur with high cumulative levels (above about 7 g) of pulsed IV methylprednisone.

“We need to be very careful with advocating the use of these agents,” Dr. Sullivan said.

A 2012 randomized study of low, intermediate, and high dosages of IV methylprednisolone concluded that an intermediate dose regimen could be used in most cases and that the highest dose regimen should be reserved for the most severe cases of Graves’ orbitopathy. In the study by Bartelena et al., patients in the intermediate group received a cumulative dose of 4.98 g in 12 weekly infusions.

Intraorbital approach

Studies of retrobulbar injection led to evaluation of periorbital administration, Dr Sullivan noted. The conclusion of a 2004 study by Ebner et al. was that triamcinolone reduced diplopia and extraocular muscle sizes in patients with recent onset thyroid-associated ophthalmopathy and also was not associated with significant systemic or ocular side effects.

These and other studies were used to develop management protocols for use of steroids and later the consensus EUGOGO guidelines for all patients with thyroid eye disease, published in 2008.

“In general, the aim should be to restore euthyroidism, stop smoking, give selenium, and institute local measures, such as lubricants,” Dr. Sullivan said. “Where there is mild disease, there's probably no need for steroids. Where this progresses and reaches the level of moderate disease, with a clinical activity score of greater than 3, then intravenous glucocorticoids or orbital radiotherapy might be considered.

“Where there is sight-threatening disease, IV steroids should be given, and where poor response is present, progression to orbital decompression should be prompt,” he said. “If there is still disease activity after decompression, there may be further need for intravenous glucocorticoids.”

In response to the published evidence and guidelines, steroids have become a widely accepted medical management option for thyroid-associated orbitopathy.

In a 2014 study by Perumal and Meyer based on a poll of members of the American Society of Ophthalmic Plastic and Reconstructive Surgery, 87% of physicians used oral steroids for their patients at some stage of treatment, 74% used them intravenously, and 28% used intraorbital injection. Radiation and orbital decompression were also commonly used.

Looking at first-line treatments, oral and intravenous steroids had a combined usage of 83%. No other option was used as first-line treatment in more than 6% of cases.

Decompression and radiotherapy were most commonly used as subsequent measures.

Timothy J. Sullivan, MBBS

E: tjs@terraceeyecentre.com.au

This article was adapted from Dr. Sullivan’s presentation during Oculoplastics Subspecialty Day at the 2014 meeting of the American Academy of Ophthalmology. Dr. Sullivan did not report any financial interests or relationships.