Long-term, Low-Dose Methimazole Reduces Hyperthyroidism Relapses

Nancy A Melville

October 24, 2017

VICTORIA, BC — Graves' disease patients treated with long-term, low-dose methimazole therapy show significantly lower rates of relapse compared with short-term exposure, with no serious side effects linked to the longer-term treatment, according to new results from a randomized study.

"Our findings show that long-term, low-dose methimazole treatment for 60 to 120 months is a safe and effective method for treatment of Graves' hyperthyroidism," said senior author Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran, in presenting the findings here at the 2017 Annual Meeting of the American Thyroid Association.

Those assigned to the longer-term treatment arm with methimazole took it for a median of 96 months (8 years).

In commenting on the study, Catherine A Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, in New Haven, Connecticut, said the study sheds important light on an issue that often challenges decision-making.

"There's a lot of debate about how long we can treat these patients, with the general thought that maybe we should stop treatment after about 1 year, or 2 at the most, and then if the patient is not in remission we should to move to definitive treatment," Dr Dinauer told Medscape Medical News.

"But there are increasing data coming out in adults, as well as some in pediatrics now, indicating it may be safe to continue these patients longer term and, for our younger patients, in particular, that might be advantageous to buy ourselves time," she noted.

"So these data are reassuring, suggesting that as long as patients are consistent with taking the methimazole and don't show signs of toxicity, longer-term treatment is a reasonable strategy."

Daily Dose of Methimazole That Was Effective Declined to < 5 mg in Long Term

While most previous studies have not shown a reduction in the rate of remission in Graves' disease with antithyroid drug treatment when administered for an optimal period of 12 to 18 months, Dr Azizi and colleagues published a meta-analysis of six articles this year that did indicate a higher remission with long-term therapy (> 24 months) compared with shorter-term therapy (Thyroid. 2017;27:1223-1231).

In conducting their own randomized trial, the Iranian researchers enrolled a group of 302 patients with a first episode of Graves' hyperthyroidism who were initially all treated with 18.8 ± 2.2 months of methimazole.

After the 18 months, 258 of the patients were randomized to either continue treatment with the drug (n = 130) or to discontinue it (n = 128).

In the long-term group, 115 patients continued methimazole treatment for at least 60 months and discontinued use of the drug after a median of 96 months.

All patients in the short- and long-term groups were followed for 48 months after discontinuation.

Among patients in the short-term group, 29% had a relapse of hyperthyroidism within 12 months of withdrawal from the drug, compared with only 3.3% of those in the long-term group.

At 48 months after methimazole withdrawal, 51% in the short-term group had a relapse compared with 16% in the long-term treatment group (< .001).

The median time to relapse after discontinuation was 6.0 months in the short-term group and 11.5 months in the long-term group.

Leading risk factors associated with relapse in the short-term group included male gender, thyroid volume, serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb), and HLA polymorphism. In the long-term group, only free-T4 levels were significantly associated with relapse.

Dr Azizi noted that the daily dose of methimazole needed to maintain TSH levels in the normal range in the long-term group declined to less than 5 mg.

"The majority in the long-term group were taking less than 5 mg of methimazole, and some only needed two or three pills per week, so it is interesting to see that as you continue there appears to be more of a response to methimazole," he commented.

Side effects associated with the treatment in the first 18 months included cutaneous reactions in 14 patients and increased liver enzymes in two patients; however, no further side effects were reported in the long-term group for up to 120 months of therapy.

"It is very reassuring that after 18 months we did not see any major complications" afterward, for up to 10 years of treatment, Dr Azizi concluded.

Dr Azizi and Dr Dinauer had no relevant financial relationships.

2017 Annual Meeting of the American Thyroid Association. October 19, 2017; Victoria, British Columbia.

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