AT ATA 2017
VICTORIA, B.C. (FRONTLINE MEDICAL NEWS) – In the debate over the optimal duration of methimazole therapy for Graves disease, findings of a new randomized, controlled trial reported at the annual meeting of the American Thyroid Association tip the balance in favor of long-term therapy.
The relapse rate among patients who stayed on the drug long term, for a median of 96 months, was about one-third that among patients who stopped after 18 months, reported lead investigator Fereidoun Azizi, MD, of the Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran. Patients staying on the drug long term did not experience any adverse effects during that time, although only those able to tolerate the drug initially were randomized.
“Long-term, low-dose methimazole treatment for 60-120 months is a safe and effective treatment for Graves hyperthyroidism and is accompanied by much higher remission rates than the usual 18-24 months of methimazole treatment,” he summarized.
There may be two explanations for this benefit of long-term therapy, according to Dr. Azizi. Long-term therapy may alter immune-related molecular signaling and cell subsets in both the thymus and periphery, ultimately shifting disease course. On the other hand, establishing and maintaining euthyroidism for a prolonged period of time may quell the autoimmune response.
“We are looking at this in depth and also at some of the [molecular factors] in order to elucidate the mechanism behind our striking findings,” he said.
One of the session cochairs, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, commented, “There is a move today away from radioactive iodine – many patients do not want radioactive iodine, and we do more surgery now because of that. So this opens up a new option that we didn’t have before.”
At the same time, the potential for rare but serious toxicity of methimazole must be taken into account, especially for certain patients, such as those who travel frequently. “That’s sometimes a consideration when somebody is [on therapy] long term, because even if they don’t develop agranulocytosis, they may develop symptoms that suggest it, creating unnecessary anxiety. In those cases where this is not an issue, long-term treatment could be another new option that we didn’t have before.”
The other session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., noted that duration of therapy frequently comes up in her practice.
“It’s similar that there is sort of a move, if we can, to keep kids on treatment potentially longer because sometimes the kids are too young or we’d rather not do definitive therapy when they are less than 10 years of age, and we want to buy ourselves some time. So this [study] is somewhat reassuring that it’s probably safe to do that as long as they are compliant, they don’t have toxicity, those sorts of things. And there is the chance that perhaps more of them will enter remission over a long period of time,” she said. “I think it just tells us we have to be more patient, perhaps, with how long we treat these patients.”
Relapse of hyperthyroidism after discontinuation of antithyroid drugs remains problematic, Dr. Azizi pointed out when introducing the study.
“Many of the major papers have noted that longer antithyroid drug treatment does not really influence remission rate of Graves, and therefore most of us treat for between 12 and 24 months with antithyroid drugs, and then we stop the medication,” he said. However, recent studies and in particular a meta-analysis ( Thyroid. 2017;27:1223-31 ) suggest there may be an advantage of long-term therapy.
Dr. Azizi and coinvestigators recruited to their trial 302 consecutive patients from a single clinic who had untreated Graves disease and were started on methimazole (Tapazole) therapy.
The 258 patients completing 18 months of therapy were randomized to stop the drug or continue on a maintenance dose long term, for 60-120 months, on a single-blind basis. (The other 44 patients withdrew mainly because of side effects, relapse, and loss to follow-up.)
Patients in the long-term therapy group stayed on the drug for a median of 96 months. The decision about specifically when to stop in this group was guided by thyroid function test results and patients’ clinical status and preferences, according to Dr. Azizi.
The rate of relapse at 48 months after stopping methimazole was 51% among patients in the short-term therapy group but just 16% among patients in the long-term therapy group (P less than or equal to .001). “Definitely, this looks like a cure of the disease if we consider this very low incidence of relapse,” he commented.
Within the group treated long term, patients who did and did not experience relapse were statistically indistinguishable with respect to temporal trends in levels of triiodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid-stimulating hormone receptor antibody (TRAb).
Additionally, the daily dose of methimazole therapy required to maintain TSH levels in the normal range fell similarly over time, to about half the initial dose, regardless of whether patients had a relapse or not.
“At the end of treatment, the majority of patients were taking less than 5 mg/day of methimazole,” Dr. Azizi reported. “Some patients needed only two or three pills of 5-mg methimazole per week, and this is very interesting to know, that after you continue, you have definitely more response to methimazole.”
Multivariate analyses showed that in the short-term therapy group, risk factors for relapse were age, sex, and end-of-therapy levels of T3, TSH, and TRAb. In the long-term therapy group, risk factors were end-of-therapy levels of free T4 and TSH.
“We are currently performing more in-depth analysis of genetic markers, including both SNPs [single nucleotide polymorphisms] and HLA [human leukocyte antigen] subtyping on these samples to assess any potential association between relapse rates and genetic background,” Dr. Azizi noted. “However, the problem is the low number of patients who have had a relapse long term.”
During the first 18 months of methimazole therapy, 16 patients had adverse effects in the first 2 months (14 had cutaneous reactions and 2 had elevation of liver enzymes). However, there were no serious complications, such as agranulocytosis.
“It’s very reassuring that after 18 months, in those who had long-term treatment, we did not see any minor or major complications throughout, up to the 120 months of treatment we have had in some of our patients,” Dr. Azizi commented.
Dr. Azizi disclosed that he had no relevant conflicts of interest.