Is there a methimazole dose effect on remission rate in Graves' disease? Results from a long-term prospective study

OBJECTIVE The optimal antithyroid drug regimen for Graves' disease remains a matter of controversy. The European Multicentre Trial Group has investigated the effects of methimazole drug dose on the long-term outcome of Graves' disease. DESIGN Extended follow-up of patients from a prospective multicentre trial, designed to study methimazole dose effects on the outcome of Graves' disease. We have reported previously that the relapse rates did not differ after a medication-free observation period of 12 months; the relapse rates were 37 and 38%, respectively. In this paper, we describe the outcome in these patients after a mean observation period of 4.3 +/- 1.3 years and have looked for potential predictors of this outcome. PATIENTS Three hundred and thirteen patients with Graves' disease were randomized to treatment with a constant dose of 10 or 40 mg of methimazole for 1 year, with levothyroxine supplementation as required. MEASUREMENTS At the time of inclusion into the trial: thyroid size, T4, T3, TSH-binding inhibiting immunoglobulins, urinary iodide excretion, thyroid uptake, Crook's therapeutic index of hyperthyroidism (a measure of clinical disease severity). At the time of follow-up examination: TSH, T4, T3, thyroid size, thyroid ultrasound, THS-binding inhibiting immunoglobulins. RESULTS The overall relapse rate was 58%. There was no difference in relapse rates between patients treated with either 10 or 40 mg of methimazole (58.3 vs. 57.8%). Five patients had become spontaneously hypothyroid, without obvious relationship to antithyroid drug dose. Patients who relapsed and patients who remained in remission did not differ with respect to: age, goitre size, ophthalmopathy, median iodine excretion, serum T4 or serum T3, Crook's therapeutic index and thyroid uptake at the time of study entry. Thus, none of these variables was potentially suitable for predicting outcome. This finding was confirmed by Cox's proportional hazard regression. Thyroid volume, measured by ultrasound, did not differ between patients in remission and patients with relapse. There was no difference in the course of endocrine eye signs, in the requirement for steroid and radiotherapy for eye signs, or in thyroid echo-structure between patients in the 10 and in the 40 mg group, nor was serum TSH different in patients who had remained in remission (0.8 +/- 0.6 mU/l in the 10 mg group, 1.0 +/- 0.8 mU/l in the 40 mg group). CONCLUSIONS The dose of methimazole in Graves' disease therapy can safely be kept to the minimal required dose. This will provide the same chance of remission as higher doses, and provide the best balance of risk and benefit.