Effect of methimazole with or without exogenous L-thyroxine on serum concentrations of thyrotropin (TSH) receptor antibodies in patients with Graves' disease.

Abstract

Medical treatment of Graves' disease involves use of antithyroid drugs with or without the addition of exogenous L-T4. There have been conflicting reports as to whether the addition of T4 reduces TSH receptor antibodies and improves remission rates more than antithyroid drugs alone. To further examine the effect of drug therapy on serum concentrations of TSH receptor antibodies. 70 patients with Graves' disease were treated with methimazole (Tapazole) alone until they were euthyroid. Then they were randomized to receive either: 1) methimazole alone in a dose sufficient to normalize TSH (0.3-5.4 mIU/L; Group 1); 2) 30 mg methimazole daily plus sufficient T4 (Synthroid) to maintain TSH in the high-normal range (2.0-5.4 mIU/L; Group 2); or 3) 30 mg methimazole daily plus sufficient T4 to suppress TSH to below 0.6 mIU/L (Group 3). The duration of treatment in all groups was 18 months. At baseline and after 6 and 18 months, TSH receptor antibodies were measured both by the ability of patients' sera to stimulate cAMP production by FRTL-5 cells (thyroid-stimulating Ig) and by the ability of patients' sera to inhibit binding of radiolabeled TSH to solubilized porcine thyroid membranes (TSH-binding, inhibiting Ig). Thyroid-stimulating Ig(TSI) and TSH-binding, inhibiting Ig(TBII) concentrations were similar among the three groups at baseline. Mean baseline TSI (expressed as the percent of normal control) for all patients combined was 306 +/- 21%. Mean baseline TBII (expressed as percent inhibition of TSH binding) was 38 +/- 2%. TSI was elevated in 85% and TBII was elevated in 75% of patients at baseline. After 18 months, TSI was elevated in 64% of patients, and TBII was elevated in 28%. Serum TSI decreased by 36 +/- 5% during the study, and there was no significant difference in the degree of reduction among the three groups (P = 0.99). Serum TBII decreased by 59 +/- 3%, and there also was no significant difference among the groups (P = 0.83). At baseline, serum TBII correlated with free T4 (r = 0.33, P < 0.01), total T3 (r = 0.55, P < 0.01), and thyroid size (r = 0.35, P < 0.01). There was no correlation between TSI and any of the baseline parameters or between TSI and TBII at any timepoint. In conclusion, we found that the addition of T4 to methimazole does not result in a greater decrease in TSH receptor antibody concentrations than treatment with methimazole alone. From these results, we would predict no difference in remission rates among these patients, but confirmation of this prediction will need to await long-term follow-up of these subjects.

Predictors of Early Remission of Hyperthyroidism in Children1

“…Hashizume et al (25) demonstrated improved remission rates, using treatment with methimazole plus T 4 , compared with methimazole alone. More recent studies, however, failed to confirm these results (22,26,27). The reason for the variability among these studies is unknown.…”

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

“…Apart from the dose factor, treatment duration has varied between 6 and 24 months in some studies to detect differences in relapse rate, with inconsistent results (Allannic et al, 1990;Garcia-Mayor et al, 1992;. Addition of levothyroxine during methimazole treatment, and continuation after stopping the antithyroid drug, has been suggested to give protection from relapse of Graves' disease (Hashizume et al, 1991), even post partum (Hashizume et al, 1992); however, two other studies did not confirm an effect on outcome (McIver et al, 1996;Rittmaster et al, 1996), or an effect on TSH receptor antibodies (Tamai et al, 1995). Our study was not intended to address either of the two potential factors, since treatment duration was for 1 year only, and levothyroxine was added in both treatment arms (but was not continued after stopping antithyroid drugs).…”

Controversies in the management of Graves' disease

“…The improved outcome was associated with a dramatic decrease in levels of anti TSH receptor antibodies. However, 5 additional studies including one designed to repeat this finding (McIver et al, 1996) and another also performed in a Japanese population (Tamai et al, 1995) have failed to confirm these results (Rittmaster et al, 1996;Pfeilschifter & Zeigler, 1997;Lucas et al, 1997). As a result, there now appears to be little evidence for an independent beneficial effect of thyroxine on relapse rates after medical therapy.…”