Effects of L-thyroxine administration, TSH-receptor antibodies and smokingon the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study

Objective: In Graves' hyperthyroidism treated with antithyroid drugs (ATD), the overall relapse rate reaches 30-50% following ATD discontinuation. Con flicting results have previously been reported with regard to the usefulnes s of combining ATD with thyroxine (L-T-4), and thereafter maintaining L-TI treatment after ATD withdrawal. Also, clinicians are in search of useful pa rameters to predict the risk of a recurrence of hyperthyroidism after ATD t reatment. Design: Eighty-two consecutive patients (70 women and 12 men; mean age 36 y ears) with a first episode of Graves' hyperthyroidism were investigated pro spectively; they were treated with ATD for a total of 15 months, combined w ith L-T4 (for at least 12 months) after they had reached euthyroidism, with the aim of maintaining serum TSH below 2.5 mU/l during the combined therap y. Following ATD discontinuation, the patients were randomly assigned (doub le-blind placebo-controlled trial) to taking 100 mug/day L-T-4 (Vs placebo) for an additional year. Methods: The following determinations were carried out at initial diagnosis : serum total T-4 and triiodothyronine (T-3), free T-4 and T-3, TSH, TSH-re ceptor antibodies (TSHR-Ab), thyroid scintigraphy and echography. During AT D treatment, serum free T-4 and T-3 and TSH concentrations were recorded af ter 1 (optional), 2, 4, 6, 9, 12 and 15 months, and echography at the end o f ATD treatment. During the randomized trial, serum free T-4 and T-3 and TS H concentrations were checked every 3 months (or until a recurrence). TSHR- Ab titers were measured at initial diagnosis, after 6 months with ATD, and at the end of ATD treatment. Results: L-T4 administration, both during and after ATD treatment, did not improve the final outcome and recurrence rates were similar in placebo and L-Ta-treated patients (30%), Two parameters were identified that might be u seful to help predict recurrence risks after ATD: (i) positive TSHR-Ab (at the end of ATD treatment) was significantly associated with a greatly incre ased recurrence risk; and (ii) despite the relatively small number of patie nts who were smokers, regular cigarette smoking was shown, for the first ti me, to be significantly associated with an increased recurrence risk. Also, the deleterious effect of smoking was shown to manifest its impact indepen dently of TSHR-Ab titers at the end of ATD treatment. Thus, compared with t he overall 30% recurrence risk, non-smoking patients with a negative TSHR-A b (at the end of ATD) had a lower (18%) recurrence risk: smoking patients w ith negative TSHR-Ab (at the end of ATD) had a 57% recurrence risk; non-smo king patients with positive TSHR-Ab (at the end of ATD) had a high (86%) re currence risk; the recurrence risk was 100% in those few patients who both smoked and maintained a positive TSHR-Ab at the end of ATD treatment. Conclusions: The present study confirmed that L-T-4 administration during a nd after ATD withdrawal did not. improve remission rate. Two factors, namel y positive TSHR-Ab at the end of ATD treatment and regular smoking habits m ay represent clinically useful (albeit not absolute) predictors of the risk of recurrence in patients with Graves' hyperthyroidism treated with ATD, H owever, due to the relatively small number of smoking patients in the prese nt cohort, this conclusion needs to be confirmed by a larger study.