Continuous low dose methimazole improves control in relapsed Graves’ disease

Daniela Barros, post graduate student of the Surgical Clinic Program at Ribeirão Preto Medical School, University of São Paulo (FMRP-USP). Ribeirão Preto, SP, Brasil.

The study Treatment outcomes in patients with relapsed Graves’ disease, suggests that continuous low dose methimazole may offer better long-term thyroid control than radioiodine therapy or a second course of antithyroid drugs in patients with relapsed Graves’ disease, without worsening thyroid eye disease, quality of life, or weight gain.

Conducted by researchers from the University of Campinas (UNICAMP), São Francisco University, PUC-Campinas, and Hospital do Servidor Público Estadual de São Paulo, Brazil, the study evaluated treatment outcomes in patients who relapsed after standard methimazole therapy for Graves’ disease. The work was led by Juliana de Andrade Carlini and colleagues and published in vol. 70, no. 3 of the Archives of Endocrinology and Metabolism (CARLINI, J. A., et al., 2026).

Graves’ disease is the leading cause of hyperthyroidism in iodine-sufficient regions and is traditionally managed with antithyroid drugs (ATDs), radioiodine therapy (RAI), or thyroidectomy. Current guidelines generally recommend 12 to 18 months of initial ATD therapy, but relapse remains common, affecting up to half of patients after treatment discontinuation. The optimal strategy after relapse, however, remains controversial.

The authors highlight that, despite growing acceptance of prolonged low dose methimazole therapy, few studies have directly compared long-term continuous methimazole, a second ATD course, and radioiodine therapy in relapsed Graves’ disease. This gap motivated the investigators to evaluate the effectiveness and safety of these different therapeutic approaches in a real-world setting.

The retrospective cohort study included 330 patients with Graves’ disease treated with methimazole for 12 to 24 months at a Brazilian university hospital center. After initial treatment discontinuation following negative TSH receptor antibody (TRAb) results, 159 patients experienced relapse and were subsequently allocated into three treatment groups according to patient preference after medical counseling: 39 patients underwent radioiodine therapy followed by levothyroxine replacement, 46 received continuous low dose methimazole, and 74 underwent a second course of methimazole continued until TRAb negativity.

Patients were followed with regular clinical and laboratory assessments, including thyroid function tests, thyroid eye disease evaluation using the Clinical Activity Score (CAS), body weight monitoring, and quality-of-life assessment through the ThyPRO-39 questionnaire. The investigators also evaluated remission predictors in patients undergoing a second methimazole course.

The results showed that patients receiving continuous low dose methimazole maintained euthyroidism more consistently over long-term follow-up than patients treated with radioiodine or a second methimazole course. Euthyroidism was achieved during 78.7% of follow-up assessments in the continuous methimazole group, compared with 51.2% in the radioiodine group and 55.4% in the second-course methimazole group (p < 0.05).

Imagem: Luiz Rogério Nunes via Unsplash

Importantly, no significant differences were observed among the three groups regarding progression of thyroid eye disease, quality of life, cardiovascular outcomes, or weight gain. All treatment groups experienced some degree of weight increase during follow-up, but differences were not statistically significant. Likewise, no major adverse effects related to prolonged methimazole use or radioiodine therapy were reported.

Among patients who underwent a second course of methimazole, nearly half relapsed again after treatment discontinuation. Specifically, 44.6% relapsed after a mean treatment duration of approximately 54 months, while remission was more likely in patients who remained on treatment longer. Treatment duration emerged as the main factor associated with sustained remission, whereas TRAb negativity alone was not a reliable predictor of long-term disease control.

The findings add to a growing body of evidence supporting long-term antithyroid drug therapy in Graves’ disease. Previous studies cited by the authors have similarly suggested lower relapse rates with prolonged methimazole treatment. For example, Azizi and colleagues reported relapse rates of only 15% after approximately eight years of continuous antithyroid therapy, compared with 53% after shorter treatment durations (AZIZI, F., et al., 2019). Korean cohort data also demonstrated progressively higher remission rates with increasing treatment duration, reaching 81% after six years of therapy (PARK, S.Y., et al., 2021).

The authors also discuss how thyroid function stability itself may influence long-term outcomes. Persistent euthyroidism has been associated with lower morbidity and mortality, including in subclinical thyroid dysfunction. In this context, the superior thyroid control observed with continuous low dose methimazole may represent an important clinical advantage over radioiodine therapy followed by levothyroxine replacement.

Another relevant aspect of the study concerns thyroid eye disease. Because radioiodine treatment has historically raised concerns about worsening ophthalmopathy, especially in susceptible patients, the comparable thyroid eye disease outcomes observed across all treatment strategies reinforce the safety of carefully monitored long-term methimazole therapy. Patients in the radioiodine group who were considered at higher risk for ophthalmopathy worsening received glucocorticoid prophylaxis according to established guidelines (BURCH, H.B., et al., 2022).

The investigators acknowledge several limitations. As a retrospective study, the analysis may be subject to selection and information bias. Quality-of-life data were collected only at the end of follow-up rather than at baseline, limiting interpretation of longitudinal changes. In addition, the relatively small number of patients with moderate-to-severe thyroid eye disease prevented more detailed subgroup analyses regarding ophthalmopathy outcomes.

Even so, the authors argue that the study addresses a highly relevant clinical dilemma frequently encountered in endocrinology practice: whether patients who relapse after standard antithyroid treatment should undergo definitive therapy or remain on prolonged low dose methimazole. According to the researchers, the results support continuous low dose methimazole as a viable and safe long-term alternative, particularly for patients wishing to avoid definitive treatments such as radioiodine therapy or surgery.

The authors conclude that if a second course of methimazole is chosen, treatment should likely be extended for longer periods, potentially beyond five years, since shorter retreatment courses appear to produce relapse rates like those observed after initial therapy. Future prospective and randomized studies will be important to better define the ideal duration of antithyroid therapy and to identify predictors of sustained remission in relapsed Graves’ disease.

To read the article, access

CARLINI, J. A., et al. Treatment outcomes in patients with relapsed Graves’ disease. Arch. Endocrinol. Metab. [online]. 2026, vol. 70, no. 3, pp. 1-9 [viewed 01 July 2026]. https://doi.org/10.20945/2359-4292-2026-0045. Available from: https://www.scielo.br/j/aem/a/9VkRYP7XyM65CG9JtWHgdqG/

References

AZIZI, F., et al. Increased Remission Rates After Long-Term Methimazole Therapy in Patients with Graves’ Disease: Results of a Randomized Clinical Trial. Thyroid. 2019, vol. 29, no. 9, pp. 1192-1200. [viewed 01 July 2026]. https://doi.org/10.1089/thy.2019.0180. Available from: https://pubmed.ncbi.nlm.nih.gov/31310160/

PARK, S.Y., et al. The longer the antithyroid drug is used, the lower the relapse rate in Graves’ disease: a retrospective multicenter cohort study in Korea. ENDOCRINE. 2021, vol. 74, no. 1, pp. 120-127. [viewed 01 July 2026]. https://doi.org/10.1007/s12020-021-02725-x. Available from: https://pubmed.ncbi.nlm.nih.gov/33860431/

BURCH, H.B., et al. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022, vol. 32, no. 12, pp. 1439-1470. [viewed 01 July 2026]. https://doi.org/10.1089/thy.2022.0251 Available from: https://pubmed.ncbi.nlm.nih.gov/36480280/

External links

Archives of Endocrinology and Metabolism – AEM