BACKGROUND
Graves’ disease is the most common type of hyperthyroidism. It is caused by antibodies the body makes that tell the thyroid cells to overproduce thyroid hormone. Those antibodies are called thyroid stimulating immunoglobulins (TSI) or thyrotropin receptor antibodies (TRAbs) because they stick to the TSH receptor in thyroid cells and turn on the cells to become overactive. Graves’ disease is an autoimmune disease, since the antibodies the body produces attack normal cells rather than infections like bacteria and viruses. Methotrexate is a drug that decreases the immune response and is an effective treatment for other autoimmune diseases, such as rheumatoid arthritis.

Graves’ disease is frequently treated with antithyroid drugs (Methimazole or PTU) to control the thyroid. Continuing the antithyroid drugs for 12-18 months may produce a remission of the Graves’ disease, allowing the antithyroid drugs to be stopped. The likelihood of remission of Graves’ disease after a course of antithyroid drugs is in the 25-30% range. Patients who have high levels of TRAbs relapse more frequently, so adding medications that could lower the immune response, such as methotrexate could help increase the likelihood of remission.

This study examined the effect of adding low dose methotrexate to antithyroid drugs on the remission rates in patients with Graves’ disease.

THE FULL ARTICLE TITLE
Xie P, et al. Effects of low-dose methotrexate with methimazole in patients with Graves’ disease: results of a randomized clinical trial. J Clin Endocrinol Metab 2025;110(2):489-497; doi: 10.1210/clinem/dgae472. PMID: 38994582.

SUMMARY OF THE STUDY
This study from China looked at 144 patients with Graves’ disease. Half of the patients were treated with methimazole alone and the other half were treated with methimazole plus methotrexate. About 75% of patients in both groups were women, and the average age was 40 years in both groups. The medications were stopped after 12-18 months if both TSH and TRAb levels became normal. After 18 months of treatment, the group of patients that received methimazole plus methotrexate had a higher chance of being off the medications (56%) as compared to the group that received methimazole only (39%). The levels of TRAb went down faster and more often in the patients who received methimazole plus methotrexate as compared to the patients who received methimazole only: 88% vs 33% had negative TRAbs, respectively. Thyroid levels were similar in both groups and the side effects were mild and similar in both groups.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study suggests that the combination of methimazole plus methotrexate can help lower the Graves’ antibodies faster and more often, and in this way be more successful at allowing stopping antithyroid drugs in patients with Graves’ disease. Methotrexate was well tolerated and safe. Methotrexate may be a helpful for those patients with Graves’ disease who have higher chances of relapse. However, it remains to be seen what the chances of relapse are in the long run after stopping both medications.

— Susana Ebner, MD

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