Summary: In untreated patients with hyperthyroid Graves disease, methotrexate 10 mg weekly added to methimazole increased protocol-defined treatment discontinuation at 18 months versus methimazole alone, 55.6% versus 38.9% (P=0.045), and accelerated TRAb decline. This open-label, single-centre trial did not establish durable remission after withdrawal.
PICO Summary
| Element | Detail |
|---|---|
| Population | 153 untreated patients with hyperthyroid Graves disease entered the study; 144 eligible patients were randomized 1:1 at an academic endocrine outpatient clinic in an open-label trial. |
| Intervention | Methotrexate 10 mg once weekly plus methimazole (n=72). The published correction confirms weekly, not daily, methotrexate dosing. |
| Comparison | Methimazole alone (n=72), adjusted according to thyroid function. |
| Outcome | At month 18, protocol-defined treatment discontinuation with biochemical euthyroidism and negative TRAb occurred in 55.6% (40/72) versus 38.9% (28/72); absolute difference 16.7 percentage points, odds ratio about 1.96 (reported 95% CI 1.011-3.815; P=0.045). TRAb declined faster with combination therapy, but FT3, FT4 and TSH did not differ significantly between groups. |
Weekly Methotrexate + Methimazole in Graves Disease
Open-label RCT - untreated Graves disease - 18 months
Weekly methotrexate added to methimazole increased protocol-defined treatment withdrawal at 18 months, but durable remission and uncommon toxicity remain uncertain.
Expert Commentary
This randomized trial asks whether modest immunomodulation can shorten antithyroid-drug treatment in newly treated Graves disease. Adding methotrexate 10 mg weekly increased successful treatment discontinuation at 18 months from 38.9% to 55.6%, an absolute difference of 16.7 points, while TRAb declined faster. The signal is interesting because persistent TRAb reflects ongoing autoimmunity, but treatment withdrawal is not the same as durable remission. The trial was open label, involved 144 randomized patients at an academic outpatient clinic, and did not report long-term relapse after withdrawal. Thyroid hormone concentrations were not materially different, and the sample was too small to define uncommon methotrexate toxicity. Can I use this with my patients? Not routinely. Methimazole remains the standard initial drug treatment, and add-on methotrexate should be viewed as investigational until multicentre trials confirm sustained remission and provide stronger safety data. Methotrexate also requires counselling about pregnancy avoidance, interactions and infection risk, with baseline and serial blood count, liver and renal monitoring. For a selected patient with difficult Graves disease, the result may justify discussion in a specialist setting or clinical trial, but it does not support off-label prescribing. The practical takeaway is proof of concept that immune-directed adjunctive therapy may improve drug withdrawal, not evidence that weekly methotrexate has become standard Graves treatment.
References
Xie P, Shen L, Peng R, 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. The corrected intervention is methotrexate 10 mg weekly: doi:10.1210/clinem/dgae698.