Background: Methotrexate (MTX), a mainstay in the treatment of autoimmune disorders such as rheumatoid arthritis, is generally well tolerated but carries a known risk of myelosuppression, particularly in settings of renal impairment, folate deficiency, or interacting medications. Methimazole (MMI), used for hyperthyroidism, is also associated with hematologic toxicity, most notably agranulocytosis. The concurrent use of both agents is rare, and data on their synergistic marrow-suppressive potential are limited. A 2025 randomized trial by Xie et al. demonstrated that low-dose MTX combined with MMI achieved faster reductions in thyroid receptor antibodies (TRAb) in patients with Graves' disease, but this benefit came at the cost of a higher rate of treatment discontinuation due to adverse effects, raising questions about safety in real-world polypharmacy. [1] We present a case of life-threatening pancytopenia in a patient on chronic MTX therapy following the addition of MMI.

Case Presentation: A middle-aged African American woman with longstanding RA, type 2 diabetes, CKD stage 3, and newly diagnosed Graves' disease presented with odynophagia, mucositis, and fever. She had been stable on MTX 20 mg weekly for over seven years without hematologic abnormalities. One month prior, she was started on MMI 20 mg daily for uncontrolled thyrotoxicosis. At presentation, she was pancytopenic: WBC 1.7×10³/µL (ANC 70), hemoglobin 10.3 g/dL, and platelets 70×10³/µL. Both MTX and MMI were discontinued immediately. Over the following 24 hours, her counts dropped precipitously—WBC 0.7×10³/µL (ANC 30), hemoglobin 8.0 g/dL, platelets 5×10³/µL. She was treated empirically for neutropenic fever with broad-spectrum antibiotics, received transfusion support, and was evaluated by hematology. Platelet transfusions were ineffective, raising concern for alloimmunization. Peripheral smear and flow cytometry were negative for hematologic malignancy or marrow infiltration.

The patient's cytopenias gradually improved after drug cessation, implicating the combination of MTX and MMI in marrow suppression. As she remained thyrotoxic but was not a surgical candidate and had deferred radioactive iodine, methimazole was cautiously reintroduced at a lower dose with daily monitoring. Her cell lines recovered (ANC >500/µL, platelets increased to 66×10³/µL), and she remained clinically stable.

Discussion: This case illustrates the potential for severe marrow suppression when MTX and MMI are co-administered. MTX preferentially affects rapidly dividing cells and its toxicity is potentiated in the presence of renal dysfunction or interacting drugs. [2] Notably, our patient had no prior cytopenias on MTX, suggesting that the addition of methimazole may have triggered a synergistic or sensitizing hematologic insult. MMI-induced agranulocytosis is unpredictable and idiosyncratic. [3] The clinical course—rapid pancytopenia after MMI introduction and recovery upon cessation—supports a dual-agent myelotoxicity mechanism. The Xie et al. trial showed that combining MTX with MMI may enhance Graves' disease remission, but also increases the risk of discontinuation due to toxicity, underscoring the need for careful selection and monitoring in patients with comorbid conditions. [1]

Conclusion: Dual-agent myelotoxicity must be considered when pancytopenia develops in patients on MTX and MMI, even if one agent has been long tolerated. This case highlights the importance of early recognition of cytopenic symptoms, interdisciplinary coordination, and cautious reintroduction of necessary therapies in high-risk patients. While MTX may have emerging roles in endocrine disease, this case underscores the necessity of individualized risk-benefit assessment in polypharmacy.

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

  • Amissah-Arthur MB, Baah W. Methotrexate-Induced Pancytopenia and Mucositis Caused by Medication Error. Ghana Med J. 2020 Mar;54(1):68-71. doi:10.4314/gmj.v54i1.10.

  • Concepcion-Zavaleta MJ, Quiroz-Aldave JE, Fabián KER, et al. Methimazole-Induced Pancytopenia in a Patient with Graves' Disease: A Case Report and Literature Review. Curr Drug Saf. 2025;20(3):371-376. doi:10.2174/0115748863305536240726053827

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