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Methotrexate — SCE Rheumatology MCQ

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EasyRheumatology PharmacologyMethotrexateSCE Rheumatology

A 45-year-old woman with rheumatoid arthritis has taken oral methotrexate 20 mg once weekly with folic acid supplementation for three years. Her mean corpuscular volume was 90 fL before starting methotrexate, rose to 108 fL during the first year of treatment and has remained stable. Haemoglobin, neutrophil count and platelet count are normal, and the blood film shows no dysplastic features. Serum vitamin B12, serum folate, thyroid function and liver function tests are normal. She does not drink alcohol and is clinically well. What is the most likely explanation for the raised mean corpuscular volume?

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Correct answer: E — Methotrexate effect on folate metabolism causing macrocytosis

Explanation lettering: D = shown as B · E = shown as D · B = shown as E

Option B is correct. Methotrexate is a folate antagonist; its intracellular effects on folate-dependent nucleotide synthesis can enlarge erythroid precursors and produce macrocytosis even when serum folate is normal and folic acid is prescribed. The rise after methotrexate initiation, subsequent stability, preserved haemoglobin, neutrophils and platelets, and non-dysplastic film make an isolated pharmacological effect most likely. This pattern does not itself establish methotrexate toxicity, although an elevated or rising MCV should prompt assessment of alternative causes and review of blood-count trends. Myelodysplastic syndrome (A) is less likely with a stable isolated abnormality and no dysplasia or cytopenias. Hypothyroidism (C) and vitamin B12 deficiency (D) are excluded by normal testing. Alcohol excess (E) is unsupported by the history and normal liver tests. Folic acid reduces several methotrexate adverse effects but does not invariably prevent macrocytosis.

Reference: Baek IW, Park KS, Kim KJ. An erythrocyte macrocytosis by methotrexate is associated with early initiation of biologic or targeted synthetic agents in patients with rheumatoid arthritis. J Rheum Dis. 2025;32(1):30-37. https://pubmed.ncbi.nlm.nih.gov/39712246/