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Methotrexate Folate Mechanism — RACP Adult Medicine MCQ

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EasyClinical PharmacologyMethotrexate Folate MechanismRACP Adult Medicine

A 55-year-old woman with rheumatoid arthritis on methotrexate 25 mg weekly develops pancytopaenia following a dose increase. Her MCV is 110 fL. Folate supplementation (folic acid 5 mg weekly) was not co-prescribed. What is the mechanism of methotrexate-induced cytopaenia?

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Correct answer: C — Iron deficiency

Methotrexate-induced cytopaenia results from inhibition of dihydrofolate reductase (DHFR), which depletes reduced folate cofactors needed for thymidylate and purine synthesis (DNA synthesis). Folic acid supplementation (5–10 mg weekly, given 24–48 hours AFTER methotrexate) reduces the risk of haematological toxicity by 80% without compromising methotrexate's anti-inflammatory efficacy. Folinic acid (leucovorin – active folate that bypasses DHFR) is used as rescue therapy for acute methotrexate toxicity. All patients on methotrexate should receive concurrent folic acid supplementation – this is a mandatory prescribing requirement.

Reference: AMH – 2025 – Methotrexate; eTG – 2025 – Rheumatology