Methotrexate Side Effects — SCE Dermatology MCQ

Correct answer: B — Methotrexate-induced megaloblastic change (antifolate effect on red cell precursors)

A) Methotrexate-induced megaloblastic change (antifolate effect on red cell precursors) is correct. Methotrexate inhibits dihydrofolate reductase, reducing intracellular folate available for thymidylate and purine synthesis, which impairs DNA synthesis in rapidly dividing erythroid precursors and produces a megaloblastic, macrocytic picture. This is a well recognised, dose-related pharmacological effect rather than a true nutritional deficiency, which is why serum B12 and folate levels remain normal despite the raised MCV. UK monitoring guidance specifically flags MCV thresholds during methotrexate therapy and recommends checking B12, folate and TSH to exclude other causes before attributing the change to methotrexate itself. In a patient established on methotrexate with normal B12 and folate, drug-induced antifolate megaloblastic change is by far the most likely explanation. Why the other options are wrong: B) B12 deficiency despite normal level: this requires a specific clinical suspicion (such as neurological signs or a borderline level with high suspicion), not routinely invoked when the serum B12 is clearly normal and there is a more obvious pharmacological explanation. C) Alcohol excess: this would typically show additional clues such as raised gamma-GT, a history of heavy intake, or other stigmata of liver disease, none of which are given in the stem. D) Myelodysplasia: this is a diagnosis of exclusion in an older patient with unexplained macrocytosis, but it is not the most likely cause here given a clear pharmacological driver (methotrexate) already present. C. Hypothyroidism: this causes macrocytosis via a different mechanism (reduced erythropoiesis turnover) and would be excluded by a normal TSH, which is part of the standard work-up in methotrexate-treated patients with raised MCV. Key point: In a patient on methotrexate, macrocytosis with normal B12 and folate is presumed to be the drug's antifolate effect on erythroid precursors until other causes are excluded on monitoring bloods (B12, folate, TSH).

Reference: NHS Specialist Pharmacy Service (SPS), Methotrexate Monitoring guidance: MCV greater than 105 fL prompts checking B12, folate and TSH levels, https://www.sps.nhs.uk/monitorings/methotrexate-monitoring/