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Drug Hepatotoxicity — SCE Rheumatology MCQ

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ModerateRheumatology PharmacologyDrug HepatotoxicitySCE Rheumatology

A 42-year-old woman with rheumatoid arthritis has taken methotrexate 20 mg once weekly for 1 year with consistently normal liver biochemistry. Leflunomide 20 mg daily was added 12 weeks ago. She drinks fewer than 2 units of alcohol per week, takes no other potentially hepatotoxic medication and has normal renal function. Pretreatment hepatitis B and C testing was negative. Her current results are: ALT 180 U/L (upper limit of normal 40), AST 155 U/L (upper limit of normal 40), ALP 95 U/L (reference range 30–130) and bilirubin 18 micromol/L (reference range less than 21). Which mechanism best explains the increased risk of liver injury associated with this drug combination?

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Correct answer: C — Additive pharmacodynamic hepatotoxicity from methotrexate and leflunomide

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

Option E is correct. The predominantly hepatocellular biochemical abnormality developed after leflunomide was added to established methotrexate therapy, with major alternative risk factors excluded. Both drugs can cause hepatotoxicity, and their combination increases this risk through additive pharmacodynamic toxicity. The leflunomide SmPC reports transaminase elevations during co-administration and explicitly states that no pharmacokinetic interaction with methotrexate was demonstrated. Leflunomide therefore does not characteristically reduce methotrexate excretion (B), and methotrexate does not inhibit leflunomide metabolism (D). A clinically important toxicity interaction is recognised, excluding C. Viral hepatitis should be considered when investigating transaminitis, but negative pretreatment testing and the temporal relationship to combination therapy make A substantially less likely here.

Reference: Electronic Medicines Compendium. Leflunomide Tillomed 20 mg Tablets, Summary of Product Characteristics, sections 4.4 and 4.5. Updated 15 April 2026. https://www.medicines.org.uk/emc/product/11363/smpc