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Causality: well established
Causality assessment · Causality: well established
Leflunomide and Hepatotoxicity: is the FAERS signal real?
A written Bradford Hill assessment of one drug–event pair. The grade is a judgement about the signal, not a statement that this drug causes this event in any one person; FAERS counts are reports, not rates.
Leflunomide ↔ Hepatotoxicity
n=1,297 co-reports · PRR 10.7 · ROR 10.8
Leflunomide, a disease-modifying drug for rheumatoid and psoriatic arthritis, carries a boxed warning for severe liver injury, including fatal cases, and requires liver-enzyme monitoring and avoidance in people with pre-existing liver disease. The risk is higher when it is combined with methotrexate or other hepatotoxic drugs. The very high FAERS count (1,297 co-reports, PRR 10.7) reflects both the drug's real hepatotoxicity and how widely it has been prescribed.
Regulatory basis: leflunomide prescribing information (boxed warning for hepatotoxicity; liver-enzyme monitoring).
| Bradford Hill viewpoint | Status | Note |
|---|---|---|
| Temporality (necessary) | met | Liver-enzyme rises occur during therapy and improve after withdrawal |
| Strength | met | PRR 11 on a very large co-report count |
| Consistency | met | Reproduced in trials and post-marketing data |
| Specificity | met | A recognised leflunomide effect, stronger than most DMARDs |
| Biological gradient | partial | Dose-related and worse with pre-existing liver disease or methotrexate |
| Plausibility | met | Direct hepatocellular toxicity is the proposed mechanism |
| Coherence | met | Coheres with the boxed warning and monitoring requirement |
| Experiment | partial | Dechallenge (withdrawal, sometimes with cholestyramine washout) reverses it; no randomized trial |
| Analogy | met | Analogous to hepatotoxicity from methotrexate and other DMARDs |
This page's own qualitative read, not an automated/citation-gated assessment.
✗ No ClinicalTrials.gov results-posting trial in the top search hits for leflunomide captured hepatitis or hepatotoxicity as a coded event; liver toxicity is captured through routine enzyme monitoring rather than coded trial endpoints.