Causality assessment · Causality: well established

Methotrexate and Hepatotoxicity: is the FAERS signal real?

n=2,128 co-reports · PRR 5.2 · ROR 5.2

Methotrexate side-effect profile All assessments See in the full list

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.

Causality: well established

Methotrexate ↔ Hepatotoxicity

n=2,128 co-reports · PRR 5.2 · ROR 5.2

Methotrexate can cause liver injury, ranging from raised transaminases to fibrosis and, rarely, cirrhosis with long-term use — which is why liver enzymes are checked periodically, alcohol is discouraged, and cumulative dose is tracked. The injury is usually dose- and duration-related rather than idiosyncratic, and risk is higher in people with fatty liver, hepatitis, or heavy alcohol use. The 2,128 co-reports (PRR 5.2) reflect methotrexate's very wide use in rheumatoid arthritis, psoriasis, and cancer.

Regulatory basis: methotrexate prescribing information (hepatotoxicity warning; liver-enzyme monitoring). Established methotrexate-hepatotoxicity literature.

Bradford Hill viewpoint	Status	Note
Temporality (necessary)	met	Liver-enzyme rises occur during therapy and usually improve after withdrawal
Strength	met	PRR 5 on a very large co-report count
Consistency	met	Reproduced across rheumatology and dermatology cohorts
Specificity	met	A recognised methotrexate effect, less typical of other DMARDs
Biological gradient	partial	Cumulative-dose- and duration-related
Plausibility	met	Folate antagonism and hepatic accumulation are the mechanisms
Coherence	met	Coheres with the labelled liver-enzyme monitoring
Experiment	partial	A trial recorded transaminase rises in the methotrexate-containing arm
Analogy	met	Analogous to hepatotoxicity from other antimetabolites and leflunomide

This page's own qualitative read, not an automated/citation-gated assessment.

✓ Trial evidence found — A Study of Subcutaneous RoActemra/Actemra (Tocilizumab) as Monotherapy or in Combination With Methotrexate or Other Non-Biologic DMARDs in Patients With Active Rheumatoid Arthritis (NCT01995201), N=744

Term (as recorded)	Phase 1: Tocilizumab Monotherapy (n=74)	Phase 1: Combination Therapy (n=327)	Phase 2 Arm A1: TCZ +/- nbDMARD Once Per Week (qw) (n=89)	Phase 2 Arm A2: TCZ +/- nbDMARD Every Two Weeks (q2w) (n=90)	Phase 2 Arm B: Participants With Low Disease Activity (n=95)	Phase 2 Arm C: Moderate EULAR Response at Week 24 (n=67)	Phase 2 Arm D: Non Responders (n=2)
Transaminases increased — Investigations	1	37	0	0	0	0	0

Raised transaminases were recorded in 37 of 327 patients on the methotrexate-containing combination arm versus 1 of 74 on monotherapy in this trial — consistent with methotrexate's hepatotoxic signal, though the trial was not designed to compare liver toxicity directly. View on ClinicalTrials.gov →