Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice

Int J Rheum Dis. 2019 Jul;22(7):1226-1232. doi: 10.1111/1756-185X.13576. Epub 2019 Apr 22.


Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT.

Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5× over the upper limit of normal (ULN) were identified by multiple regression analysis.

Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5× ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure.

Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines.

Keywords: liver toxicity; liver transaminases; methotrexate; non-alcoholic fatty liver disease; rheumatoid arthritis.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alanine Transaminase / blood*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / drug therapy*
  • Biomarkers / blood
  • Chemical and Drug Induced Liver Injury / blood
  • Chemical and Drug Induced Liver Injury / diagnosis*
  • Chemical and Drug Induced Liver Injury / etiology
  • Clinical Enzyme Tests
  • Drug Monitoring / methods
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects*
  • Male
  • Methotrexate / administration & dosage
  • Methotrexate / adverse effects*
  • Middle Aged
  • Predictive Value of Tests
  • Retrospective Studies
  • Time Factors
  • Treatment Outcome
  • Up-Regulation
  • Young Adult


  • Biomarkers
  • Immunosuppressive Agents
  • Alanine Transaminase
  • Methotrexate