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Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated
Edmond Atallah1, Jane I Grove1, Colin Crooks1
1Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK.
Background & Aims:
The risk of significant liver fibrosis from prolonged methotrexate (MTX) exposure has been estimated at around 5%, prompting intensive monitoring strategies. However, the evidence is derived from retrospective studies that under-reported risk factors for liver disease. We evaluated the risk of long-term MTX therapy on liver fibrosis in a longitudinal cohort study using two non-invasive markers.
Method:
Between 2014-2021, adult patients diagnosed with rheumatoid arthritis (RA) or psoriasis for ≥2 years were recruited prospectively from six UK sites. The MTX group included patients who received MTX for ≥6 months, whereas the unexposed group included those who never received MTX. All patients underwent full liver profiling, with transient elastography (TE) and enhanced liver fibrosis (ELF) marker measurements.
Results:
A total of 999 patients (mean age 60.8 ± 12 years, 62.3% females) were included. Of 976 with valid TE values, 149 (15.3%) had liver stiffness ≥7.9 kPa. Of 892 with a valid ELF, 262 (29.4%) had ELF ≥9.8. Age and BMI were independently associated with elevated liver stiffness and ELF. Neither MTX cumulative dose nor duration was associated with elevated liver stiffness. Diabetes was the most significant risk factor associated with liver stiffness ≥7.9 kPa (adjusted odds ratio = 3.19; 95% CI 1.95-5.20; p <0.001). Regular use of non-steroidal anti-inflammatory drugs showed the strongest association with ELF ≥9.8 (odds ratio = 1.76; 95% CI 1.20-2.56; p = 0.003), suggesting the degree of joint inflammation in RA may confound ELF as a non-invasive marker of liver fibrosis.
Conclusion:
The risk of liver fibrosis attributed to MTX itself might have been previously overestimated; there is a need to consider modifying current monitoring guidelines for MTX.
Impact And Implications:
Current guidelines recommend intensive (2-3 monthly) monitoring strategies for patients on long-term methotrexate therapy due to the potential risk of liver fibrosis. Evaluation of the association using two validated non-invasive markers of liver fibrosis, liver stiffness and enhanced liver fibrosis score, in a large cohort of patients with rheumatoid arthritis or psoriasis shows that the reported risk has previously been overestimated. The clinical focus should be to improve patients' metabolic risk factors, diabetes and BMI, that are independently associated with liver stiffness. There is a need to consider modifying current treatment monitoring guidelines for methotrexate.
Insights
Long-term methotrexate (MTX) therapy for rheumatoid arthritis or psoriasis may not significantly increase liver fibrosis risk. This study suggests current monitoring guidelines for MTX may be overly cautious, recommending a re-evaluation based on new evidence.
Area of Science:
- Hepatology
- Rheumatology
- Pharmacology
Background:
- Prolonged methotrexate (MTX) use is associated with liver fibrosis risk, leading to intensive monitoring.
- Previous risk estimations stem from retrospective studies with under-reported confounding factors.
- This study aimed to reassess MTX's impact on liver fibrosis using non-invasive markers in a prospective cohort.
Purpose of the Study:
- To evaluate the association between long-term methotrexate therapy and liver fibrosis in patients with rheumatoid arthritis or psoriasis.
- To compare the risk of liver fibrosis in MTX-exposed versus unexposed patient groups.
- To investigate the utility of transient elastography (TE) and enhanced liver fibrosis (ELF) scores in assessing liver health during MTX therapy.
Main Methods:
- Prospective longitudinal cohort study of 999 adult patients with rheumatoid arthritis or psoriasis from 2014-2021.
- Patients were categorized into MTX-exposed (≥6 months) and unexposed groups.
- Liver fibrosis was assessed using transient elastography (TE) for liver stiffness and enhanced liver fibrosis (ELF) marker measurements.
Main Results:
- Neither MTX cumulative dose nor duration correlated with elevated liver stiffness.
- Diabetes (aOR=3.19) and non-steroidal anti-inflammatory drug use (aOR=1.76) were significantly associated with elevated liver stiffness and ELF scores, respectively.
- Age and BMI were independently linked to increased liver stiffness and ELF scores.
Conclusions:
- The risk of liver fibrosis directly attributed to methotrexate may have been previously overestimated.
- Current intensive monitoring guidelines for MTX therapy warrant reconsideration.
- Clinical focus should shift towards managing metabolic risk factors like diabetes and BMI in patients on long-term MTX therapy.
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