Risk for Liver Fibrosis Induced by Methotrexate in Rheumatoid Arthritis According to Fibrosis-4 index

Abstract

Introduction: Methotrexate (MTX) is the most effective drug and has been used as the main drug in the treatment of rheumatoid arthritis to maintain remission of disease activity. However, long-term use of MTX may have side effects on liver function and cause liver fibrosis.

Objectives: To study the association of the risk of liver fibrosis from Methotrexate in patients with rheumatoid arthritis by comparing the cumulative dose of more than 4 g with the cumulative dose of less than 4 g for at least three years. The amount of liver fibrosis was calculated using fibrosis-4 as the main indicator in the study.

Methods: This study was a prognostic factor research-observation retrospective cohort design in patients with rheumatoid arthritis at Sawanpracharak Hospital from 2012 to 2022. Data was collected from medical records in a computer system containing basic information on clinical manifestations, comorbidities, laboratory findings, liver function, complete blood count, and combination drug treatment information. The primary outcome was factors associated with liver fibrosis, a comparison between low doses (< 4 grams) and high doses (≥ 4 grams) of Methotrexate, and fibrosis-4 score in this population. Statistical analytic methods were the Chi-square test, Fisher’s exact test, t-test, and multivariable logistic regression.

Results: Of the 335 rheumatoid arthritis patients who met the study criteria, 282 (84%) were female, and 53 (16%) were male, from 1,329 treated rheumatoid arthritis patients. There were patients with cumulative methotrexate doses for the less than 4 g group (115 patients) with a mean age of 61.3 years and a mean Methotrexate usage dose of 2.7 g. Among 220 patients who received Methotrexate greater than or equal to 4 g, the mean age was 60 years. In the latter group, the mean Methotrexate dose was 5.3 g, and the duration of treatment was 5.3 and 7 years, respectively. The association between the occurrence of liver fibrosis and treatment with Methotrexate for a total dose greater than or equal to 4 g and a dose less than 4 g, using the fibrosis-4 index to predict the likelihood of liver fibrosis. Methotrexate greater than or equal to 4 g increased the likelihood of liver fibrosis by 1.14 times (95% confidence interval: 0.8 - 1.5) but with no statistical significance (p-value = 0.490) from multivariable logistic regression analyses. Based on multivariate logistic regression analyses, patients taking Leflunomide significantly increased the likelihood of developing liver fibrosis by 1.46 times (95% confidence interval 1.1-1.9, p-value < 0.006) without dependent on body mass index, other comorbidities and the use of other disease-modifying rheumatic drugs other than Leflunomide.

Conclusion: Rheumatoid arthritis patients who have been treated with Methotrexate for more than three years and with a total dose greater than 4 g had a fibrosis-4 index that was not different from those taking a dose less than 4 g. Using Methotrexate use was probably not associated with liver fibrosis. However, adding Leflunomide to Methotrexate increased the fibrosis-4 index. More further studies are required.

Keywords: Rheumatoid arthritis, Methotrexate, Liver fibrosis, The fibrosis-4 index