Background/Purpose: Methotrexate is an immunomodulatory agentu sed in several inflammatory diseases, such as rheumatoid arthritis (RA), spondyloarthritis (SpA) or inflammatory bowel disease (IBD). Despite being previously associated with the development of liver damage, recent studies have showed significant less hepatotoxicity. The aim of our study was to evaluate the prevalence and development of liver injury in methotrexate-treated patients with inflammatory diseases.

Methods: We performed a cross-sectional study where consecutive patients followed at the Rheumatology and Gastroenterology Departments of a tertiary center, diagnosed with RA, SpA or IBD, treated with methotrexate, were submitted to liver elastography and liver function tests. Clinical and laboratory data were collected, including duration of treatment and cumulative dose of methotrexate. The cutoff for significant fibrosis was ≥7.1 kPa. Comparisons between groups (significant versus non-significant fibrosis) was evaluated using chi-square, t test and Mann-Whitney U test. Spearman’s correlation was used to assess associations between two or more continuous variables. Logistic regression was performed to determine predictors of significant fibrosis.

Results: A total of 101 patients were included, 60 (59.4%) females, aged 46.2±12.6 years at the start of methotrexate. Forty-nine patients (48.5%) had RA, 17 (16.8%) SpA and 35 (34.7%) IBD, and 35 (34.7%) consumed alcohol daily. Patients were exposed to methotrexate for a median of 204 (72-146) weeks, with a median cumulative dose of 2385 (940-5200) mg. Eleven patients (10.9%) had significant fibrosis, with a median score of 4.8 (4.1-5.9) kPa.

Patients with significant fibrosis had higher rates of daily alcohol consumption (63.6% vs 31.1%, p=0.045), but there were no differences in methotrexate’s exposure time or cumulative dose. There was a very significant correlation between exposure time to methotrexate and cumulative dose (Spearman’s rho 0.904, p< 0.001), but no correlations were found between cumulative dose and elastography scores. Methotrexate exposure time (OR 1.001, 95% CI 0.999-1.003, p=0.549) and cumulative dose (OR 1.000, 95% CI 1000-1000, p=0.629) were shown not to be predictors of significant fibrosis, unlike alcohol (OR 3.875, 95%CI 1.049-014319, p=0.042). In multivariate logistic regression analysis, methotrexate cumulative and exposure times were not predictors of significant fibrosis, even when adjusted for alcohol consumption.

Another analysis was performed with the division of groups at the median – ≤4.8kPa (n=55) and >4.8 kPa (n=46). Methotrexate exposure time (OR 1.000, 95% CI 0.999-1.002, p=0.607) and cumulative dose (OR 1.000, 95% CI 1.000-1.000, p=0.376) were also shown not to be predictors of fibrosis in patients on methotrexate.

Conclusion: In this study, we found that fibrosis detected on hepatic elastography was not associated with the cumulative dose or time of exposure to methotrexate, unlike alcohol. Therefore, it is of paramount importance to redefine risk factors for liver toxicity In patients with inflammatory diseases under treatment with methotrexate.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cumulative-dose-and-exposure-time-to-methotrexate-were-not-shown-to-be-predictors-of-hepatic-fibrosis-by-elastography-a-monocentric-cohort-study/