Methotrexate Use Not Linked to an Increased Risk of Fibrosis

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The results show methotrexate exposure time and cumulative doses were not predictors for fibrosis, but alcohol was a predictor.

While there was some belief that methotrexate treatment for diseases like inflammatory bowel disease (IBD) and some rheumatological conditions, increases the risk of fibrosis, new research shows methotrexate use does not in fact increase this risk.1

A team, led by Filipe Oliveira Pinheir, Rheumatology Department, Centro Hospitalar Universitário de São João, evaluated the prevalence of liver injuries in patients with inflammatory diseases treated with methotrexate.


Methotrexate is a common treatment for various inflammatory conditions, including rheumatoid arthritis, spondyloarthritis, and inflammatory bowel disease.

However, use of this treatment has been controversial because of the potential liver toxicity of methotrexate, especially since the use of newer techniques.

In the cross-sectional study, the investigators examined 101 consecutive patients with rheumatoid arthritis, spondyloarthritis, or IBD treated with methotrexate that were submitted for liver elastography. The cutoff for fibrosis was at least 7.1 kPa.

The patient population included 11 (10.9%) patients with fibrosis and a median score of 4.8 kPa. Patients with fibrosis also had higher rates of daily alcohol consumption(63.6% vs 31.1%, P = 0.045).

The investigators compared the different groups using chi-square, t test, and Mann-Whitney U test and made correlations between continuous variables using Spearman correlation.

Finally, they performed logistic regression to determine predictors of fibrosis.


The results show methotrexate exposure time (odds ratio [OR], 1.001; 95% confidence interval [CI], 0.999-1.003; P = 0.549) and cumulative doses (OR, 1.000l 95% CI, 1000-1000; P = 0.629) were not predictors for fibrosis.

However, alcohol (OR, 3.875; 95% CI, 1.049-14.319; P = 0.042) was a predictor of fibrosis.

The multivariate logistic regression analysis showed methotrexate cumulative and exposure times were not predictors of significant fibrosis, even after they adjusted for alcohol consumption.

“In this study, we found that fibrosis detected on hepatic elastography was not associated with methotrexate, unlike alcohol,” the authors wrote. “Therefore, it is of paramount importance to redefine risk factors for liver toxicity in patients with inflammatory diseases under treatment with methotrexate.”

Methotrexate and Vaccines

An increased risk of insufficient humoral response to the COVID-19 vaccination was seen in elderly patients with rheumatoid arthritis receiving concomitant methotrexate. A methotrexate pause of about 2 weeks during the third booster vaccination period may be beneficial for this patient population.

In the retrospective analysis, investigators examined the humoral immune response against a third dose of COVID-19 vaccination in 136 patients with RA who were receiving methotrexate and/or biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Antibody response to RBD, which was determined using the SARS-CoV-2 IgG II Quant assay on the Alinity i (Abbott), was reported in 97.1% (n = 132) of patients with RA. In elderly patients receiving concomitant methotrexate, anti-RBD IgG was significantly reduced when compared with elderly patients treated with either monotherapy b/tsDMARDs or methotrexate (64.8 [20.8, 600.3] binding antibody units per mL [BAU/mL] vs 1106.0 [526.3, 4965.2] BAU/mL vs 1743.8 [734.5, 6779.6] BAU/mL, respectively).

There were no differences in humoral anti-RBD response between elderly patients receiving methotrexate monotherapy and elderly patients receiving bDMARD or tsDMARDs monotherapy.

Further, methotrexate monotherapy had no significant impact on humoral response when compared with patients who were not receiving antirheumatic treatment (1743.8 [659.1, 5091.0] BAU/mL vs 1475.5 [727.1, 5228.4] BAU/mL, respectively).


Oliveira Pinheiro F, Gaspar R, Fernandes BM, et al. Cumulative dose and length of methotrexate treatment were not shown to be predictors of hepatic fibrosis by elastography - a monocentric cohort study. ARP Rheumatology. 2023 Feb. PMID: 36811460.