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Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment

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Mori S1, Arima N2, Ito M3, Fujiyama S4, Kamo Y5, Ueki Y6. PLoS One. 2018 Aug 24;13(8):e0203084. doi: 10.1371/journal.pone.0203084. eCollection 2018.


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1 Department of Rheumatology, Clinical Research Center for Rheumatic Diseases, NHO Kumamoto Saishunsou National Hospital, Kohshi, Kumamoto, Japan.

2 Department of Pathology, Kumamoto Shinto General Hospital, Kumamoto, Japan.

3 Department of Pathology, Clinical Research Center, NHO Nagasaki Medical Center, Omura, Nagasaki, Japan.

4 Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan.

5 Gastrointestinal Endoscopy Center, Sasebo Chuo Hospital, Sasebo, Nagasaki, Japan.

6 Rheumatic and Collagen Disease Center, Sasebo Chuo Hospital, Sasebo, Nagasaki, Japan.


OBJECTIVE: The mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA).

METHODS: Between October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined.

RESULTS: We followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity.

CONCLUSION: Risk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.