The hepatotoxicity associated with the chronic use of methotrexate (MTX) at doses used to treat rheumatic disease can result in hepatic fibrosis and cirrhosis.1 The depletion of hepatic folate stores by MTX has been identified as a possible contributing factor in hepatotoxicity.

To examine the risk of liver cirrhosis among patients with rheumatoid arthritis (RA) and chronic hepatitis B (CHB) infection taking long-term MTX, Kuo-Tun Tang, MD, and colleagues from the Taichung Veterans General Hospital, Taichung, Taiwan, retrospectively analyzed data from a nationwide health insurance database. A total of 631 incident cases of RA among CHB patients were identified, including 358 patients treated with MTX and 273 patients MTX-naïve, from January 1, 1998 to December 31, 2007.

Researchers found that among the patients with RA and CHB, 41 patients (6.5%) developed liver cirrhosis after a median follow-up period of more than 6 years.2 The patients with cirrhosis were identified as predominantly older and female.


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Patients with RA and GHB taking MTX were found to have similar proportions of liver cirrhosis (6.2% vs 7.0%) and decompensated liver cirrhosis (1.1% vs. 0.7%) compared with patients not taking MTX.2 Risk factors associated with the development of liver cirrhosis included older ages and male sex. 

No increased hazard was found for liver cirrhosis in MTX users and MTX-naïve patients with RA and GHB. Liver cirrhosis did not occur in any of the 56 patients with RA and CHB receiving MTX after 97 months’ treatment.

It was noted, however, that the concomitant use of additional hepatotoxic drugs such as corticosteroids resulted in increased rates of hepatitis B reactivation.

Summary and Clinical Applicability

In this population-based study, chronic MTX therapy among RA patients with CHB was not associated with an increased risk of liver cirrhosis.2 These findings were limited by the observational design of the study, which limited assessments of medication adherence, and the lack of randomization to treatment arms. 

This finding is clinically significant because it indicates that certain patients with RA and co-morbid CHB taking chronic MTX may not have an increased risk of developing liver cirrhosis, suggesting that chronic MTX therapy may not be absolutely contraindicated in these patients. 

Caution must be used prior to using these results to guide clinical decisions, as there may have been selection bias introduced into the cohort evaluated in this study. Additionally, a longer term follow-up period capturing the effects of increased cumulative doses of MTX may be required to uncover potential risk of cirrhosis. 

Regardless of the findings of this study, a detailed history and physical examination should be done prior to initiating chronic MTX for RA, with particular emphasis on alcohol intake, potential exposure to viral hepatitis, and family history of liver disease. 

The American College of Rheumatology (ACR) does not currently recommend routine liver biopsy in RA patients who use MTX.3 However, pretreatment liver biopsy may be considered in certain patients at higher risk of liver dysfunction, including patients with a history of excessive alcohol consumption or persistently abnormal AST or ALT values.

Reference

1.     Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology (Oxford). 2009;48(9):1107.

2.    Tang,K.-T, Hung W-T, Chen Y-H, et al. Methotrexate is not associated with increased liver cirrhosis in a population-based cohort of rheumatoid arthritis patients with chronic hepatitis B. Sci. Rep. 2016;6, 22387.

3. Kremer JM, Alarcón GS, Lightfoot RW, et al.  Methotrexate for rheumatoid arthritis: Suggested guidelines for monitoring of liver toxicity.Arthritis Rheum. 1994. 37, 316–328.