What are the implications of hepatic cirrhosis in a patient with Rheumatoid Arthritis (RA)?

From the Guidelines

Hepatic cirrhosis in a rheumatoid arthritis patient requires careful management of both conditions with special attention to medication choices, and methotrexate should be avoided completely due to its hepatotoxicity, as evidenced by the high incidence of abnormal ALT/AST levels and fibrosis/cirrhosis in patients on methotrexate 1. Treatment should focus on controlling rheumatoid arthritis while minimizing liver toxicity.

• Hydroxychloroquine (200-400mg daily) is generally safe for liver disease patients and can be used as first-line therapy.
• Low-dose prednisone (5-10mg daily) may be used for flares but should be minimized due to potential complications in cirrhosis.
• TNF inhibitors like etanercept (50mg weekly) or adalimumab (40mg every other week) are often well-tolerated in compensated cirrhosis, although there have been reports of liver injury associated with these agents 1. Methotrexate should be stopped if there is a confirmed increase in ALT/AST greater than three times the upper limit of normal (ULN), but may be reinstituted at a lower dose following normalisation, however, in patients with hepatic cirrhosis, it is recommended to avoid it altogether due to the high risk of hepatotoxicity. Regular liver function monitoring is essential, with tests every 1-3 months depending on medication regimen.
• Patients should be evaluated for complications of cirrhosis including varices, ascites, and hepatic encephalopathy.
• Alcohol abstinence is crucial, and hepatitis vaccination should be considered if not already immune. This approach balances the need to control joint inflammation while preventing further liver damage, as many traditional rheumatoid arthritis medications can worsen liver function in cirrhotic patients.
• Leflunomide and sulfasalazine should also be used with extreme caution or avoided due to their potential hepatotoxicity. It is also important to consider other causal factors, including non-steroidal anti-inflammatory drugs, obesity, and alcohol, and to use diagnostic procedures other than liver biopsy in the case of persistently elevated liver enzymes after the discontinuation of methotrexate 1.

From the FDA Drug Label

Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. Chronic toxicity is potentially fatal; it generally has occurred after prolonged use (generally two years or more) and after a total dose of at least 1.5 grams. In studies in psoriatic patients, hepatotoxicity appeared to be a function of total cumulative dose and appeared to be enhanced by alcoholism, obesity, diabetes, and advanced age. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; other risk factors, similar to those observed in psoriasis, may be present in rheumatoid arthritis but have not been confirmed to date. Persistent abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this population There is a combined reported experience in 217 rheumatoid arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of at least 1.5 g) and in 714 patients with a biopsy only during treatment. There are 64 (7%) cases of fibrosis and 1 (0.1%) case of cirrhosis.

Hepatic Cirrhosis Risk in Rheumatoid Arthritis Patients

• Methotrexate can cause hepatotoxicity, including fibrosis and cirrhosis, especially with prolonged use (more than 2 years) and cumulative doses over 1.5 grams.
• Risk factors for hepatotoxicity in rheumatoid arthritis patients include age at first use, duration of therapy, and possibly other factors like alcoholism, obesity, and diabetes.
• Liver function tests should be performed at baseline and at 4-8 week intervals in patients receiving methotrexate for rheumatoid arthritis.
• Liver biopsy should be performed if there are persistent liver function test abnormalities or a decrease in serum albumin.
• Methotrexate should be discontinued in patients with moderate to severe liver changes or cirrhosis. 2

From the Research

Hepatic Cirrhosis in Rheumatoid Arthritis Patients

• Hepatic cirrhosis is a potential complication in rheumatoid arthritis (RA) patients, particularly those treated with methotrexate (MTX) 3, 4.
• Factors that may contribute to liver toxicity in RA patients include diabetes, congestive heart failure, Felty's syndrome, pulmonary fibrosis, and obesity 3.
• The risk of severe liver disease, including cirrhosis, is relatively low in RA patients treated with low-dose MTX (less than 3%) 3.
• Non-alcoholic fatty liver disease (NAFLD) is a pre-existing liver condition that may be worsened by medication, and patients with NAFLD are at increased risk for methotrexate hepatotoxicity 4, 5.
• The use of MTX in RA patients with chronic hepatitis C does not appear to increase the risk of liver cirrhosis 6.
• Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (tsDMARDs) are less likely to cause liver damage compared to conventional disease-modifying antirheumatic drugs (DMARDs) 5.
• Regular monitoring of liver function and careful consideration of the potential risks and benefits of different treatments are essential in managing RA patients with liver disease 4, 7, 5.