What is the relationship between Rheumatoid Arthritis (RA) and cirrhosis?

From the Guidelines

Rheumatoid arthritis patients have a low risk of developing cirrhosis due to methotrexate use, with a reported incidence of 0.5% after a mean of 4.1 years on the medication 1. The relationship between rheumatoid arthritis (RA) and cirrhosis is complex, with several factors to consider. Patients with RA may develop liver complications due to their medications, particularly methotrexate, which can cause drug-induced liver injury that may progress to fibrosis or cirrhosis with long-term use 1. Some key points to consider include:

• The cumulative incidence of abnormal ALT/AST in RA patients on methotrexate is 48.9% above the upper limit of normal (ULN) and 16.8% above two ULN 1.
• The incidence of mild and severe fibrosis and cirrhosis in RA patients on methotrexate is 15.3%, 1.3%, and 0.5%, respectively, after a mean of 4.1 years on the medication 1.
• Methotrexate-induced fibrosis/cirrhosis is rare, and other causal factors such as non-steroidal anti-inflammatory drugs, obesity, and alcohol should be considered in cases of persistently elevated liver enzymes 1. The management of RA patients with cirrhosis requires careful medication management, with regular liver function monitoring and potential dose adjustments or alternatives to hepatotoxic medications 1. In terms of specific medications, methotrexate should be stopped if there is a confirmed increase in ALT/AST greater than three times the ULN, but may be reinstituted at a lower dose following normalization 1. Overall, while there is a potential relationship between RA and cirrhosis, particularly with regards to methotrexate use, the risk is relatively low, and careful management and monitoring can help minimize this risk 1.

From the FDA Drug Label

Methotrexate has the potential for acute (elevated transaminases) and chronic (fibrosis and cirrhosis) hepatotoxicity. In rheumatoid arthritis, age at first use of methotrexate and duration of therapy have been reported as risk factors for hepatotoxicity; 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.

The relationship between rheumatoid arthritis and cirrhosis is that rheumatoid arthritis patients treated with methotrexate are at risk of developing cirrhosis, particularly with prolonged use and high cumulative doses of the drug.

• Risk factors for hepatotoxicity in rheumatoid arthritis patients include age at first use and duration of therapy.
• Liver function tests should be performed at baseline and at 4 to 8 week intervals in patients receiving methotrexate for rheumatoid arthritis.
• Liver biopsy should be performed if there are persistent liver function test abnormalities or there is a decrease in serum albumin below the normal range.
• Methotrexate should be discontinued in any patient who displays persistently abnormal liver function tests and refuses liver biopsy or in any patient whose liver biopsy shows moderate to severe changes 2.

From the Research

Rheumatoid Arthritis and Cirrhosis Relationship

• Rheumatoid arthritis (RA) patients are more susceptible to associated autoimmune liver disease, and medications used in rheumatology can be hepatotoxic, making it difficult to differentiate between hepatic manifestations of the primary disease and potential hepatotoxicity of the administered medications 3.
• Liver damage during RA can progress to cirrhosis, and timely diagnosis and treatment of liver disease in RA patients can significantly influence the course and outcome of rheumatoid arthritis 3.
• The co-existence of RA and primary biliary cirrhosis can be challenging, but treatment options like infliximab can control both diseases and stabilize liver function 4.
• Methotrexate, a common treatment for RA, has been associated with liver-related adverse events, including liver fibrosis, but the prevalence rate of hepatic fibrosis in patients with rheumatoid arthritis under methotrexate is low 5.
• Long-term methotrexate use is not associated with an increased risk for liver cirrhosis among RA patients with chronic hepatitis C 6.
• Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (tsDMARDs) are less likely to cause liver damage, but various manifestations, from a transient elevation of transaminases to autoimmune hepatitis and acute liver failure, have been described 7.