What is the risk of hepatitis induced by Methotrexate (MT- (DMARD) - disease modifying antirheumatic drug)?

From the Guidelines

Methotrexate-induced hepatitis is a serious potential complication of methotrexate therapy that requires careful monitoring and management, and if suspected, the medication should be temporarily discontinued and liver function tests should be obtained immediately. The diagnosis is typically made based on elevated liver enzymes (AST, ALT), often greater than 3 times the upper limit of normal, in a patient taking methotrexate with no other clear cause of liver injury 1. Risk factors include alcohol consumption, obesity, diabetes, pre-existing liver disease, and higher cumulative methotrexate doses 1. Prevention strategies include:

• Baseline liver function testing before starting therapy
• Regular monitoring (typically every 1-3 months depending on risk factors)
• Limiting alcohol intake
• Maintaining a healthy weight
• Considering folic acid supplementation (1-5 mg daily) which may reduce hepatotoxicity 1 For patients with persistent liver enzyme elevations, a dose reduction or complete switch to an alternative medication may be necessary. In severe cases with jaundice, coagulopathy, or encephalopathy, immediate hospitalization is required. The mechanism of methotrexate hepatotoxicity involves its antifolate effects, which can deplete hepatic folate stores and lead to decreased DNA synthesis and repair in liver cells, resulting in hepatocellular damage. Recovery typically occurs within weeks to months after discontinuation of the medication. Key considerations for management include:
• Noninvasive baseline liver fibrosis assessment is recommended before starting treatment with methotrexate 1
• Annual GI/hepatology referral or vibration-controlled transient elastography, or both, should be performed if methotrexate is continued despite abnormal baseline liver fibrosis laboratory results 1
• Methotrexate can be continued only if the risk of cirrhosis is low 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. Special caution is indicated in the presence of preexisting liver damage or impaired hepatic function. Liver function tests, including serum albumin, should be performed periodically prior to dosing but are often normal in the face of developing fibrosis or cirrhosis. These lesions may be detectable only by biopsy The usual recommendation is to obtain a liver biopsy at 1) pretherapy or shortly after initiation of therapy (2 to 4 months), 2) a total cumulative dose of 1.5 grams, and 3) after each additional 1 to 1. 5 grams. Moderate fibrosis or any cirrhosis normally leads to discontinuation of the drug; mild fibrosis normally suggests a repeat biopsy in 6 months.

Methotrexate-induced hepatitis is a potential side effect of methotrexate therapy, particularly with prolonged use or high cumulative doses.

• Risk factors for hepatotoxicity include alcoholism, obesity, diabetes, and advanced age.
• Monitoring of liver function tests, including serum albumin, is recommended periodically prior to dosing.
• Liver biopsy is recommended at certain intervals to detect potential liver damage.
• Discontinuation of methotrexate is recommended in cases of moderate to severe liver damage or cirrhosis. 2 2

From the Research

Methotrexate Induced Hepatitis

• Methotrexate (MTX) is a commonly used medicine in the treatment of psoriatic arthritis and rheumatoid arthritis, but it can produce steatosis and cirrhosis, and rarely, autoimmune hepatitis 3.
• The pathophysiologic mechanisms of drug-induced autoimmunity are unclear and complex, and it is essential to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis 3.
• Patients with non-alcoholic fatty liver disease (NAFLD) are at increased risk for methotrexate hepatotoxicity, and methotrexate can worsen the course of NAFLD 4.
• Understanding the mechanisms of acute hepatotoxicity can facilitate the interpretation of elevated concentrations of liver enzymes in this context, and liver fibrosis and the mechanisms of fibrogenesis also need to be considered in relation to chronic exposure to methotrexate 4.

Risk Factors and Management

• The incidence rate of elevated liver enzymes in the first three years of MTX use was 13/100 patient-years with a cumulative incidence of 31%, and MTX was permanently discontinued in 7%, paused or reduced in 26% and continued without any adjustment in 67% of patients with an abnormal test 5.
• Cumulative MTX dose and serial liver enzyme elevations among other risk factors are related to liver pathology, and cirrhosis is relatively rare 5.
• The combination of MTX and leflunomide was associated with a greater risk of elevated liver enzymes compared with either monotherapy, and the risks were incrementally greater in those with psoriatic arthritis and in those receiving MTX (> or =10 mg/day) + leflunomide 6.
• Serial liver function tests were not useful in determining which patients would have a toxic reaction to methotrexate, especially in patients with sarcoidosis who have a high frequency of liver involvement 7.

Liver Toxicity and Monitoring

• Liver biopsy is a useful tool for detecting methotrexate-induced liver damage, especially in patients with sarcoidosis, and can help identify patients with toxic reactions to methotrexate 7.
• Non-invasive tests for liver fibrosis are available for use in patients with rheumatic disease, in addition to liver biopsy, which can be appropriate for particular individuals 4.
• Practical suggestions for pretreatment screening and long-term monitoring of methotrexate therapy can be made for patients who have (or are at risk for) chronic liver disease, based on the available evidence 4.