Summary

The combination of methotrexate and leflunomide significantly increases the risk of hepatotoxicity and bone marrow suppression. This interaction requires careful monitoring and is generally avoided due to the potential for serious liver damage and blood disorders.

Introduction

Methotrexate is a disease-modifying antirheumatic drug (DMARD) and antimetabolite commonly used to treat rheumatoid arthritis, psoriasis, and certain cancers. It works by inhibiting dihydrofolate reductase and interfering with DNA synthesis. Leflunomide is another DMARD used primarily for rheumatoid arthritis and psoriatic arthritis. It functions as an immunomodulatory agent by inhibiting pyrimidine synthesis through blockade of dihydroorotate dehydrogenase, effectively reducing lymphocyte proliferation.

Mechanism of Interaction

Both methotrexate and leflunomide are hepatically metabolized and can cause liver toxicity through different but potentially synergistic mechanisms. Methotrexate inhibits folate metabolism, leading to cellular toxicity, while leflunomide's active metabolite (teriflunomide) can cause direct hepatocellular damage. When used together, these drugs may have additive hepatotoxic effects, overwhelming the liver's capacity to process and eliminate toxic metabolites. Additionally, both drugs can suppress bone marrow function, potentially leading to cumulative hematologic toxicity.

Risks and Symptoms

The primary risk of combining methotrexate and leflunomide is severe hepatotoxicity, which can progress to liver failure in rare cases. Patients may experience elevated liver enzymes (ALT, AST), hepatocellular necrosis, and cholestatic liver injury. Additional risks include increased bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. The combination may also increase the risk of serious infections due to enhanced immunosuppression. Gastrointestinal toxicity, including mucositis and diarrhea, may be more pronounced when these drugs are used together.

Management and Precautions

The combination of methotrexate and leflunomide is generally contraindicated due to the high risk of hepatotoxicity. If concurrent use is absolutely necessary, it requires intensive monitoring including baseline and frequent liver function tests (every 2-4 weeks initially, then monthly), complete blood counts, and renal function assessment. Patients should be counseled about signs of liver toxicity (jaundice, abdominal pain, fatigue) and instructed to seek immediate medical attention if symptoms occur. Consider alternative DMARD combinations with better safety profiles. If hepatotoxicity develops, both drugs should be discontinued immediately, and cholestyramine washout may be necessary for leflunomide elimination.

Methotrexate interactions with food and lifestyle

Alcohol consumption should be avoided or strictly limited while taking methotrexate due to increased risk of liver toxicity and hepatotoxicity. Both methotrexate and alcohol can cause liver damage, and their combination significantly increases this risk. Patients should also maintain adequate hydration and avoid excessive sun exposure, as methotrexate can increase photosensitivity. Folic acid supplementation is commonly recommended to reduce certain side effects, though this should be discussed with a healthcare provider as timing and dosing are important.

Leflunomide interactions with food and lifestyle

Alcohol consumption should be avoided or limited while taking leflunomide due to increased risk of liver toxicity. Both leflunomide and alcohol can cause liver damage, and their combination may significantly increase this risk. Patients should discuss alcohol use with their healthcare provider and follow recommendations for liver function monitoring. Additionally, live vaccines should be avoided during leflunomide treatment due to the drug's immunosuppressive effects, which may reduce vaccine effectiveness and increase infection risk.