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 immunosuppressive agent by inhibiting pyrimidine synthesis through blockade of dihydroorotate dehydrogenase. Both medications are metabolized by the liver and can cause hepatotoxicity as individual agents.

Mechanism of Interaction

The interaction between methotrexate and leflunomide occurs through additive hepatotoxic effects and potential pharmacokinetic interactions. Both drugs are hepatically metabolized and can cause liver enzyme elevations independently. Leflunomide's active metabolite, teriflunomide, has a very long half-life (2 weeks) and may accumulate, potentially interfering with methotrexate clearance. Additionally, both medications can cause folate depletion, which may exacerbate methotrexate's toxicity. The combination also increases the risk of bone marrow suppression through additive immunosuppressive effects.

Risks and Symptoms

The primary risks of combining methotrexate and leflunomide include severe hepatotoxicity, which can progress to liver failure in rare cases. Patients may experience elevated liver enzymes (ALT, AST), hepatitis, and potentially irreversible liver damage. Additional risks include increased bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. There is also an elevated risk of serious infections due to enhanced immunosuppression. Gastrointestinal toxicity, including nausea, vomiting, and mucositis, may be more pronounced. The interaction is considered clinically significant and potentially life-threatening.

Management and Precautions

The combination of methotrexate and leflunomide is generally contraindicated and should be avoided. If concurrent use is absolutely necessary, intensive monitoring is required 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 on signs of hepatotoxicity (jaundice, abdominal pain, fatigue) and bone marrow suppression (unusual bleeding, infections, fatigue). Folic acid supplementation should be continued with methotrexate. Consider alternative DMARD combinations or sequential therapy instead of concurrent use. If leflunomide must be discontinued, cholestyramine washout may be necessary due to its long half-life.

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.