Summary

Methotrexate and sulfasalazine can interact through their effects on folate metabolism, potentially increasing the risk of methotrexate toxicity. This interaction is particularly relevant in patients with rheumatoid arthritis or inflammatory bowel disease who may receive both medications.

Introduction

Methotrexate is an antifolate medication classified as an antimetabolite and immunosuppressant, primarily used to treat rheumatoid arthritis, psoriasis, and certain cancers. It works by inhibiting dihydrofolate reductase, which interferes with DNA synthesis and cell division. Sulfasalazine is an anti-inflammatory drug belonging to the disease-modifying antirheumatic drug (DMARD) class, commonly prescribed for rheumatoid arthritis, ulcerative colitis, and Crohn's disease. It consists of sulfapyridine and 5-aminosalicylic acid (mesalamine) linked by an azo bond, and works by reducing inflammation in the joints and gastrointestinal tract.

Mechanism of Interaction

The interaction between methotrexate and sulfasalazine occurs through their combined effects on folate metabolism. Methotrexate directly inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis. Sulfasalazine can interfere with folate absorption in the small intestine and may also inhibit folate-dependent enzymes. When used together, sulfasalazine may potentiate methotrexate's antifolate effects, leading to enhanced folate depletion and increased risk of methotrexate-related toxicity, including bone marrow suppression, gastrointestinal toxicity, and hepatotoxicity.

Risks and Symptoms

The primary clinical risks of combining methotrexate and sulfasalazine include increased bone marrow suppression manifesting as leucopenia, thrombocytopenia, or anemia. Patients may experience enhanced gastrointestinal toxicity, including nausea, vomiting, diarrhea, and mucositis. There is also an elevated risk of hepatotoxicity, with potential for elevated liver enzymes and, in severe cases, hepatic fibrosis. The interaction may increase the likelihood of methotrexate-induced pulmonary toxicity and nephrotoxicity. Patients with pre-existing folate deficiency, renal impairment, or advanced age are at particularly high risk for these adverse effects.

Management and Precautions

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.

Sulfasalazine interactions with food and lifestyle

Sulfasalazine should be taken with food or after meals to reduce gastrointestinal irritation and improve tolerance. Patients should maintain adequate fluid intake while taking sulfasalazine. Alcohol consumption should be limited as it may increase the risk of gastrointestinal side effects and potentially interfere with the medication's effectiveness. Patients should avoid prolonged sun exposure and use sunscreen, as sulfasalazine can increase photosensitivity reactions. Folic acid supplementation is often recommended during sulfasalazine therapy, as the medication can interfere with folate metabolism.