Methotrexate is a cornerstone disease-modifying antirheumatic drug (DMARD) with potent immunosuppressive and anti-inflammatory properties. Originally developed as an antineoplastic agent, its immunomodulatory effects at lower doses have established it as a first-line therapy for numerous autoimmune and inflammatory disorders. This folate antagonist exerts its therapeutic effects through competitive inhibition of dihydrofolate reductase, ultimately impairing DNA synthesis and cellular replication. Its established efficacy, extensive clinical history, and cost-effectiveness make it a fundamental agent in rheumatology, dermatology, and gastroenterology protocols worldwide.

Features

• Chemical structure: 4-amino-10-methylfolic acid
• Available formulations: oral tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg), subcutaneous injection, intramuscular injection, intravenous solution
• Mechanism: competitive dihydrofolate reductase inhibitor, impairing purine and pyrimidine synthesis
• Bioavailability: approximately 60% for oral administration, with significant interpatient variability
• Protein binding: approximately 50%
• Half-life: 3-10 hours for parent drug; polyglutamated metabolites exhibit prolonged intracellular persistence
• Metabolism: hepatic, via aldehyde oxidase and folylpolyglutamate synthetase
• Excretion: primarily renal (80-90%)

Benefits

• Provides sustained suppression of disease activity in rheumatoid arthritis, preventing joint erosion and deformity
• Induces and maintains remission in moderate to severe Crohn’s disease and ulcerative colitis
• Controls severe, disabling psoriasis unresponsive to conventional therapies
• Serves as a steroid-sparing agent, reducing corticosteroid requirements and associated adverse effects
• Offers cost-effective long-term management compared to biologic alternatives
• Demonstrates predictable pharmacokinetics with established monitoring parameters for dose optimization

Common use

Methotrexate is FDA-approved for the management of severe, active rheumatoid arthritis in adults and children who have had insufficient response to or are intolerant of an adequate trial of first-line therapy. It is also indicated for the symptomatic control of severe, recalcitrant psoriasis that is inadequately responsive to other forms of therapy. Additionally, it carries approval for the palliation of certain neoplastic diseases, including gestational trophoblastic neoplasia, acute lymphoblastic leukemia, and various solid tumors. Beyond labeled indications, it is widely used off-label for numerous autoimmune conditions, including psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, dermatomyositis, and various forms of vasculitis. Its steroid-sparing properties make it particularly valuable in giant cell arteritis and polymyalgia rheumatica management.

Dosage and direction

Dosage varies significantly based on indication. For rheumatoid arthritis and psoriasis, the typical starting dose is 7.5 mg once weekly, which may be gradually increased to a maximum of 25 mg weekly based on clinical response and tolerability. For neoplastic conditions, doses range from 3-5 mg/m² for maintenance therapy to 12 g/m² or higher for high-dose regimens with leucovorin rescue. Administration should always occur on the same designated day each week to maintain therapeutic consistency. Tablets may be taken with or without food, though administration with food may reduce gastrointestinal discomfort. For patients experiencing gastrointestinal intolerance or requiring higher doses, subcutaneous administration often provides improved bioavailability and reduced side effects. Folic acid supplementation (1-5 mg daily, or at least 5 mg weekly taken 24-48 hours after methotrexate) is strongly recommended to mitigate adverse effects without compromising efficacy.

Precautions

Routine monitoring is essential throughout therapy. Baseline assessment should include complete blood count, renal function tests, liver function tests, hepatitis serologies, and chest radiography. During treatment, monitor complete blood count and liver function tests every 2-4 weeks initially, then every 8-12 weeks once stable. Renal function should be assessed at least quarterly. Patients should be educated to recognize signs of bone marrow suppression (fever, sore throat, bruising), hepatotoxicity (jaundice, dark urine), and pneumonitis (dry cough, dyspnea). Alcohol consumption should be strictly avoided due to increased hepatotoxicity risk. Vaccination with live vaccines is contraindicated during therapy. Women of childbearing potential and men must use effective contraception during and for at least 3 months after treatment cessation due to teratogenic risks.

Contraindications

Absolute contraindications include pregnancy, breastfeeding, pre-existing blood dyscrasias, clinically significant immunodeficiency, and hypersensitivity to methotrexate or any component of the formulation. Relative contraindications include active infection, peptic ulcer disease, pre-existing liver disease or abnormal liver function tests, renal impairment (creatinine clearance <60 mL/min), pleural or peritoneal effusions, and unreliable patients who cannot comply with monitoring requirements. Concomitant administration with other hepatotoxic drugs, proton pump inhibitors (which may reduce renal clearance), or live vaccines should be avoided.

Possible side effect

Common adverse effects (≥10%) include nausea, vomiting, abdominal discomfort, stomatitis, elevated liver transaminases, and fatigue. Frequent effects (1-10%) comprise leukopenia, thrombocytopenia, anemia, alopecia, dermatological reactions, and dizziness. Serious but less common side effects (<1%) include pancytopenia, hepatotoxicity (fibrosis and cirrhosis), methotrexate-induced pneumonitis, severe mucositis, neurotoxicity, and increased susceptibility to opportunistic infections. Rare complications include lymphoproliferative disorders, osteonecrosis, and anaphylactoid reactions. Most adverse effects are dose-dependent and may be mitigated by folic acid supplementation, dose adjustment, or route modification.

Drug interaction

Methotrexate interacts significantly with numerous medications. NSAIDs, probenecid, and salicylates may decrease renal clearance and increase toxicity. Penicillins, sulfonamides, and proton pump inhibitors may similarly elevate methotrexate levels. Hepatotoxic agents (including azathioprine, leflunomide, and isoniazid) compound liver injury risk. Trimethoprim-sulfamethoxazole increases hematologic toxicity risk due to synergistic folate antagonism. Retinoids may enhance hepatotoxicity. Live vaccines are contraindicated due to immunosuppression. Protein-bound drugs may displace methotrexate from binding sites, increasing free fraction. Any new medication should be evaluated for potential interactions before initiation.

Missed dose

If a weekly dose is missed, it should be taken as soon as remembered unless it is nearly time for the next scheduled dose. In that case, the missed dose should be skipped, and the regular dosing schedule resumed. Patients should never take a double dose to make up for a missed dose. If uncertain about proper management of a missed dose, patients should contact their healthcare provider for guidance. Consistent weekly administration is critical for maintaining therapeutic effect and minimizing toxicity.

Overdose

Methotrexate overdose constitutes a medical emergency that may result in severe myelosuppression, mucositis, renal failure, and hepatotoxicity. Symptoms may include oral ulceration, hematemesis, melena, hematuria, and signs of infection. Management requires immediate hospitalization, leucovorin rescue (administered within 24-48 hours for optimal efficacy), vigorous hydration, urinary alkalinization to enhance elimination, and supportive care including blood product transfusions and granulocyte colony-stimulating factor as needed. Serum methotrexate levels should be monitored every 24 hours until levels fall below 0.05 micromolar. Hemodialysis is ineffective for removal due to high protein binding, but high-flux hemodialysis may be considered in severe cases.

Storage

Store at controlled room temperature (20-25°C or 68-77°F) in the original container, protected from light and moisture. Keep tightly closed and away from heat sources. Do not freeze. Oral formulations should be stored in child-resistant containers and kept out of reach of children. Injectable solutions should be inspected for particulate matter and discoloration before administration. Unused portions should be discarded appropriately according to institutional guidelines for cytotoxic medications. Do not use beyond the expiration date printed on the packaging.

Disclaimer

This information is provided for educational purposes only and does not constitute medical advice. Treatment decisions should be made exclusively by qualified healthcare professionals based on individual patient characteristics. Dosage and administration must be tailored to specific clinical circumstances with appropriate monitoring. The prescriber should be familiar with complete prescribing information including boxed warnings regarding hepatotoxicity, myelosuppression, and teratogenicity. Patients should be thoroughly counseled on risks, benefits, and necessary precautions before initiating therapy.

Reviews

“Methotrexate remains the gold standard anchor drug in rheumatoid arthritis management. Its predictable efficacy and extensive safety profile across decades of use provide confidence in long-term administration. While monitoring requirements are substantial, the benefits typically outweigh risks when managed appropriately.” - Rheumatology Specialist, 15 years experience

“As a dermatologist treating severe psoriasis, methotrexate offers a reliable option for patients failing topical and phototherapies. The weekly dosing improves adherence compared to daily regimens, and most patients tolerate it well with proper folic acid supplementation.” - Dermatology Consultant, 12 years experience

“While biologics have expanded our therapeutic arsenal, methotrexate’s cost-effectiveness and synergistic effects in combination regimens maintain its fundamental position in treatment algorithms. Its steroid-sparing capabilities are particularly valuable in chronic inflammatory conditions.” - Clinical Pharmacologist, 20 years experience