Methotrexate is a cornerstone therapeutic agent in both rheumatology and oncology, valued for its potent immunomodulatory and cytotoxic properties. As a folate antagonist, it interferes with cellular replication and inflammatory pathways, offering a mechanism-based approach to disease management. Its established efficacy, extensive clinical history, and versatility across multiple indications make it a fundamental option in treatment protocols. Proper patient selection, monitoring, and dosing are critical to maximizing therapeutic outcomes while minimizing risks.

Features

• Chemical structure: 4-amino-10-methylfolic acid
• Available formulations: oral tablets, subcutaneous injection, intravenous solution
• Mechanism: dihydrofolate reductase inhibitor, impairing DNA synthesis and repair
• Half-life: approximately 3–10 hours in low doses; variable in high-dose regimens
• Metabolism: hepatic, primarily via aldehyde oxidase
• Excretion: renal (80–90%)

Benefits

• Provides significant reduction in disease activity and symptom burden in autoimmune disorders such as rheumatoid arthritis and psoriasis
• Induces and maintains remission in certain hematologic and solid tumor malignancies
• Slows radiographic progression of joint damage in inflammatory arthritides
• Offers flexible administration routes tailored to patient needs and clinical context
• Cost-effective compared to many biologic and targeted synthetic DMARDs
• Well-established long-term safety profile with appropriate monitoring

Common use

Methotrexate is indicated for the management of moderate to severe rheumatoid arthritis, juvenile idiopathic arthritis, and severe psoriasis. It is also used in the treatment of certain neoplastic diseases including acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, and breast cancer. Off-label uses include Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, and ectopic pregnancy management.

Dosage and direction

Dosage varies significantly by indication. For autoimmune conditions: typically 7.5–25 mg once weekly, orally or subcutaneously. For oncologic uses: doses range from 30–40 mg/m² weekly up to high-dose regimens of 1–12 g/m² with leucovorin rescue. Administration should always be weekly, not daily. Patients must be instructed clearly on the once-weekly schedule to avoid fatal toxicity. Tablets may be taken with or without food; injection techniques should be demonstrated properly.

Precautions

Regular monitoring of complete blood count, liver enzymes, and renal function is mandatory. Alcohol consumption should be avoided due to increased hepatotoxicity risk. Use effective contraception during and for at least 3 months after treatment cessation. Pneumocystis jirovecii pneumonia prophylaxis may be indicated in immunocompromised patients. Vaccination with live vaccines is contraindicated.

Contraindications

Hypersensitivity to methotrexate or any component of the formulation; pregnancy or breastfeeding; pre-existing blood dyscrasias; significant hepatic impairment; alcoholism or chronic liver disease; pre-existing immunodeficiency; concomitant use of other hepatotoxic or myelosuppressive drugs without careful monitoring.

Possible side effect

Common: nausea, vomiting, stomatitis, fatigue, alopecia, elevated transaminases. Serious: myelosuppression (neutropenia, thrombocytopenia), hepatotoxicity (fibrosis, cirrhosis), pulmonary fibrosis, severe dermatologic reactions, nephrotoxicity, opportunistic infections. Long-term use may rarely be associated with lymphoproliferative disorders.

Drug interaction

Notable interactions include: probenecid (increased methotrexate levels), NSAIDs (potential increased toxicity), trimethoprim/sulfamethoxazole (additive myelosuppression), phenytoin (reduced phenytoin levels), retinoids (increased hepatotoxicity). Protein-bound drugs may displace methotrexate, increasing free fraction.

Missed dose

If a weekly dose is missed, administer as soon as remembered unless it is nearly time for the next scheduled dose. Do not double the dose. Contact healthcare provider for guidance, particularly if more than 2 days have passed since the missed dose.

Overdose

Overdose is a medical emergency requiring immediate hospitalization. Symptoms include myelosuppression, mucositis, renal failure, and neurotoxicity. Treatment involves rapid administration of leucovorin (folinic acid), hydration, urinary alkalinization, and supportive care. Hemodialysis may be considered in severe cases.

Storage

Store at 20–25°C (68–77°F). Protect from light. Keep in original container. Do not freeze. Oral formulations should be kept tightly closed. Injectable solutions should be inspected for particulate matter or discoloration before use.

Disclaimer

This information is for educational purposes and does not replace professional medical advice. Dosage and treatment decisions must be made by a qualified healthcare provider based on individual patient characteristics. Always refer to the full prescribing information and clinical guidelines.

Reviews

“Methotrexate remains a first-line agent in our rheumatoid arthritis treatment algorithm. Its efficacy and cost-effectiveness are well-documented, though vigilant monitoring is non-negotiable.” – Rheumatologist, 15 years experience.

“In pediatric oncology, high-dose methotrexate with leucovorin rescue has dramatically improved outcomes in ALL. Protocol adherence and therapeutic drug monitoring are critical.” – Pediatric Oncologist.