Methotrexate is a cornerstone disease-modifying antirheumatic drug (DMARD) with potent immunosuppressive and anti-inflammatory properties. Originally developed as a chemotherapeutic agent, its lower-dose formulations have revolutionized the management of autoimmune and inflammatory disorders. This folate antagonist exerts its therapeutic effects through competitive inhibition of dihydrofolate reductase, impairing DNA synthesis and cellular replication. Its established efficacy, extensive clinical history, and cost-effectiveness make it a first-line agent in numerous therapeutic protocols under specialist supervision.

Features

• Chemical structure: 4-amino-10-methylfolic acid analog
• Available formulations: oral tablets (2.5 mg), subcutaneous injection (25 mg/mL), intravenous solution
• Mechanism: competitive dihydrofolate reductase inhibition
• Bioavailability: approximately 60% oral, near-complete parenteral
• Protein binding: 35-50% to serum albumin
• Elimination half-life: 3-10 hours (dose-dependent)
• Primary excretion: renal (80-90% unchanged)

Benefits

• Induces clinical remission in rheumatoid arthritis by reducing synovial inflammation and preventing joint erosion
• Provides sustained disease control in psoriasis by normalizing epidermal hyperproliferation and modulating T-cell activity
• Enables steroid-sparing management in inflammatory bowel disease and systemic lupus erythematosus
• Demonstrates proven efficacy in juvenile idiopathic arthritis with predictable safety profile
• Offers cost-effective long-term disease modification compared to biologic agents
• Provides flexible administration routes with established titration protocols

Common use

Methotrexate is FDA-approved for rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, and psoriasis. Off-label applications include Crohn’s disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, and ectopic pregnancy management. In oncology, high-dose regimens treat gestational trophoblastic neoplasia, acute lymphoblastic leukemia, and osteosarcoma. Rheumatologic indications typically utilize weekly dosing regimens ranging from 7.5-25 mg, while oncologic applications employ significantly higher doses with leucovorin rescue.

Dosage and direction

Rheumatologic indications: Initiate at 7.5 mg weekly orally or subcutaneously, titrating by 2.5 mg increments every 2-4 weeks to maximum 25 mg weekly. Administer as single weekly dose; daily administration causes severe toxicity. Psoriasis: 10-25 mg weekly, adjusting based on clinical response and tolerability. Oncologic use: Varies by protocol (e.g., 100 mg/m² for osteosarcoma with leucovorin rescue). Always coordinate with folate supplementation (1-5 mg daily except methotrexate day). Rotate subcutaneous injection sites and avoid areas with psoriasis plaques.

Precautions

Require baseline CBC, hepatic and renal function tests before initiation. Monitor hematologic parameters weekly during dose escalation, then monthly when stable. Assess hepatic enzymes every 4-8 weeks; consider liver biopsy if persistent abnormalities occur. Screen for latent tuberculosis and hepatitis B/C before treatment. Maintain adequate hydration to prevent renal precipitation. Use effective contraception during and for 3 months after treatment (6 months for males). Avoid live vaccines during therapy. Exercise caution in patients with pleural effusions or ascites due to risk of delayed clearance.

Contraindications

Absolute contraindications include pregnancy (Category X), breastfeeding, pre-existing blood dyscrasias, clinically significant immunodeficiency, active infectious diseases, and hypersensitivity to methotrexate. Relative contraindications encompass hepatic impairment (Child-Pugh B/C), renal insufficiency (CrCl <60 mL/min), peptic ulcer disease, pre-existing pulmonary fibrosis, and excessive alcohol consumption. Concurrent use with other antifolate medications (trimethoprim-sulfamethoxazole) requires extreme caution.

Possible side effect

Common (>10%): nausea, vomiting, stomatitis, fatigue, elevated transaminases, alopecia. Less common (1-10%): leukopenia, thrombocytopenia, photosensitivity, pulmonary cough/dyspnea. Rare (<1%): pancytopenia, hepatic fibrosis, opportunistic infections, neurotoxicity, Stevens-Johnson syndrome. Oncologic doses: mucositis, myelosuppression, nephrotoxicity. Most adverse effects are dose-dependent and reversible with dose reduction or discontinuation. Pulmonary toxicity may occur idiosyncratically at any dose.

Drug interaction

High-risk interactions: Probenecid, NSAIDs, and penicillins compete for renal tubular secretion, increasing methotrexate levels. Live vaccines pose infection risk. Moderate interactions: Sulfonamides, phenytoin, and retinoids potentiate hematologic toxicity. Protein-bound drugs (warfarin, sulfonylureas) may be displaced. Hepatotoxic agents (leflunomide, azathioprine) require enhanced monitoring. Always review full medication list including OTC products before initiation.

Missed dose

If remembered within 2 days of scheduled weekly dose, administer immediately. If >2 days have passed, skip dose and resume normal schedule next week. Never double dose or administer two doses within same week. Contact treating physician for guidance if multiple doses missed or uncertainty exists about timing. Maintain consistent weekly scheduling to ensure stable therapeutic levels.

Overdose

Acute overdose causes severe myelosuppression, mucositis, and hepatorenal toxicity. Leucovorin rescue must begin within 24-36 hours: administer 10 mg/m² every 6 hours until methotrexate levels <0.05 micromolar. Maintain urinary pH >7 through alkaline hydration and sodium bicarbonate. Monitor methotrexate levels, CBC, and renal function every 24 hours. High-flux hemodialysis may be considered in renal impairment. Supportive care includes granulocyte colony-stimulating factor for neutropenia and platelet transfusions for bleeding.

Storage

Store tablets at 20-25°C in original container protected from light and moisture. Injectable solutions remain stable at room temperature; avoid freezing. Discard unused portions of multidose vials within 28 days of initial puncture. Keep securely closed and away from children and pets. Never transfer between containers or mix with other medications unless specifically instructed. Check expiration dates before each administration.

Disclaimer

This information does not replace professional medical advice. Methotrexate requires prescription and specialist supervision. Individual response and dosing may vary based on clinical status, comorbidities, and concomitant medications. Always follow your healthcare provider’s instructions regarding administration, monitoring, and adverse effect management. Report any new symptoms or concerns promptly to your treating physician.

Reviews

“Methotrexate remains the gold standard initial DMARD in our rheumatology practice. Its predictable efficacy and decades of safety data make it indispensable despite newer biologic options.” - Rheumatology Specialist, 15 years experience

“Our pediatric patients achieve remarkable disease control with weekly methotrexate, particularly when combined with appropriate folate supplementation and monitoring protocols.” - Pediatric Rheumatologist

“While gastrointestinal side effects can be challenging, subcutaneous administration and antiemetic premedication have significantly improved tolerability in our psoriasis cohort.” - Dermatology Specialist

“The cost-effectiveness profile makes methotrexate accessible for long-term management in resource-limited settings where biologics aren’t feasible.” - Global Health Practitioner