Methotrexate is a cornerstone antimetabolite and disease-modifying antirheumatic drug (DMARD) with established efficacy across multiple therapeutic domains. As a folate antagonist, it exerts cytostatic and immunomodulatory effects by inhibiting dihydrofolate reductase, thereby impeding DNA synthesis and cellular replication. Its clinical utility spans severe inflammatory conditions, certain malignancies, and off-label uses where immune dysregulation or rapid cell proliferation is pathologic. This agent demands respect for its mechanism, nuanced dosing protocols, and requisite monitoring to maximize therapeutic outcomes while mitigating risks.

Features

• Chemical structure: Analog of folic acid
• Mechanism: Competitive inhibition of dihydrofolate reductase (DHFR)
• Formulations: Oral tablets (2.5 mg, 5 mg, 7.5 mg, 10 mg), subcutaneous injection, intravenous solution
• Bioavailability: Dose-dependent, with subcutaneous administration offering more consistent absorption at higher doses
• Half-life: Approximately 3–10 hours for low doses; prolonged in renal impairment
• Metabolism: Hepatic, to active polyglutamated metabolites
• Excretion: Primarily renal (80–90%)

Benefits

• Induces remission and maintains disease control in rheumatoid arthritis, psoriatic arthritis, and other autoimmune disorders
• Provides effective treatment for certain neoplastic conditions, including acute lymphoblastic leukemia and gestational trophoblastic neoplasia
• Slows radiographic progression of joint damage in inflammatory arthritides
• Offers flexible administration routes (oral, subcutaneous, intravenous) tailored to indication and patient tolerance
• Cost-effective compared to many biologic DMARDs
• Well-established long-term safety profile with appropriate monitoring

Common use

Methotrexate is FDA-approved for the management of severe, active rheumatoid arthritis (RA) in adults and polyarticular juvenile idiopathic arthritis (JIA) in children, particularly after an inadequate response to first-line therapies. It is also indicated for the treatment of certain malignancies, including acute lymphoblastic leukemia (as part of combination chemotherapy), non-Hodgkin lymphoma, and gestational trophoblastic neoplasia. Dermatologic applications include severe, recalcitrant psoriasis. Off-label uses encompass other autoimmune conditions such as Crohn’s disease, lupus, and vasculitides, where its immunomodulatory properties help control disease activity and reduce corticosteroid dependence.

Dosage and direction

Dosing is highly indication-specific. For rheumatoid arthritis and psoriasis, typical starting doses are 7.5–10 mg orally once weekly, titrated gradually to 15–25 mg/week based on efficacy and tolerability. Higher doses (up to 30 mg/week or more) may be used subcutaneously for improved bioavailability. For oncologic indications, doses range from 15 mg/m²/week to high-dose regimens (e.g., 1–12 g/m²) requiring leucovorin rescue and inpatient monitoring. Administration must strictly be weekly—not daily—to avoid toxicity. Take with food to minimize gastrointestinal upset. Folic acid supplementation (1–5 mg daily, omitting the methotrexate dose day) is standard to reduce adverse effects.

Precautions

Routine monitoring is imperative: obtain complete blood count, liver function tests, and serum creatinine at baseline and every 2–4 weeks initially, then every 8–12 weeks once stable. Avoid in significant renal impairment (CrCl <60 mL/min requires dose adjustment; avoid if <30 mL/min) or hepatic disease. Use with caution in patients with pleural or peritoneal effusions, which may enhance toxicity due to delayed clearance. Vaccination with live vaccines is contraindicated. Pregnancy must be excluded before initiation and avoided during and after therapy (for both males and females); effective contraception is mandatory. Counsel patients to report symptoms of infection, mucositis, or respiratory distress promptly.

Contraindications

Absolute contraindications include pregnancy, breastfeeding, pre-existing blood dyscrasias (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia), clinically significant anemia, hypersensitivity to methotrexate, and active infectious disease. Relative contraindications comprise peptic ulcer disease, ulcerative colitis, hepatic or renal dysfunction, and alcoholism. Concomitant use with other hepatotoxic drugs, proton pump inhibitors (may increase exposure), or nephrotoxic agents warrants extreme caution.

Possible side effect

Common adverse effects include nausea, vomiting, stomatitis, diarrhea, alopecia, and elevated transaminases. Myelosuppression (leukopenia, thrombocytopenia, pancytopenia) is a serious, dose-related toxicity. Pulmonary complications (interstitial pneumonitis, fibrosis) may occur idiosyncratically. Hepatotoxicity ranges from transient enzyme elevations to cirrhosis with long-term use. Renal impairment, dermatologic reactions, and neurotoxicity (e.g., leukoencephalopathy with high doses) are also documented. Rarely, opportunistic infections may emerge due to immunosuppression.

Drug interaction

Methotrexate interacts significantly with NSAIDs, salicylates, and proton pump inhibitors, which can reduce renal clearance and increase toxicity. Penicillins, sulfonamides, and other nephrotoxic agents may similarly elevate methotrexate levels. Concomitant folate antagonists (e.g., trimethoprim-sulfamethoxazole) increase myelosuppression risk. Hepatotoxic drugs (including alcohol) compound liver injury potential. Live vaccines are contraindicated. Biologic DMARDs may heighten immunosuppressive effects.

Missed dose

If a weekly dose is missed, administer as soon as remembered unless close to the next scheduled dose. Never double the dose or take missed medication within a few days of the next dose; resume the regular weekly schedule. Inform the prescribing clinician of the missed dose, particularly if consistent adherence is challenging.

Overdose

Overdose, including accidental daily instead of weekly dosing, is a medical emergency presenting with severe myelosuppression, mucositis, renal failure, and dermatologic sloughing. Management includes immediate leucovorin rescue (dosed based on methotrexate levels and time since exposure), vigorous hydration, urinary alkalinization, and supportive care. Glucarpidase may be indicated in cases of significant renal impairment or high methotrexate concentrations. Hospitalization and hematologic monitoring are essential.

Storage

Store at room temperature (20–25°C/68–77°F) in the original container, protected from light and moisture. Keep out of reach of children and pets. Do not use if discolored or containing particulate matter. Dispose of unused or expired medication via take-back programs; do not flush.

Disclaimer

This information is for educational purposes and does not replace professional medical advice, diagnosis, or treatment. Consult a qualified healthcare provider for personalized recommendations. Dosage, indications, and safety profiles may vary; always follow the guidance of the prescribing physician and approved product labeling.

Reviews

“Methotrexate remains a first-line DMARD for rheumatoid arthritis due to its efficacy and cost-effectiveness. Its role in inducing and maintaining remission is well-documented, though vigilant monitoring for hepatic and hematologic toxicity is non-negotiable.” – Rheumatology Specialist

“In pediatric oncology, high-dose methotrexate with leucovorin rescue is a critical component of curative protocols for ALL. Meticulous management of hydration, urine pH, and drug levels is essential to avoid life-threatening toxicities.” – Pediatric Oncologist

“Long-term use in psoriasis requires balancing efficacy with cumulative hepatotoxicity risks. Regular liver biopsies are less common now with noninvasive monitoring, but the drug demands respect and patient education.” – Dermatologist