Methotrexate: DHFR Inhibitor for Rheumatology, Oncology, and Dermatology
Methotrexate (MTX) is a folate antagonist that inhibits dihydrofolate reductase (DHFR), blocking DNA synthesis and cell division. At low doses (weekly), it has anti-inflammatory effects beyond folate inhibition; at high doses, it is a cytotoxic chemotherapy agent.
One of the most widely used disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis, psoriatic arthritis, and psoriasis. Also used in oncology (ALL, lymphoma) and ectopic pregnancy.
Mechanism of Action
Inhibits DHFR, reducing tetrahydrofolate and purine synthesis, impairing rapidly dividing cells. At low rheumatic doses, additional anti-inflammatory effects occur via adenosine release, inhibition of T-cell proliferation, and cytokine reduction.
Indications & Use
Rheumatoid arthritis (anchor DMARD), psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, inflammatory myositis, vasculitis. Oncology: ALL, lymphoma, osteosarcoma. Ectopic pregnancy (IM). Combination with biologics (anti-TNF) for enhanced efficacy and reduced immunogenicity.
Dosage
RA: 7.5–25 mg/week (oral or SC). Always with folic acid supplementation (5 mg/week — NOT on methotrexate day). Oncology: 100 mg/m² to >1 g/m² IV (with leucovorin rescue at high doses). Never daily for rheumatic indications.
Side Effects
Nausea, mouth ulcers, fatigue (reduced by folic acid). Hepatotoxicity (fibrosis/cirrhosis with cumulative dose >1.5 g — monitor LFTs). Myelosuppression. Pulmonary toxicity (MTX pneumonitis). Highly teratogenic.
Drug Interactions
NSAIDs: increase MTX levels (reduce renal clearance) — caution, especially at high doses. Trimethoprim: additive folate antagonism — avoid. Proton pump inhibitors: may reduce MTX clearance. Alcohol: additive hepatotoxicity — avoid. Leucovorin rescues from MTX toxicity in overdose.
Contraindications
Pregnancy (highly teratogenic — category X), breastfeeding, severe hepatic/renal impairment, active infection, alcoholism, immunodeficiency. Women and men must use contraception for ≥3 months after stopping.
Frequently Asked Questions
Why must folic acid be taken with methotrexate?
Folic acid reduces MTX side effects (nausea, mouth ulcers, hair thinning) without reducing its efficacy for RA/psoriasis. Take 5 mg of folic acid once weekly on a different day than methotrexate.
Why is methotrexate taken only once a week for RA?
At weekly low doses, MTX's anti-inflammatory mechanisms (adenosine release, cytokine inhibition) are effective. Daily dosing is not used for RA — accidental daily dosing is a known cause of severe toxicity and deaths.
How long must contraception be used after stopping methotrexate?
Methotrexate is stored in tissues and eliminated slowly. Both women and men must use reliable contraception for at least 3 months after stopping. Pregnancy should be planned with physician guidance.
References
- NICE NG100: RA 2020 (updated 2023)
- EMA Methotrexate SPC 2023
- Weinblatt ME et al. NEJM 1985
Medical Disclaimer: This information is for educational purposes only and does not replace professional medical advice.