MTX (Methotrexate): Effect, Dosage & Important Notes
MTX is the established abbreviation for methotrexate, a folate antagonist that has been used in medicine for over 70 years. Depending on the dose, MTX acts as an immunosuppressant in low doses and as a cytostatic agent in high doses. This dual profile makes it one of the most versatile drugs in modern medicine.
In rheumatology, MTX is the anchor therapy for rheumatoid arthritis and other inflammatory joint diseases. In oncology, high-dose MTX protocols are used in leukemia, lymphoma, and osteosarcoma. The broad therapeutic spectrum and decades of clinical experience make MTX an indispensable drug despite the need for careful monitoring.
Mechanism of Action
MTX inhibits dihydrofolate reductase (DHFR), the enzyme that converts dihydrofolate to tetrahydrofolate. Tetrahydrofolate is essential for the synthesis of purines and thymidylate, which are building blocks of DNA. In high doses used in oncology, MTX effectively halts DNA synthesis in rapidly dividing cells. In low rheumatological doses, the anti-inflammatory effect is mediated additionally via the accumulation of adenosine and inhibition of pro-inflammatory cytokines, including TNF-alpha and interleukin-6.
Indications
Low-dose MTX (7.5 to 25 mg weekly) is the gold standard for rheumatoid arthritis, psoriatic arthritis, and is used in ankylosing spondylitis, dermatomyositis, and inflammatory bowel disease. Dermatology uses MTX for moderate to severe psoriasis. In oncology, MTX protocols range from 1 g/m² to over 12 g/m² in acute lymphoblastic leukemia, primary CNS lymphoma, and osteosarcoma. Intrathecal MTX is administered for CNS prophylaxis in leukemia.
Dosage and Administration
In rheumatological indications, MTX is given once weekly, not daily, as daily administration significantly increases toxicity. Starting dose is typically 10 to 15 mg per week, titrated to 20 to 25 mg/week based on response and tolerability. Folic acid 5 mg once weekly (taken on a different day than MTX) is routinely co-prescribed to reduce gastrointestinal and hepatic side effects. Oncological high-dose regimens require leucovorin rescue to prevent life-threatening toxicity and must be conducted in specialized centers with MTX level monitoring.
Side Effects
Nausea, vomiting, and mucositis are the most common acute side effects and are substantially reduced by folic acid supplementation. Hepatotoxicity is a significant concern with long-term use; liver fibrosis and cirrhosis can develop, making regular monitoring of liver enzymes and, in some cases, elastography or biopsy necessary. Bone marrow suppression with pancytopenia is rare at low doses but requires monitoring of blood counts. MTX-associated lung disease (pneumonitis) is an idiosyncratic reaction occurring in approximately 1 to 5 percent of patients and requires immediate discontinuation. Renal function affects MTX clearance; impaired kidneys lead to accumulation and increased toxicity.
Interactions
Non-steroidal anti-inflammatory drugs (NSAIDs) reduce renal MTX excretion and can lead to dangerous accumulation; this combination should be used with caution or avoided. Trimethoprim, sulfamethoxazole, and proton pump inhibitors can increase MTX toxicity. Penicillins and probenecid inhibit renal tubular secretion of MTX. Alcohol significantly increases hepatotoxicity and should be avoided. Vaccinations with live vaccines are contraindicated during MTX therapy.
Special Notes
MTX is a prescription-only medicine and teratogenic. Reliable contraception is mandatory during treatment and for at least three months after discontinuation in women; men should use contraception for at least three months after stopping MTX. Pregnancy must be excluded before starting therapy. The weekly dosing schedule must be clearly communicated to patients, as daily intake errors have caused fatal outcomes. Patients should carry a treatment card and be advised not to take additional folate antagonists without medical consultation.
Related Topics
Frequently Asked Questions
Why is MTX taken only once a week?
The weekly interval is not primarily about the half-life but about toxicity reduction. Daily intake at the same total dose leads to severe bone marrow suppression and mucositis. The weekly schedule has been established over decades as the optimal balance between efficacy and tolerability.
How long can MTX be taken?
In rheumatoid arthritis, MTX is often used for many years as a long-term therapy. With regular monitoring of blood count, liver values, and kidney function, long-term use is possible and well-established in clinical practice.
Why must folic acid be taken alongside MTX?
MTX inhibits folate metabolism. Supplementing with folic acid compensates for this inhibition in normal cells without significantly reducing the anti-inflammatory effect, thereby substantially reducing side effects such as nausea, mucositis, and mild liver enzyme elevations.
Sources
- EULAR Guidelines: Rheumatoid Arthritis Management 2022
- Smolen JS et al: Methotrexate in rheumatoid arthritis. Nat Rev Rheumatol 2023
- Fachinformation Methotrexat-Lederle, aktueller Stand