Reviewed by MedNext Clinical Team
Methotrexate is a disease-modifying antirheumatic drug (DMARD) used in rheumatoid arthritis, psoriasis, psoriatic arthritis, and certain inflammatory conditions. It is also used at much higher doses in oncology. In rheumatology and dermatology, methotrexate is highly effective and widely used — but it is one of the most frequently implicated drugs in serious prescribing errors, largely due to confusion between weekly and daily dosing [1].
CRITICAL: Weekly Dosing Only
For rheumatoid arthritis, psoriasis, and other non-oncological indications, methotrexate is prescribed ONCE WEEKLY — not daily. Accidental daily dosing has caused multiple patient deaths from bone marrow suppression and mucositis. Prescriptions must clearly state the day of the week on which the dose is to be taken. Patients should receive clear written and verbal education that this is a once-weekly medication. This error is one of the most preventable fatal medication errors in clinical practice and requires vigilance from all healthcare professionals involved in prescribing, dispensing, and administering the drug.
Folic Acid Supplementation
Methotrexate inhibits dihydrofolate reductase, reducing folate availability for DNA synthesis. This is the basis of its immunosuppressive and anti-proliferative effect, but it also causes folate-deficiency adverse effects including mucositis, nausea, macrocytosis, and bone marrow suppression. Folic acid 5 mg once weekly (taken on a different day to methotrexate) significantly reduces these adverse effects without compromising efficacy. Folic acid supplementation should be prescribed for all patients on methotrexate for inflammatory conditions [1].
Blood Monitoring
Regular monitoring is mandatory during methotrexate therapy. At initiation and with each dose increase, check full blood count (FBC), liver function tests (LFTs), renal function (U&E/eGFR), and albumin. Once on a stable dose, monitoring is typically performed every 2–3 months (or per local protocol). Thresholds for dose reduction, interruption, or permanent discontinuation exist for:
- Bone marrow suppression: A sudden fall in white cell count, neutrophils, or platelets requires immediate dose interruption and specialist review.
- Hepatotoxicity: Persistent or significant LFT elevation (particularly ALT more than twice the upper limit of normal on two consecutive tests) warrants dose reduction or temporary discontinuation. Cumulative hepatotoxicity and fibrosis risk increases with dose, alcohol use, obesity, and diabetes.
- Renal impairment: Methotrexate is renally excreted; reduced GFR increases toxicity. Use with significant caution in renal impairment — avoid if eGFR is below 30 mL/min/1.73m².
Pulmonary Toxicity (Methotrexate Pneumonitis)
Methotrexate pneumonitis is an idiosyncratic hypersensitivity reaction that can occur at any time during treatment, typically presenting with dyspnoea, dry cough, fever, and bilateral pulmonary infiltrates on imaging. It is not dose-dependent. If suspected, methotrexate must be stopped immediately and the patient assessed urgently. It should not be restarted after confirmed pneumonitis.
Teratogenicity
Methotrexate is a potent teratogen and abortifacient. It is absolutely contraindicated in pregnancy and during breastfeeding. Effective contraception is mandatory for both female and male patients during treatment and for at least 3–6 months after stopping. Patients of childbearing potential must be counselled clearly, and pregnancy should be excluded before initiating treatment [1].
Drug Interactions
NSAIDs reduce methotrexate renal clearance and can markedly increase plasma levels, precipitating toxicity — particularly bone marrow suppression. Co-prescription requires careful consideration and close monitoring. Trimethoprim and co-trimoxazole are contraindicated as they act synergistically to impair folate metabolism.
References
- Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis. 2009;68:1094-1099.