Methotrexate Prescribing and Monitoring

Methotrexate is a folate antagonist used once each week as the anchor disease-modifying drug in rheumatoid arthritis, and as a steroid-sparing or disease-controlling drug in psoriasis, psoriatic arthritis, vasculitis, polymyalgia rheumatica, juvenile idiopathic arthritis and some forms of uveitis. Daily dosing by mistake is the commonest fatal prescribing error with this drug.

Weekly dosing rule. Write the dose and the named day of the week on every prescription, dispense a single strength of 2.5 mg tablets, and confirm the patient and carer can state that the drug is taken once weekly. Never write “daily” or “as directed”.

Mechanism. Low-dose weekly methotrexate acts mainly through adenosine release and inhibition of purine synthesis, not by classical cytotoxic effect. Response takes 6 to 12 weeks.

Contraindications. Pregnancy and breastfeeding, eGFR under 30 mL/min, significant liver disease or heavy alcohol use, active serious infection, pre-existing interstitial lung disease, severe marrow suppression, and co-trimoxazole or trimethoprim use.

Rheumatoid arthritis, first line.

• Start methotrexate 7.5 to 15 mg orally or subcutaneously once weekly.
• Increase by 2.5 to 5 mg every 2 to 4 weeks to a usual target of 20 to 25 mg weekly (maximum 25 mg weekly), depending on response and tolerance.
• Use the subcutaneous route from 15 mg weekly, or when nausea limits oral use, because absorption plateaus over about 15 mg orally.
• Give folic acid 5 mg orally once weekly, on a different day from methotrexate (alternative: 1 mg daily on 6 days).

Psoriasis and psoriatic arthritis. Start 7.5 to 10 mg once weekly and increase by 2.5 to 5 mg every 2 to 4 weeks to 15 to 25 mg weekly; stop if no response by 12 to 16 weeks at an adequate dose.

Vasculitis, polymyalgia rheumatica and giant cell arteritis (steroid sparing). 10 to 20 mg once weekly with folic acid 5 mg once weekly.

Combination use. Methotrexate with hydroxychloroquine and sulfasalazine (triple therapy), or with a biologic or JAK inhibitor, improves response; biologics such as infliximab need concurrent methotrexate to limit anti-drug antibodies.

Ectopic pregnancy, specialist only. 50 mg/m2 IM as a single dose; do not give folic acid.

Oncology and rescue. High-dose methotrexate regimens for malignancy need leucovorin rescue and specialist units; they are not covered by the weekly low-dose regimen. Methotrexate toxicity from any cause: leucovorin 15 mg orally or IV every 6 hours until the level is under 0.05 micromol/L; glucarpidase 50 units/kg IV in delayed clearance.

Kidney impairment. eGFR 60 mL/min or more: no change. eGFR 30 to 59 mL/min: reduce the dose by about 50%. eGFR under 30 mL/min: avoid. Methotrexate is cleared by the kidney and accumulates quickly.

Liver impairment. Avoid with cirrhosis, alcohol excess or persistent ALT or AST over twice the upper limit. Limit alcohol to under 14 units weekly.

Older adults. Start at 5 to 7.5 mg weekly and titrate slowly; check creatinine before each increase.

Obesity and low body weight. Dose is fixed, not weight based.

Interactions.

• Trimethoprim and co-trimoxazole: contraindicated, risk of severe marrow aplasia.
• Penicillins, probenecid, NSAIDs at analgesic doses (especially with kidney impairment), proton pump inhibitors, and ciprofloxacin: reduce renal clearance.
• Leflunomide and azathioprine: additive hepatotoxicity and marrow suppression.
• Live vaccines: avoid.

Pregnancy and breastfeeding. Stop at least 3 months before conception in women and in men. Exposure in pregnancy: stop at once, give folic acid 5 mg daily and arrange a detailed foetal scan. Avoid during breastfeeding.

Vaccination. Give inactivated influenza, pneumococcal and recombinant zoster vaccines; response to some vaccines is blunted, so consider a 2 week methotrexate hold after influenza vaccination in stable disease.

Regional. Screen for hepatitis B, hepatitis C, HIV and tuberculosis before starting; the first two raise liver risk and tuberculosis may reactivate.

Baseline. Full blood count, creatinine and eGFR, ALT or AST, albumin, hepatitis B and C serology, HIV, chest radiograph and a pregnancy test.

Ongoing. Full blood count, creatinine and liver tests every 2 weeks until the dose has been stable for 6 weeks, then monthly for 3 months, then every 8 to 12 weeks.

Withhold and review for any of: white cell count under 3.5 x 10⁹/L, neutrophils under 1.6 x 10⁹/L, platelets under 140 x 10⁹/L, ALT or AST over twice the upper limit, a fall in eGFR of 30% or more, new cough or breathlessness (possible pneumonitis), mouth ulcers or unexplained bruising.

Stop and escalate. Stop for neutrophils under 1.0 x 10⁹/L, ALT or AST over 3 times the upper limit on repeat testing, methotrexate pneumonitis, or serious infection. Give leucovorin for suspected overdose or marrow toxicity and arrange urgent specialist review. A new sore throat, fever or bleeding in a patient on methotrexate needs a same-day blood count.