Methotrexate

Methotrexate is a folate antagonist and antimetabolite used at low, once weekly doses as the anchor conventional synthetic disease-modifying drug in rheumatoid arthritis, psoriatic arthritis, psoriasis and several vasculitides and inflammatory conditions. Its anti-inflammatory effect at low dose is not explained by dihydrofolate reductase blockade alone, and onset takes 6 to 12 weeks.

Class. Antimetabolite, conventional synthetic disease-modifying anti-rheumatic drug, folate antagonist.

Mechanism. Polyglutamated metabolites inhibit dihydrofolate reductase and AICAR transformylase, raising intracellular and extracellular adenosine, which suppresses T cell activation and neutrophil function. Thymidylate synthase and purine synthesis inhibition dominate at high oncology doses.

Pharmacokinetics. Oral bioavailability is about 70 percent at 15 mg or less and falls and becomes erratic at higher doses, which is why the subcutaneous route is used over 15 mg. Elimination is mainly renal by glomerular filtration and tubular secretion, with a terminal half-life of 6 to 9 hours at low dose. Polyglutamates persist in cells for weeks.

All regimens are once WEEKLY. The most serious prescribing error is daily dosing, which can be fatal through marrow failure and mucositis.

Rheumatoid arthritis and psoriatic arthritis (first line conventional drug).

• Start 7.5 to 15 mg once weekly, orally or subcutaneously.

• Loading dose: none.

• Titrate by 2.5 to 5 mg every 2 to 4 weeks to 20 to 25 mg once weekly.

• Maximum dose: 25 mg once weekly (30 mg is used by some specialists).

• Switch to subcutaneous injection when the oral dose is over 15 mg or when nausea limits oral use.

• Duration: long term, reviewed at least every 6 months once stable.

Chronic plaque psoriasis. 7.5 to 15 mg once weekly, increased to a maximum of 25 mg once weekly as response allows. Maintenance is the lowest effective dose.

Juvenile idiopathic arthritis. 10 to 15 mg/m2 once weekly, up to 20 to 25 mg/m2 once weekly in specialist hands. Subcutaneous route is preferred when oral absorption is poor.

Vasculitis, polymyalgia rheumatica and giant cell arteritis (steroid sparing, specialist). 10 to 25 mg once weekly with a glucocorticoid taper. Methotrexate is used for non-organ-threatening ANCA vasculitis remission induction and for maintenance after induction therapy in selected patients.

Crohn disease (specialist). Induction 25 mg once weekly by subcutaneous or intramuscular injection for up to 16 weeks, then maintenance 15 mg once weekly.

Ectopic pregnancy (specialist, obstetric). Single intramuscular dose of 50 mg/m2 with repeat dosing at day 4 to 7 if hCG fall is inadequate. This is a distinct single-dose use with strict eligibility criteria.

Folic acid supplement. Folic acid 5 mg once weekly (a different day, usually 24 to 72 hours after methotrexate) or 1 mg daily on the other six days. It lowers gastrointestinal, mucosal and hepatic toxicity without reducing efficacy.

Contraindications. Pregnancy and breastfeeding, severe renal impairment (eGFR under 30 mL/min), significant hepatic impairment or heavy alcohol use, active serious infection, severe bone marrow suppression, and known hypersensitivity.

Boxed-warning-level risks. Embryofoetal toxicity and foetal death, hepatotoxicity and fibrosis, bone marrow suppression, pneumonitis, severe skin reactions, serious infections and lymphoproliferative disorders. Mucositis and pancytopenia follow dosing errors or renal decline.

Adverse effects. Common: nausea, mouth ulcers, fatigue, raised transaminases, headache, hair thinning. Serious: pancytopenia, interstitial pneumonitis (dry cough, dyspnoea, fever; stop and investigate), hepatic fibrosis, opportunistic infection including Pneumocystis, accelerated nodulosis, Epstein-Barr virus lymphoproliferative disease.

Major interactions. Trimethoprim and co-trimoxazole (severe pancytopenia, avoid), penicillins, probenecid and high dose NSAIDs and salicylates (reduced renal clearance), proton pump inhibitors (delayed clearance, mainly at high dose), nitrous oxide anaesthesia, other hepatotoxic or myelosuppressive drugs, leflunomide and acitretin (hepatotoxicity), live vaccines (avoid).

Common prescribing errors. Daily instead of weekly dosing; failing to give folic acid; co-prescribing co-trimoxazole; continuing through falling eGFR; confusing 2.5 mg tablet strengths.

Special groups.

• Pregnancy: contraindicated. Stop at least 3 months before conception in women and men, with reliable contraception throughout.

• Breastfeeding: avoid.

• Children: dosed by body surface area; weekly regimen only.

• Older adults: reduce starting dose (often 5 to 7.5 mg once weekly) because of reduced renal clearance.

• Kidney impairment: eGFR 60 to 89 mL/min, caution and closer monitoring; 30 to 59 mL/min, reduce dose by about one third to one half; under 30 mL/min, avoid.

• Liver impairment: avoid in significant disease; check alcohol intake, hepatitis B and C status.

• Region: in East Africa screen for HIV, hepatitis B and C and latent tuberculosis before starting, and avoid casual co-trimoxazole use for febrile illness while on treatment.

Formulations and administration. Oral 2.5 mg tablets and liquid; subcutaneous prefilled pens or vials (7.5 to 25 mg) given once weekly on a fixed day. Label the day on the prescription and the container.

Baseline. Full blood count, urea, creatinine and eGFR, liver enzymes and albumin, hepatitis B and C and HIV serology, chest radiograph if respiratory disease is suspected, pregnancy test, and vaccination review (pneumococcal, influenza, hepatitis B; no live vaccines).

Monitoring. Full blood count, liver enzymes and creatinine every 2 weeks until the dose has been stable for 6 weeks, then monthly for 3 months, then every 3 months. Repeat after each dose increase.

Stop or hold thresholds.

• White cell count under 3.5 x 10^9/L, neutrophils under 1.6 x 10^9/L, or platelets under 140 x 10^9/L: hold and repeat.

• ALT or AST over twice the upper limit of normal: hold and investigate.

• Unexplained fall in albumin, new cough or dyspnoea, severe mouth ulceration, fever with rash, or eGFR under 30 mL/min: stop.

Toxicity and rescue. Stop methotrexate, give folinic acid (leucovorin) at doses titrated to serum methotrexate level and clinical picture, and use intravenous hydration with urine alkalinisation in high-level exposure. Glucarpidase is used for toxic levels with renal failure.

Referral and escalation. Refer to a rheumatologist for persistent disease activity after 3 months at an optimal dose, for any unexplained cytopenia, or for suspected pneumonitis.