Methotrexate in Inflammatory Disease

Methotrexate at low weekly doses is the first-choice DMARD for rheumatoid arthritis and a core drug in psoriasis, psoriatic arthritis, juvenile idiopathic arthritis, Crohn disease, sarcoidosis and vasculitis. At 7.5 to 25 mg weekly it works mainly through adenosine release and T cell effects, not through folate depletion alone. A single wrong daily dose can be fatal.

Mechanism. Methotrexate polyglutamates inhibit AICAR transformylase, raising adenosine, and also reduce purine synthesis in lymphocytes. Folate depletion causes toxicity, so folic acid is co-prescribed.

Pharmacokinetics. Oral bioavailability falls over 15 mg weekly (about 70% at 15 mg), so subcutaneous dosing is used for higher doses. Half-life 3 to 10 hours; polyglutamates persist for weeks; 80% renal excretion.

Dosing.

• Start 7.5 to 15 mg once weekly; increase by 2.5 to 5 mg every 2 to 4 weeks to 20 to 25 mg weekly.
• Switch to subcutaneous injection if oral doses of 15 mg or more fail or gastrointestinal effects occur.
• Folic acid 5 mg once weekly (on a different day) or 1 mg daily except on the methotrexate day.
• Children: 10 to 15 mg/m2 weekly (maximum 25 mg).
• Taper to the lowest effective dose after sustained remission.

Oral presentations. Use only 2.5 mg tablets, one strength, to avoid errors. Write the day of the week on the prescription.

Other uses. Psoriasis 10 to 25 mg weekly; Crohn disease 25 mg subcutaneously weekly; ectopic pregnancy (single dose 50 mg/m2); medical abortion regimens; high-dose chemotherapy with folinic acid rescue (specialist only).

• First-line. Moderate to severe rheumatoid arthritis, psoriatic arthritis, polyarticular juvenile arthritis, plaque psoriasis.
• Alternative. Combination with a biologic to reduce antidrug antibodies (adalimumab, infliximab).
• Specialist. Vasculitis, sarcoidosis, uveitis, myositis, morphoea and Crohn disease steroid sparing.
• Emergency. Methotrexate toxicity: stop the drug, give folinic acid 15 mg every 6 hours, hydrate, alkalinise urine, and consider glucarpidase.

Selection. Use in patients without liver disease, heavy alcohol use, renal impairment or pregnancy plans. Choose subcutaneous dosing for better absorption and fewer gastrointestinal effects.

Contraindications. Pregnancy and breastfeeding; creatinine clearance under 30 mL/min; significant liver disease or heavy alcohol use; active serious infection; marrow failure; active peptic ulcer (oral high dose); hypersensitivity.

Serious adverse effects.

• Nausea, mouth ulcers, fatigue, hair thinning (folic acid reduces).
• Raised transaminases, rarely fibrosis or cirrhosis.
• Pancytopenia, especially with renal impairment or interacting drugs.
• Pneumonitis (acute dry cough, fever and breathlessness; stop and treat).
• Teratogenicity and fetal loss; infections including herpes zoster.

Major interactions. Trimethoprim and co-trimoxazole (severe marrow failure; avoid); NSAIDs (higher doses), penicillins, probenecid, proton pump inhibitors and ciprofloxacin reduce clearance; leflunomide and alcohol raise liver toxicity; live vaccines contraindicated.

Common prescribing errors.

• Daily dosing instead of weekly.
• Missing folic acid.
• Treating infection with co-trimoxazole.
• Continuing during acute illness with dehydration and falling renal function.
• Pregnancy without washout.

Special groups.

• Pregnancy: stop at least 3 months before conception (men and women); use effective contraception.
• Breastfeeding: avoid.
• Children: weight and surface area based dosing; specialist.
• Older adults: lower doses; check creatinine clearance often.
• Kidney: avoid under 30 mL/min; reduce 50% at 30 to 59 mL/min.
• Liver: avoid in active disease or alcohol excess.
• East Africa: screen for hepatitis B and C, HIV and tuberculosis before starting; co-trimoxazole is widely used for HIV prophylaxis and is dangerous with methotrexate, so check every prescription; confirm folic acid supply.

Monitoring. Full blood count, creatinine and liver tests every 2 weeks until the dose is stable for 6 weeks, then monthly for 3 months, then every 3 months. Chest X-ray at baseline. Stop and review for white cells under 3.5 x 10^9/L, neutrophils under 1.6 x 10^9/L, platelets under 140 x 10^9/L, or transaminases over twice the upper limit.

Referral and escalation. Pneumonitis; severe mouth ulcers or fever with low counts; transaminases persistently raised; suspected overdose (early folinic acid and hospital care); pregnancy.

Comparison with alternative classes. Methotrexate is the best studied and cheapest DMARD, effective alone or with biologics. Leflunomide is similar in efficacy; sulfasalazine and hydroxychloroquine are weaker alone but safer in pregnancy.