What is the initial dose of methotrexate for an adult patient with rheumatoid arthritis?

Methotrexate Dosing for Rheumatoid Arthritis

Start methotrexate at 15 mg orally once weekly and escalate by 5 mg every 2-4 weeks to reach 20-25 mg weekly within 4-6 weeks, switching to subcutaneous administration if oral therapy proves inadequate or poorly tolerated. 1

Initial Dosing Strategy

• Begin with oral methotrexate 15 mg once weekly rather than lower starting doses, as this provides superior disease control without compromising safety 2, 1
• The FDA-approved starting dose for rheumatoid arthritis is 7.5 mg once weekly, though this represents a conservative minimum rather than an optimal starting point 3
• Starting doses of 7.5 mg weekly delay achieving therapeutic effect and optimal disease control compared to 15 mg weekly 1
• Higher starting doses (25 mg/week) are associated with greater clinical effect sizes but also increased gastrointestinal adverse events 2

Dose Escalation Protocol

• Escalate the dose by 5 mg increments every 2-4 weeks until reaching 20-25 mg weekly (up to a maximum of 30 mg weekly) based on clinical response and tolerability 2, 1, 4
• Fast escalation (5 mg/month) to 25-30 mg/week demonstrates higher efficacy compared to slow escalation (5 mg/3 months), though with increased toxicity as a limiting factor 2, 1
• The mean tolerable effective dose is 17-20 mg/week 2
• Continue dose escalation as long as ALT/AST remains below 3 times the upper limit of normal and there is no cytopenia 1

Route of Administration

• Start with oral administration as the initial route 2, 1, 4
• Switch to subcutaneous methotrexate if oral therapy at 15-20 mg/week is not achieving target response, maintaining the same dose rather than increasing it 1, 4
• Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy, though with potentially more withdrawal due to toxicity in early RA 2
• In longstanding RA, after failure on 15-20 mg/week orally, switching to 15 mg/week intramuscularly with subsequent dose escalation did not result in increased efficacy 2

Folic Acid Supplementation

• Prescribe at least 5 mg of folic acid per week to reduce gastrointestinal and other adverse effects without compromising methotrexate efficacy 1, 4
• Increase the folic acid dose if tolerability issues arise 1
• Folic acid should be given daily except on the day of methotrexate administration 2

Treatment Monitoring and Response Assessment

• Assess treatment response at 3 months; if no improvement is seen, modify treatment 1
• The treatment target is remission or low disease activity within 6 months 1
• Full therapeutic effect often requires 12 weeks or longer, though improvement in joint pain and swelling may begin within 3-6 weeks 1, 3
• Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until a stable dose is reached, then every 1-3 months 4

Safety Monitoring Requirements

• Before initiating therapy, obtain CBC, serum transaminases (ALT/AST), albumin, creatinine with creatinine clearance calculation, and chest radiograph (within the previous year) 1, 4
• Screen for hepatitis B/C and latent tuberculosis 1
• Stop methotrexate if ALT/AST increases to greater than 3 times the upper limit of normal, and consider reinstituting at a lower dose after normalization of liver enzymes 1, 4

Common Pitfalls to Avoid

• Do not start at doses below 10-15 mg weekly, as this delays achieving therapeutic effect and optimal disease control 1
• Do not switch to alternative DMARDs prematurely; continue oral methotrexate for at least 6 months (as long as some response is seen within 3 months) before declaring treatment failure 1
• Do not exceed 20 mg once weekly without careful consideration, as dosages above this threshold result in a significantly increased risk of serious adverse reactions, including myelosuppression 3, 5
• Methotrexate must not be used during pregnancy or for at least 3 months before planned pregnancy in both men and women 1

Managing Inadequate Response or Intolerance

• If oral methotrexate is not achieving target response, switch to subcutaneous methotrexate before adding or switching to other DMARDs, maintaining the same dose rather than increasing it 1, 4
• Try split dosing of oral methotrexate over 24 hours, or switch to weekly subcutaneous injections, and/or increase folic acid supplementation 1, 4
• Methotrexate monotherapy is preferred over combination with biologics or targeted synthetic DMARDs in DMARD-naive patients with moderate-to-high disease activity, as many patients will reach their treatment goal on methotrexate alone 1