What is the recommended starting dose and titration schedule for methotrexate in an adult with rheumatoid arthritis or moderate‑to‑severe psoriasis, including dose adjustments for impaired renal function and required laboratory monitoring?

Methotrexate Dosing for Rheumatoid Arthritis and Psoriasis

Starting Dose and Route

For rheumatoid arthritis, start methotrexate at 15 mg orally once weekly and escalate by 5 mg every 4 weeks to a target of 25–30 mg weekly or the highest tolerable dose. 1 This approach balances efficacy against toxicity better than starting at lower doses (7.5 mg) or escalating more slowly. 1

• The 2021 American College of Rheumatology conditionally recommends titrating to at least 15 mg weekly within 4–6 weeks for optimal efficacy. 1
• Oral administration is preferred initially over subcutaneous because of ease of use and similar bioavailability at typical starting doses. 1, 2
• For psoriasis, start at 7.5–15 mg orally once weekly (not exceeding 0.2 mg/kg body weight), escalating by 5 mg every 2–4 weeks to a target of 15–25 mg weekly. 3, 4 Doses above 25 mg weekly are not recommended for psoriasis. 3

Dose Escalation Strategy

Increase the weekly dose by 5 mg every 2–4 weeks until adequate disease control is achieved or toxicity limits further escalation. 2, 3

• Wait at least 4 weeks after each dose increase before assessing clinical response, as improvement takes this long to manifest. 2, 3
• Faster escalation (5 mg monthly) produces higher efficacy but also more gastrointestinal adverse events compared to slower escalation (5 mg every 3 months). 1
• Do not escalate more frequently than every 2 weeks, as insufficient time will have elapsed to assess therapeutic response or identify delayed toxicities. 2, 3

When to Switch to Subcutaneous Administration

If the patient shows inadequate response at 15–20 mg oral weekly or develops gastrointestinal intolerance, switch to subcutaneous administration at the same dose before further dose escalation. 1, 2, 3

• Subcutaneous methotrexate has higher bioavailability than oral at doses above 15 mg weekly. 5
• The 2021 ACR conditionally recommends switching to subcutaneous methotrexate over adding or switching to alternative DMARDs for patients not at target on oral therapy. 1
• In longstanding RA, switching from oral to intramuscular at the same dose (15 mg weekly) with subsequent escalation did not increase efficacy. 1

Mandatory Folic Acid Supplementation

All patients on methotrexate must receive folic acid supplementation to reduce toxicity without compromising efficacy. 2, 3, 6

• For weekly methotrexate doses ≥12.5 mg, prescribe at least 5 mg folic acid weekly. 2, 6
• Two acceptable regimens: 5 mg once weekly on a different day than methotrexate, or 1 mg daily except on the methotrexate day. 2, 3, 6
• Never administer folic acid on the same day as methotrexate, as it may compete for cellular uptake and reduce efficacy. 6
• Use folic acid rather than folinic acid (leucovorin) for routine supplementation; folinic acid offers no advantage and is significantly more expensive. 6

Dose Adjustments for Renal Impairment

Reduce the methotrexate dose by 50% if creatinine clearance is 20–50 mL/min; avoid methotrexate entirely if creatinine clearance is below 20 mL/min. 2

• For GFR >90 mL/min: use normal dose. 2
• For GFR 20–50 mL/min: reduce dose by 50%. 2
• For GFR <20 mL/min: avoid methotrexate entirely. 2
• Serum creatinine must be normal and creatinine clearance must be greater than 60 mL/min before initiating high-dose methotrexate therapy. 4

Laboratory Monitoring Schedule

During the first month, check CBC, liver function tests, and creatinine every 7–14 days to detect early bone marrow suppression or hepatotoxicity. 3

• During months 2–3 (dose escalation phase), check CBC, liver enzymes, and creatinine every 2–3 weeks. 3
• Once stable on maintenance therapy, check CBC and liver enzymes every 2–3 months. 3
• Withhold methotrexate temporarily if: white blood cell count <3.5 × 10⁹/L, neutrophils <2 × 10⁹/L, platelets <100 × 10⁹/L, or transaminases >2× upper limit of normal on repeat testing. 3
• Watch for downward trends in blood counts even if absolute values remain within normal range. 2

Pre-Treatment Requirements

Before the first dose, obtain: complete blood count with differential and platelets, liver function tests (AST, ALT, albumin), serum creatinine with calculated clearance, serum urea and electrolytes, and a chest radiograph. 3

• Effective contraception must be established and maintained for at least one menstrual cycle after stopping methotrexate because the drug is highly teratogenic. 3
• An optional test dose of 2.5–5 mg with a CBC 5–7 days later may be used in low-risk patients to assess bone marrow sensitivity. 3

Critical Patient Education

Methotrexate is prescribed for once-weekly dosing only; accidental daily administration has caused fatal toxicity. 3

• Instruct patients to seek urgent medical review for: oral ulcers, unexpected bruising or bleeding, fever, persistent cough, dyspnea, severe nausea/vomiting, or dark urine. 3
• Therapeutic response usually begins within 3–6 weeks and may continue to improve for another 12 weeks. 4, 7

Drug Interactions to Avoid

Trimethoprim-sulfamethoxazole is contraindicated because it can precipitate severe bone marrow suppression. 3

• NSAIDs reduce renal clearance of methotrexate and increase toxicity risk. 3
• Salicylates, probenecid, and phenytoin displace methotrexate from albumin or impair tubular secretion, heightening toxicity. 3

Common Pitfalls

Do not prescribe methotrexate on an "as-needed" basis or use daily dosing regimens; daily administration increases liver toxicity and is less effective than weekly dosing. 3

• Do not exceed 20 mg weekly in patients with risk factors for toxicity such as advanced age, renal impairment, or significant alcohol use. 2
• Do not continue escalating if the patient achieves adequate disease control at lower doses; use the minimum effective dose to minimize cumulative toxicity. 2, 3
• Limited experience shows a significant increase in serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/week in adults. 4