What is the appropriate methotrexate dosing regimen for an adult with rheumatoid arthritis and normal renal function (creatinine clearance ≥ 60 mL/min)?

Methotrexate Dosing for Rheumatoid Arthritis with Normal Renal Function

For an adult with rheumatoid arthritis and normal renal function (creatinine clearance ≥ 60 mL/min), start methotrexate at 15 mg orally once weekly and escalate by 5 mg every 4 weeks to a target of 25–30 mg weekly, switching to subcutaneous administration at the same dose if inadequate response occurs at 15–20 mg oral weekly. 1, 2

Starting Dose and Initial Route

• Begin with 15 mg orally once weekly in patients with normal renal function, as this aggressive starting dose optimizes early disease control without requiring prolonged titration. 1, 2
• The FDA-approved starting range is 7.5 mg weekly, but evidence demonstrates that starting at 15 mg achieves therapeutic benefit faster. 3, 1
• Oral administration is preferred initially because it provides comparable bioavailability to parenteral routes at typical starting doses and is more convenient for patients. 2

Dose Escalation Protocol

• Increase the dose by 5 mg every 4 weeks until reaching 25–30 mg weekly or the maximum tolerated dose. 1, 2
• Wait at least 4 weeks after each dose increase before assessing response, as clinical improvement requires this interval to manifest. 4, 2
• The FDA label permits doses up to 30 mg weekly, though doses exceeding 20 mg weekly carry significantly higher risk of bone marrow suppression. 3
• More aggressive escalation (5 mg monthly) yields greater efficacy than slower escalation (5 mg every 3 months), but with modestly increased gastrointestinal adverse events. 4

When to Switch to Subcutaneous Administration

• Switch to subcutaneous methotrexate at the same milligram dose if the patient shows inadequate response at 15–20 mg oral weekly or develops gastrointestinal intolerance (nausea, vomiting, diarrhea). 1, 4, 2
• Subcutaneous administration provides higher bioavailability than oral dosing, particularly at doses above 15 mg weekly, due to saturable intestinal absorption. 1, 2
• One randomized trial demonstrated that 15 mg subcutaneous weekly produced superior clinical response compared to 15 mg oral weekly. 1
• Do not add or switch to another DMARD before attempting subcutaneous methotrexate at the same dose; this route change alone may restore efficacy. 2

Mandatory Folic Acid Supplementation

• Prescribe folic acid 5 mg once weekly on a day different from methotrexate (e.g., if methotrexate is Monday, give folic acid on Thursday). 1, 4, 2
• Alternative regimen: 1 mg folic acid daily except on the methotrexate day. 4, 2
• Never administer folic acid on the same day as methotrexate, as concurrent dosing may compete for cellular uptake and reduce therapeutic effect. 1, 2
• Folic acid reduces mucosal ulcers, gastrointestinal side effects, and possibly hepatotoxicity without compromising methotrexate efficacy. 1, 5
• Use folic acid rather than folinic acid (leucovorin) for routine supplementation; folinic acid offers no efficacy advantage and costs substantially more. 1, 2

Laboratory Monitoring Schedule

• First month: Obtain CBC, liver enzymes (AST/ALT), and serum creatinine every 7–14 days to detect early bone marrow suppression or hepatotoxicity. 2, 5
• Months 2–3 (dose escalation phase): Repeat CBC, liver enzymes, and creatinine every 2–3 weeks. 2
• Maintenance phase (stable dose): Monitor CBC and liver enzymes every 2–3 months. 2, 5
• Temporarily withhold methotrexate if WBC < 3.5 × 10⁹/L, neutrophils < 2 × 10⁹/L, platelets < 100 × 10⁹/L, or transaminases > 2 × upper limit of normal on repeat testing. 2
• Pay attention to downward trends in blood counts even when absolute values remain within normal range, as this may herald impending toxicity. 4, 2

Pre-Treatment Requirements

• Before the first dose, obtain CBC with differential and platelets, liver function tests (AST, ALT, albumin), serum creatinine with calculated creatinine clearance, and chest radiograph. 2, 5
• Creatinine clearance must be documented as ≥ 60 mL/min before initiating therapy. 3
• Check hepatitis B and C serology to identify patients at risk for hepatotoxicity. 5
• Ensure effective contraception is established and maintained for at least one menstrual cycle after discontinuing methotrexate due to high teratogenicity. 2

Critical Patient Education

• Emphasize that methotrexate is prescribed for once-weekly dosing only; accidental daily administration can cause fatal pancytopenia. 2
• Instruct patients to seek urgent medical review for oral ulcers, unexpected bruising or bleeding, fever, persistent cough, dyspnea, severe nausea/vomiting, or dark urine. 2
• Therapeutic response typically begins within 3–6 weeks, with continued improvement for up to 12 weeks or more. 3

Drug Interactions to Avoid

• Trimethoprim-sulfamethoxazole is contraindicated because it precipitates severe bone marrow suppression through dual folate antagonism. 2, 6
• NSAIDs reduce renal clearance of methotrexate and increase toxicity risk, though they are commonly co-prescribed; monitor more closely. 2, 6
• Probenecid and salicylates can displace methotrexate from albumin or impair tubular secretion, heightening toxicity. 2, 6

Common Pitfalls to Avoid

• Do not exceed 20 mg weekly in patients with risk factors such as advanced age, even mild renal impairment, hypoalbuminemia, or significant alcohol use. 4, 2
• Do not continue escalating once adequate disease control is achieved at a lower dose; use the minimum effective dose to minimize cumulative toxicity. 1, 4, 2
• Do not increase the dose more frequently than every 2 weeks, as insufficient time will have elapsed to assess therapeutic response or identify delayed toxicities. 4, 2
• Do not use divided-dose schedules (e.g., 2.5 mg every 12 hours for 3 doses); while FDA-approved, once-weekly single dosing is simpler and equally effective. 3

Dose Adjustments for Borderline Renal Function

• Although the question specifies normal renal function, be aware that methotrexate dose must be reduced by 50% when creatinine clearance is 20–50 mL/min, and the drug should be avoided entirely if creatinine clearance is < 20 mL/min. 1, 2
• If creatinine increases by 50% or more during therapy, remeasure creatinine clearance even if the absolute value remains within normal range. 3