What is the recommended starting dose and titration schedule for methotrexate, the appropriate folic acid supplementation regimen, monitoring requirements, and contraindications in rheumatoid arthritis?

Methotrexate and Folic Acid Dosing in Rheumatoid Arthritis

Start methotrexate at 10–15 mg orally once weekly, escalate by 5 mg every 2–4 weeks to a target of 20–30 mg weekly, and prescribe at least 5 mg folic acid weekly on a different day than methotrexate. 1

Starting Dose and Route of Administration

• Begin with 10–15 mg oral methotrexate once weekly as the initial dose, which balances efficacy against tolerability better than lower starting doses of 5–10 mg weekly. 1

• Oral administration is the preferred initial route due to ease of use and adequate bioavailability at typical starting doses. 2

• A test dose of 2.5–5 mg with repeat complete blood count 5–7 days later may be considered in patients at higher risk for bone marrow suppression (those with renal impairment, drug interactions, or significant comorbidities), though starting directly at therapeutic doses is also reasonable. 1, 2

Dose Escalation Strategy

• Increase the dose by 5 mg every 2–4 weeks until achieving disease control or reaching 20–30 mg weekly, depending on clinical response and tolerability. 1

• Rapid escalation (5 mg monthly) provides superior efficacy compared to slow escalation (5 mg every 3 months), though it carries a modestly higher risk of gastrointestinal adverse events. 1, 2

• Wait at least 4 weeks after each dose increase before assessing clinical response, as therapeutic benefit requires this interval. 2

• The evidence shows that starting doses of 12.5–20 mg weekly are more effective than 5–10 mg weekly without increased toxicity, supporting an aggressive initial approach. 1

When to Switch to Parenteral Administration

• Switch to subcutaneous or intramuscular methotrexate at the same dose if the patient shows inadequate response at 15–20 mg oral weekly or develops gastrointestinal intolerance (nausea, vomiting, diarrhea). 1, 2

• Parenteral administration offers higher bioavailability than oral dosing, particularly at doses above 15 mg weekly, due to saturable intestinal absorption. 1, 2

• A randomized trial demonstrated that 15 mg subcutaneous weekly produced superior clinical response compared to 15 mg oral weekly. 2

• However, in patients with longstanding rheumatoid arthritis who previously failed oral methotrexate plus other DMARDs, switching to intramuscular administration at 15 mg weekly with subsequent dose escalation did not improve efficacy. 1

Folic Acid Supplementation (Mandatory)

• Prescribe at least 5 mg folic acid per week for all patients on methotrexate, which is strongly recommended with Grade A evidence. 1, 3, 4

• Acceptable regimens include either 5 mg folic acid once weekly on a different day than methotrexate (e.g., methotrexate Monday, folic acid Thursday) or 1 mg daily except on the methotrexate day. 3, 2, 4

• Never administer folic acid on the same day as methotrexate, as concurrent dosing may compete for cellular uptake and reduce therapeutic effect. 2, 4

• Folic acid supplementation reduces gastrointestinal side effects by 26% (relative risk 0.74), hepatotoxicity by 77% (relative risk 0.23), and overall treatment discontinuation by 61% (relative risk 0.39) without compromising methotrexate efficacy. 3, 5

• Use folic acid rather than folinic acid (leucovorin) for routine supplementation, as folinic acid offers no efficacy advantage, costs significantly more, and at doses >5 mg weekly may paradoxically increase joint tenderness and swelling. 3, 4, 5

• If gastrointestinal symptoms persist despite standard supplementation, consider increasing folic acid to 5 mg daily (except methotrexate day) or higher doses of 10–30 mg weekly. 3, 4

Pre-Treatment Work-Up

• Before starting methotrexate, obtain clinical assessment of risk factors for toxicity (including alcohol intake), patient education, AST, ALT, albumin, complete blood count, creatinine, and chest x-ray (within the previous year). 1

• Consider additional testing including serology for HIV, hepatitis B/C, fasting blood glucose, lipid profile, and pregnancy test. 1

• Ensure effective contraception is established, as methotrexate must be avoided for at least 3 months before planned pregnancy in both men and women and is contraindicated during pregnancy and breastfeeding. 1, 2

Monitoring Requirements

• During the first month: Check ALT (with or without AST), creatinine, and complete blood count every 1–1.5 months when starting methotrexate or increasing the dose. 1

• Once dose is stable: Monitor these same parameters every 1–3 months thereafter. 1

• More intensive monitoring (every 7–14 days) may be warranted during the first month in higher-risk patients to detect early bone marrow suppression or hepatotoxicity. 2

• Perform clinical assessment for side effects and risk factors at each visit. 1

Managing Elevated Liver Enzymes

• Stop methotrexate if there is a confirmed increase in ALT/AST greater than 3 times the upper limit of normal, but may reinstitute at a lower dose following normalization. 1

• If ALT/AST levels are persistently elevated up to 3 times the upper limit of normal, adjust the methotrexate dose downward. 1

• Consider diagnostic procedures if ALT/AST remains more than 3 times the upper limit of normal after discontinuation. 1

Dose Adjustments for Renal Impairment

• Reduce the methotrexate dose by 50% when creatinine clearance is 20–50 mL/min. 2

• Avoid methotrexate entirely if creatinine clearance is <20 mL/min. 2

• Use standard dosing when glomerular filtration rate is >90 mL/min. 2

Critical Patient Education and Safety

• Emphasize that methotrexate is prescribed for once-weekly dosing only—accidental daily administration can cause fatal toxicity. 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

• Daily dosing regimens (2.5 mg daily for 6 days weekly) are less effective than weekly dosing and cause more liver enzyme elevation. 1

Important Drug Interactions

• Trimethoprim-sulfamethoxazole is contraindicated with methotrexate because it can precipitate severe bone marrow suppression. 2

• Non-steroidal anti-inflammatory drugs (NSAIDs) reduce renal clearance of methotrexate and increase toxicity risk. 2

• Salicylates, probenecid, and phenytoin can displace methotrexate from albumin or impair tubular secretion, heightening toxicity. 2

Long-Term Use and Combination Therapy

• Based on its acceptable safety profile, methotrexate is appropriate for long-term use. 1

• In DMARD-naive patients, the efficacy/toxicity balance favors methotrexate monotherapy over combination with other conventional DMARDs. 1

• Methotrexate should be considered as the anchor for combination therapy when monotherapy does not achieve disease control. 1

Perioperative Management

• Methotrexate can be safely continued in the perioperative period in rheumatoid arthritis patients undergoing elective orthopedic surgery. 1

Common Pitfalls to Avoid

• Do not start at doses lower than 10 mg weekly, as this delays achieving therapeutic benefit without reducing toxicity. 1

• Do not escalate doses more frequently than every 2 weeks, as insufficient time is available to evaluate response or delayed toxicities. 2

• Do not withhold folic acid due to concerns about reducing methotrexate efficacy—this concern has been definitively disproven. 3, 5

• Do not use folinic acid at doses >5 mg weekly, as this may reduce methotrexate effectiveness. 3

• Once adequate disease control is achieved at a lower dose, do not continue escalating—use the minimum effective dose to minimize cumulative toxicity. 2