How should methotrexate be initiated, dosed, administered, and monitored in rheumatoid arthritis?

How to Give Methotrexate in Rheumatoid Arthritis

Start methotrexate at 15 mg orally once weekly and escalate by 5 mg every 2–4 weeks to reach 25–30 mg weekly, switching to subcutaneous administration if oral therapy proves inadequate or poorly tolerated at 15–20 mg weekly. 1, 2, 3

Initial Dosing Strategy

• Begin with 15 mg orally once weekly rather than the FDA-approved starting dose of 7.5 mg, as this provides superior disease control without compromising safety and accelerates early therapeutic benefit. 1, 2, 3
• Do not start below 10–15 mg weekly; lower doses delay achieving therapeutic effect and optimal disease control. 2, 3
• The FDA label lists 7.5 mg weekly as the recommended starting dose for rheumatoid arthritis, but contemporary guideline evidence strongly supports 15 mg as the optimal starting point. 4, 5

Dose Escalation Protocol

• Increase the weekly dose by 5 mg every 2–4 weeks until reaching 20–25 mg weekly (maximum 30 mg weekly) based on clinical response and tolerability. 1, 2, 3
• Target a weekly dose of at least 15 mg within 4–6 weeks of initiation to achieve optimal efficacy. 1, 2
• Fast escalation (5 mg monthly) to 25–30 mg weekly demonstrates higher clinical efficacy than slow escalation (5 mg every 3 months), though with modestly increased gastrointestinal adverse events. 6, 2
• Wait at least 4 weeks after each dose increase before assessing clinical response, as therapeutic benefit typically requires this interval. 2
• Once adequate disease control is achieved at a lower dose, do not continue escalating; maintain the minimum effective dose to limit cumulative toxicity. 2

Route of Administration

• Oral administration is the preferred initial route because it is easy to use and provides similar bioavailability to subcutaneous administration at typical starting doses. 6, 2
• Switch to subcutaneous methotrexate at the same milligram dose (do not increase) if the patient shows inadequate response at 15–20 mg oral weekly or develops gastrointestinal intolerance (nausea, vomiting, diarrhea). 6, 1, 2, 3
• Subcutaneous delivery yields higher bioavailability than oral dosing, especially at doses >15 mg weekly, because intestinal absorption becomes saturable at higher oral doses. 6, 2
• A randomized trial demonstrated that 15 mg subcutaneous weekly produced superior clinical response compared with 15 mg oral weekly in early rheumatoid arthritis. 6, 2
• In longstanding rheumatoid arthritis after failure on oral methotrexate, switching to intramuscular 15 mg weekly with subsequent escalation did not improve efficacy. 6, 2
• Alternative strategies for oral intolerance include split dosing over 24 hours or increasing folic acid supplementation before switching routes. 1, 3

Mandatory Folic Acid Supplementation

• Prescribe at least 5 mg folic acid once weekly on a day different from methotrexate (e.g., methotrexate Monday, folic acid Thursday) to reduce gastrointestinal, mucosal, and hepatic toxicity without compromising efficacy. 1, 2, 3
• Acceptable regimens are either 5 mg folic acid once weekly on a different day or 1 mg daily except on the methotrexate day. 2
• Never administer folic acid on the same day as methotrexate, as concurrent dosing may compete for cellular uptake and reduce therapeutic effect. 2
• Use folic acid rather than folinic acid (leucovorin); folinic acid offers no efficacy advantage and is substantially more expensive. 2
• Increase the folic acid dose if tolerability issues arise. 3

Pre-Treatment Requirements

• Obtain complete blood count with differential and platelets, liver function tests (AST, ALT, albumin), serum creatinine with calculated creatinine clearance, and chest radiograph (within the past year). 1, 2
• Screen for hepatitis B/C and latent tuberculosis. 3
• Consider HIV serology, fasting glucose, and lipid profile. 2, 3
• Ensure effective contraception is established; methotrexate must be discontinued at least 3 months before a planned pregnancy in both men and women due to high teratogenicity. 1, 2, 3
• An optional test dose of 2.5–5 mg with a repeat complete blood count 5–7 days later may be used in low-risk patients to assess bone-marrow sensitivity. 2

Monitoring Protocol

• First month after initiation or dose increase: check ALT (±AST), serum creatinine, and complete blood count every 1–1.5 months (or every 7–14 days per some protocols). 1, 2
• After dose stabilization: repeat the same laboratory panel every 1–3 months (or every 2–3 months per some protocols). 1, 2
• Conduct a clinical review for adverse effects and emerging risk factors at each visit. 1, 2
• Pay attention to downward trends in blood counts even when absolute values remain within the normal range. 2

Management of Laboratory Abnormalities

• Stop methotrexate if ALT/AST increases to greater than 3 times the upper limit of normal on repeat testing; the drug may be restarted at a lower dose after normalization. 1, 2
• If ALT/AST remain ≤3 times upper limit of normal but are persistently elevated, reduce the methotrexate dose. 2
• Should ALT/AST stay >3 times upper limit of normal despite discontinuation, pursue further diagnostic evaluation (e.g., imaging, hepatology referral). 2
• Temporarily withhold methotrexate if WBC <3.5 × 10⁹/L, neutrophils <2 × 10⁹/L, or platelets <100 × 10⁹/L. 2

Dose Adjustments for Renal Impairment

• Use the standard dose when glomerular filtration rate >90 mL/min or creatinine clearance ≥60 mL/min. 2, 5
• 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

Treatment Response Assessment

• Assess treatment response at 3 months; if no improvement is seen, modify treatment. 3
• The treatment target is remission or low disease activity within 6 months. 3
• Full therapeutic effect often requires 12 weeks or longer, though improvement in joint pain and swelling may begin within 3–6 weeks. 3
• Continue oral methotrexate for at least 6 months (as long as some response is seen within 3 months) before declaring treatment failure. 3, 7

Combination Therapy Considerations

• 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. 3
• Methotrexate monotherapy is conditionally recommended over dual or triple conventional DMARD therapy due to the higher burden of combination therapy outweighing the moderate evidence for greater disease activity improvements. 3
• When monotherapy fails to achieve disease control, methotrexate should serve as the anchor drug for combination regimens. 2
• If another rheumatoid arthritis treatment is necessary to control the disease, maintain the methotrexate dosage and route of administration, with titration as needed. 7

Glucocorticoid Use

• Short-term glucocorticoids (<3 months) are conditionally recommended, with the goal of tapering to 5 mg daily by week 8 and continuing to taper over 2–4 months total. 3
• Initial dosing of 5–10 mg prednisone daily combined with methotrexate provides superior disease control and slows radiographic progression, achieving remission in 40–50% of patients. 3
• Longer-term glucocorticoid therapy (≥3 months) is strongly discouraged due to significant toxicity. 3

Critical Patient Education

• 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 any of the following: oral ulcers, unexpected bruising or bleeding, fever, persistent cough, dyspnea, severe nausea/vomiting, or dark urine. 2

Drug Interactions to Avoid

• Trimethoprim-sulfamethoxazole is contraindicated because it can precipitate severe bone-marrow suppression. 2
• Non-steroidal anti-inflammatory drugs 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

Perioperative Management

• Methotrexate can be continued safely during the perioperative period for elective orthopedic surgery in rheumatoid arthritis patients. 2

Common Pitfalls to Avoid

• 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. 2
• Avoid exceeding 20 mg weekly in patients with risk factors such as advanced age, renal impairment, or significant alcohol use. 2
• 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. 3
• Doses of more than 20 mg once weekly result in an increased risk of serious adverse reactions, including myelosuppression, per FDA labeling. 4