What is the recommended treatment approach for a patient with rheumatoid arthritis, including dosing and monitoring for methotrexate and leflunomide?

Methotrexate and Leflunomide Treatment in Rheumatoid Arthritis

First-Line Treatment: Methotrexate as Anchor Drug

Methotrexate is strongly recommended as the first-line DMARD for patients with rheumatoid arthritis and moderate-to-high disease activity, with leflunomide serving as the best alternative when methotrexate is contraindicated or not tolerated. 1

Methotrexate Dosing Protocol

• Start with oral methotrexate at 10-15 mg weekly 1, 2
• Titrate to at least 15 mg weekly within 4-6 weeks for optimal efficacy 1, 3
• Maximum dose can be escalated up to 20-25 mg weekly based on response and tolerability 1, 2, 4
• Oral administration is preferred initially despite moderate evidence for superior subcutaneous bioavailability, due to ease of administration and similar bioavailability at typical starting doses 1
• If oral methotrexate is not tolerated (gastrointestinal side effects), switch to subcutaneous or intramuscular administration or consider split dosing over 24 hours 1, 2

Mandatory Folic Acid Supplementation

• Prescribe folic acid at minimum 5 mg once weekly, taken at a distance from the methotrexate dose 1, 2
• This reduces gastrointestinal and hematological toxicity without compromising efficacy 2

Methotrexate Monitoring Requirements

Baseline investigations (mandatory): 2

• Complete blood count
• Serum transaminases (ALT/AST)
• Serum creatinine with creatinine clearance calculation
• Chest radiograph
• Hepatitis B and C serologies (recommended)
• Serum albumin (recommended)

Ongoing monitoring: 1, 5, 2

• ALT must be monitored monthly for the first 6 months, then every 6-8 weeks thereafter
• Complete blood count and creatinine every 4-12 weeks after initial 3-month period of monthly monitoring
• For ALT elevations 2-3× ULN: reduce dose to 10 mg/day and monitor closely 5
• For ALT elevations >3× ULN: discontinue methotrexate immediately and administer cholestyramine or activated charcoal for drug elimination 5

Leflunomide as Alternative First-Line Therapy

Leflunomide is conditionally recommended over other csDMARDs when methotrexate cannot be used, though methotrexate remains preferred due to greater dosing flexibility, lower cost, and proven value in combination regimens 1

Leflunomide Dosing Protocol

• Loading dose: 100 mg daily for 3 days only 5
• Maintenance dose: 20 mg daily thereafter 5
• Leflunomide demonstrates comparable clinical and radiographic efficacy to methotrexate in established and early RA 1, 5

Leflunomide Monitoring Requirements

Baseline and ongoing monitoring (same as methotrexate): 5

• ALT monitored monthly for first 6 months, then every 6-8 weeks
• Complete blood count and creatinine regularly
• For ALT elevations 2-3× ULN: reduce to 10 mg daily 5
• For ALT elevations >3× ULN: discontinue immediately and initiate drug elimination procedure with cholestyramine or activated charcoal 5

Critical Leflunomide Safety Considerations

• Leflunomide is absolutely contraindicated in pregnancy due to teratogenic risk 5
• Women of childbearing potential must use reliable contraception and have negative pregnancy test before initiation 5
• If pregnancy is desired or occurs, immediately discontinue and perform drug elimination procedure to achieve plasma M1 metabolite levels <0.02 mg/L 5
• Drug elimination procedure: cholestyramine 8 g three times daily for 11 days or activated charcoal 50 g four times daily for 11 days, with verification of plasma levels 5

Comparative Efficacy: Methotrexate vs Leflunomide

• Clinical efficacy is comparable between methotrexate and leflunomide in head-to-head trials 1, 5, 6
• Both demonstrate similar ACR20 response rates (approximately 50-65% at 12 months) 5
• Leflunomide shows equivalent radiographic protection to methotrexate in slowing structural damage 1
• Withdrawal rates due to adverse events are similar (approximately 20-23% for both drugs in first year) 5

Treatment Strategy and Disease Activity Monitoring

Target remission or low disease activity as the primary therapeutic endpoint 1, 3

Monitoring Schedule

• Assess disease activity every 1-3 months until remission is achieved 1, 3
• Use validated composite measures: DAS28, CDAI, or SDAI 3
• Include tender/swollen joint counts, patient and physician global assessments, ESR, and CRP 1

Treatment Adjustment Algorithm

• If no improvement by 3 months or target not reached by 6 months: adjust therapy 3
• For inadequate response to methotrexate monotherapy: add biologic DMARD (TNF inhibitor preferred) rather than switching to leflunomide 1, 3
• Combination of methotrexate plus TNF inhibitor provides superior efficacy compared to either monotherapy 1

Glucocorticoid Use: Minimize Duration

• Short-term glucocorticoids (<3 months) are conditionally recommended as bridge therapy when initiating DMARDs 1, 7
• Longer-term glucocorticoids (≥3 months) are strongly recommended against due to significant toxicity including increased cardiovascular mortality at doses >7.5 mg/day prednisone equivalent 1, 7
• If used, taper to lowest effective dose and discontinue as rapidly as clinically feasible 7, 3

Common Pitfalls to Avoid

• Do not start methotrexate at doses <10 mg weekly – this delays achieving therapeutic effect 2
• Do not omit folic acid supplementation – this increases toxicity unnecessarily 1, 2
• Do not delay dose escalation – if inadequate response, increase dose at 6-week intervals up to 20 mg weekly 2
• Do not continue either drug with persistent ALT >3× ULN – this risks severe hepatotoxicity 5
• Do not use leflunomide in women of childbearing potential without confirmed contraception and negative pregnancy test 5
• Do not combine methotrexate with leflunomide as initial therapy – evidence does not support routine combination of these two agents, and hepatotoxicity risk increases 5