What are the guidelines for using methotrexate (disease-modifying antirheumatic drug) in treating conditions like rheumatoid arthritis?

Methotrexate Guidelines for Rheumatoid Arthritis

Start oral methotrexate at 10-15 mg weekly, escalate by 5 mg every 2-4 weeks to 20-30 mg weekly based on response, and always prescribe at least 5 mg folic acid weekly to reduce toxicity. 1

Pre-Treatment Work-Up

Before initiating methotrexate, obtain the following baseline assessments 1:

• Clinical assessment: Evaluate alcohol intake, risk factors for toxicity, and provide patient education about weekly (not daily) dosing
• Laboratory tests: AST, ALT, albumin, complete blood count (CBC), creatinine
• Imaging: Chest X-ray (within previous year)
• Consider: Hepatitis B/C serology, HIV serology, fasting glucose, lipid profile, pregnancy test

Dosing and Administration

Initial Dosing Strategy

Oral route is preferred initially 1:

• Start at 10-15 mg weekly 1
• Escalate by 5 mg every 2-4 weeks 1
• Target dose: 20-30 mg weekly depending on clinical response and tolerability 1
• Titrate to at least 15 mg within 4-6 weeks 1

Route Optimization

Switch to parenteral (subcutaneous) administration if 1:

• Inadequate clinical response at highest tolerable oral dose
• Gastrointestinal intolerance to oral formulation
• Patient not at treatment target despite oral therapy

Parenteral methotrexate demonstrates greater bioavailability and may provide superior efficacy with less gastrointestinal toxicity 1.

Mandatory Folic Acid Supplementation

Prescribe at least 5 mg folic acid weekly with all methotrexate therapy 1:

• Reduces gastrointestinal side effects (OR 0.42) 1
• Reduces hepatotoxicity (OR 0.17 with 1 mg daily) 1
• Does not reduce methotrexate efficacy 1
• Higher doses may be needed with higher methotrexate doses 1

Monitoring Protocol

Frequency of Laboratory Monitoring 1

During dose escalation or initiation:

• ALT ± AST, creatinine, CBC every 1-1.5 months until stable dose reached

After stable dose achieved:

• ALT ± AST, creatinine, CBC every 1-3 months
• Clinical assessment for side effects and risk factors at each visit

Managing Elevated Liver Enzymes 1

If ALT/AST >3× upper limit of normal (ULN):

• Stop methotrexate immediately
• Confirm elevation with repeat testing
• May reinstitute at lower dose after normalization

If ALT/AST persistently elevated 1-3× ULN:

• Adjust methotrexate dose downward
• Continue monitoring

If ALT/AST persistently >3× ULN after discontinuation:

• Pursue diagnostic procedures to identify alternative causes 1
• Consider obesity, alcohol, NSAIDs, other medications 1

Treatment Strategy

DMARD-Naive Patients with Moderate-to-High Disease Activity

Methotrexate monotherapy is preferred over combination therapy with conventional DMARDs 1:

• Superior efficacy/toxicity balance favors monotherapy initially
• Methotrexate serves as anchor drug for combination therapy if monotherapy fails to achieve disease control
• Combination with biologics or targeted synthetic DMARDs reserved for inadequate response to methotrexate optimization

DMARD-Naive Patients with Low Disease Activity 1

Consider alternative agents in this population:

• Hydroxychloroquine preferred (better tolerated, favorable risk profile)
• Sulfasalazine over methotrexate (less immunosuppressive)
• Methotrexate still appropriate for higher end of low disease activity range or poor prognostic factors

Long-Term Safety

Methotrexate is appropriate for long-term use based on acceptable safety profile 1:

• Reduced cardiovascular mortality (HR 0.3) compared to no methotrexate 1
• Lower overall mortality in RA patients on methotrexate 1
• Most common toxicity is gastrointestinal; serious hepatic fibrosis/cirrhosis is rare (0.5%) 1

Special Situations

Perioperative Management

Continue methotrexate through elective orthopedic surgery 1:

• No increased postoperative complications
• Reduces risk of RA flares perioperatively
• Exception: Consider interruption for major surgeries with comorbidities 2

Infections Requiring Antibiotics

Interrupt methotrexate during active infection requiring antibiotics 2:

• Resume after recovery and completion of antibiotic treatment
• Monitor for inflammatory flare during interruption
• May temporarily add NSAIDs to control symptoms during interruption

Pregnancy and Contraception

Methotrexate is absolutely contraindicated in pregnancy (Category X) 1, 3:

• Discontinue at least 3 months before planned pregnancy for both men and women 1
• Do not use during pregnancy or breastfeeding 1, 3
• Causes embryotoxicity, abortion, fetal defects, and impaired fertility 3

Critical Drug Interactions

NSAIDs and Salicylates 3

Exercise caution with concomitant NSAID use:

• Do NOT use NSAIDs with high-dose methotrexate (e.g., osteosarcoma treatment) 3
• Low-dose methotrexate (7.5-15 mg weekly) for RA typically combined safely with NSAIDs in clinical practice 1, 3, 4
• NSAIDs may reduce tubular secretion of methotrexate and enhance toxicity 3
• Risk increases with renal impairment 5

High-Risk Combinations to Avoid 3

Trimethoprim/sulfamethoxazole: Increased bone marrow suppression risk (additive antifolate effect) 3

Probenecid: Reduces renal tubular transport of methotrexate 3

Nitrous oxide anesthesia: Potentiates antifolate effects; avoid concomitant use 3

Toxicity Management

Common Adverse Effects 6, 7

Gastrointestinal toxicity (most common):

• Nausea, vomiting, diarrhea, stomatitis
• Manage with split dosing over 24 hours, switch to subcutaneous route, or increase folic acid dose 1

If oral methotrexate not tolerated 1:

1. Try split dose over 24 hours OR
2. Switch to weekly subcutaneous injections OR
3. Increase folic/folinic acid dose
4. Only switch to alternative DMARD if above strategies fail

Serious Toxicities

Bone marrow suppression 2, 3:

• Interrupt if WBC <3.5×10⁹/L or neutrophils <2×10⁹/L 2
• Profound granulocytopenia with fever requires immediate evaluation and broad-spectrum antibiotics 3

Pulmonary toxicity: Consider in patients with new respiratory symptoms; pulmonary function tests useful if baseline available 3

Elderly Patients

Use lower doses and monitor closely in older adults 3, 5:

• Declining renal function increases toxicity risk
• Decreased folate stores
• More frequent bone marrow suppression, thrombocytopenia, pneumonitis 3
• Measure creatinine clearance (serum creatinine overestimates renal function in elderly) 3
• Consider therapeutic drug monitoring 5

Other Rheumatic Conditions

Methotrexate recommended as steroid-sparing agent in 1:

• Giant cell arteritis (higher prednisone discontinuation rate, HR 2.84)
• Polymyalgia rheumatica (fewer relapses, lower cumulative steroid dose)

Can be considered in:

• Systemic lupus erythematosus
• Juvenile dermatomyositis