Why do patients on methotrexate (disease-modifying antirheumatic drug) need folic acid?

Folic Acid Supplementation in Methotrexate Therapy

Patients on methotrexate require folic acid supplementation to reduce methotrexate-associated toxicity, particularly hepatotoxicity, gastrointestinal side effects, and myelosuppression, without compromising treatment efficacy. 1

Mechanism and Benefits of Folic Acid Supplementation

Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase, disrupting folate metabolism. This mechanism is responsible for both its therapeutic effects and adverse reactions. Folic acid supplementation:

• Reduces hepatotoxicity by 35.8% according to systematic reviews 2
• Decreases gastrointestinal side effects such as nausea, anorexia, and stomatitis 3
• Minimizes mucocutaneous reactions and fatigue 1
• Helps prevent myelosuppression, which is one of the most serious potential complications 3
• Allows patients to remain on methotrexate therapy longer (reduces discontinuation rates) 4

Recommended Dosing

• A minimum of 5 mg folic acid per week is strongly recommended 3, 1
• Higher doses (up to 5 mg daily) may be needed for patients on higher methotrexate doses or those experiencing side effects despite standard supplementation 1
• Folic acid should be taken on days when methotrexate is not administered to avoid potential interference with efficacy 1
• For patients with persistent side effects, increasing the folic acid dose should be considered before switching to alternative medications 1

Evidence Supporting Folic Acid Use

Multiple guidelines and studies support folic acid supplementation:

• The American College of Rheumatology and American Academy of Dermatology recommend folic acid to reduce methotrexate-associated side effects 1
• A meta-analysis showed that folic acid supplementation significantly reduces hepatotoxicity (OR 0.17; 95% CI 0.09 to 0.32) 3
• Randomized controlled trials demonstrate that folic acid supplementation reduces toxicity-related discontinuation of methotrexate from 38% to 17% 4
• Early studies showed that even 1 mg daily of folic acid significantly lowered toxicity scores without affecting treatment efficacy 5

Common Pitfalls to Avoid

1. Underdosing folic acid - Using less than 5 mg weekly may not provide adequate protection against methotrexate side effects 1
2. Administering folic acid on the same day as methotrexate - This may theoretically reduce methotrexate efficacy by competing for cellular uptake 1, 6
3. Discontinuing methotrexate due to side effects without optimizing folic acid dose - Increasing folic acid may resolve side effects and allow continued methotrexate therapy 1
4. Confusing folic acid with folinic acid (leucovorin) - Folic acid is more cost-effective and generally preferred for routine supplementation 1, 2

Monitoring

Despite folic acid supplementation, regular monitoring remains essential:

• Complete blood count (CBC)
• Liver function tests (ALT/AST)
• Renal function tests

These should be performed every 1-1.5 months when starting methotrexate or increasing the dose, and every 1-3 months thereafter 3.

Folic Acid vs. Folinic Acid

• Folic acid is preferred for routine supplementation due to lower cost and similar efficacy to folinic acid 2
• Folinic acid should be reserved for treating actual methotrexate toxicity rather than prevention 6
• When folinic acid is used at doses >5 mg/week, it may reduce methotrexate efficacy 3

By providing adequate folic acid supplementation, clinicians can significantly improve the safety profile of methotrexate therapy while maintaining its therapeutic benefits.