How does methotrexate work and why is folic acid (Vitamin B9) supplementation necessary?

Methotrexate Mechanism and Folic Acid Supplementation

Methotrexate works as a folate antagonist that inhibits dihydrofolate reductase, interfering with purine and pyrimidine synthesis, and folic acid supplementation is necessary to reduce toxicity without compromising treatment efficacy. 1

Mechanism of Action of Methotrexate

• Methotrexate functions as a folic acid antagonist, which interferes with purine and pyrimidine synthesis, thus impairing nucleotide production 2
• At low doses used for inflammatory conditions, methotrexate primarily decreases proliferation of lymphoid cells through direct immunosuppressive effects rather than affecting epidermal cells 2
• Methotrexate competitively inhibits dihydrofolate reductase, decreasing folate cofactors required for nucleic acid synthesis 3
• Polyglutamate derivatives of methotrexate act as inhibitors of dihydrofolate reductase and thymidylate synthetase, which can remain in tissues for extended periods 3
• Methotrexate also increases endogenous adenosine, an anti-inflammatory molecule, through inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase 2

Necessity of Folic Acid Supplementation

• The American Academy of Dermatology strongly recommends folate supplementation for all patients taking methotrexate to reduce the incidence of adverse effects 2, 1
• Folic acid supplementation helps replenish folate stores depleted by methotrexate, reducing side effects while maintaining therapeutic efficacy 1
• Without folate supplementation, patients are at higher risk for developing:
  • Gastrointestinal toxicity (nausea, vomiting, stomatitis) 4
  • Bone marrow suppression (leucopenia) 5
  • Hepatotoxicity (elevated liver enzymes) 6
  • Fatigue and malaise 4

Dosing Recommendations for Folic Acid

• Standard recommendation is 1-5 mg of folic acid daily, except on the day(s) of methotrexate administration 1, 4
• Folic acid should be taken 6 days per week (avoiding the day of methotrexate) to prevent interference with methotrexate efficacy 1
• At minimum, at least 5 mg of folic acid per week is strongly recommended 1
• Folic acid is preferred over folinic acid (leucovorin) for routine supplementation due to lower cost and similar effectiveness 1, 6

Evidence for Folic Acid Benefits

• Systematic reviews have demonstrated that folic acid supplementation reduces hepatic side effects by approximately 35.8% in patients on methotrexate 6
• Daily use of folic acid does not appear to affect methotrexate efficacy, whereas folinic acid given close to methotrexate administration may reduce effectiveness 7
• Studies show folate supplementation reduces the discontinuation rate of methotrexate therapy due to side effects 8
• Folate supplementation has been shown to decrease methotrexate-induced hyperhomocysteinemia, which may have cardiovascular benefits 8

Common Pitfalls and Caveats

• Avoid administering folic acid on the same day as methotrexate to prevent potential interference with efficacy 1
• Do not confuse folic acid (for routine supplementation) with folinic acid/leucovorin (used primarily for methotrexate toxicity rescue) 7
• Regular monitoring of complete blood counts, liver function, and renal function remains essential even with folate supplementation 4
• Patients with renal insufficiency require dose adjustments of methotrexate, as impaired clearance increases toxicity risk 2, 3
• Nausea is one of the most common side effects of methotrexate (up to 25% of patients), and folic acid supplementation can help reduce this symptom 2

By understanding the mechanism of methotrexate and implementing appropriate folic acid supplementation, clinicians can significantly reduce toxicity while maintaining therapeutic efficacy in inflammatory conditions.