Why Methotrexate and Folic Acid Are Given Alternately in Rheumatoid Arthritis
Folic acid should be given on all days except the day(s) when methotrexate is administered because folic acid may theoretically compete with methotrexate for cellular uptake when both are present simultaneously, potentially reducing methotrexate's therapeutic efficacy. 1
Mechanistic Rationale
The alternating schedule is based on a specific pharmacological concern:
Methotrexate functions as a folic acid antagonist, inhibiting folate-dependent enzymes (particularly dihydrofolate reductase) that are essential for purine and pyrimidine synthesis, which is the basis of its anti-inflammatory effect in RA 2, 3
When folic acid and methotrexate are given simultaneously, folic acid may compete for the same cellular uptake mechanisms, potentially preventing methotrexate from entering cells and exerting its therapeutic action 1
By giving folic acid on non-methotrexate days, you allow methotrexate to work unimpeded on its designated day while still replenishing folate stores throughout the rest of the week to prevent toxicity 1
Evidence-Based Dosing Schedule
The specific timing recommendation is clear:
Prescribe folic acid 1-5 mg daily (or at least 5 mg per week total), instructing patients to skip the dose on the day they take methotrexate 2, 1
For patients on split-dose methotrexate regimens, also skip folic acid the day after methotrexate administration 1
A pragmatic approach is 5 mg of oral folic acid given on the morning following the day of methotrexate administration 4
Critical Evidence Supporting This Practice
The alternating schedule achieves two essential goals simultaneously:
Folic acid supplementation reduces methotrexate toxicity by 79% for gastrointestinal side effects (OR 0.21) and 77% for hepatotoxicity (OR 0.23) without compromising therapeutic efficacy 2, 5, 6
Studies demonstrate that folic acid at doses ≤5 mg/week does not reduce methotrexate efficacy in RA when dosed appropriately (i.e., on separate days) 1, 5, 3
Meta-analysis of 788 RA patients confirmed that proper folic acid supplementation reduces gastrointestinal side effects (OR 0.42), hepatotoxicity (OR 0.17), and drug discontinuation (OR 0.39) without affecting disease activity parameters like tender/swollen joint counts 2
Important Clinical Caveats
Common pitfall to avoid: Do not confuse this routine supplementation schedule with leucovorin (folinic acid) rescue therapy. Leucovorin is the antidote for methotrexate overdose or severe toxicity and should be administered immediately in those situations, regardless of timing concerns 1
Key distinction: While the theoretical concern about competition exists, the clinical evidence shows that when folic acid is given on non-methotrexate days at appropriate doses (≤5 mg/week), there is no measurable reduction in methotrexate's efficacy for treating RA 5, 4, 6
Warning about higher doses: Folinic acid at doses >5 mg/week was associated with increased tender and swollen joints (OR 6.27 and 5.3 respectively), suggesting potential interference with efficacy at higher doses, which reinforces the importance of both appropriate dosing and timing 2
Practical Implementation
Start folic acid supplementation at the initiation of methotrexate therapy—do not wait for side effects to develop 7, 4
Use folic acid (not folinic acid) for routine supplementation due to lower cost and similar effectiveness 2, 1
For patients on methotrexate >15 mg/week, consider increasing to 7-10 mg folic acid weekly, still avoiding methotrexate days 2, 1
Continue regular monitoring (liver function tests, CBC, creatinine) every 1-3 months even with folic acid supplementation, as folate does not eliminate all toxicity risk 2, 1