A 65-year-old man on methotrexate for rheumatoid arthritis develops macrocytic anemia with megaloblastic changes on bone marrow. B12 and folate levels are low-normal. Which is the drug of choice to prevent and treat methotrexate-induced megaloblastic anemia?

Question

Accepted Answer

B. Folinic acid (leucovorin) 5 mg orally daily on non-methotrexate days. ## Diagnosis: Methotrexate-Induced Megaloblastic Anemia

Methotrexate (MTX) inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate (THF). This causes functional folate deficiency and megaloblastic anemia, even when serum folate is low-normal.

## First-Line Prevention & Treatment: Folinic Acid (Leucovorin)

**Key Point:** Folinic acid (5-formyl-THF, leucovorin) is the drug of choice for MTX-induced megaloblastic anemia because it **bypasses the DHFR block** and directly replenishes the THF pool.

**High-Yield:** Standard dosing:
- **5 mg orally once daily** on non-MTX days (e.g., if MTX given weekly, give folinic acid on days 2–7)
- Alternative: 5 mg twice weekly on non-MTX days
- This prevents and treats MTX-induced folate deficiency

## Why Folinic Acid (Not Folic Acid) in MTX Therapy?

| Feature | Folic Acid | Folinic Acid (Leucovorin) |
|---------|---|---|
| **Requires DHFR?** | Yes | No |
| **Effective in MTX therapy?** | No (DHFR blocked) | Yes (bypasses block) |
| **First-line for MTX prevention** | No | Yes |
| **Cost** | Lower | Higher |
| **Onset of action** | Slow | Rapid |

**Clinical Pearl:** Folic acid is ineffective in MTX-induced deficiency because MTX blocks its conversion to THF. Folinic acid works because it is already in the active form (5-formyl-THF) and does not require DHFR.

**Mnemonic:** **FOLINIC = Folinic for MTX** — Folinic acid is the rescue agent for methotrexate toxicity because it bypasses the DHFR block.

Answer

A. Folic acid 1 mg orally daily

Answer

C. Methylfolate 5 mg orally daily

Answer

D. Cyanocobalamin 1000 mcg intramuscularly monthly

A 65-year-old man on methotrexate for rheumatoid arthritis develops macrocytic anemia with megaloblastic changes on bone marrow. B12 and folate levels are low-normal. Which is the drug of choice to prevent and treat methotrexate-induced megaloblastic anemia?

Explanation

Diagnosis: Methotrexate-Induced Megaloblastic Anemia

First-Line Prevention & Treatment: Folinic Acid (Leucovorin)

Why Folinic Acid (Not Folic Acid) in MTX Therapy?

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Feature	Folic Acid	Folinic Acid (Leucovorin)
Requires DHFR?	Yes	No
Effective in MTX therapy?	No (DHFR blocked)	Yes (bypasses block)
First-line for MTX prevention	No	Yes
Cost	Lower	Higher
Onset of action	Slow	Rapid