A 42-year-old woman with a 10-year history of rheumatoid arthritis on long-term methotrexate therapy presents with macrocytic anemia and hypersegmented neutrophils. Serum B12 and folate levels are both low. Which is the most common cause of megaloblastic anemia in this patient?

Question

Accepted Answer

A. Methotrexate-induced folate deficiency. ## Methotrexate-Induced Megaloblastic Anemia

**Key Point:** In patients on long-term methotrexate therapy, methotrexate-induced folate deficiency is the most common cause of megaloblastic anemia. Methotrexate inhibits dihydrofolate reductase, blocking the conversion of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis.

**High-Yield:** Methotrexate is a folate antagonist used in:
- Rheumatoid arthritis (RA)
- Psoriasis
- Inflammatory bowel disease
- Hematologic malignancies
- Autoimmune conditions

Megaloblastic anemia is a well-recognized toxicity of long-term methotrexate use.

## Mechanism of Methotrexate-Induced Megaloblastic Anemia

```mermaid
flowchart TD
  A[Methotrexate administered] --> B[Inhibits dihydrofolate reductase]
  B --> C[Blocks conversion of dihydrofolate to tetrahydrofolate]
  C --> D[Decreased one-carbon transfer reactions]
  D --> E[Impaired dTMP and purine synthesis]
  E --> F[Defective DNA synthesis]
  F --> G[Megaloblastic anemia]
  G --> H[Hypersegmented neutrophils]
```

## Comparison: Methotrexate vs. Other Causes in This Context

| Cause | Mechanism | Clinical Context | Reversibility |
|-------|-----------|-----------------|----------------|
| **Methotrexate-induced folate deficiency** | Inhibits dihydrofolate reductase | Long-term MTX therapy (RA, psoriasis) | **Reversible with folinic acid (leucovorin)** |
| Pernicious anemia | Autoimmune gastritis; anti-IF antibodies | Autoimmune disease (can coexist with RA) | Irreversible; requires B12 supplementation |
| Dietary folate deficiency | Inadequate intake | Malnutrition, alcoholism | Reversible with dietary supplementation |
| Nitrous oxide inhalation | Inactivates B12 cofactor | Substance abuse | Reversible if caught early |

**Clinical Pearl:** Methotrexate-induced megaloblastic anemia is **preventable and reversible** with folinic acid (leucovorin) supplementation. Patients on long-term methotrexate should receive concurrent folinic acid to prevent folate deficiency.

**Mnemonic: MTX TOXICITY** — Methotrexate → Teratogenic, Oral ulcers, Xerostomia, Immunosuppression, Cirrhosis, Infection, Thrombocytopenia, Yeast overgrowth (plus megaloblastic anemia)

## Why Methotrexate Is the Most Common Cause in This Patient

1. **Clear temporal relationship:** Patient has been on methotrexate for 10 years
2. **Mechanism is direct:** Methotrexate directly inhibits folate metabolism
3. **Both B12 and folate are low:** This pattern is consistent with methotrexate-induced folate deficiency (B12 may be secondarily low due to impaired absorption from intestinal damage)
4. **Reversibility:** Folinic acid supplementation will correct the anemia, confirming methotrexate as the cause

**Warning:** Do not confuse methotrexate-induced folate deficiency with pernicious anemia. While both can coexist in RA patients (RA is an autoimmune disease), the primary cause here is methotrexate toxicity given the 10-year history of therapy.

Answer

B. Concurrent pernicious anemia

Answer

C. Dietary folate insufficiency

Answer

D. Nitrous oxide inhalation

A 42-year-old woman with a 10-year history of rheumatoid arthritis on long-term methotrexate therapy presents with macrocytic anemia and hypersegmented neutrophils. Serum B12 and folate levels are both low. Which is the most common cause of megaloblastic anemia in this patient?

Explanation

Methotrexate-Induced Megaloblastic Anemia

Mechanism of Methotrexate-Induced Megaloblastic Anemia

Comparison: Methotrexate vs. Other Causes in This Context

Why Methotrexate Is the Most Common Cause in This Patient

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Cause	Mechanism	Clinical Context	Reversibility
Methotrexate-induced folate deficiency	Inhibits dihydrofolate reductase	Long-term MTX therapy (RA, psoriasis)	Reversible with folinic acid (leucovorin)
Pernicious anemia	Autoimmune gastritis; anti-IF antibodies	Autoimmune disease (can coexist with RA)	Irreversible; requires B12 supplementation
Dietary folate deficiency	Inadequate intake	Malnutrition, alcoholism	Reversible with dietary supplementation
Nitrous oxide inhalation	Inactivates B12 cofactor	Substance abuse	Reversible if caught early