A 45-year-old man with rheumatoid arthritis has been on methotrexate 20 mg weekly for 8 months. He has achieved good clinical response (DAS28-CRP 3.2) and his inflammatory markers have normalized. However, he now presents with fatigue, mild dyspnea on exertion, and pallor. Laboratory findings show Hb 9.2 g/dL (normal 13.5–17.5), MCV 72 fL, serum ferritin 8 ng/mL, and iron studies consistent with iron deficiency. His renal function and liver function tests are normal. What is the most likely cause of his anemia, and what is the appropriate management?

Explanation

## Clinical Analysis **Key Point:** The anemia profile (low Hb, low MCV, low ferritin, normal renal/hepatic function) is consistent with iron deficiency, NOT methotrexate toxicity or anemia of chronic disease. ## Differential Diagnosis of Anemia in RA | Cause | MCV | Ferritin | B₁₂/Folate | RBC Morphology | Mechanism | | --- | --- | --- | --- | --- | --- | | **Iron deficiency** | Low | Low | Normal | Microcytic, hypochromic | GI blood loss (NSAIDs, RA inflammation) | | **Methotrexate toxicity** | Normal/High | Normal | Low | Macrocytic | Folate antagonism | | **Anemia of chronic disease** | Normal/Low | High/Normal | Normal | Normocytic | Hepcidin-mediated iron sequestration | | **B₁₂ deficiency** | High | Normal | Low B₁₂ | Macrocytic | Pernicious anemia (RA association) | ## Why Iron Deficiency in This Patient? 1. **Microcytic picture** (MCV 72 fL, low ferritin) is pathognomonic for iron deficiency 2. **Normal renal function** excludes erythropoietin deficiency 3. **Normal liver function** excludes methotrexate-induced hepatotoxicity 4. **Normalized inflammatory markers** argue against anemia of chronic disease (which improves with RA control) 5. **RA itself** increases GI blood loss risk via: - Chronic NSAID use (if patient was on NSAIDs pre-methotrexate) - Intestinal inflammation in RA - Potential occult GI bleeding **Clinical Pearl:** Iron deficiency anemia is common in RA patients due to chronic inflammation, NSAID use, and GI mucosal damage. It is NOT a contraindication to continuing methotrexate if the drug is otherwise effective and well-tolerated. ## Appropriate Management 1. **Iron supplementation:** Ferrous sulfate 325 mg daily (or ferrous fumarate 200 mg daily) with vitamin C to enhance absorption 2. **Investigate GI source:** Consider fecal occult blood test, upper/lower endoscopy if bleeding suspected 3. **Continue methotrexate:** Effective RA control reduces overall inflammatory burden and secondary anemia 4. **Monitor:** Repeat Hb, ferritin, iron studies at 6–8 weeks 5. **Optimize RA therapy:** Ensure NSAIDs are minimized; use gastroprotection if NSAIDs are necessary **Warning:** Do NOT reduce methotrexate dose or switch to a biologic solely because of iron deficiency anemia—this would compromise RA control unnecessarily. Iron deficiency is manageable with supplementation. [cite:Harrison 21e Ch 297; KD Tripathi 8e Ch 12]