What is the most likely diagnosis for a patient with rheumatoid arthritis (RA) and macrocytic anemia, who recently restarted methotrexate (MTX) therapy, presenting with severe anemia, fatigue, and shortness of breath?

Methotrexate-Induced Megaloblastic Anemia

The most likely diagnosis is methotrexate-induced folate deficiency causing megaloblastic anemia. The combination of macrocytic anemia (MCV 108) with severe anemia (hemoglobin 7 g/dL) in a patient who restarted methotrexate four months ago, presenting with progressive fatigue and shortness of breath, is classic for methotrexate-induced folate deficiency 1, 2, 3.

Why Methotrexate-Induced Folate Deficiency is Most Likely

Methotrexate directly causes folate deficiency by inhibiting dihydrofolate reductase, leading to megaloblastic anemia with elevated MCV and normal or low reticulocytes 2, 3. The timeline is consistent—symptoms developed three months after restarting methotrexate, which aligns with the typical onset of folate-depleted erythropoiesis 3.

Key Distinguishing Features:

• Macrocytic anemia (MCV 108) with severe anemia (Hb 7) strongly suggests megaloblastic process, not anemia of chronic disease which typically presents as normocytic or microcytic 2
• The temporal relationship is critical: symptoms began 1 month after methotrexate restart and progressed over 3 months, consistent with methotrexate-induced folate depletion 3
• Methotrexate can cause isolated erythrocytic bone marrow suppression, presenting as severe megaloblastic anemia even with normal white blood cell and platelet counts initially 3

Why Other Diagnoses Are Less Likely

Iron Deficiency:

• Iron deficiency causes microcytic anemia (low MCV), not macrocytic 2
• The MCV of 108 essentially rules out iron deficiency as the primary cause

B12 Deficiency:

• While B12 deficiency causes macrocytic anemia, it would not explain the temporal relationship with methotrexate restart 4, 5
• B12 deficiency typically develops over years, not months 5
• However, concurrent B12 deficiency can potentiate methotrexate toxicity and should be evaluated 4

Anemia of Chronic Disease:

• Anemia of chronic disease from rheumatoid arthritis typically presents with normocytic or microcytic anemia (not macrocytic), serum ferritin >100 μg/L, and transferrin saturation <20% 2
• The macrocytic picture (MCV 108) makes this diagnosis unlikely as the primary cause

Hypothyroidism:

• While hypothyroidism can cause mild macrocytic anemia, it would not explain the severity (Hb 7) or the temporal relationship with methotrexate 5
• Hypothyroidism-related anemia is typically mild and develops gradually

Critical Risk Factors Present

This patient likely has multiple risk factors that contributed to severe methotrexate toxicity 1, 2:

• Age 50 years (advanced age increases toxicity risk) 1, 6
• Likely lack of folate supplementation (most common preventable risk factor) 7, 1, 2
• Possible renal impairment (should be evaluated, as it dramatically increases toxicity) 1, 8
• Potential drug interactions (NSAIDs commonly used in RA reduce methotrexate clearance) 1, 8

Immediate Management Required

Discontinue methotrexate immediately and check complete blood count with differential to assess for pancytopenia 1, 8, 2. The presence of severe anemia warrants urgent evaluation for bone marrow suppression.

Specific Actions:

• Administer leucovorin (folinic acid) rescue therapy if severe bone marrow suppression is confirmed, with initial dose up to 100 mg/m² every 6 hours until hematological abnormalities normalize 8, 2
• Check serum methotrexate level to assess for delayed excretion, particularly if multiple risk factors are present 9
• Evaluate for concurrent B12 deficiency in any rheumatoid arthritis patient with macrocytic anemia, as this can potentiate methotrexate toxicity 4
• Assess renal function with creatinine clearance (not just serum creatinine, which overestimates function in elderly patients) 6
• Review all medications for interactions, particularly NSAIDs, trimethoprim-sulfamethoxazole, and other drugs that interfere with methotrexate clearance 1, 8

Prevention for Future Methotrexate Use

All patients on methotrexate must receive folate supplementation (1 mg daily or 5 mg weekly, except on the day of methotrexate administration) to prevent gastrointestinal, liver, and hematologic toxicity 7, 1, 2. This patient's severe anemia likely could have been prevented with appropriate folate supplementation.

Regular monitoring with complete blood counts every 3-4 months is essential to detect early signs of folate deficiency and impending toxicity 7, 2. An increase in MCV may be a useful early indicator of folate deficiency before severe anemia develops 3.