What is the cause of the elevated Rheumatoid Factor (RF) and macrocytic anemia, as indicated by a high Mean Corpuscular Volume (MCV), in this patient?

Macrocytic Anemia with Elevated MCV in a Patient on Methotrexate

Direct Answer

The macrocytic anemia (MCV 107 fL, previously 100 fL) is most likely caused by methotrexate therapy, which inhibits folate metabolism and causes non-megaloblastic macrocytosis through impaired DNA synthesis. 1, 2 The rheumatoid factor of 13.1 IU/mL is within normal limits and does not indicate rheumatoid arthritis or other autoimmune disease. 3

Understanding the Macrocytosis

Methotrexate as the Primary Cause

• Methotrexate inhibits dihydrofolate reductase, blocking conversion to tetrahydrofolic acid and causing macrocytosis through impaired DNA synthesis rather than true vitamin deficiency. 1
• The progressive increase in MCV from 100 to 107 fL over 4 months is consistent with methotrexate-induced macrocytosis, which occurs in 21.6% of RA patients on this medication. 4
• This drug-induced macrocytosis is non-megaloblastic, meaning the peripheral smear will not show macro-ovalocytes or hypersegmented neutrophils that characterize B12/folate deficiency. 1

Why Other Causes Are Less Likely

Vitamin B12 deficiency is excluded because:

• The B12 level is 330 pg/mL (normal range 232-1245), which is adequate. 1
• There is no history of ileal resection >30 cm or active inflammatory bowel disease with ileal involvement that would impair B12 absorption. 1
• The MCV of 107 fL is relatively modest; B12 deficiency typically produces MCV >114 fL and can exceed 130 fL. 5

Folate deficiency is excluded because:

• Serum folate is 8.5 (normal), making this diagnosis unlikely. 1
• The patient has no documented alcoholism or malnutrition. 1

Hemolysis is excluded because:

• The reticulocyte count would be elevated in hemolysis, but this patient's stable hemoglobin (14.3 g/dL) and lack of anemia argue against active hemolysis. 1, 6
• Haptoglobin and LDH were not reported as abnormal. 6

Hypothyroidism is excluded because TSH is normal at 1.230 uIU/mL. 1

Liver disease is excluded because the comprehensive metabolic panel is normal. 1

Rheumatoid Factor Interpretation

The RF of 13.1 IU/mL is normal and does not indicate rheumatoid arthritis. 3

• In systemic juvenile idiopathic arthritis and adult-onset Still's disease, RF positivity occurs in only 4% of patients. 3
• The patient's joint symptoms (right ring finger swelling, left hand distal phalanx swelling) with achy pain could represent osteoarthritis or other non-inflammatory arthropathy given the normal RF and lack of systemic inflammatory features. 3

Critical Diagnostic Pitfall to Avoid

Do not give folic acid supplementation before definitively excluding B12 deficiency, even though B12 appears normal, because folate can mask B12 depletion and precipitate subacute combined degeneration of the spinal cord. 1

However, in this case:

• B12 is documented as normal (330 pg/mL). 1
• The macrocytosis is clearly drug-induced from methotrexate. 1, 2
• Folate supplementation may actually be beneficial in patients on methotrexate to reduce toxicity, as noted in FDA labeling that "certain toxicities may be reduced by folate supplementation" in chronic use. 2

Concurrent Iron Deficiency Consideration

Check iron studies carefully despite the macrocytosis:

• The patient's ferritin is 62 ng/mL with iron saturation of 24%, which is borderline. 1
• In inflammatory conditions, ferritin <100 μg/L may still indicate iron deficiency. 1
• The MCH of 32.6 pg (upper limit of normal 33.0) is more sensitive than MCV for detecting concurrent iron deficiency when macrocytosis is present. 1
• The MCHC is low at 30.6 g/dL (normal 31.5-35.7), which suggests possible concurrent iron deficiency masked by the macrocytosis. 1
• Concurrent iron deficiency with macrocytosis produces falsely normal MCV as microcytosis and macrocytosis cancel out, but elevated RDW (15.2, upper limit 15.4) suggests a mixed picture. 1

Management Recommendations

Continue methotrexate but monitor closely:

• The macrocytosis itself is not an indication to stop methotrexate unless accompanied by significant anemia or other toxicity. 2
• Liver function tests should be performed every 1-2 months, and complete blood count monthly. 2
• Consider low-dose folate supplementation (1 mg daily) to reduce methotrexate toxicity without compromising efficacy. 2

Address the possible concurrent iron deficiency:

• Given the low MCHC, borderline ferritin, and elevated RDW, consider a trial of iron supplementation. 1
• Recheck CBC in 4-6 weeks to assess response. 1

Monitor for methotrexate toxicity:

• Watch for persistent liver function test abnormalities, which may precede fibrosis. 2
• Monitor for bone marrow suppression (leukopenia, thrombocytopenia), which increases with age. 2
• The patient should be informed that weekly dosing is critical and daily use has led to fatal toxicity. 2