Review Question - QID 103475

This patient is suffering from folic acid deficiency, macrocytic anemia secondary to her chronic methotrexate therapy. Folic acid supplementation with folinic acid is recommended to mitigate the risk of developing folic acid deficiency in patients on long-term, low-dose methotrexate therapy.

Methotrexate is a folic acid antagonist that inhibits dihydrofolate reductase (DHFR). This decreases the formation of FH4, a coenzyme necessary for the production of RNA, DNA, and proteins. Folic or folinic acid supplementation in patients undergoing methotrexate therapy bypasses the inhibited DHFR enzyme and replenishes the folate pool. Folic/folinic acid supplementation should not be utilized in patients receiving methotrexate therapy as a chemotherapeutic agent, as folic acid supplementation may limit the efficacy of methotrexate at inhibiting cell division.

Kaferle et al. reviews macrocytic anemia, focusing specifically on folate deficiency. Medications that may affect folate metabolism include methotrexate, 5-fluorouracil, hydroxyurea, pyrimethamine, trimethoprim/sulfamethoxazole, pentamidine, triamterene, phenytoin. Certain medications may affect absorption of folate in the GI tract, including metformin and cholestyramine.

Shea et al. conducted a Cochrane systematic review assessing the efficacy of folic acid supplementation at reducing the side effects of methotrexate therapy in patients with rheumatoid arthritis. The authors report a protective effect of folic or folinic acid supplementation in those patients with rheumatoid arthritis undergoing treatment with methotrexate. Supplementation led to decreased GI side effects, improved hepatic function, reduced stomatitis, and improved patient tolerance/adherence of the medication.

Figure A shows the hand findings of a patient with rheumatoid arthritis; note the ulnar deviation of the MCP joints as well as the swan-neck deformity in the fingers. Figure B shows a tongue with glossitis, a common manifestation in both folic acid and vitamin B12 deficiency macrocytic anemia. Figure C is a peripheral blood smear showing a hypersegmented neutrophil and macrocytes consistent with a macrocytic anemia.

Incorrect Answers:
Answer 1: Triamterene is a diuretic that may be used in the treatment of hypertension; however, triamterene itself may interfere with folate metabolism and thereby worsen this patient's folate deficiency.
Answers 2,3: Vitamin B12 supplementation would not be helpful in this patient with folate deficiency secondary to chronic methotrexate therapy.
Answer 5: Metformin may interfere with folate utilization; addition of this medication could worsen this patient's existing folic acid deficiency resulting from chronic methotrexate therapy.