Methotrexate-Induced Folate Deficiency Anemia
This patient has methotrexate-induced folate deficiency anemia, which is the most likely diagnosis given the macrocytic anemia (MCV 108) and severe hemoglobin of 7 in the context of recent methotrexate initiation without adequate folate supplementation. 1
Diagnostic Reasoning
Macrocytic anemia with elevated MCV is the hallmark finding of folate deficiency from methotrexate, which precisely matches this patient's presentation. 1 The mechanism is straightforward: methotrexate inhibits dihydrofolate reductase, depleting folate stores needed for DNA synthesis and red blood cell production. 1
Several key features confirm this diagnosis:
- Early bone marrow toxicity from methotrexate manifests as increased mean corpuscular volume, which is consistent with this patient's MCV of 108. 1
- Four months of methotrexate use without folate supplementation is a critical risk factor for developing folate deficiency. 1
- The FDA label explicitly warns that methotrexate can suppress hematopoiesis and cause anemia, with bone marrow suppression occurring more frequently in elderly patients. 2
Anemia of chronic disease is excluded because it typically presents as normocytic or microcytic anemia, not macrocytic, making it incompatible with this patient's elevated MCV of 108. 1
Immediate Management
Discontinue methotrexate immediately until hematologic parameters normalize. 1 This is the critical first step, as continuing the medication will worsen bone marrow suppression.
The severity of anemia (hemoglobin 7) warrants urgent intervention:
- If the patient is symptomatic or hemodynamically unstable, consider blood transfusion for rapid correction. 2
- Initiate folinic acid (leucovorin) rescue therapy if there is concern for acute methotrexate toxicity, particularly if the patient has additional risk factors such as renal impairment or concurrent NSAID use. 3, 4
- Leucovorin at 10 mg/m² should be administered immediately, with subsequent doses every 6 hours if severe toxicity is suspected. 3
Prevention and Long-Term Management
When restarting methotrexate, mandatory folate supplementation with 1-5 mg daily is essential (except on the day of methotrexate dosing) to prevent recurrence. 3, 1 The Annals of the Rheumatic Diseases recommends at least 5 mg per week of folic acid supplementation to reduce gastrointestinal and liver toxicity without compromising methotrexate efficacy. 1
Monitoring recommendations include:
- CBC should be monitored every 3-4 months after the first 1-2 months of therapy. 1
- Withhold or decrease methotrexate dose if MCV exceeds 105 fL, as this indicates early folate depletion. 1
- More frequent monitoring is required in patients with risk factors including advanced age, renal impairment, or concurrent medications that interfere with methotrexate metabolism. 2
Critical Pitfalls to Avoid
Do not overlook vitamin B12 deficiency as a contributing factor. While folate deficiency is the primary diagnosis, vitamin B12 deficiency can coexist and exacerbate macrocytic anemia in rheumatoid arthritis patients. 5 Testing for vitamin B12 levels is warranted, especially if the anemia does not fully resolve with folate repletion alone.
Avoid restarting methotrexate without addressing the underlying cause. The patient clearly was not on adequate folate supplementation, which is a preventable risk factor. 1 Ensure compliance with daily folate supplementation before resuming therapy.
Be aware that pancytopenia can occur after even a single dose of methotrexate in patients with risk factors such as renal impairment, hypoalbuminemia, or concurrent use of drugs that interfere with methotrexate metabolism (particularly NSAIDs). 1, 2 The FDA label warns that unexpectedly severe bone marrow suppression has been reported with concomitant NSAID use. 2