MKSAP Quiz: 3-year history of severe rheumatoid arthritis
A 67-year-old woman is evaluated for a 3-year history of severe rheumatoid arthritis. After some changes in therapy, she has done well with tocilizumab and methotrexate over the past year. She notes several months of prominent fatigue. Lab studies demonstrate anemia. What is its most likely cause?
A 67-year-old woman is evaluated for a 3-year history of severe rheumatoid arthritis. She had an inadequate response to methotrexate and low-dose prednisone. She responded well to the addition of infliximab, but eventually the drug lost effect and she required a change in biologic therapy. She has done well with tocilizumab and methotrexate over the past year. She notes several months of prominent fatigue. History is also significant for type 2 diabetes mellitus, hypertension, and hyperlipidemia. Current medications are methotrexate, folic acid, tocilizumab, basal insulin, lisinopril, metoprolol, atorvastatin, ibuprofen, and omeprazole.
On physical examination, vital signs are normal. Joint examination reveals no swollen or tender joints. The remainder of the physical examination is normal.
Laboratory studies:
| Hemoglobin | 9.3 g/dL (93 g/L) |
| Leukocyte count | 5600/µL (5.6 × 109/L) |
| Mean corpuscular volume | 111 fL |
| Platelet count | 330,000/µL (330 × 109/L) |
Which of the following is the most likely cause of the anemia?
A. Inflammation
B. Iron deficiency
C. Methotrexate
D. Tocilizumab
MKSAP Answer and Critique
The correct answer is C. Methotrexate. This content is available to MKSAP 18 subscribers as Question 43 in the Rheumatology section. More information about MKSAP is available online.
The most likely diagnosis is methotrexate-induced anemia. Methotrexate can cause stomatitis, hepatic inflammation and fibrosis, and myelotoxicity, including megaloblastic anemia and pancytopenia. Folic acid supplementation is mandatory in all patients receiving methotrexate and can prevent the development of stomatitis and hepatotoxicity (as measured by elevated aminotransferase levels). Hematologic toxicity, however, can occur even with folic acid supplementation. In this patient, a rise in mean corpuscular volume (MCV) indicates a likely megaloblastic anemia, and methotrexate is the likely cause. Guidelines from the American College of Rheumatology recommend periodic monitoring of the complete blood count every 4 weeks during the first 3 months of therapy, every 8 to 12 weeks from 3 to 6 months, and every 8 to 12 weeks thereafter.
Inflammatory anemia (anemia of chronic disease) is a common manifestation of rheumatoid arthritis and is usually a mild, normocytic anemia. Most patients experience symptoms related to their underlying disease rather than the anemia. Inflammatory anemia would not present with this degree of anemia or macrocytosis.
Typical features of iron deficiency are identical to those of any symptomatic anemia but may be subtle owing to an insidious onset of the condition. Headache and pica (craving for typically undesirable items such as ice, dirt, clay, paper, and laundry starch) are frequently associated symptoms; other less common symptoms include restless legs syndrome and hair loss. The hallmark of iron deficiency is a microcytic hypochromic anemia. However, this is usually only seen in advanced iron deficiency, and anemia tends to precede morphologic changes in the cells. The presence of macrocytosis makes iron deficiency unlikely.
Tocilizumab is not associated with a macrocytic anemia. Through its anti-inflammatory properties, it may decrease the likelihood of inflammatory-induced anemia in patients with rheumatoid arthritis.
Key Point
- Methotrexate use can result in a megaloblastic anemia or pancytopenia; periodic monitoring of the complete blood count is recommended.