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Case Study: Neutropenia in a Patient with Rheumatoid Arthritis

A 53-year-old man presents to your office for a routine assessment. He has a history of rheumatoid arthritis (RA), which was previously treated with prednisone and azathioprine. He also has hyperlipidemia and hypertension treated with simvastatin and lisinopril, respectively. Physical examination is normal with no lymphadenopathy or splenomegaly. He previously had mild anemia of chronic inflammation but no abnormalities of his white blood cell or platelet counts. A complete blood count with differential shows the following:

Hemoglobin 11.2 g/dL (13.0-16.0 g/dL)
WBC 4,200/µL (4,000-11,000/µL)
Platelet count 104,000/µL (150,000-400,000/µL)
Absolute neutrophil count 560/µL (>1,800/µL)


The interpretation of the peripheral blood film is as follows: “Normal morphology of all cells, but decrease in absolute neutrophil count. Excess of lymphocytes with azurophilic granules.”

What is the most likely etiology of the patient’s neutropenia?

  1. Large granular lymphocyte leukemia
  2. Progression of rheumatoid arthritis
  3. Previous use of azathioprine
  4. Hypersensitivity reaction to simvastatin
  5. Felty’s syndrome


The most likely etiology is large granular lymphocyte (LGL) leukemia, a clonal disorder of CD3+ cytotoxic T cells or CD3-natural killer (NK) cells. Clinical features include anemia, neutropenia and rheumatoid arthritis (RA). Lymphocytes containing azurophilic granules are seen on the peripheral blood film. Diagnosis is confirmed with flow cytometry demonstrating a mature post-thymic phenotype (T-LGL: CD3+CD8+CD57+ vs. NK-LGL: CD3-CD56+). Clonality is demonstrated using TCRγ-polymerase chain reaction for evidence of TCR-γ gene rearrangement. Somatic mutations of signal transducer and activator of transcription 3 gene (STAT3) have been reported in 40 percent of patients with LGL.

RA alone does not typically lead to neutropenia. While azathioprine can cause cytopenias, the patient is not currently taking the drug. Hypersensitivity reactions do not typically lead to neutropenia. Felty’s syndrome is characterized by the classic triad of RA, splenomegaly, and neutropenia; this patient does not have splenomegaly.


  1. How I treat LGL leukemia. Blood. 2011;117:2764-2774.
  2. Zhang D, Loughran TP Jr. Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and treatment. Hematology Am Soc Hematol Educ Program. 2012;2012:652-659.
  3. Koskela HL, Eldfors S, Ellonen P, et al. Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med. 2012;366:1905-1913.

Case study submitted by Mary-Beth Percival, MD, Stanford University, Stanford, CA.