Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus

Abstract

Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Felty's syndrome and systemic lupus erythematosus. Felty's syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patient's clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Felty's syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony-stimulating factor dose and frequency should be adjusted at the lowest effective dose.

Introduction

Autoimmune neutropenia (AIN), the presence of autoantibodies produced by the patient's own immune system against antigens which are present on the surface of neutrophils, has been seen in different clinical conditions including febrile and severe pulmonary transfusion reactions, drug-induced neutropenia, refractoriness to granulocyte transfusions, and immune neutropenia after hematopoietic stem cell transplantation. However, autoimmune neutropenia is mostly associated with Felty's syndrome (FS), systemic lupus erythematosus (SLE), and large granular lymphocytes (LGL) leukemia. This potentially fatal clinical condition can be divided into primary and secondary forms. Primary AIN is an uncommon condition in the adult population, but secondary AIN is probably as common as autoimmune disorders of red blood cells and platelets. However, symptoms of secondary AIN are less overt and in contrast to hemoglobin in hemolytic anemia there are no reliable markers for in vivo neutrophil lysis, and often is not diagnosed. AIN is usually associated with autoimmune disorders, hematological and non-hematological malignancies and drug exposure (Table 1) [1].

The number of neutrophils in the circulation is determined by the rate of their production and destruction. Neutrophils have a very high turn-over rate (10⁹ cells/day), and under normal conditions bone marrow is the exclusive site for their production. Neutrophils have a very short life span. Normally, the majority of neutrophils are in the bone marrow storage pool where they spend 6–7 days, and then they are released into the blood circulation where their half-life is 6 to 7 h. Circulating neutrophils comprise less than 5% of the total body neutrophils mass. After bone marrow the bulk of mature neutrophils are located in the tissues where their half-life may extend to 24–48 h and they offer local defense. In addition to neutrophils in circulation and tissues, there is a large marginated pool which allows for rapid recruitment. Chronic neutropenia is defined by an absolute neutrophil count (ANC) below 1500 cells/μL of blood lasting for at least 6 months. Neutrophil counts can be lower in certain ethnic and racial groups such as Africans, African-Americans, and Yemenite Jews. Neutropenia is classified based on the ANC as mild (1000–1500/μL), moderate (500–1000/μL) and severe (< 500/μL). Neutropenia is associated with an increased risk of infection, particularly if ANC falls below 500/μL. Bacterial infections, particularly intermittent stomatitis and gingivitis, perirectal abscess and cellulitis are more common than pneumonia and septicemia. Fungal infections are unusual, but oral candidiasis is common; and there is usually no increased risk for viral or parasitic infections. Chronic fatigue is a frequent symptom among patients.

Early reports on autoimmune neutropenia were published in 1950s when it was demonstrated that infusion of plasma from neutropenic patients into normal recipients caused leucopenia [2]. It was not until 1960, that Lalezari et al. showed that fetal–maternal neutrophil incompatibility causes neonatal neutropenia [3], a study that led to the discovery of neutrophil specific antigens [4]. In 1975 Lalezari et al. showed that chronic neutropenia can be caused by autoantibodies against neutrophil-specific antigens [5].