Presse Med. 2014; 43: e105–e118 ß 2014 Elsevier Masson SAS All rights reserved.

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AUTOIMMUNE CYTOPENIAS

Quarterly Medical Review Autoimmune neutropenia Aline Autrel-Moignet1, Thierry Lamy1,2

1. CHU de Rennes, service d’hématologie clinique, Rennes 35043, France 2. Université Rennes 1, Rennes 35043, France

Correspondence:

In this issue Immune thrombocytopenic purpura: major progress in knowledge of the pathophysiology and the therapeutic strategy, but still a lot of issues Bertrand Godeau Pathogenesis of immune thrombocytopenia Douglas B Cines, Adam Cuker, John W Semple ITP and international guidelines, what do we know, what do we need? Francesco Rodeghiero, Marco Ruggeri Thrombopietic agents: There is still much to learn James B. Bussel, Madhavi Lakkaraja Is B-cell depletion still a good strategy for treating immune thrombocytopenia? Bertrand Godeau, Roberto Stasi Novel treatments for immune thrombocytopenia Andrew Shih, Ishac Nazi, John G. Kelton, Donald M. Arnold Warm autoimmune hemolytic anemia: advances in pathophysiology and treatment Marc Michel Autoimmune neutropenia Aline Moignet, Thierry Lamy

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Thierry Lamy, CHU de Rennes, hôpital Pontchaillou, service d’hématologie clinique, 2, rue Henri-le-Guilloux, 35000 Rennes, France. [email protected]

Summary Autoimmune neutropenia (AIN) is a rare entity caused by antibodies directed against neutrophil-specific antigens. It includes primary and secondary autoimmune neutropenia. Acute autoimmune neutropenia can be related to drug-induced mechanism or viral infections. Chronic autoimmune neutropenias occur in the context of autoimmune diseases, hematological malignancies, such as large granular lymphocyte leukemia, primary immune deficiency syndromes or solid tumors. The therapeutic management depends on the etiology. Granulocyte growth factor is the main therapeutic option, raising the question of their long-term utilization safety. Corticosteroids or immunosuppressive therapy are indicated in infection-related AIN or in case of symptomatic autoimmune disease or LGL leukemia.

A

utoimmune neutropenia (AIN) is a rare and heterogeneous group of diseases with variable clinical manifestations coming from asymptomatic to severe forms associated with infectious complications [1]. AIN is characterized by the presence of autoantibodies directed against neutrophils and leading to their destruction. However, anti-neutrophils antibodies are not easily detected due to the weak sensitivity of available tests. This review will focus on the description of neutrophils cells (regulation, function and consequence of neutropenia), the methods of antineutrophils antibodies detection and the physiopathology of autoimmune neutropenias. We will discuss the clinical spectrum of AIN and finally propose how to manage patient with AIN.

Polymorphonuclear neutrophils (PMN) How PMN homeostasis is regulated? In physiological situation, bone marrow produces about 109 PMN per kilo of body weight per day [2,3]. Progenitors, precursors and marrow mature neutrophils represent 95% of PNN reserves [4]. Myeloid stem cells and progenitors will divide four or five times before beginning the maturation

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phase. During this maturation stage, the nucleus segments and the primary and secondary cytoplasmic granules appear. Primary granules contain bactericidal proteins (MPO, proteinase 3, elastase or cathepsin G) whereas secondary granules’ proteins are involved in the neutrophil migration and in the maintaining of the inflammatory response (lysozyme, cathelicidin, leukolysin, collagenase and lactoferrin). Each maturation stage, mitotic and post-mitotic, lasts for seven days. The mature neutrophil is a 12 to 14 mm cell with a lobulated nucleus. It exits from the bone marrow through a barrier formed by the basal membrane, endothelial cells and post-capillary venule adventitial cells [5,6]. Five percent of PNN are in the circulation or in the post-capillary venule endothelium. Once neutrophils have moved into tissues, their lifetime is short, between 6 and 8 hours [7]. Neutrophils traffic is regulated by various mechanisms. SDF-1, also called CXCL-12, is produced by osteoblasts [8] and binds to CXCR4, which is found on the neutrophils’ surface. This interaction keeps neutrophils inside the bone marrow compartment. G-CSF acts on this SDF-1/CXCR4 axis in two ways:  it reduces CXCR4 expression on neutrophils surface [9];  it reduces SDF-1 level by limiting osteoblasts proliferation. Therefore, it promotes neutrophils release in the peripheral circulation. Finally, G-CSF production is reduced when a large amount of neutrophils cells are present in tissues [10,11]. This latter cytokine is the main regulator of granulopoiesis. G-CSF-R (G-CSF-receptor) also activates granulopoiesis specific transcription factors: C/EPB (CCAAT/enhancer binding protein), PU1, GFI-1 or CBF and c-Myb. The combination of these transcription factors is characteristic of granulopoiesis.

The normal PMN count and the consequences of neutropenia

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Normal neutrophils level ranges between 1500 and 7000/mm3 during adulthood [3]. A neutrophil count below 1500/mm3 defines the term neutropenia. This neutropenia is severe when neutrophils are below 500/mm3, moderate between 1000 and 500/mm3 and mild between 1000 and 1500/mm3. Neutrophil count depends on age, sex and ethnic origin. At birth, the normal value of PMN is between 12,000 and 15,000/ mm3 and reaches adult’s standard after one year old. The American Registry NHANES (National Health and Nutrition Examination Survey) studied leukocytes and neutrophils levels in a cohort of 25,222 subjects. This study confirms that sex, smoking status, age and ethnicity impact on neutrophil values [12]. Smokers and females present a higher neutrophil mean than non-smokers or males. There is a higher prevalence of neutropenia (below 1500/mm3) among African-American subjects (4.5%) than Hispanic or Caucasian Americans (respectively 0.38 and 0.49%). Eighty percent of those subjects present a mild neutropenia. Moderate or severe neutropenia remain rare with a prevalence of less than 1% (0.57% to 0.08% depending

on the ethnic groups). This lower quantity of neutrophils among the African-American population may correspond to the ethnic or benign neutropenia. This entity is poorly understood; the genetic transmission type is still unknown but seems to be multifactorial. At the individual level, this entity remains unclear, but it is defined by four simple criteria: mild or moderate neutropenia, absence of infection due to neutropenia, any identified etiology and a compatible ethnicity. Explorations have been reported in a very limited number of subjects and are strictly normal, especially the bone marrow, which showed no quantitative or qualitative abnormalities.

Neutrophil functions and clinical manifestations of chronic neutropenia Infection risk is well described when neutropenia is chemotherapy-induced or in case of severe congenital neutropenia. Neutropenia severity, installation velocity and duration modulate the infectious risk. When neutropenia is severe and lasts for at least two weeks, 80% of the patients are infected and nearly 100% after three weeks, mainly due to mycotic infections, such as aspergillosis or candidemia [13]. In the case of chronic AIN, the infectious risk has been poorly investigated. This risk appears to be correlated to the number of neutrophils when it is lower than 500/mm3 [14]. In case of AIN, the infectious risk is lower than observed during drug-induced neutropenia. This observation could be based on the fact that neutropenia is isolated in the chronic immune case whereas it is associated to monocytopenia in the drug-induced case. Those monocytes may counterbalance the neutropenia defect in the innate immune system. In the case of chronic AIN, infections are mainly caused by bacteria: Staphylococcus aureus and Gramnegative Bacilli are the most frequent germs. The nearly absence of symptom is explained by the absence of pus formation. The evolution is usually necrotic. Patients frequently present gingivitis, aphtoses, stomatitis, periodontitis and cutaneous infections, like perirectal abscess and cellulitis [15]. Severe and profound infections, such as pneumonia or digestive tract infections are rarely described. Those data have been described from series with mild or moderate chronic neutropenic patients. They might underestimate the severity and the frequency of infection in severe chronic AIN. The neutrophil count itself is not sufficient to define patient risk groups and to propose a prophylactic strategy. The soluble fraction of FcRIIIb or CD16 (receptor to immunoglobin Fc fragment) amount was measured in neutropenic patients by Koene et al. and they showed a correlation between a lower rate of FcRIIIb soluble and the occurrence of infections [16].

Physiopathology of autoimmune neutropenias The acquired autoimmune neutropenia are characterized by the presence of an antibody, usually of immunoglobulin G (IgG) tome 43 > n84 > avril 2014

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Human neutrophil alloantigen and their methods of detection Anti-neutrophil antibodies, called Human Neutrophil Alloantigen (HNA) antibodies are directed against neutrophil surface glycoproteins. The last nomenclature, written in 1998, is based on the glycoprotein location. HNA antibodies are responsible for several clinical conditions: autoimmune neutropenia but also transfusion-related acute lung injury (TRALI), febrile transfusion reactions, immune neutropenia after bone marrow transplantation and drug-induced immune neutropenia. Seven antigens have been described in the HNA system and they have been classed into five groups (table I). HNA-1 or CD16b and HNA-2 or CD177 (NB1 glycoprotein) are the major immunogenic molecules of the neutrophil membrane. They are both specific for the neutrophil cell. HNA-1 exhibits three polymorphisms (HNA-1a, 1b and -1c). It is located on the Fcg receptor IIIb, which presents a low affinity for IgG1 and IgG3. It binds to the Fc fragment of polymeric IgG antibodies. It links to either immune complexes

Table I Neutrophil antigen nomenclature Antigenic system HNA-1

Antigen

Glycoprotein

Acronym

clearing them from the circulation or to opsonized microorganism in order to phagocyte them [22]. Detection methods of HNA antibodies are based on the tests described below.

Direct or cell test: Granulocyte Immunofluorescence Test (GIFT) Paraformaldehyde-fixed neutrophils are incubated with serum to allow neutrophil reactive antibodies to bind to the antigenic epitopes. The neutrophils are then washed and incubated with a reagent blend of fluorescence-labeled F(ab0 )2 anti-human globulin IgG, IgM and IgA. The labeled neutrophils are then analyzed by flow cytometry or by fluorescence microscopy (figure 1) [23]. The feasibility of this test is limited by the difficulty to obtain a patient neutrophil cell suspension (especially in case of severe neutropenia).

Indirect or serum: Granulocyte Agglutination Test (GAT) The agglutination of neutrophils produced by IgG antibodies in the GAT is an active process, which occurs in two phases: during the first stage, neutrophil reactive antibodies bind to native antigens on unfixed neutrophils, sensitizing the cells. During the second stage, sensitized neutrophils undergo chemotaxis and move towards other PMNs to form microscopic agglutinates (figure 2) [23]. This test is less sensitive, except for the detection of anti-HNA-3a. To get reliable results, typed panel cells must be isolated from healthy donor each day of investigation. For both GIFT and GAT test, the presence of a large amount of HLA antibodies or immunes complexes can lead to false positive results. The use of the former test may identify HLA antibodies and confirm HNA antibody specificity.

Monoclonal antibody immobilization of granulocyteantigen (MAIGA) In the first stage, antibodies from the test sample bind to antigens on unfixed, phenotyped neutrophils. Selected monoclonals antibodies to HNA or HLA carrier glycoproteins are then added to label the human Ab complexed with the PMN antigen on the cell surface (figure 3) [23]. This relatively stable antigen– antibody (Ag–Ab) complex is captured and immobilized in goat anti-mouse antibody-coated microtitre wells in the second stage of the test. The specific Ag–Ab reaction is visualized by the detection of captured human Ab with alkaline phosphatase labelled anti-human IgG. Currently, it is recommended to combine the GIFT and GAT tests to optimize the detection of the anti-neutrophil antibodies and used MAIGA test to confirm its specificity.

HNA-1a

FcgRIIIb/CD16

NA1

HNA-1b

FcgRIIIb/CD16

NA2

HNA-1c

FcgRIIIb/CD16

SH

HNA-2

HNA-2a

gp50-64

NB1

HNA-3

HNA-3a

gp70-95

5b

HNA-4

HNA-4a

CD11b

MART

Spectrum of AIN

HNA-5

HNA-5a

CD11a

OND

Autoimmune neutropenia may display acute or chronic evolution. Every type of neutropenia discussed in this review comes

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directed against PMN specific antigens. These autoantibodies agglutinate neutrophils, which are then phagocytized. Those opsonized neutrophils are cleared from the circulation by the spleen and by various tissues containing phagocytic cells. There are also central mechanisms to immune neutropenia: lymphocytes from patients with Felty’s syndrome or systemic lupus have been shown to inhibit colony-forming unit colonies (CFUC). Moreover, an increased T-cell mediated cytotoxicity and production of IFN-g have been found in those latter patients. There is no a direct correlation between the amount of autoantibodies and the degree of neutropenia. This observation may be explained by the complement activation, which amplifies neutrophils destruction [17]. Furthermore, antibodies can be targeted against a progenitor or a mature cell. The younger the targeted cell is the more severe is the neutropenia [18–20]. Finally, antibodies can affect neutrophils function in a qualitative way by causing a defective response to chemotaxis [21].

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Figure 1 GIFT (granulocyte immunofluorescence test)

Figure 2 GAT (granulocyte agglutination test)

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under a combination of physiopathology mechanisms, including a variable part of autoimmunity. Acute neutropenia lasts by definition less than 3 months. It is mostly explained by druginduced mechanisms in adulthood and by viral infections during childhood. Chronic neutropenia is rare but can be associated with various clinical conditions. It can be related to an acquired or a congenital issue. Congenital neutropenia are mostly diagnosed in childhood [24]. However, cyclic neutropenia (ELANE mutation) or WHIM syndrome (CXCR4 mutation) can be diag-

nosed in adulthood because some of the patients present an asymptomatic form during childhood. Acquired chronic neutropenia can be divided into two classes: immune and nonimmune neutropenia. Toxic neutropenia (chemotherapy, benzene) is classified in this latter group and will not be discussed in this review. Autoimmune neutropenia is divided into two categories: primary or secondary, according to the absence or the presence of an underlying autoimmune disease participating in the occurrence of the cytopenia. Primary AIN are mainly

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MAIGA (monoclonal antibody immobilization of granulocyte-antigen)

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Figure 3

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Table II Etiologies of autoimmune neutropenias Acute autoimmmune neutropenia

Drug-related neutropenia Infections related neutropenia: influenza, HHV-6, enterovirus, parvo B19, VHC, VHB, EBV, CMV, HIV

Chronic autoimmune neutropenia Primary autoimmune neutropenia Secondary autoimmune neutropenia

Related to AI diseases: RA and FS, SLE, SS Related to hematological malignancies: LGL leukemia, CLL, Waldenström macroglobulinemia, Hodgkin lymphoma Related to solid tumors: thymoma Reated to immunodeficiency syndroms: APLS, CVID

AI: autoimmune; ALPS: lymphoproliferative syndrome with autoimmune manifestations; CMV: cytomegalovirus; CLL: chronic lymphocytic leukemia; CVID: common variable immunodeficiency; EBV: Epstein–Barr virus; FS: Felty syndrome; HHV-6: human herpes virus-6; HIV: human immunodeficiency virus; LGL: large granular lymphocyte; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; SS: Sjögren syndrome; Viral hepatitis B (VHB); Viral hepatitis C (VHC).

observed in children whereas secondary AIN are seen in adults. All the different etiologies of autoimmune neutropenia are summarized in (table II).

Acute neutropenia Associated to infectious diseases

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There are several studies [25,26] reporting an infectious origin of AIN. Responsible infectious agents for neutropenia are mostly virus: human herpes virus-6 (HHV-6), enterovirus, influenza, parvoB19, Epstein–Barr virus (EBV), cytomegalovirus (CMV) with a variable frequency according to series. The large majority of these children was younger than 2 years and presented transient neutropenia (less than 2 months). These viral primo infections could be accompanied by a transient neutropenia. They are rarely described during adulthood, except for the following viral infections, which could be described in the chronic neutropenia section. Infectious mononucleosis is the main manifestation of EBV. Mild neutropenia is a common figure (40%) during mononucleosis whereas severe neutropenia is rare, only some cases being published [27]. Neutropenia occurs 14 to 40 days following the first symptoms and lasts for 3 to 7 days [28]. Bone marrow examination usually found a late blockage of maturation but a humoral explanation is also possible. Schooley et al. described the presence of anti-neutrophils antibodies during mononucleosis but it was not associated to neutropenia in each case [29]. CMV primo infection is responsible for mild neutropenia. The virus may affect granulopoiesis and induce myelodysplasia [30,31]. ParvoB19 virus has been rarely associated with primary immune neutropenia. Neutropenia could be related to hemophagocytosis but the isolated neutropenia presentation remains rare [32,33]. Viral hepatitis C (VHC) screening could be

recommended in case of misunderstanding neutropenia. Two studies described a variable incidence of neutropenia, ranged from 3 to 20% of VHC patient population [34,35]. Autoimmune neutropenia has been described in association with VHC in some case reports. No correlation has been shown between the presence of severe neutropenia and Model for End Stage Liver Disease (MELD) scores, portal hypertension, splenomegaly, viral load and viral type. The risk of severe infection associated neutropenia is low. The positive impact of antiviral therapy on autoimmune neutropenia has been underlined [36– 38]. Neutropenia during B hepatitis (VHB) is usually druginduced (IFN-a). Aplastic anemia is well described with B hepatitis but rarely isolated neutropenia has been associated with acute hepatitis. The antiviral therapy could be effective in case of VHB induced AIN [39]. HIV infection associated neutropenia is commonly observed. It occurs in 5 to 10% of asymptomatic patients and in 50 to 70% of profoundly immunocompromised patients [40]. The mechanisms causing neutropenia are numerous. Granulopoiesis and bone marrow environment are affected by the virus itself. HIV could modify the marrow environment and induce bone marrow dysplasia [41]. Opportunistic bacterial infections, such as atypical mycobacterial intracellular tuberculosis or viral infections, such as CMV, EBV, dengue, HHV-8 or leishmaniasis can infiltrate the bone marrow and interfere with the granulopoiesis. Anti-neutrophil antibodies are found in 30% of HIV positive patients but are not consistently associated with neutropenia. The occurrence of AIN associated with Castleman disease (HHV8) has also been described [42]. Finally, immunocompromised patient are more likely to develop lymphoproliferative syndromes and monoclonal plasma cell proliferations that could interfere with hematopoiesis. Functional disturbances of PMN are induced by chemotaxis and phagocytosis defects. It may be

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Drug-induced neutropenia (DIN) Idiosyncratic drug-induced neutropenia (DIN) is an adverse reaction to drugs due to abnormal susceptibility, peculiar to the individual. Patients present a severe reduction of granulocytes (agranulocytosis) with an absolute neutrophil count under 500/mm3 and usually under 100/mm3. The disorder may be life-threatening (10%). An international multi-center study estimated that drugs caused 62% (in Europe) of all severe neutropenia cases in a general population [51]. The incidence has remained remarkably stable over the last decades (about 3–16 cases per million inhabitants per year). The incidence is higher among older people (more than 65) and some studies reveal that female could be more susceptible for DIN [52]. However, in a recent study it has shown no gender difference. A few drugs are collectively responsible for 70% of cases (box 1) [53]. The DIN mechanisms were traditionally classified in toxic or immune. This dichotomy seems not completely relevant nowadays. The generation of reactive oxygen species (ROS) appears to be a central mechanism. It is generated by the NADPH oxidase and myeloperoxidase of neutrophils. This reaction is initiated within seconds after the stimulation of neutrophils and leads to the production of hypochlorous acid. This acid represents a major system for oxidizing a susceptible drug to a reactive product, which may be covalent to cellular molecules and, subsequently, serves as a hapten, inducing antibodies. Some have postulated that the oxidized metabolite confers Tcell mediated immune reaction mainly against neutrophils and neutrophil precursors in the bone marrow but this hypothesis has not yet been demonstrated. It seems that active drug metabolites rather than the drug itself may cause DIN. In some case, the reactive metabolites may affect not only neutrophil lineage cells but also the bone marrow stroma, interfering with the granulopoiesis regulation. Genetic susceptibility or epigenetic modulations may explain the important variations among the population in front of the same drug. Several studies suspect single nucleotide polymorphisms in genes belonging to human leukocyte antigens (HLA) to take part in the development of DIN. tome 43 > n84 > avril 2014

Box 1 Drugs often reported to be involved in drug-induced neutropenia (drugs in italics are among the most frequently reported) Antithyroids (tiamazole, metimazole) Clozapine (olanzapine) Pyrithyldione Deferiprone Mianserine Phenothiazines (alimemazine) Lamotrigine Quinine/quinidine Antiretroviral (HIV) therapy Fluconazole, ketoconazole Beta-lactams, cefipime Trimethoprim sulfametoxazole Sulfasalazine Vancomycin, rifampicin Furosemide, spironolactone Dipyrone (metamizole) Calcium dobesilate Rituximab Infliximab, etanercept

Immunological mechanisms have been widely described as an important phenomenon in DIN. Immune complex, hapten and autoimmune mechanisms are three main humoral mechanisms. They led to cell lysis, formation of leucoagglutinins and reticuloendothelial elimination. Cellular mechanisms have also been suspected: T-lymphocyte cytotoxicity by perforin and granzyme way or apoptic induction by the proliferation of large granular lymphocyte (LGL). Drug may, under certain circumstances, form an immune complex by binding to an antibody. This immune complex could secondarily bind to neutrophils’glycoprotein, inducing neutropenia. A hapten is a small molecule, which is capable of eliciting the production of antibodies when it binds to a carrier molecule, usually a protein. Drug or its metabolite can play this hapten role and the modified protein can subsequently binds to neutrophils, inducing neutropenia. The drug or its metabolite can induce an autoimmune reaction and those autoantibodies can be pointed at neutrophils [54]. Rituximab has become one of the essential molecules for the B lymphoproliferative disorders and more recently for some autoimmune diseases, such as rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). During the past decade, more than two million people have been exposed. Concomitantly with this widespread use, several delayed adverse effects have been described: B hepatitis reactivation, interstitial pneumonia, intestinal perforations, immune reconstitution

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explained by the presence of viral particles at the cell surface [43]. The main mechanism of neutropenia remains the haematological toxicity of the drugs commonly used in these patients (antiretrovirals, antibiotics. . .). Typhoid fever (Salmonella typhi) is commonly associated to neutropenia. A series of 191 patients reports an incidence of neutropenia in 25% of the patient. The principal mechanism of this neutropenia comes from haemophagocytosis, which can lead to pancytopenia [44–47]. Helicobacter pylori infections associated with chronic misunderstood neutropenia have also been described [48,49]. Leishmaniasis has also been associated to neutropenia due to marrow infiltration [50].

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defects, late cytopenias and particularly late-onset neutropenia (LON) [55]. It is defined by a grade 3/4 neutropenia occurring three to four weeks after the last rituximab infusion, while neutrophils count was initially normal [56,57]. The first case was described in 2003 [58] and was followed by several studies showing an incidence of LON varying from 3 to 27% of patients [59]. The time to onset of LON is 77 to 175 days and the median duration of neutropenia varies between 5 and 77 days. A number of rituximab infusions greater than 4, a prior exposure to chemotherapy and an advanced disease appear to constitute LON development risk factors [60]. The risk of infection of LON is variable, ranging from 0 to 19% according to the population studied depending on the comorbidity and the number of previous treatment. Cases of pneumocystis pneumonia, tuberculosis, sepsis, pneumonia and reactivation of the varicella– zoster virus (VZV) or CMV have been described with LON. There is no comparative study, which compares the efficacy of G-CSF in this situation, but it is commonly used especially in case of severe neutropenia or infected patient. The question of rituximab reintroduction after LON occurring has not been resolved and should be discussed case by case. The pathophysiology of this type of neutropenia is not formally established. Various hypotheses have been proposed: an immune cause with the involvement of anti-neutrophils antibodies, T-LGL proliferation or infectious origin with a reactivation of parvovirus B19. A study suggests the role of the B-cell recovery based on the fact that LON occurs during the post-therapy B-lymphocyte recovery phase. This recovery phase could induce growth factor perturbation including SDF-1, which could lead to a delay in the neutrophil egress from the bone marrow [53,61].

Chronic autoimmune neutropenia Primary autoimmune neutropenia Primary autoimmune neutropenia is mainly diagnosed at the age of 5 to 15 months. Spontaneous remission occurred for nearly all the patients during the first or the second year following the neutropenia apparition. Autoantibodies are not easily detected and the screening had to be repeated several times. About 35% of the autoantibodies showed preferential binding to NA1 and NA2 granulocytes human alloantigen type. Rarely these young patients present serious infections despite severe neutropenia [62].

Secondary autoimmune neutropenia The secondary immune neutropenia are much more common in adulthood. They can be related to autoimmune diseases, hematological conditions, solid tumors or to immunological deficiency syndromes. AIN related to autoimmune diseases

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The three main autoimmune diseases associated to autoimmune neutropenia are in order of decreasing frequency: rheu-

matoid arthritis, systemic lupus erythematosus and Sjögren syndrome (SS). Rheumatoid arthritis Felty syndrome (FS) was initially characterized by the association of RA, neutropenia and splenomegaly. Several studies agree that the absence of splenomegaly does not change the patient profile [63]. This syndrome remains rare, described in old series in 1 to 3% of RA. It concerns preferentially women [64]. Synovitis and joint destruction are typically most severe. FS occurrence is usually a sign of RA worsening. Neutropenia is often less than 1000/mm3 and increases the infectious risk. Patients contract more respiratory tract and cutaneous infections [65]. It is often associated with high rheumatoid factor and antinuclear factor titers. RA associated neutropenia is due to the combination of peripheral and central factors. Antineutrophil antibodies are found in 30–60% of the patients, but their specificity is difficult to establish because of the concomitant presence of circulating immune complexes. It has been suggested that the target of the anti-neutrophil antibodies could be the nuclear elongation factor-1A-1 antigen (eEF1A-1) [66]. It has been shown that during apoptosis, eEF1A1 is translocated from the nucleus to the cell membrane. This process may explain the mechanism by which such antibodies bind to neutrophil membranes. This finding needs to be validated. A German team has described the presence of anti-G-CSF antibodies in the serum of such patients, which could induce a maturation arrest of granulopoiesis [67]. The role of spleen role in FS is still discussed. The speen analysis of 27 splenectomized patients did not show any arguments for sequestration or destruction of mature neutrophils. Evidence of leukophagocytosis was not observed in any of the cases [68]. Finally, the degree of neutropenia does not correlate with the degree of splenomegaly in contrast to anemia and thrombocytopenia [69]. On the other hand, if the spleen is not a direct actor of neutropenia, it is obvious that it plays an immunological role. Histopathology of the spleen from FS revealed hyperplastic germinal centers with increased sinusoidal plasma cells and immunoblasts, which are the morphologic hallmarks of active immunoglobulin secretion. Neutropenia is also due to central mechanisms. Bone marrow analysis of FS is very heterogeneous. A majority of patients seems to present a myeloid hyperplasia with a left shifted neutrophil maturation, which may speak up for a predominant peripheral destruction. Granulopoiesis could be inhibited by cytotoxic T-lymphocytes [70]. The most important point is that in more than 40% of cases, a Tcell clonal expansion is detected in neutropenic RA patients with the appearance of a proliferation of large granular lymphocytes (LGL) [69,71]. Blood and bone marrow immunophenotyping should be performed in order to detected LGL expansion. Eighty to 90% of patients with LGL leukemia and FS share the same HLA DR-4 profile, which reinforces the idea of tome 43 > n84 > avril 2014

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Systemic lupus erythematosus Neutropenia is rare (only 5% of patients have neutropenia lower than 1000 PMN/mm3) [77,78]. Kurien et al. have shown in vitro the specificity of the anti-SSA autoantibodies (Ro) in SLE neutropenia [79]. It has been found an increase in Fas-mediated neutrophils apoptosis in SLE neutropenic patients. They also present a decrease in the clearance of these apoptotic neutrophils by macrophages [80]. The importance of neutrophil apoptosis is correlated with disease activity. It could be the initial start of autoantibody synthesis by the membrane presentation of antigenic components [81]. Marrow hypoplasia and Fas-mediated apoptosis of CD34+ hematopoietic progenitor cells are also correlated to SLE-associated cytopenias. However, the correlation between the level of neutropenia and the degree of apoptosis was not demonstrated. Marrow hypoplasia and Fas-mediated apoptosis of CD34+ hematopoietic progenitor cells are also correlated to SLE-associated cytopenias. In clinical practice, the primary cause of neutropenia in the lupus patient is iatrogenic. Infections are the second death cause in SLE after cardiovascular complications. The correlation between neutrophils level and the infectious risk has not been demonstrated [82]. Low serum soluble receptor FcRIIIb and a high level of G-CSF are correlated to the infectious risk. Sjögren syndrome The Sjögren syndrome is an autoimmune disorder characterized by the infiltration by CD4+ mononuclear cell of exocrine glands, especially salivary and lachrymal glands type, responsible for xerophthalmia and xerostomia. It may be primitive or secondary to an underlying autoimmune disease, such as RA or SLE. In the systemic form of the disease, lungs and peripheral nerves are affected. In a series of 300 primary SS patients, the incidence of neutropenia was 12% with 2% of severe neutropenia [83]. No significant differences were found in the main clinical features according to the presence of neutropenia but immunological features reveled differences. Patients with neutropenia (< 1500/mm3) had a higher frequency of altered immunological markers, such as anti-Ro/SSA antibodies tome 43 > n84 > avril 2014

(68% versus 22%, P < 0.001) and RF (68% versus 32%, P < 0.001). Hypocomplementemia was also more frequent in patients with neutropenia in comparison with patients without neutropenia. All these patients have increased risk of infection and are more likely to present other cytopenias. AIN related to hematological conditions Large granular lymphocyte (LGL) leukemia LGL leukemia is a rare chronic lymphoproliferative syndrome. The typical presentation is a combination of recurrent infections due to a severe neutropenia, splenomegaly and autoimmune disease, RA most of the time. The World Health organization (WHO) classification has recognized LGL leukemia as a specific entity among mature peripheral T-cell neoplasms, including CD3+ T-cell LGL (T-LGL) and CD3–natural killer (NK)-LGL leukemia subtypes. T-LGL leukemias are characterized by a CD3+, CD8+, CD57+, CD45RA+ and CD62L negative phenotype compatible with a terminal effector memory T-cell expansion due to antigen-driven T-cell activation. NK-LGL leukemias include chronic NK-LGL lymphocytosis, usually an indolent disease, and aggressive NK-LGL leukemia. They share the following phenotype: CD3–/CD8+/CD16+/CD56+. LGL leukemia diagnosis is based on the association of the three following criteria: a LGL expansion above 500/mm3, chronic (lasting more than 6 months) and clonal. This latter point is easily proved for T-LGL leukemia by the analysis of TCR rearrangement (using PCR analysis or VBeta repertory analysis). It is difficult to assess clonality in case of NK-LGL leukemia, and it may rely on preferential KIR expression in some cases. T-LGL leukemias represent 85% of LGL leukemia and are well describe in various series. The median age for diagnosis is 60 without gender predominance. At diagnosis, the majority of the patients are symptomatic with recurrent infections, splenomegaly (30%), and more rarely B symptoms. Half of the patients are neutropenic and 25% of them present severe neutropenia. LGL count is usually high with 50% of the patients who exhibit more than 4000/mm3 circulating LGL. Anemia and thrombopenia are less frequent. Bone marrow is infiltrated in a large majority of patients. Depending on the series, 15 to 40% of the patients present an autoimmune disease associated to LGL leukemia. RA is the more frequent but SS, SLE, vascularitis, celiac disease, endocrinopathy are also reported [84–86]. T and NK-LGL leukemias share many clinico-biological characteristic however, the incidence of RA is higher in T-LGL subtype and those of ITP higher in NK-LGL subtype. Nearly half patients will eventually receive a treatment whatever the T or NK subtype [84]. Leukemic T-LGLs display the phenotype of mature, terminal effector memory cells and are probably expanded in a context of an antigen-driven immune response. Under physiological conditions, these cells undergo programmed apoptosis through activation-induced cell death (AICD) pathway. It is hypothesized that the dysregulation of several signaling pathways

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a continuum between these two entities [72,73]. The common immunogenetic feature and the presence of CTL clonal expansion strongly suggest that FS and T-LGL leukemia represent the same disease process. Finally, in 2014, whether or not FS still exists is debated. The treatment of RA associated neutropenia is empirical. Most experts recommend the use of low oral dose of methotrexate as a first-line therapy [74,75]. Rituximab has been tried in this indication and a systematic review of the literature report a neutrophil count improvement in 5 patients out of 8 after the first cycle of treatment. After a median follow-up of 9 months (range, 6–14), only one out of the 5 patients relapse. The same review reports a systematic failure of anti-TNFa treatment in this indication [76].

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promotes constitutively active clonal cell population, which is resistant to Fas-mediated apoptosis [87]. One of these key proteins in LGL leukemia is signal transducer and activator of transcription 3 (STAT3). Recent studies have found that nearly 40% of the patients exhibit a mutation of Stat3 in both LGL subtypes [88,89]. Whether or not mutated patients display more aggressive diseased as compared to unmutated patients is still discussed. Moreover, clonal LGL cells present other activated pathways, which promote the cell survival: Ras/ MEK/ERK, PI3Kinase/Akt and sphingolipids pathway with the expression of shingosine-1-phophate 5 (S1PR5) receptor. The overexpression of PDGF (platelet-derived growth factor) and both IL-6 and IL-15 contribute also to promote LGL leukemic cell survival. Mechanism of neutropenia in LGL leukemia is not entirely understood but several studies indicate that both cellular and humoral mechanisms take part in this process. LGL leukemia is characterized by a Fas-apoptosis resistance in a context of an elevated soluble Fas-ligand [90]. Mature neutrophils express CD95 antigen at their surface and are sensitive to Fas-induced apoptosis. Immature neutrophils do not express Fas at their surface unless they are co-cultured with IFN-g and TNF-a. LGL leukemic cell are known to produce spontaneously both IFN-g and TNF-a. Moreover, a correlation between myeloid progenitor apoptosis and the amount of bone marrow Fas-L and IFN-g has been shown in unexplained neutropenic patient. All these factors suggest an inhibitory effect of LGL leukemic cell on granulopoiesis (expression of Fas on CD34+ granulocyte precursor and their apoptosis). It appears that immune complexes rather than anti-neutrophils antibodies are responsible for peripheral neutrophils opsonization even these latter specifics antibodies are frequently detected [69,91]. Others hematological malignancies Immune neutropenia can be seen in the context of B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia, Waldenstrom’s macroglobulinemia and Hodgkin lymphoma. Neutropenia can be isolated or associated with other autoimmune cytopenias. It is noteworthy that autoimmune neutropenia can occur both during an active phase of the disease or during a remission period. In this latter case, it is not necessary synonymous of relapsing [92]. In the different published series, the incidence of autoimmune neutropenia remains low compared to cases of hemolytic autoimmune anemia and thrombocytopenia [93]. In this context, an immunological neutropenia is usually associated with a poor prognosis, mainly because of infectious complications.

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Evans syndrome Evans syndrome is a combination of at least two autoimmune cytopenias, usually hemolytic autoimmune anemia and autoimmune thrombocytopenia. Autoimmune neutropenia remains rare. In the 68 patient series described by Michel et al., only

10 patients (14.7%) presented an Evans syndrome with an autoimmune neutropenia [94]. AIN related to solid tumors Some cases of autoimmune neutropenia have been reported with thymic epithelial tumors. They are much less common than other autoimmune manifestations (myasthenia, SLE, aplastic anemia, autoimmune anemia, pemphigus, autoimmune thyroid disease, etc.) and only thirteen reported cases are available in the literature [95]. Autoreactive thymic T-cells could be responsible for those autoimmune disorders [96]. Good’s syndrome is an immune deficiency (hypogammaglobulinemia) occurring in a patient with thymoma, which may be associated with acquired autoimmune neutropenia [97]. AIN related to primary immunodeficiency syndromes Autoimmune cytopenias are also described in the context of primary immunodeficiency syndromes. Common variable immune deficiency (CVID) is a rare disease, probably genetic [98], which is characterized by an immunoglobulin (Ig) production defect resulting in hypogammaglobulinemia (< 5 g/L). The diagnosis is most often made during adulthood and hypogammaglobulinemia could be associated with autoimmune manifestations [99]. Twelve percent of patients present an autoimmune cytopenia with the following decreasing order of frequency: thrombocytopenia, anemia and rare cases of autoimmune neutropenia [100]. The X-linked autoimmune lymphoproliferative syndrome (ALPS) is exceptional (400 cases described). It is an inherited, non-malignant, disease characterized by the combination lymphadenopathy, splenomegaly, cytopenias, hypergammaglobulinemia. It is associated with an increased risk of lymphoproliferative B syndrome. This is due to an accumulation of lymphocytes secondarily to an apoptosis defect (Fas gene mutation). Autoimmune cytopenias are very common, related to the emergence of dual negative CD4–CD8– T-cells and autoreactive B-lymphocytes. The presence of antibodies anti-neutrophil with or without neutropenia has been described in these patients [101].

How to manage neutropenic patients? Laboratory explorations to determine the etiology are depicted in (table III). When a drug-related neutropenia is suspected, medication has to be suspended. In febrile patients, empirical broad-spectrum antibiotics are needed after blood, urine, and site-specific cultures. G-CSF is commonly used especially in patients with poor prognostic factors, such as bacteremia, renal insufficiency, advanced age, very low neutrophil count, bone marrow hypoplasia and shock even if the only comparative study found no difference between patients treated with G-CSF and those not [53]. A bone marrow smear and several blood cell counts have to be done. Pharmacovigilance procedure is mandatory in this situation. tome 43 > n84 > avril 2014

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Table III Which exams ask in a neutropenic patient? Clinical information

Blood test

Clinical history Daily occupation Drug list and chronology Viral infection arguments (contact, clinical symptoms) Autoimmune disease history, hematologic diseases Blood cell counts: twice weekly during 2 months ! Acute or chronic neutropenia? Viral serologies: EBV, CMV, VHC, VHB, HIV, ParvoB19 and more specific tests if clinical arguments (influenza, enterovirus, etc.) Immunologic tests: ANA (anti-SSA, -SSB, -DNA), ANCA, FR, Anti-CCP Specific research Anti-HNA antibodies: GAT, GIFT and MAIGA test Sera protein electrophoresis and dosage of immunoglobins (IgA/IgM/IgG) Blood immunofixation Immunophenotyping  TCR rearrangement analysis

Bone marrow

Bone marrow smear Karyotype

ANAs: Antinuclear antibodies; ANCA: anti-neutrophil cytoplasmic antibodies; CMV: cytomegalovirus; EBV: Epstein–Barr virus; FR: Rheumatoid factor; GAT: granulocyte agglutination test; GIFT: granulocyte immunofluorescence test; HIV: human immunodeficiency virus; MAIGA: monoclonal antibody immobilization of granulocyte-antigen; TCR: T-cell receptor; Viral hepatitis B (VHB); Viral hepatitis C (VHC).

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When neutropenia is associated to LGL leukemia, a treatment is proposed when PMN is lower than 500/mm3 or when the patient is symptomatic. The treatment is based on immunosuppressive agents, such as methotrexate, cyclophosphamide or cyclosporine A [106]. Steroid may be associated with the immunosuppressive agent but has not shown efficacy as a single agent [85]. Methotrexate was historically the first-line therapy because it was the first immunosuppressive agent to show efficacy [107]. Cyclophosphamide was given in case of anemia associated to pure red cell aplasia. A recent retrospective study shows that cyclophosphamide may induce very good response rates in both anemic and neutropenic LGL patients [108]. A prospective randomized trial comparing methotrexate to cyclophosphamide is ongoing in France. In a recent study, rituximab has shown remarkable efficacy in two patients having RA and LGL leukemia [109]. G-CSF long-term utilization has been studied by the chronic neutropenia registry workgroup [110]. Leukemic transformation has not been suspected in the context of AIN. On the other hand, flare effect on associated disease (i.e. RA symptoms exacerbation, spleen enlargement) have been reported. If the reduction of infectious complications is certain, we recommend using the minimal efficient dosage. In case of asymptomatic neutropenia, watch and wait attitude is recommended.

Conclusions The diagnosis of autoimmune neutropenia is based on the presence of anti-neutrophil antibodies associated neutropenia. The spectrum of the disease includes primary, secondary auto-

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Viral related neutropenia in children are usually just watched. Blood cell counts are repeated and empirical broad-spectrum antibiotics are given if necessary. There is no recommendation about the use of G-CSF in these situations. In case of autoimmune neutropenia associated with VHC or VHB infections, the initiation of the antiviral therapy may be efficient on neutrophil count recovery. When chronic neutropenia is diagnosed, treatment options depend on the etiology and the occurrence or not of infectious complications. Primary autoimmune neutropenia (mainly observed during childhood) does not justify curative therapy since the occurrence of infection is very low and the neutropenia reversible spontaneously. In case of infections, the treatment is based on broad-spectrum antibiotics and GCSF. Prophylactic antibiotics or long-term G-CSF therapy are not recommended. In case of secondary AIN, the risk of infections is unpredictable. Patients having gingivitis or recurrent aphtosis may be treated with G-CSF alone but the long-term efficacy is disappointing. Furthermore, neutrophil count normalization does not last after G-CSF stopping. For symptomatic patients, and especially for those having failed to G-CSF alone, immunosuppressive therapy is recommended. The therapy depends on the underlying disease. In case of Sjögren syndrome or SLE, steroids are the best option. However, corticodependence is frequently observed leading to the switch for immunosuppressive agents such as cyclosporine A or analogs [102–104]. Rituximab has been occasionally used with disappointing results [105].

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immune neutropenia and drug-induced immune neutropenia in adult patients. Laboratory diagnostic tests are not easily detected and have to be repeated over time. G-CSF is the first treatment option for AIN. Immunosuppressive agents are proposed for chronic AIN, especially in the context of underlying

autoimmune diseases. A better understanding of the AIN physiopathology and the mechanism of granulopoiesis inhibition is warranted to propose more adapted therapy. Disclosure of interest: the authors declare that they have no conflicts of interest concerning this article.

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tome 43 > n84 > avril 2014

Autoimmune neutropenia.

Autoimmune neutropenia (AIN) is a rare entity caused by antibodies directed against neutrophil-specific antigens. It includes primary and secondary au...
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