Autoimmunity Reviews 13 (2014) 574–576
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Diagnostic criteria for autoimmune neutropenia Pierre Youinou ⁎, Christophe Jamin, Laëtitia Le Pottier, Yves Renaudineau, Sophie Hillion, Jacques-Olivier Pers EA2216 Immunologie et Pathologie, LabEx IGO, SFR ScInBioS, Université de Brest et Université Européenne de Bretagne, Brest, France
a r t i c l e
i n f o
a b s t r a c t
Article history: Accepted 13 November 2013 Available online 11 January 2014
Autoimmune neutropenia denotes that the number of circulating polymorphonuclear neutrophils is below 1.5 × 109/L. This encompasses a wide range of disorders from primary conditions to complications of systemic autoimmune diseases or hematological neoplasms. Antineutrophil autoantibodies are particularly difficult to detect, and their amount does not correlate with the degree of neutropenia. Granulocyte colony-stimulating factor is the first-line therapy, but should be restricted to patients with total absence of neutrophils and/or severe infections. © 2014 Published by Elsevier B.V.
Keywords: Polymorphonuclear neutrophil Autoantibody
Contents 1. Introduction . . . . 2. Pathogenesis . . . . 3. Clinical presentation 4. Blood abnormalities 5. Serological tests . . 6. Therapy . . . . . . Acknowledgments . . . . References . . . . . . .
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1. Introduction The term neutropenia refers to a decrease in the number of blood polymorphonuclear neutrophils down to 1.5 × 109/L for at least six months. This disorder is autoimmune in essence when the excessive destruction of neutrophils proceeds from the harnessing of their plasma membrane with antibodies. Nonetheless, given the controversy over the role of immune complexes, such autoantibodies have proved difficult to endorse with the pathophysiology in all the patients [1]. These primary autoimmune neutropenia occur as isolated clinical entities, especially in infancy, where the frequency is 1 in 100,000 newborns. Secondary autoimmune neutropenia is more common and set against a background of connective tissue disease, such as primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), primary biliary cirrhosis, and rheumatoid arthritis (RA), or complicating hematological neoplasms, such as large granular lymphocyte leukemia, autoimmune lymphoproliferative syndrome and even Wilms' tumor and Hodgkin's ⁎ Corresponding author at: Laboratory of Immunology, Brest University Medical School Hospital, BP 824, F 29609 Brest, France, Tel.: +33 298 22 33 84; fax: +33 298 22 38 47. E-mail address: [email protected] (P. Youinou). 1568-9972/$ – see front matter © 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.autrev.2014.01.001
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574 574 575 575 575 576 576 576
disease. Knowledge has recently been advanced in the pathogenesis of these confused situations. 2. Pathogenesis Approximately, one-third of grown-up patients [2] and almost 80% of newborn with autoimmune neutropenia [3] present with serum antineutrophil antibodies. These autoantibodies are set apart from Fcgamma receptor (FcγR)II and FcγRIIIb-bound immune complexes in the adults, and from neonatal alloimmune antibodies in the infants. The source of immunization is currently unknown. Consistent with their heightened number in the circulation of patients with SLE [4], apoptotic neutrophils might course the release of antigens. The source of immunization might also be alteration of neutrophil antigens after exposure to drugs, such as procainamide. There is no definite evidence as to the mechanism and location of cell destruction and ensuing phagocytosis. Unlike autoimmune hemolytic anemia and idiopathic thrombopenic purpura where complement-mediated or antibodydependent cell cytotoxicity operate, these antineutrophil antibodies generate opsonic activity and thereby encourage phagocytosis of sensitized cells by the reticulo-histiocytic system. However, although the
P. Youinou et al. / Autoimmunity Reviews 13 (2014) 574–576
patients show features of a survival defect, the degree of neutropenia does not fit with the level of autoantibody. Not only is the clearance of neutrophils offset by a commensurate raise in the production of neutrophils, but also such responses can even be inverted. That is, a subset of antineutrophil antibodies have the capacity to delay spontaneous apoptosis of senescent cells, through the synthesis of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor and the ensuing down-regulation of Bax which is proapoptotic [5]. Thus their life span is extended, but their functions are adversely affected.
575
Table 2 Clinical features associated with large granular lymphocyte leukemia. Based on reference [12]. Clinical feature
Frequency (%)
Age N50 years Male : female Recurrent infection Splenomegaly Fever, night swears and weight loss Bone marrow involvement Hepatomegaly Lymphadenopathy
70 1 20–40 20–50 20–30 25–80 b20 b5
3. Clinical presentation The clinical course of primary autoimmune neutropenia is relatively benign, or at any rate self-limiting. In fact, this is much more frequent than originally stated, due to bias. On one side, asymptomatic individuals do not give rise to investigation, so that their neutropenia is discovered by chance. On the other side neutrophil counts vary considerably from day to day, so that cases described as cyclic neutropenia are possibly autoimmune neutropenia [6]. Conversely, a normal count can be maintained, despite the presence of antineutrophil antibody, through accelerated turn-over of the cells. Autoantibodies may rather impair the function of the cells [7]. It has long been recognized that the degree and length of neutropenia augment the risk of infection. The most frequent complications are outlined in Table 1: various Gram-positive and Gram-negative bacterial infections, and fungal infections with Candida and Aspergillus have been reported in infants [8], as well as in adults [2]. In secondary autoimmune neutropenia, infections have been noticed to be worse during relapse of the underlying pathology. With respect to autoimmune settings, the messages are that neutropenia is rarely seen in patients with primary SS [9], detected in up to half of those with SLE [10], and associated with RA and variable splenomegaly [11] in the Felty's syndrome. Autoimmune neutropenia can also accompany hematological diseases, and indeed one-fourth of the large granular lymphocyte leukemia patients who experience RA resemble those with Felty's syndrome [12]. There is an obvious need for clarification of the relationship between these two diseases, since they are just distinguished by T-cell clonality which exists in large granular lymphocyte leukemia, but not in Felty's syndrome. The clinical features in common are presented in Table 2. Of note, rheumatologic manifestations are more severe in Felty's syndrome, compared with RA. Another condition associated with neutrophil-binding and platelet-binding antibodies is autoimmune lymphoproliferative syndrome [13]. In this intriguing disease, it is uncertain as to why blood cells are such a common target for anti-self responses, and not the various organ systems, as seen in systemic autoimmune diseases. 4. Blood abnormalities Laboratory findings are summarized in Table 3. Around 60% of the patients have isolated neutropenia, while the remaining 40% combine their neutropenia with anemia and/or thrombocytemia [2,8]. The
Table 1 Infections present at the time of diagnosis. Based on references [2,8]. Infection
Frequency (%)
Upper respiratory infections Otitis media Pyoderma Fever of unknown origin Abscess Gastroenteritis Pneumonia
20 17 12 12 10 10 8
majority of them show normal or increased cellularity in the bonemarrow, with a normal or low number of mature neutrophils. Phagocytosis of these cells by bone-marrow macrophages is occasionally observed.
5. Serological tests Given that no single method can pick up all possible antineutrophil antibodies, a number of assays have been devised. The screening procedure should include a minimum of two of them [14]. Several assays may be chosen, such as the granulocyte agglutination test and the granulocyte immunofluorescence test, both based on the use of netrophils from blood donors as the substrate. Formal quality assurance schemes have recently confirmed that, although the granulocyte agglutination test has low sensitivity compared with the granulocyte immunofluorescence test, it is the only reliable method for detecting particular neutrophil-binding antibodies [15]. Most of them recognize human neutrophil antigens HNA-1a, HNA-1b and HNA-1c on FcγRIIIb referred to as CD16, FcγRII referred to as CD32, complement receptor 1 referred to as CD35, and HNA-4a and HNA-5a on CD11b and CD11a respectively (Table 4) [8,16]. The antibody-binding characteristics and the antigen site density contribute to the sensitivity of all assays. Monoclonal antibody immobilization of granulocyte antigen assay is indicated to decipher complex mixtures of antibodies, or in which confirmatory tests are required [15]. In practice, the analysis of neutrophil antibodies is difficult because they are present in low titer and bind to their targets with poor avidity. Neutrophil antibodies have also been detected using an indirect immunofluorescence flow (IIF) cytometric test with fluoresceinated antihuman IgG antibody as the second layer, coupled with an enzymelinked immunosorbent assay (ELISA) with recombinant FcγRIIIb as a capture agent, such autoantibodies detected in half of the patients with primary SS, and the sera categorized on the basis of positivity for the two methods as IIF + ELISA+, IIF + ELISA- and IIF-ELISA+ [17]. Their presence does not necessarily imply that the patients are neutropenic. More recently, antibodies to myeloid precursors have been recognized in pure white cell aplasia [18], and antibodies against G-CSF identified in neutropenic patients with SLE or Felty's syndrome [19]. In yet other patients, there is evidence for anti-Ro antibodies crossreacting with neutrophil membrane antigens in patients with SLE or primary SS [20]. Given the mounting evidence that anti-neutrophil cytoplasmic antibodies (ANCAs) are implicated in the pathogenesis of Table 3 Hematological features in primary autoimmune neutropenia. Based on references [2,8,14]. Finding
Frequency (%)
Isolated neutropenia Neutropenia + anemia and/or thrombocytopenia Normal bone-marrow Reduced no. of mature neutrophils Hypercellular with reduced no. of mature neutrophils
60 40 30 15 20
576
P. Youinou et al. / Autoimmunity Reviews 13 (2014) 574–576
References
Table 4 Neutrophil antibodies in primary autoimmune neutropenia. Based on references [2,8]. Autoantibody specificity
Glycoprotein
Frequency (%)
CD16 CD11b CD35 CD32
FcγRIIIb
30 25 15 5
CR1 FcγRII
secondary auto-immune neutropenia, considering laboratory tests for ANCAs as part of the neutropenia work-up is reasonable.
6. Therapy To date, G-CSF is the sole therapy allowing recovery of the circulating neutrophil count and better control of infection in primary autoimmune neutropenia and Felty's syndrome. This treatment should be all the more restricted to severe cases. Importantly, RA and SLE patients are at risk of flaring on G-CSF. In patients with severe infections, remission can be achieved by treatment with corticosteroids, intravenous immunoglobulin. In addition to commonsense precautions to avoid infections, of benefic can also be the humanized monoclonal anti-CD52 antibody Campath-1H. Parenthetically, although it can induce neutropenia, intravenous immunoglobulin has met transient remission. It stands to reason that control of the underlying disease is of the utmost importance in secondary autoimmune neutropenia. In conclusion, there is a need for standardization of the tests for antineutrophil antibodies. These may accompany numerous pathological settings, such as bone-marrow or organ transplantation, treatment with Rituximab or fludarabine, and infection with parvorirus B19 or human immunodeficiency virus. Still, several issues remain areas of intense investigation.
Acknowledgments Thanks are due to Geneviève Michel and Simone Forest for the excellent secretarial assistance.
[1] Boxer LA, Greenberg MS, Boxer GJ, Stossel TP. Autoimmune neutropenia. N Engl J Med 1975;293:748–53. [2] Logue GL, Shastri KA, Laughlin M, Shimm DS, Ziolkowski LM, Iglehart JL. Idiopathic neutropenia: antineutrophil antibodies and clinical correlations. Am J Med 1991;90:211–6. [3] Lalezari P, Khorshidi M, Petrosova M. Autoimmune neutropenia of infancy. J Pediatr 1986;109:764–9. [4] Courtney PA, Crockard AD, Williamson K, Irvine AE, Kennedy RJ, Bell AL. Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann Rheum Dis 1999;58:309–14. [5] Durand V, Renaudineau Y, Pers JO, Youinou P, Jamin C. Cross-linking of human FcgammaRIIIb induces the production of G-CSF and GM-CSF by polymorphonuclear neutrophils. J Immunol 2001;167:3996–4007. [6] Hammond WP, Miller JE, Starkebaum G, Zweerink HJ, Rosenthal AS, Dale DC. Suppression of in vitro granulocytopoiesis by captopril and penicillamine. Exp Hematol 1988;16:674–80. [7] Durand V, Pers JO, Renaudineau Y, Saraux A, Youinou P, Jamin C. Differential effects of anti-Fc gamma RIIIb autoantibodies on polymorphonuclear neutrophil apoptosis and function. J Leukoc Biol 2001;69:233–40. [8] Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood 1998;91:181–6. [9] Friedman J, Klepfish A, Miller EB, Ognenovski V, Ike RW, Schattner A. Agranulocytosis in Sjogren's syndrome: two case reports and analysis of 11 additional reported cases. Semin Arthritis Rheum 2002;31:338–45. [10] Nossent JC, Swaak AJ. Prevalence and significance of haematological abnormalities in patients with systemic lupus erythematosus. Q J Med 1991;80:605–12. [11] Spivak JL. Felty's syndrome: an analytical review. Johns Hopkins Med J 1977;141:156–62. [12] Burks EJ, Loughran Jr TP. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev 2006;20:245–66. [13] Kwon SW, Procter J, Dale JK, Straus SE, Stroncek DF. Neutrophil and platelet antibodies in autoimmune lymphoproliferative syndrome. Vox Sang 2003;85:307–12. [14] Bux J, Chapman J. Report on the second international granulocyte serology workshop. Transfusion 1997;37:977–83. [15] Lucas G, Rogers S, de Haas M, Porcelijn L, Bux J. Report on the Fourth International Granulocyte Immunology Workshop: progress toward quality assessment. Transfusion 2002;42:462–8. [16] Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther 2005;7:208–14. [17] Lamour A, Le Corre R, Pennec YL, Cartron J, Youinou P. Heterogeneity of neutrophil antibodies in patients with primary Sjogren's syndrome. Blood 1995;86:3553–9. [18] Levitt LJ, Ries CA, Greenberg PL. Pure white-cell aplasia. Antibody-mediated autoimmune inhibition of granulopoiesis. N Engl J Med 1983;308:1141–6. [19] Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A. Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum 2002;46:2384–91. [20] Kurien BT, Newland J, Paczkowski C, Moore KL, Scofield RH. Association of neutropenia in systemic lupus erythematosus with anti-Ro and binding of an immunologically cross-reactive neutrophil membrane antigen. Clin Exp Immunol 2000;120:209–17.
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Diagnostic criteria for autoimmune neutropenia Pierre Youinou ⁎, Christophe Jamin, Laëtitia Le Pottier, Yves Renaudineau, Sophie Hillion, Jacques-Olivier Pers EA2216 Immunologie et Pathologie, LabEx IGO, SFR ScInBioS, Université de Brest et Université Européenne de Bretagne, Brest, France
a r t i c l e
i n f o
a b s t r a c t
Article history: Accepted 13 November 2013 Available online 11 January 2014
Autoimmune neutropenia denotes that the number of circulating polymorphonuclear neutrophils is below 1.5 × 109/L. This encompasses a wide range of disorders from primary conditions to complications of systemic autoimmune diseases or hematological neoplasms. Antineutrophil autoantibodies are particularly difficult to detect, and their amount does not correlate with the degree of neutropenia. Granulocyte colony-stimulating factor is the first-line therapy, but should be restricted to patients with total absence of neutrophils and/or severe infections. © 2014 Published by Elsevier B.V.
Keywords: Polymorphonuclear neutrophil Autoantibody
Contents 1. Introduction . . . . 2. Pathogenesis . . . . 3. Clinical presentation 4. Blood abnormalities 5. Serological tests . . 6. Therapy . . . . . . Acknowledgments . . . . References . . . . . . .
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1. Introduction The term neutropenia refers to a decrease in the number of blood polymorphonuclear neutrophils down to 1.5 × 109/L for at least six months. This disorder is autoimmune in essence when the excessive destruction of neutrophils proceeds from the harnessing of their plasma membrane with antibodies. Nonetheless, given the controversy over the role of immune complexes, such autoantibodies have proved difficult to endorse with the pathophysiology in all the patients [1]. These primary autoimmune neutropenia occur as isolated clinical entities, especially in infancy, where the frequency is 1 in 100,000 newborns. Secondary autoimmune neutropenia is more common and set against a background of connective tissue disease, such as primary Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), primary biliary cirrhosis, and rheumatoid arthritis (RA), or complicating hematological neoplasms, such as large granular lymphocyte leukemia, autoimmune lymphoproliferative syndrome and even Wilms' tumor and Hodgkin's ⁎ Corresponding author at: Laboratory of Immunology, Brest University Medical School Hospital, BP 824, F 29609 Brest, France, Tel.: +33 298 22 33 84; fax: +33 298 22 38 47. E-mail address: [email protected] (P. Youinou). 1568-9972/$ – see front matter © 2014 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.autrev.2014.01.001
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574 574 575 575 575 576 576 576
disease. Knowledge has recently been advanced in the pathogenesis of these confused situations. 2. Pathogenesis Approximately, one-third of grown-up patients [2] and almost 80% of newborn with autoimmune neutropenia [3] present with serum antineutrophil antibodies. These autoantibodies are set apart from Fcgamma receptor (FcγR)II and FcγRIIIb-bound immune complexes in the adults, and from neonatal alloimmune antibodies in the infants. The source of immunization is currently unknown. Consistent with their heightened number in the circulation of patients with SLE [4], apoptotic neutrophils might course the release of antigens. The source of immunization might also be alteration of neutrophil antigens after exposure to drugs, such as procainamide. There is no definite evidence as to the mechanism and location of cell destruction and ensuing phagocytosis. Unlike autoimmune hemolytic anemia and idiopathic thrombopenic purpura where complement-mediated or antibodydependent cell cytotoxicity operate, these antineutrophil antibodies generate opsonic activity and thereby encourage phagocytosis of sensitized cells by the reticulo-histiocytic system. However, although the
P. Youinou et al. / Autoimmunity Reviews 13 (2014) 574–576
patients show features of a survival defect, the degree of neutropenia does not fit with the level of autoantibody. Not only is the clearance of neutrophils offset by a commensurate raise in the production of neutrophils, but also such responses can even be inverted. That is, a subset of antineutrophil antibodies have the capacity to delay spontaneous apoptosis of senescent cells, through the synthesis of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor and the ensuing down-regulation of Bax which is proapoptotic [5]. Thus their life span is extended, but their functions are adversely affected.
575
Table 2 Clinical features associated with large granular lymphocyte leukemia. Based on reference [12]. Clinical feature
Frequency (%)
Age N50 years Male : female Recurrent infection Splenomegaly Fever, night swears and weight loss Bone marrow involvement Hepatomegaly Lymphadenopathy
70 1 20–40 20–50 20–30 25–80 b20 b5
3. Clinical presentation The clinical course of primary autoimmune neutropenia is relatively benign, or at any rate self-limiting. In fact, this is much more frequent than originally stated, due to bias. On one side, asymptomatic individuals do not give rise to investigation, so that their neutropenia is discovered by chance. On the other side neutrophil counts vary considerably from day to day, so that cases described as cyclic neutropenia are possibly autoimmune neutropenia [6]. Conversely, a normal count can be maintained, despite the presence of antineutrophil antibody, through accelerated turn-over of the cells. Autoantibodies may rather impair the function of the cells [7]. It has long been recognized that the degree and length of neutropenia augment the risk of infection. The most frequent complications are outlined in Table 1: various Gram-positive and Gram-negative bacterial infections, and fungal infections with Candida and Aspergillus have been reported in infants [8], as well as in adults [2]. In secondary autoimmune neutropenia, infections have been noticed to be worse during relapse of the underlying pathology. With respect to autoimmune settings, the messages are that neutropenia is rarely seen in patients with primary SS [9], detected in up to half of those with SLE [10], and associated with RA and variable splenomegaly [11] in the Felty's syndrome. Autoimmune neutropenia can also accompany hematological diseases, and indeed one-fourth of the large granular lymphocyte leukemia patients who experience RA resemble those with Felty's syndrome [12]. There is an obvious need for clarification of the relationship between these two diseases, since they are just distinguished by T-cell clonality which exists in large granular lymphocyte leukemia, but not in Felty's syndrome. The clinical features in common are presented in Table 2. Of note, rheumatologic manifestations are more severe in Felty's syndrome, compared with RA. Another condition associated with neutrophil-binding and platelet-binding antibodies is autoimmune lymphoproliferative syndrome [13]. In this intriguing disease, it is uncertain as to why blood cells are such a common target for anti-self responses, and not the various organ systems, as seen in systemic autoimmune diseases. 4. Blood abnormalities Laboratory findings are summarized in Table 3. Around 60% of the patients have isolated neutropenia, while the remaining 40% combine their neutropenia with anemia and/or thrombocytemia [2,8]. The
Table 1 Infections present at the time of diagnosis. Based on references [2,8]. Infection
Frequency (%)
Upper respiratory infections Otitis media Pyoderma Fever of unknown origin Abscess Gastroenteritis Pneumonia
20 17 12 12 10 10 8
majority of them show normal or increased cellularity in the bonemarrow, with a normal or low number of mature neutrophils. Phagocytosis of these cells by bone-marrow macrophages is occasionally observed.
5. Serological tests Given that no single method can pick up all possible antineutrophil antibodies, a number of assays have been devised. The screening procedure should include a minimum of two of them [14]. Several assays may be chosen, such as the granulocyte agglutination test and the granulocyte immunofluorescence test, both based on the use of netrophils from blood donors as the substrate. Formal quality assurance schemes have recently confirmed that, although the granulocyte agglutination test has low sensitivity compared with the granulocyte immunofluorescence test, it is the only reliable method for detecting particular neutrophil-binding antibodies [15]. Most of them recognize human neutrophil antigens HNA-1a, HNA-1b and HNA-1c on FcγRIIIb referred to as CD16, FcγRII referred to as CD32, complement receptor 1 referred to as CD35, and HNA-4a and HNA-5a on CD11b and CD11a respectively (Table 4) [8,16]. The antibody-binding characteristics and the antigen site density contribute to the sensitivity of all assays. Monoclonal antibody immobilization of granulocyte antigen assay is indicated to decipher complex mixtures of antibodies, or in which confirmatory tests are required [15]. In practice, the analysis of neutrophil antibodies is difficult because they are present in low titer and bind to their targets with poor avidity. Neutrophil antibodies have also been detected using an indirect immunofluorescence flow (IIF) cytometric test with fluoresceinated antihuman IgG antibody as the second layer, coupled with an enzymelinked immunosorbent assay (ELISA) with recombinant FcγRIIIb as a capture agent, such autoantibodies detected in half of the patients with primary SS, and the sera categorized on the basis of positivity for the two methods as IIF + ELISA+, IIF + ELISA- and IIF-ELISA+ [17]. Their presence does not necessarily imply that the patients are neutropenic. More recently, antibodies to myeloid precursors have been recognized in pure white cell aplasia [18], and antibodies against G-CSF identified in neutropenic patients with SLE or Felty's syndrome [19]. In yet other patients, there is evidence for anti-Ro antibodies crossreacting with neutrophil membrane antigens in patients with SLE or primary SS [20]. Given the mounting evidence that anti-neutrophil cytoplasmic antibodies (ANCAs) are implicated in the pathogenesis of Table 3 Hematological features in primary autoimmune neutropenia. Based on references [2,8,14]. Finding
Frequency (%)
Isolated neutropenia Neutropenia + anemia and/or thrombocytopenia Normal bone-marrow Reduced no. of mature neutrophils Hypercellular with reduced no. of mature neutrophils
60 40 30 15 20
576
P. Youinou et al. / Autoimmunity Reviews 13 (2014) 574–576
References
Table 4 Neutrophil antibodies in primary autoimmune neutropenia. Based on references [2,8]. Autoantibody specificity
Glycoprotein
Frequency (%)
CD16 CD11b CD35 CD32
FcγRIIIb
30 25 15 5
CR1 FcγRII
secondary auto-immune neutropenia, considering laboratory tests for ANCAs as part of the neutropenia work-up is reasonable.
6. Therapy To date, G-CSF is the sole therapy allowing recovery of the circulating neutrophil count and better control of infection in primary autoimmune neutropenia and Felty's syndrome. This treatment should be all the more restricted to severe cases. Importantly, RA and SLE patients are at risk of flaring on G-CSF. In patients with severe infections, remission can be achieved by treatment with corticosteroids, intravenous immunoglobulin. In addition to commonsense precautions to avoid infections, of benefic can also be the humanized monoclonal anti-CD52 antibody Campath-1H. Parenthetically, although it can induce neutropenia, intravenous immunoglobulin has met transient remission. It stands to reason that control of the underlying disease is of the utmost importance in secondary autoimmune neutropenia. In conclusion, there is a need for standardization of the tests for antineutrophil antibodies. These may accompany numerous pathological settings, such as bone-marrow or organ transplantation, treatment with Rituximab or fludarabine, and infection with parvorirus B19 or human immunodeficiency virus. Still, several issues remain areas of intense investigation.
Acknowledgments Thanks are due to Geneviève Michel and Simone Forest for the excellent secretarial assistance.
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