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Review
Management of neutropenia in patients with rheumatoid arthritis Estibaliz Lazaro a,∗ , Jacques Morel a,b a b
Service de médecine interne, hôpital du Haut-Lévêque, université de Bordeaux, 33604 Pessac, France Département de rhumatologie, hôpital Lapeyronie, université de Montpellier 1, 34295 Montpellier cedex 5, France
a r t i c l e
i n f o
Article history: Accepted 10 December 2014 Available online xxx Keywords: Neutropenia Rheumatoid arthritis Felty syndrome Large granular lymphocytic leukemia Growth factors Infection
a b s t r a c t Neutropenia is defined as a neutrophil count lower than 1.5 g/L, with categorization as mild, moderate, or severe when the count is 1.5–1 g/L, 1–0.5 g/L, or < 0.5 g/L, respectively. The main complication is infection, whose risk increases with the depth and duration of the neutropenia. Comprehensive etiological investigations are mandatory to determine the best treatment strategy. Constitutional neutropenia is rarely seen in everyday rheumatology practice. It predominantly affects patients of African descent and is usually moderate and well tolerated. Congenital neutropenia due to genetic abnormalities is severe and chiefly seen in the pediatric population. Most cases of neutropenia in patients with rheumatoid arthritis (RA) are acquired. Medications are the most common causes, making detailed history-taking crucial. Many medications used to treat RA can induce neutropenia. Folic acid deficiency should be sought routinely in patients taking methotrexate. A less common cause of neutropenia is an RA-related autoimmune reaction. Splenomegaly suggests Felty’s syndrome, which is accompanied with large granular lymphocytic (LGL) leukemia in 40% of cases. The treatment depends on the depth of the neutropenia and findings from the etiological workup. A neutrophil count below 0.5 g/L, a fever, and the presence of clinical signs indicate a life-threatening condition requiring emergent treatment. In other patients, the first step is immediate discontinuation of any possibly involved drugs, simultaneously with the etiological workup. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Background: red flags Neutrophils are granulocytes that differentiate from the myeloid lineage. The normal peripheral neutrophil count in adults is 1.5 to 7 g/L [1]. A number of factors, including glucocorticoids, lead the neutrophils to detach from the vessel walls, a phenomenon known as demargination that increases the neutrophil counts in the bloodstream. Neutropenia is defined as a neutrophil count lower than 1.5 g/L, regardless of the normal ranges for the laboratory. Four grades are distinguished: 1.9–1.5 g/L (grade I), minimal; 1.5–1 g/L (grade II), mild; 1–0.5 g/L (grade III), moderate; and < 0.5 g/L (grade IV) or agranulocytosis, severe. Acute agranulocytosis is a life-threatening emergency [2]. The risk of infection depends on the neutropenia grade, the pace of the neutrophil drop, and the duration of neutropenia when longer than 10 days. Other factors that influence the severity of neutropenia include the presence of other cytopenias (anemia, thrombocytopenia) or of lymphocytosis. The risk of infection is increased in patients with chronic foci of infection, particularly in the upper or lower airways or ears; and in those with comorbidities such as kidney, respiratory,
∗ Corresponding author. Tel.: +33 557 656 483; fax: +33 557 656 484. E-mail address: [email protected] (E. Lazaro).
or heart failure. The main incident infections are due to bacteria (Staphylococcus aureus and Gram-negative bacilli) and fungi; there is no excess risk of viral or parasitic infections [3]. The risk of infection increases with the duration of the neutropenia. Acute agranulocytosis is the main reason for emergent hospital admission.
2. Pathophysiology Most neutrophils reside in the bone marrow. Fewer than 10% are located in the vascular compartment, including 45% circulating in the bloodstream and 55% adhering to the vessel walls (marginated pool). In patients with neutropenia, three mechanisms should be considered (Fig. 1) [4]: • peripheral destruction by an autoimmune reaction or toxic agent; • sequestration in the splenic or endothelial tissues (excessive margination); • and inadequate neutrophil production due to a congenital abnormality, bone marrow invasion, vitamin deficiency, or toxic agent.
http://dx.doi.org/10.1016/j.jbspin.2015.01.005 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Lazaro E, Morel J. Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.01.005
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Fig. 1. The main causes of neutropenia.
3. Causes of neutropenia Although congenital neutropenia should be considered as a matter of principle in children and young adults, neutropenia in patients with rheumatoid arthritis (RA) is usually acquired. 3.1. Acquired neutropenia Drugs are the main cause of neutropenia in RA. The culprits include synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate; and immunosuppressants such as cyclophosphamide and azathioprine, which are used only in systemic forms of RA. Many other drugs prescribed by rheumatologists can induce neutropenia, including nonsteroidal anti-inflammatory drugs, antimalarials, and sulfasalazine. More recently, neutropenia has been reported in patients taking biological agents such as rituximab, tocilizumab, and TNF␣ antagonists, although these drugs theoretically have little myelosuppressive potential. In rituximabtreated patients, the incidence of neutropenia has ranged across studies from 3% to 27%. The neutropenia is delayed (median time to development, 6 months) and correlates both with the depth of B-cell depletion and with an increased risk of infection [5–7]. With tocilizumab, neutropenia has been estimated to occur in 1/100 to 1/10 patients and develops within a few days after the infusion [8]. A correlation between the depth of neutropenia and the efficacy of tocilizumab was suggested but not confirmed by a recent cohort study [9,10]. TNF␣ antagonists has been reported to induce neutropenia with an incidence that varied but was lower than 1/10 patients overall. The pathophysiological mechanisms involved in biotherapy-induced neutropenia remain unclear. Recent work by Wright et al. established that tocilizumab has no pro-apoptotic effects on neutrophils [11]. The concomitant use of DMARDs in most patients complicates the assessment of a causal link between biotherapies and neutropenia and probably increases the risk of neutropenia. Therefore, a routine detailed inventory of all drug exposures must be established in all patients with neutropenia in order to detect a possible iatrogenic cause, before conducting investigations for other etiologies. Folic acid deficiency should be considered, most notably in patients taking methotrexate. Neutropenia may also be related to deficiencies in other substances, such as vitamin B12 or copper. Autoimmunity with the production of antibodies against granulocytes can cause neutropenia [12]. In patients with RA, the autoimmune process is usually related either to the RA itself or to concomitant Sjögren’s syndrome [12,13]. In this situation, autoantibodies against granulocytes exhibit pan-RF␥IIIb (pan-CD16b) activity. Primary autoimmune neutropenia is rare in adults. Women are affected in 70% of cases, and the course is usually chronic. Although spontaneous resolution does not occur, the disease is generally mild. Anti-granulocyte antibodies are detected in only 35% of cases and the diagnosis is therefore one of elimination [14]. In pediatric patients, primary autoimmune neutropenia is the leading
cause of neutropenia, with an estimated incidence of about 1/105 between 5 and 15 months of age [15]. The neutropenia is usually moderate to profound, and concomitant monocytosis is present in 30% of cases. The autoantibodies are chiefly directed against the RFc␥IIIb receptor group (HNA-1), principally the HNA-1a antigen. These autoantibodies cause excessive destruction of peripheral neutrophils. The bone marrow is usually normal. Associated infections are non-serious in most cases. Autoimmune neutropenia has also been reported in patients exposed to drugs. The autoimmune nature of the neutropenia is difficult to establish, as the diagnostic tests are extraordinarily difficult to interpret. A few cases of autoimmune neutropenia occur in patients with primary immune deficiencies such as common variable immune deficiency, Good syndrome, and IPEX syndrome. When there is no evidence that a drug, autoimmune process, or deficiency is responsible for the neutropenia, Felty’s syndrome or large granular lymphocytic (LGL) leukemia should be considered [16,17]. Felty’s syndrome is defined as the combination of neutropenia, RA, and splenomegaly. The neutropenia may be induced by antibodies directed against elongation factor A1, which is found in the nucleus but may be expressed on the cell membrane during apoptosis [18]. Neutrophil apoptosis may be induced by an interaction between the soluble pro-apoptotic cytokine FasL and the Fas receptor expressed on neutrophils. Among cases of Felty’s syndrome, 40% are related to LGL leukemia, which is characterized by proliferation of a T-cell or NK-cell clone. LGL leukemia should be considered in patients with moderate-to-severe neutropenia and lymphocytosis [17] (Fig. 2). The diagnosis rests on immunophenotyping of the blood lymphocytes: the results show expansion of CD3+, CD8+, CD57+, CD56− T cells or of CD3−, CD16+, CD56+ NK cells. The clonal nature of the proliferation should then be established, by TCR rearrangement or V repertoire tests for T cells and by KIR receptor or CD94 expression tests for NK cells. Neutropenia in patients with LGL leukemia is multifactorial: anti-granulocyte antibodies are produced, and neutrophil apoptosis is excessive. The prognosis depends chiefly on the risk of infection, with a 20% mortality rate after 4 years and a median survival longer than 10 years [19]. Finally, bone marrow invasion should be suspected, particularly when the neutropenia is accompanied with other cytopenias and/or the serum protein electrophoresis shows monoclonal gammopathy. 3.2. Congenital neutropenia Congenital forms of neutropenia are seen mainly in pediatric patients [20]. The three classical forms are severe congenital neutropenia, cyclic neutropenia, and WHIM syndrome. Severe congenital neutropenia or Kostmann syndrome is characterized by increased myeloid cell apoptosis [21]. A mutation in the ELA2 gene is identified in 50% of cases. Profound neutropenia is the rule, and there may be other biological abnormalities such as thrombocytosis or hypergammaglobulinemia. Patients are at risk for severe infections and secondary acute leukemia. Osteoporosis is often present in children and should be sought routinely. In contrast to severe congenital neutropenia, cyclic neutropenia and WHIM syndrome may produce only minimal symptoms, so that the diagnosis is not made until adulthood. Cyclic neutropenia is inherited on an autosomal dominant basis [22]. Episodes of neutropenia occur in 3-week-long cycles. Mutations in the ELA2 gene have been found. WHIM is the acronym for “warts, hypogammaglobulinemia, infections, myelokathexis”. WHIM syndrome is a rare autosomal dominant disease due to an activating mutation in the gene that encodes the chemokine receptor CXCR4 [7]. The depth of the neutropenia is variable.
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Fig. 2. Diagnostic strategy in patients with suspected large granular lymphocyte (LGL) leukemia.
3.3. Constitutional or ethnic neutropenia Constitutional or ethnic neutropenia has been reported in patients of African descent [23]. The neutropenia is generally mild, with counts that rarely drop below 1000/mm3 . Ethnic neutropenia correlates with absence of homozygous expression of the gene encoding the Duffy antigen/chemokine receptor (DARC). As DARC is among the targets of Plasmodium, the DARC-null phenotype confers protection against malaria, which explains its predominance among African populations. The link with neutropenia remains unclear but may involve decreased neutrophil migration through the endothelial cells that do not express DARC [23].
Table 1 Management of a patient with neutropenia. Evaluation for signs of severity
Etiological workup History taking
Investigations Evidence of infection Etiological test
4. Diagnostic management Patients with neutropenia should be asked about drug exposures, infections before or after the diagnosis of neutropenia, and any recent contact with a person who had an infectious disease. Ethnic origin from Africa should also be recorded. An evaluation of previous blood cell counts may indicate whether the neutropenia is chronic or cyclic. The physical examination should focus on abnormalities of the lymphoid organs (lymph nodes, spleen, and tonsils) and on signs suggesting an infection (fever, candidiasis, crepitant rales) (Table 1). Emergency hospital admission is required in the event of severe neutropenia and/or a fever. Otherwise, investigations can be performed on an outpatient basis [12]. A postprandial neutrophil count is mandatory. Demargination tests involving the administration of adrenaline or glucocorticoids are no longer used in clinical practice. Viral serological tests should include an HbS antigen assay and tests for the hepatitis C virus, cytomegalovirus, Epstein-Barr virus, and HIV. Polymerase chain reaction assays or serological tests for other agents may be performed if dictated by the clinical setting. Among tests for dysimmunity, assays for antinuclear antibodies and anti-cyclic citrullinated peptides should be performed. An anti-granulocyte antibody assay is part of the etiological workup but is difficult to interpret due to the high false-positive rate [4,12]. Serum protein
Neutropenia depth: < 0.5 g/L; 0.5–1 g/L; 1–1.5 g/L Clinical signs (fever, infection, aphthosis) Ethnicity History of infections History of neutropenia Exposure to medications Collection of samples for microbiological tests Viral serological tests Tests for autoimmunity Serum protein electrophoresis Immunophenotyping of blood lymphocytes Assays of vitamin B12, folic acid, and copper Bone marrow biopsy
electrophoresis to look for a monoclonal gammopathy should be performed routinely. Other routine tests include blood lymphocyte immunophenotyping and assays of vitamin B12, folic acid, and copper. When none of these tests identifies a cause to the neutropenia, investigation of the bone marrow may be considered to look for a cause of inadequate neutrophil production. 5. Therapeutic management Symptomatic treatment according to the standard of care in oncology is the first step. The cause should be treated as soon as it is identified. 5.1. Symptomatic treatment Emergency antibiotic therapy should be given as soon as an infection is suspected. The treatment should comply with the
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European recommendations issued at the 2011 consensus conference [24] Among other symptomatic treatments for neutropenia, only growth factor therapy seems useful [4]. Splenectomy is not effective and increases the risk of infections with encapsulated organisms. Polyvalent immunoglobulins have not been proven effective. Growth factors are reserved for patients with symptomatic neutropenia (recurrent infections and/or persistent aphthosis) [4]. In patients with RA, however, they may induce joint pain. If possible, growth factors should be administered only for short periods. If long-term therapy is required, the dosage should be adjusted to keep the neutrophil count between 0.5 and 1.5 g/L. No cases of leukemia induction have been reported in adults given long-term growth factor therapy. Data from registries in France and other countries show that the risk of myelodysplasia and acute leukemia correlates with the severity of the neutropenia (depth and infections), the cumulative dose, and the mean dose per granulocyte colony-stimulating factor (G-CSF) injection [19]. These treatment-related risks should be weighed against the risk of infection. The risk of osteoporosis has been found elevated in patients with constitutional neutropenia and may be further increased by G-CSF therapy [19,20]. Given the risk of infection, immunizations should be kept up to date in neutropenic patients [25]. The BCG is the only contraindicated vaccine. All other vaccines, including those containing live organisms, can be used, even in patients with severe neutropenia. There is a particularly strong recommendation to administer the seasonal influenza vaccine, pneumococcus vaccine, and varicellaherpes zoster vaccine. Nevertheless, the administration of live vaccines is not advisable in patients taking a biotherapy, immunosuppressants, or long-term glucocorticoid therapy in a daily dosage greater than 10 mg/d for at least 2 weeks. The appropriateness of prophylactic treatment should be discussed on a case-by-case basis, depending on the comorbidities and on the depth and duration of the neutropenia. Prophylactic antifungal therapy with itraconazole or voriconazole may deserve consideration in patients with prolonged neutropenia and counts lower than 0.5 g/L. Neither penicillin V nor cotrimoxazole has been proven effective for prophylaxis. 5.2. Etiological treatment Discontinuation of any drug possibly responsible for the neutropenia is mandatory. The patient should be interviewed in great detail about self-medication. The case should be reported routinely to the pharmacovigilance center. In patients with Felty’s syndrome, methotrexate is classically used, on an empirical basis. Three main immunosuppressants are used to treat LGL leukemia: methotrexate, ciclosporin, and cyclophosphamide, with overall response rates ranging from 40 to 60% [12,19]. Methotrexate is the most widely administered drug in patients with RA and neutropenia, as it is effective on both conditions. Ciclosporin is generally used in patients with concomitant erythroblastopenia or as a second-line drug after methotrexate. Presence of HLA DR4 seems strongly predictive of the therapeutic response to cyclosporine. However, long-term ciclosporin therapy carries a risk of kidney dysfunction and hypertension. Thus, the use of ciclosporin is currently very limited in patients with RA. Oral cyclophosphamide in a daily dosage of 50–100 mg is an alternative to methotrexate or ciclosporin, as the first-line drug or in the event of failure of the other two drugs, and tends to produce higher response rates [22]. The effectiveness of these immunosuppressants is usually evaluated after 4 months of treatment, at which point a change in the treatment regimen may be considered. Other treatment options in patients who fail to respond to these three immunosuppressants consist of purine analogs, alemtuzumab, and
splenectomy. Given the small number of patients treated with these strategies, the indications remain unclear [17]. In patients with autoimmune neutropenia, immunosuppressant therapy may be considered, although the treatment strategy is not well standardized [19]. Neither rituximab nor polyvalent immunoglobulins have been proven effective in this setting. Glucocorticoid therapy may be tried then continued in the event of a good response.
6. Conclusion Neutropenia is commonly encountered in rheumatology. Although many patients have minimal symptoms, emergency admission is mandatory in the event of very low neutrophil counts or a fever. The risk is the development of infections, which are chiefly due to bacteria, although fungal infections may occur if the neutropenia is prolonged. Drug-induced neutropenia should be considered first. Nevertheless, in patients with RA autoimmune neutropenia or Felty’s syndrome with or without LGL leukemia are other possible diagnoses. The therapeutic management depends on the depth of the neutropenia and on the results of the etiological workup.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
References [1] Price TH, Chatta GS, Dale DC. Effect of recombinant granulocyte colonystimulating factor on neutrophil kinetics in normal young and elderly humans. Blood 1996;88:335–40. [2] Youinou P, Jamin C, Le Pottier L, et al. Diagnostic criteria for autoimmune neutropenia. Autoimmun Rev 2014;13:574–6. [3] Elting LS, Rubenstein EB, Rolston KV, et al. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis 1997;25:247–59. [4] Donadieu J, Fenneteau O, Beaupain B, et al. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis 2011;6:26. [5] Carlsson G, Aprikyan AA, Tehranchi R, et al. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 2004;103:3355–61. [6] Horwitz M, Benson KF, Person RE, et al. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet 1999;23:433–6. [7] Aprikyan AA, Liles WC, Park JR, et al. Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. Blood 2000;95:320–7. [8] Thobakgale CF, Ndung’u T. Neutrophil counts in persons of African origin. Curr Opin Hematol 2014;21:50–7. [9] Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood 2014;124:1251–8. [10] Abdulkader R, Dharmapalaiah C, Rose G, et al. Late-onset neutropenia in patients with rheumatoid arthritis after treatment with rituximab. J Rheumatol 2014;41:858–61. [11] Autrel-Moignet A, Lamy T. Autoimmune neutropenia. Presse Med 2014;43: e105–18. [12] Bux J, Behrens G, Jaeger G, et al. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240 cases. Blood 1998;91:181–6. [13] Capsoni F, Sarzi-Puttini P, Zanella A. Primary and secondary autoimmune neutropenia. Arthritis Res Ther 2005;7:208–14. [14] Bux J, Kissel K, Nowak K, et al. Autoimmune neutropenia: clinical and laboratory studies in 143 patients. Ann Hematol 1991;63:249–52. [15] Liu X, Loughran Jr TP. The spectrum of large granular lymphocyte leukemia and Felty’s syndrome. Curr Opin Hematol 2011;18:254–9. [16] Lazaro E, Duffau P, Chaigne Delalande S, et al. [Large granular lymphocyte leukemia: clinical and pathogenic aspects]. Rev Med Interne 2013;34:553–60. [17] Ditzel HJ, Masaki Y, Nielsen H, et al. Cloning and expression of a novel human antibody-antigen pair associated with Felty’s syndrome. Proc Natl Acad Sci U S A 2000;97:9234–9. [18] Lamy T, Loughran Jr TP. How I treat LGL leukemia. Blood 2011;117:2764–74.
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[19] Dale DC, Bolyard AA, Schwinzer BG, et al. The severe chronic neutropenia international registry: 10-year follow-up report. Support Cancer Ther 2006;3: 220–31. [20] Borzutzky A, Reyes ML, Figueroa V, et al. Osteoporosis in children with severe congenital neutropenia: bone mineral density and treatment with bisphosphonates. J Pediatr Hematol Oncol 2006;28:205–9. [21] Vaccinations des personnes immunodéprimées ou aspléniques. Recommandations Haut Conseil de la santé publique; 2012. [22] Moignet A, Hasanali Z, Zambello R, et al. Cyclophosphamide as a first-line therapy in LGL leukemia. Leukemia 2014;28:1134–6.
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[23] Thobakgale CF, Ndung’u T. Neutrophil counts in persons of African origin. Curr Opin Hematol 2014;21:50–7. [24] Averbuch D, Orasch C, Cordonnier C, et al. European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia. Haematologica 2013;98:1826–35. [25] Vaccinations des personnes immunodéprimées ou aspléniques. Recommandations haut conseil de la santé publique; 2012.
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ARTICLE IN PRESS Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Review
Management of neutropenia in patients with rheumatoid arthritis Estibaliz Lazaro a,∗ , Jacques Morel a,b a b
Service de médecine interne, hôpital du Haut-Lévêque, université de Bordeaux, 33604 Pessac, France Département de rhumatologie, hôpital Lapeyronie, université de Montpellier 1, 34295 Montpellier cedex 5, France
a r t i c l e
i n f o
Article history: Accepted 10 December 2014 Available online xxx Keywords: Neutropenia Rheumatoid arthritis Felty syndrome Large granular lymphocytic leukemia Growth factors Infection
a b s t r a c t Neutropenia is defined as a neutrophil count lower than 1.5 g/L, with categorization as mild, moderate, or severe when the count is 1.5–1 g/L, 1–0.5 g/L, or < 0.5 g/L, respectively. The main complication is infection, whose risk increases with the depth and duration of the neutropenia. Comprehensive etiological investigations are mandatory to determine the best treatment strategy. Constitutional neutropenia is rarely seen in everyday rheumatology practice. It predominantly affects patients of African descent and is usually moderate and well tolerated. Congenital neutropenia due to genetic abnormalities is severe and chiefly seen in the pediatric population. Most cases of neutropenia in patients with rheumatoid arthritis (RA) are acquired. Medications are the most common causes, making detailed history-taking crucial. Many medications used to treat RA can induce neutropenia. Folic acid deficiency should be sought routinely in patients taking methotrexate. A less common cause of neutropenia is an RA-related autoimmune reaction. Splenomegaly suggests Felty’s syndrome, which is accompanied with large granular lymphocytic (LGL) leukemia in 40% of cases. The treatment depends on the depth of the neutropenia and findings from the etiological workup. A neutrophil count below 0.5 g/L, a fever, and the presence of clinical signs indicate a life-threatening condition requiring emergent treatment. In other patients, the first step is immediate discontinuation of any possibly involved drugs, simultaneously with the etiological workup. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Background: red flags Neutrophils are granulocytes that differentiate from the myeloid lineage. The normal peripheral neutrophil count in adults is 1.5 to 7 g/L [1]. A number of factors, including glucocorticoids, lead the neutrophils to detach from the vessel walls, a phenomenon known as demargination that increases the neutrophil counts in the bloodstream. Neutropenia is defined as a neutrophil count lower than 1.5 g/L, regardless of the normal ranges for the laboratory. Four grades are distinguished: 1.9–1.5 g/L (grade I), minimal; 1.5–1 g/L (grade II), mild; 1–0.5 g/L (grade III), moderate; and < 0.5 g/L (grade IV) or agranulocytosis, severe. Acute agranulocytosis is a life-threatening emergency [2]. The risk of infection depends on the neutropenia grade, the pace of the neutrophil drop, and the duration of neutropenia when longer than 10 days. Other factors that influence the severity of neutropenia include the presence of other cytopenias (anemia, thrombocytopenia) or of lymphocytosis. The risk of infection is increased in patients with chronic foci of infection, particularly in the upper or lower airways or ears; and in those with comorbidities such as kidney, respiratory,
∗ Corresponding author. Tel.: +33 557 656 483; fax: +33 557 656 484. E-mail address: [email protected] (E. Lazaro).
or heart failure. The main incident infections are due to bacteria (Staphylococcus aureus and Gram-negative bacilli) and fungi; there is no excess risk of viral or parasitic infections [3]. The risk of infection increases with the duration of the neutropenia. Acute agranulocytosis is the main reason for emergent hospital admission.
2. Pathophysiology Most neutrophils reside in the bone marrow. Fewer than 10% are located in the vascular compartment, including 45% circulating in the bloodstream and 55% adhering to the vessel walls (marginated pool). In patients with neutropenia, three mechanisms should be considered (Fig. 1) [4]: • peripheral destruction by an autoimmune reaction or toxic agent; • sequestration in the splenic or endothelial tissues (excessive margination); • and inadequate neutrophil production due to a congenital abnormality, bone marrow invasion, vitamin deficiency, or toxic agent.
http://dx.doi.org/10.1016/j.jbspin.2015.01.005 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Lazaro E, Morel J. Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.01.005
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Fig. 1. The main causes of neutropenia.
3. Causes of neutropenia Although congenital neutropenia should be considered as a matter of principle in children and young adults, neutropenia in patients with rheumatoid arthritis (RA) is usually acquired. 3.1. Acquired neutropenia Drugs are the main cause of neutropenia in RA. The culprits include synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate; and immunosuppressants such as cyclophosphamide and azathioprine, which are used only in systemic forms of RA. Many other drugs prescribed by rheumatologists can induce neutropenia, including nonsteroidal anti-inflammatory drugs, antimalarials, and sulfasalazine. More recently, neutropenia has been reported in patients taking biological agents such as rituximab, tocilizumab, and TNF␣ antagonists, although these drugs theoretically have little myelosuppressive potential. In rituximabtreated patients, the incidence of neutropenia has ranged across studies from 3% to 27%. The neutropenia is delayed (median time to development, 6 months) and correlates both with the depth of B-cell depletion and with an increased risk of infection [5–7]. With tocilizumab, neutropenia has been estimated to occur in 1/100 to 1/10 patients and develops within a few days after the infusion [8]. A correlation between the depth of neutropenia and the efficacy of tocilizumab was suggested but not confirmed by a recent cohort study [9,10]. TNF␣ antagonists has been reported to induce neutropenia with an incidence that varied but was lower than 1/10 patients overall. The pathophysiological mechanisms involved in biotherapy-induced neutropenia remain unclear. Recent work by Wright et al. established that tocilizumab has no pro-apoptotic effects on neutrophils [11]. The concomitant use of DMARDs in most patients complicates the assessment of a causal link between biotherapies and neutropenia and probably increases the risk of neutropenia. Therefore, a routine detailed inventory of all drug exposures must be established in all patients with neutropenia in order to detect a possible iatrogenic cause, before conducting investigations for other etiologies. Folic acid deficiency should be considered, most notably in patients taking methotrexate. Neutropenia may also be related to deficiencies in other substances, such as vitamin B12 or copper. Autoimmunity with the production of antibodies against granulocytes can cause neutropenia [12]. In patients with RA, the autoimmune process is usually related either to the RA itself or to concomitant Sjögren’s syndrome [12,13]. In this situation, autoantibodies against granulocytes exhibit pan-RF␥IIIb (pan-CD16b) activity. Primary autoimmune neutropenia is rare in adults. Women are affected in 70% of cases, and the course is usually chronic. Although spontaneous resolution does not occur, the disease is generally mild. Anti-granulocyte antibodies are detected in only 35% of cases and the diagnosis is therefore one of elimination [14]. In pediatric patients, primary autoimmune neutropenia is the leading
cause of neutropenia, with an estimated incidence of about 1/105 between 5 and 15 months of age [15]. The neutropenia is usually moderate to profound, and concomitant monocytosis is present in 30% of cases. The autoantibodies are chiefly directed against the RFc␥IIIb receptor group (HNA-1), principally the HNA-1a antigen. These autoantibodies cause excessive destruction of peripheral neutrophils. The bone marrow is usually normal. Associated infections are non-serious in most cases. Autoimmune neutropenia has also been reported in patients exposed to drugs. The autoimmune nature of the neutropenia is difficult to establish, as the diagnostic tests are extraordinarily difficult to interpret. A few cases of autoimmune neutropenia occur in patients with primary immune deficiencies such as common variable immune deficiency, Good syndrome, and IPEX syndrome. When there is no evidence that a drug, autoimmune process, or deficiency is responsible for the neutropenia, Felty’s syndrome or large granular lymphocytic (LGL) leukemia should be considered [16,17]. Felty’s syndrome is defined as the combination of neutropenia, RA, and splenomegaly. The neutropenia may be induced by antibodies directed against elongation factor A1, which is found in the nucleus but may be expressed on the cell membrane during apoptosis [18]. Neutrophil apoptosis may be induced by an interaction between the soluble pro-apoptotic cytokine FasL and the Fas receptor expressed on neutrophils. Among cases of Felty’s syndrome, 40% are related to LGL leukemia, which is characterized by proliferation of a T-cell or NK-cell clone. LGL leukemia should be considered in patients with moderate-to-severe neutropenia and lymphocytosis [17] (Fig. 2). The diagnosis rests on immunophenotyping of the blood lymphocytes: the results show expansion of CD3+, CD8+, CD57+, CD56− T cells or of CD3−, CD16+, CD56+ NK cells. The clonal nature of the proliferation should then be established, by TCR rearrangement or V repertoire tests for T cells and by KIR receptor or CD94 expression tests for NK cells. Neutropenia in patients with LGL leukemia is multifactorial: anti-granulocyte antibodies are produced, and neutrophil apoptosis is excessive. The prognosis depends chiefly on the risk of infection, with a 20% mortality rate after 4 years and a median survival longer than 10 years [19]. Finally, bone marrow invasion should be suspected, particularly when the neutropenia is accompanied with other cytopenias and/or the serum protein electrophoresis shows monoclonal gammopathy. 3.2. Congenital neutropenia Congenital forms of neutropenia are seen mainly in pediatric patients [20]. The three classical forms are severe congenital neutropenia, cyclic neutropenia, and WHIM syndrome. Severe congenital neutropenia or Kostmann syndrome is characterized by increased myeloid cell apoptosis [21]. A mutation in the ELA2 gene is identified in 50% of cases. Profound neutropenia is the rule, and there may be other biological abnormalities such as thrombocytosis or hypergammaglobulinemia. Patients are at risk for severe infections and secondary acute leukemia. Osteoporosis is often present in children and should be sought routinely. In contrast to severe congenital neutropenia, cyclic neutropenia and WHIM syndrome may produce only minimal symptoms, so that the diagnosis is not made until adulthood. Cyclic neutropenia is inherited on an autosomal dominant basis [22]. Episodes of neutropenia occur in 3-week-long cycles. Mutations in the ELA2 gene have been found. WHIM is the acronym for “warts, hypogammaglobulinemia, infections, myelokathexis”. WHIM syndrome is a rare autosomal dominant disease due to an activating mutation in the gene that encodes the chemokine receptor CXCR4 [7]. The depth of the neutropenia is variable.
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Fig. 2. Diagnostic strategy in patients with suspected large granular lymphocyte (LGL) leukemia.
3.3. Constitutional or ethnic neutropenia Constitutional or ethnic neutropenia has been reported in patients of African descent [23]. The neutropenia is generally mild, with counts that rarely drop below 1000/mm3 . Ethnic neutropenia correlates with absence of homozygous expression of the gene encoding the Duffy antigen/chemokine receptor (DARC). As DARC is among the targets of Plasmodium, the DARC-null phenotype confers protection against malaria, which explains its predominance among African populations. The link with neutropenia remains unclear but may involve decreased neutrophil migration through the endothelial cells that do not express DARC [23].
Table 1 Management of a patient with neutropenia. Evaluation for signs of severity
Etiological workup History taking
Investigations Evidence of infection Etiological test
4. Diagnostic management Patients with neutropenia should be asked about drug exposures, infections before or after the diagnosis of neutropenia, and any recent contact with a person who had an infectious disease. Ethnic origin from Africa should also be recorded. An evaluation of previous blood cell counts may indicate whether the neutropenia is chronic or cyclic. The physical examination should focus on abnormalities of the lymphoid organs (lymph nodes, spleen, and tonsils) and on signs suggesting an infection (fever, candidiasis, crepitant rales) (Table 1). Emergency hospital admission is required in the event of severe neutropenia and/or a fever. Otherwise, investigations can be performed on an outpatient basis [12]. A postprandial neutrophil count is mandatory. Demargination tests involving the administration of adrenaline or glucocorticoids are no longer used in clinical practice. Viral serological tests should include an HbS antigen assay and tests for the hepatitis C virus, cytomegalovirus, Epstein-Barr virus, and HIV. Polymerase chain reaction assays or serological tests for other agents may be performed if dictated by the clinical setting. Among tests for dysimmunity, assays for antinuclear antibodies and anti-cyclic citrullinated peptides should be performed. An anti-granulocyte antibody assay is part of the etiological workup but is difficult to interpret due to the high false-positive rate [4,12]. Serum protein
Neutropenia depth: < 0.5 g/L; 0.5–1 g/L; 1–1.5 g/L Clinical signs (fever, infection, aphthosis) Ethnicity History of infections History of neutropenia Exposure to medications Collection of samples for microbiological tests Viral serological tests Tests for autoimmunity Serum protein electrophoresis Immunophenotyping of blood lymphocytes Assays of vitamin B12, folic acid, and copper Bone marrow biopsy
electrophoresis to look for a monoclonal gammopathy should be performed routinely. Other routine tests include blood lymphocyte immunophenotyping and assays of vitamin B12, folic acid, and copper. When none of these tests identifies a cause to the neutropenia, investigation of the bone marrow may be considered to look for a cause of inadequate neutrophil production. 5. Therapeutic management Symptomatic treatment according to the standard of care in oncology is the first step. The cause should be treated as soon as it is identified. 5.1. Symptomatic treatment Emergency antibiotic therapy should be given as soon as an infection is suspected. The treatment should comply with the
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European recommendations issued at the 2011 consensus conference [24] Among other symptomatic treatments for neutropenia, only growth factor therapy seems useful [4]. Splenectomy is not effective and increases the risk of infections with encapsulated organisms. Polyvalent immunoglobulins have not been proven effective. Growth factors are reserved for patients with symptomatic neutropenia (recurrent infections and/or persistent aphthosis) [4]. In patients with RA, however, they may induce joint pain. If possible, growth factors should be administered only for short periods. If long-term therapy is required, the dosage should be adjusted to keep the neutrophil count between 0.5 and 1.5 g/L. No cases of leukemia induction have been reported in adults given long-term growth factor therapy. Data from registries in France and other countries show that the risk of myelodysplasia and acute leukemia correlates with the severity of the neutropenia (depth and infections), the cumulative dose, and the mean dose per granulocyte colony-stimulating factor (G-CSF) injection [19]. These treatment-related risks should be weighed against the risk of infection. The risk of osteoporosis has been found elevated in patients with constitutional neutropenia and may be further increased by G-CSF therapy [19,20]. Given the risk of infection, immunizations should be kept up to date in neutropenic patients [25]. The BCG is the only contraindicated vaccine. All other vaccines, including those containing live organisms, can be used, even in patients with severe neutropenia. There is a particularly strong recommendation to administer the seasonal influenza vaccine, pneumococcus vaccine, and varicellaherpes zoster vaccine. Nevertheless, the administration of live vaccines is not advisable in patients taking a biotherapy, immunosuppressants, or long-term glucocorticoid therapy in a daily dosage greater than 10 mg/d for at least 2 weeks. The appropriateness of prophylactic treatment should be discussed on a case-by-case basis, depending on the comorbidities and on the depth and duration of the neutropenia. Prophylactic antifungal therapy with itraconazole or voriconazole may deserve consideration in patients with prolonged neutropenia and counts lower than 0.5 g/L. Neither penicillin V nor cotrimoxazole has been proven effective for prophylaxis. 5.2. Etiological treatment Discontinuation of any drug possibly responsible for the neutropenia is mandatory. The patient should be interviewed in great detail about self-medication. The case should be reported routinely to the pharmacovigilance center. In patients with Felty’s syndrome, methotrexate is classically used, on an empirical basis. Three main immunosuppressants are used to treat LGL leukemia: methotrexate, ciclosporin, and cyclophosphamide, with overall response rates ranging from 40 to 60% [12,19]. Methotrexate is the most widely administered drug in patients with RA and neutropenia, as it is effective on both conditions. Ciclosporin is generally used in patients with concomitant erythroblastopenia or as a second-line drug after methotrexate. Presence of HLA DR4 seems strongly predictive of the therapeutic response to cyclosporine. However, long-term ciclosporin therapy carries a risk of kidney dysfunction and hypertension. Thus, the use of ciclosporin is currently very limited in patients with RA. Oral cyclophosphamide in a daily dosage of 50–100 mg is an alternative to methotrexate or ciclosporin, as the first-line drug or in the event of failure of the other two drugs, and tends to produce higher response rates [22]. The effectiveness of these immunosuppressants is usually evaluated after 4 months of treatment, at which point a change in the treatment regimen may be considered. Other treatment options in patients who fail to respond to these three immunosuppressants consist of purine analogs, alemtuzumab, and
splenectomy. Given the small number of patients treated with these strategies, the indications remain unclear [17]. In patients with autoimmune neutropenia, immunosuppressant therapy may be considered, although the treatment strategy is not well standardized [19]. Neither rituximab nor polyvalent immunoglobulins have been proven effective in this setting. Glucocorticoid therapy may be tried then continued in the event of a good response.
6. Conclusion Neutropenia is commonly encountered in rheumatology. Although many patients have minimal symptoms, emergency admission is mandatory in the event of very low neutrophil counts or a fever. The risk is the development of infections, which are chiefly due to bacteria, although fungal infections may occur if the neutropenia is prolonged. Drug-induced neutropenia should be considered first. Nevertheless, in patients with RA autoimmune neutropenia or Felty’s syndrome with or without LGL leukemia are other possible diagnoses. The therapeutic management depends on the depth of the neutropenia and on the results of the etiological workup.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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