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Abstract
Objective
This study estimated the prevalence and explored possible risk factors associated with neutropenia in hospitalized patients with systemic lupus erythematosus (SLE).
Methods
This review included 160 admissions of 85 SLE patients between 2006 and 2013. Neutropenia was defined as absolute neutrophil count (ANC) below 1,500/mm3. The baseline characteristics of the patients were compared between patients who experienced neutropenia and those who did not. Clinical and serological factors related to neutropenia episodes during admission were analyzed.
Results
Thirty-five (21.9%) neutropenic episodes were found among the 160 admissions. Most of the neutropenic episodes were mild to moderate. Severe neutropenia of ANC ＜500/mm3 occurred in 3.1% of the cases. Patients with neutropenia had higher frequencies of ANA (100.0% vs. 86.8%, p=0.042) and anti-double stranded DNA (87.5% vs. 60.4%, p=0.008), and satisfied more SLE classification criteria at the time of diagnosis than those without (5.1 vs. 4.6, p=0.009). Anemia, leukopenia, thrombocytopenia and low complement levels were frequently accompanied with neutropenia. Chronic kidney disease (odds ratio, 11.17; 95% confidence interval, 1.46∼85.27; p=0.020) was associated with neutropenia.
REFERENCES
1. Kaplan MJ. Neutrophils in the pathogenesis and manifestations of SLE. Nat Rev Rheumatol. 2011; 7:691–9.
2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997; 40:1725.
3. Keeling DM, Isenberg DA. Haematological manifestations of systemic lupus erythematosus. Blood Rev. 1993; 7:199–207.
4. Nossent JC, Swaak AJ. Prevalence and significance of haematological abnormalities in patients with systemic lupus erythematosus. Q J Med. 1991; 80:605–12.
5. Budman DR, Steinberg AD. Hematologic aspects of systemic lupus erythematosus. Current concepts. Ann Intern Med. 1977; 86:220–9.
6. Martínez-Baños D, Crispín JC, Lazo-Langner A, Sánchez-Guerrero J. Moderate and severe neutropenia in patients with systemic lupus erythematosus. Rheumatology (Oxford). 2006; 45:994–8.
7. Rustagi PK, Currie MS, Logue GL. Complement-activating antineutrophil antibody in systemic lupus erythematosus. Am J Med. 1985; 78:971–7.
8. Boxer LA, Greenberg MS, Boxer GJ, Stossel TP. Autoimmune neutropenia. N Engl J Med. 1975; 293:748–53.
9. Yamasaki K, Niho Y, Yanase T. Granulopoiesis in systemic lupus erythematosus. Arthritis Rheum. 1983; 26:516–21.
10. Starkebaum G, Price TH, Lee MY, Arend WP. Autoimmune neutropenia in systemic lupus erythematosus. Arthritis Rheum. 1978; 21:504–12.
11. Lee SW, Park MC, Lee SK, Park YB. Adjusted neutropenia is associated with early serious infection in systemic lupus erythematosus. Mod Rheumatol. 2013; 23:509–15.
12. Doria A, Iaccarino L, Ghirardello A, Zampieri S, Arienti S, Sarzi-Puttini P, et al. Long-term prognosis and causes of death in systemic lupus erythematosus. Am J Med. 2006; 119:700–6.
13. Bernatsky S, Boivin JF, Joseph L, Manzi S, Ginzler E, Gladman DD, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum. 2006; 54:2550–7.
14. Carli L, Tani C, Vagnani S, Signorini V, Mosca M. Leukopenia, lymphopenia, and neutropenia in systemic lupus erythematosus: Prevalence and clinical impact–A systematic literature review. Semin Arthritis Rheum. 2015; 45:190–4.
15. Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med. 2005; 353:2550–8.
16. Hughes WT, Armstrong D, Bodey GP, Brown AE, Edwards JE, Feld R, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis. 1997; 25:551–73.
17. Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis. 2014; 63:713–35.
18. Beyan E, Beyan C, Turan M. Hematological presentation in systemic lupus erythematosus and its relationship with disease activity. Hematology. 2007; 12:257–61.
19. Dias AM, do Couto MC, Duarte CC, Inês LP, Malcata AB. White blood cell count abnormalities and infections in one-year follow-up of 124 patients with SLE. Ann N Y Acad Sci. 2009; 1173; 103–7.
20. Kramers C, Hylkema MN, van Bruggen MC, van de Lagemaat R, Dijkman HB, Assmann KJ, et al. Anti-nucleo-some antibodies complexed to nucleosomal antigens show anti-DNA reactivity and bind to rat glomerular basement membrane in vivo. J Clin Invest. 1994; 94:568–77.
21. Ren Y, Tang J, Mok MY, Chan AW, Wu A, Lau CS. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus. Arthritis Rheum. 2003; 48:2888–97.
22. Donnelly S, Roake W, Brown S, Young P, Naik H, Words-worth P, et al. Impaired recognition of apoptotic neutrophils by the C1q/calreticulin and CD91 pathway in systemic lupus erythematosus. Arthritis Rheum. 2006; 54:1543–56.
23. Kurien BT, Newland J, Paczkowski C, Moore KL, Scofield RH. Association of neutropenia in systemic lupus erythematosus (SLE) with anti-Ro and binding of an immunolog-ically cross-reactive neutrophil membrane antigen. Clin Exp Immunol. 2000; 120:209–17.
24. Hsieh SC, Yu HS, Lin WW, Sun KH, Tsai CY, Huang DF, et al. Anti-SSB/La is one of the antineutrophil autoantibodies responsible for neutropenia and functional impairment of polymorphonuclear neutrophils in patients with systemic lupus erythematosus. Clin Exp Immunol. 2003; 131:506–16.
25. Brito-Zerón P, Soria N, Muñoz S, Bové A, Akasbi M, Belenguer R, et al. Prevalence and clinical relevance of autoimmune neutropenia in patients with primary Sjögren's syndrome. Semin Arthritis Rheum. 2009; 38:389–95.
26. Duckham DJ, Rhyne RL Jr, Smith FE, Williams RC Jr. Retardation of colony growth of in vitro bone marrow culture using sera from patients with Felty's syndrome, disseminated lupus erythematosus (SLE), rheumatoid arthritis, and other disease states. Arthritis Rheum. 1975; 18:323–33.
27. Lortholary O, Lefort A, Tod M, Chomat AM, Darras-Joly C, Cordonnier C. Club de Reflexion sur les Infections en Onco-Hématologie. Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia. Lancet Infect Dis. 2008; 8:612–20.
28. Wang Z, Wang Y, Zhu R, Tian X, Xu D, Wang Q, et al. Long-term survival and death causes of systemic lupus erythematosus in China: a systemic review of observational studies. Medicine (Baltimore). 2015; 94:e794.
29. Vasiliu IM, Petri MA, Baer AN. Therapy with granulocyte colony-stimulating factor in systemic lupus erythematosus may be associated with severe flares. J Rheumatol. 2006; 33:1878–80.
30. Kim YG, Kim SR, Hwang SH, Jung JY, Kim HA, Suh CH. Mesenteric vasculitis after G-CSF administration in a severe neutropenic patient with systemic lupus erythematosus. Lupus. 2016; 25:1381–4.
Table 1.
Initial characteristics of SLE patients at the time of SLE diagnosis according to the presence of neutropenia during hospitalization (n=85)
| Variable | With neutropenia (n=32) | Without neutropenia (n=53) | p-value |
|---|---|---|---|
| Female | 31 (96.9) | 47 (88.7) | 0.247 |
| Age at diagnosis (yr) | 32.8±11.7 | 31.1±11.7 | 0.253 |
| SLE criteria satisfaction | 5.1±1.1 | 4.6±1.3 | 0.009∗ |
| Manifestation at diagnosis | |||
| Malar rash | 11 (34.4) | 19 (35.8) | 0.890 |
| Discoid rash | 6 (18.8) | 11 (20.8) | 0.050 |
| Photosensitivity | 9 (28.1) | 11 (20.8) | 0.602 |
| Oral ulcer | 12 (37.5) | 13 (24.5) | 0.203 |
| Arthritis | 14 (43.8) | 31 (58.5) | 0.187 |
| Serositis | 5 (15.6) | 6 (11.3) | 0.740 |
| Hematologic | 23 (71.9) | 29 (54.7) | 0.116 |
| Renal | 10 (31.3) | 9 (17.0) | 0.126 |
| Neuropsychiatric | 2 (6.3) | 2 (3.8) | 0.630 |
| Autoantibody† | |||
| ANA | 32 (100) | 46 (86.8) | 0.042∗ |
| Anti-dsDNA | 28 (87.5) | 32 (60.4) | 0.008∗ |
| Anti-Sm | 7 (21.9) | 10 (18.9) | 0.737 |
| Anti-RNP | 11 (34.4) | 11 (20.8) | 0.165 |
| Anti-SSA/Ro | 15 (46.9) | 15 (28.3) | 0.083 |
| Anti-SSB/La | 6 (18.8) | 9 (17.0) | 0.836 |
| Lupus anticoagulant | 16 (50.0) | 20 (37.7) | 0.268 |
| Anticardiolipin antibody | 14 (43.8) | 22 (41.5) | 0.839 |
Table 2.
Characteristics of admissions with neutropenia in patients with SLE
| Variable | Total (n=35) |
Neutropenia |
||
|---|---|---|---|---|
| Mild* (n=17) | Moderate† (n=13) | Severe‡ (n=5) | ||
| Cause of admission | ||||
| Infection | 5 (14.3) | 1 (5.9) | 2 (15.4) | 2 (40.0) |
| SLE flare § | 27 (77.1) | 13 (76.5) | 11 (84.6) | 3 (60.0) |
| Others§ | 3 (8.6) | 3 (17.6) | 0 (0.0) | 0 (0.0) |
| Neutropenia duration (d) | 7.9±4.4 | 7.5±4.6 | 7.0±2.4 | 12.4±5.8 |
| Use of G-CSF | 2 (5.7) | 0 (0) | 0 (0) | 2 (40.0) |
| Neutropenic fever | 10 (28.6) | 0 (0) | 6 (46.2) | 4 (80.0) |
Table 3.
Comparison of clinical characteristics of admissions with and without neutropenia in patients with SLE
| Variable | With neutropenia (n=35) | Without neutropenia (n=125) | p-value |
|---|---|---|---|
| Age at admission (yr) | 36.7±11.8 | 36.9±11.2 | 0.971 |
| Disease duration (yr) | 5.3±8.1 | 4.9±5.0 | 0.690 |
| Cause of admission | |||
| Infection | 5 (14.3) | 21 (16.8) | 0.714 |
| SLE | 27 (77.1) | 95 (76.0) | 0.741 |
| Others† | 3 (8.6) | 9 (7.2) | 0.978 |
| Comorbidities | |||
| DM | 1 (2.9) | 3 (2.4) | 0.839 |
| Hypertension | 4 (11.4) | 13 (10.4) | 0.904 |
| Chronic kidney disease | 7 (20.0) | 2 (1.6) | 0.004∗ |
| Sjögren's syndrome | 3 (8.6) | 4 (3.2) | 0.234 |
| Medication in use | |||
| Glucocorticoid | 20 (57.1) | 95 (76.0) | 0.050 |
| Dose of glucocorticoid (mg) | 6.79±8.03 | 8.32±9.01 | 0.319 |
| Hydroxychloroquine | 13 (37.1) | 60 (48.0) | 0.153 |
| Cyclophosphamide | 2 (5.7) | 1 (0.8) | 0.104 |
| Azathioprine | 6 (17.1) | 20 (16.0) | 0.827 |
| MMF | 1 (2.9) | 5 (4.0) | 0.763 |
| Mizoribine | 3 (8.6) | 7 (5.6) | 0.383 |
| SLEDAI | 11.3±6.4 | 10.2±7.5 | 0.576 |
| Hemoglobin (mg/dL) | 10.3±1.9 | 11.2±2.1 | 0.029∗ |
| Leukocyte (/mm3) | 2,029.4±6,668.2 | 6,534.2±3,337.1 | 0.001∗ |
| Platelet (×103/mm3) | 149.0±71.9 | 190.9±93.1 | 0.029∗ |
| ESR (mm/h) | 21.23±16.81 | 24.47±19.92 | 0.250 |
| CRP (mg/dL) | 2.13±5.62 | 2.95±4.77 | 0.535 |
| Decreased C3 | 29 (82.9) | 68 (54.4) | 0.005∗ |
| Decreased C4 | 19 (54.3) | 35 (28.0) | 0.012∗ |
| Rise in anti-dsDNA titer | 27 (77.1) | 79 (63.2) | 0.207 |
| Presence of proteinuria‡ | 9 (25.7) | 28 (22.4) | 0.766 |
Values are presented as number (%) or mean±standard deviation. SLE: systemic lupus erythematosus, DM: diabetes mellitus, MMF: mycophenolate mofetil, SLEDAI: systemic lupus erythematosus disease activity index, ESR: erythrocyte sediment rate, CRP: C-reactive protein, C: complement, Anti-dsDNA: anti-double stranded deoxyribonucleic acid.
Table 4.
Risk factors associated with neutropenia during hospitalization in patients with SLE in univariate and multivariate analysis
| Variable |
Univariate |
Multivariate |
||||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | p-value | Odds ratio | 95% CI | p-value | |
| Age at admission | 0.99 | 0.96∼1.04 | 0.971 | - | - | - |
| Disease duration | 1.02 | 0.94∼1.09 | 0.690 | - | - | - |
| Cause of admission | ||||||
| Infection | 0.84 | 0.32∼2.18 | 0.714 | - | - | - |
| SLE | 1.16 | 0.49∼2.71 | 0.741 | - | - | - |
| Others† | 0.98 | 0.27∼3.63 | 0.978 | - | - | - |
| Comorbidities | ||||||
| DM | 1.27 | 0.12∼13.04 | 0.839 | - | - | - |
| Hypertension | 0.91 | 0.21∼4.02 | 0.904 | - | - | - |
| Chronic kidney disease | 16.38 | 2.44∼109.85 | 0.004∗ | 11.17 | 1.46∼85.27 | 0.020∗ |
| Sjögren's syndrome | 3.14 | 0.48∼20.67 | 0.234 | - | - | - |
| Medication in use | ||||||
| Glucocorticoid | 0.44 | 0.19∼1.00 | 0.050 | 0.51 | 0.18∼1.48 | 0.217 |
| Dose of glucocorticoid | 0.98 | 0.93∼1.03 | 0.319 | - | - | - |
| Hydroxychloroquine | 0.56 | 0.25∼1.24 | 0.153 | 0.70 | 0.22∼2.24 | 0.543 |
| Cyclophosphamide | 5.76 | 0.70∼47.72 | 0.104 | 5.57 | 0.89∼34.96 | 0.067 |
| Azathioprine | 1.12 | 0.41∼3.09 | 0.827 | - | - | - |
| MMF | 0.78 | 0.16∼3.90 | 0.763 | - | - | - |
| Mizoribine | 1.61 | 0.55∼4.73 | 0.383 | - | - | - |
| SLEDAI | 1.01 | 0.97∼1.06 | 0.576 | - | - | - |
| Hemoglobin | 0.82 | 0.68∼0.98 | 0.029∗ | 1.00 | 0.82∼1.22 | 0.995 |
| Leukocyte | 0.99 | 0.995∼0.998 | 0.001∗ | - | - | - |
| Platelet | 0.82 | 0.68∼0.98 | 0.029∗ | 1.00 | 0.99∼1.00 | 0.183 |
| ESR | 0.99 | 0.97∼1.01 | 0.250 | - | - | - |
| CRP | 0.97 | 0.86∼1.08 | 0.535 | - | - | - |
| Decreased C3 | 3.70 | 1.49∼9.18 | 0.005∗ | 2.130 | 0.69∼6.60 | 0.190 |
| Decreased C4 | 2.90 | 1.26∼6.65 | 0.012∗ | 1.635 | 0.52∼5.17 | 0.402 |
| Increased anti-dsDNA | 1.75 | 0.73∼4.15 | 0.207 | - | - | - |
| Presence of proteinuria‡ | 1.14 | 0.48∼2.69 | 0.766 | - | - | - |
SLE: systemic lupus erythematosus, CI: confidence interval, DM: diabetes mellitus, MMF: mycophenolate mofetil, SLEDAI: systemic lupus erythematosus disease activity index, ESR: erythrocyte sediment rate, CRP: C-reactive protein, C: complement, Anti-dsDNA: anti-double stranded deoxyribonucleic acid, −: not applicable.
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