Lupus (2014) 23, 1512–1516 http://lup.sagepub.com
CONCISE REPORT
Serious infections in systemic lupus erythematosus with a focus on pneumococcal infections RKMAC Luijten, BVJ Cuppen, JWJ Bijlsma and RHWM Derksen Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands
Background: Infections are important denominators of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Pneumococcus pneumoniae has been identified as a relatively frequent cause of serious infections in SLE and vaccination against this pathogen is possible. We analysed the incidence of serious infections in a cohort of SLE patients, focussing on Streptococcus pneumoniae. Methods: We retrospectively screened the medical records of all SLE patients who were regularly seen in the outpatient clinic of our department between January 2010 and December 2012. We registered all infections that necessitated admission to the hospital (serious infection) and compared relevant clinical and laboratory parameters and immunomodulating/immunosuppressive treatment in patients with and without serious infections. Results: In the total cohort of 260 patients, there were 132 episodes of serious infection in 70 patients, with a median follow-up per patient of 11.4 years (range 0 to 50.2 years). S. pneumoniae accounted for 11/132 (8.3%) serious infection episodes and eight of 11 episodes were invasive. With a follow-up of 3970.6 years for the total cohort, this leads to an incidence of 201/100.000 patient-years. In the multivariate analysis neither clinical parameters nor use of immunosuppressive drugs correlated with occurrence of serious infections. Conclusions: Compared to the incidence of invasive pneumococcal infections in the Dutch population (15.6/100.000 patient years), the incidence in SLE patients is 13 times higher. This, in combination with the absence of a relation to use of immunosuppressive drugs, is a strong argument to recommend vaccination against S. pneumoniae in all SLE patients. Lupus (2014) 23, 1512–1516. Key words: Systemic lupus erythematosus; infections; vaccination
Introduction Infections are common in systemic lupus erythematous (SLE) patients and have major impact on morbidity and mortality.1 Infections account for approximately a quarter of overall mortality in this disease,2 and up to half of all patients suffer from at least one severe infection (defined as infection leading to hospital admission) during the course of their disease.3 Apart from intrinsic abnormalities in the adaptive and innate immune system in patients with SLE, such as complement deficiency, decreased phagocytosis by polynuclear neutrophils and macrophages and functional asplenia,4 immunosuppressive treatment predisposes to Correspondence to: Remco Luijten, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. Email: [email protected] Received 13 February 2014; accepted 30 May 2014
infections. Streptococcus pneumoniae is a common pathogen in SLE patients.5 In our unit we advise yearly vaccination against influenza virus for all SLE patients. However, in contrast to recent recommendations we prevailingly vaccinated for S. pneumoniae in relation to splenectomy. The discrepancy between daily practice over the last 25 years and the recent recommendations was the reason for this retrospective study on serious infections in SLE patients followed in our unit.
Patients and methods Included in the study were all SLE patients with at least one regular visit between November 2010 and June 2012 in the outpatient clinic of the Department of Rheumatology and Clinical Immunology of the University Medical Center Utrecht, The Netherlands.
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
10.1177/0961203314543918
Serious infections in SLE with a focus on pneumococcal infections RKMAC Luijten et al.
1513
100 90 80 70 60 50 40 30 20 10 0
Total Study cohort With serious infecnos Without serious infecons
Figure 1 Cumulative American College of Rheumatology criteria per patient category.
Baseline characteristics included age, sex, year of diagnosis, years of follow-up and the American College of Rheumatology (ACR) criteria for the classification of SLE fulfilled cumulatively (Figure 1) and prednisone and cyclophosphamide use ever. The medical records of all SLE patients were screened for the occurrence of serious infections since the diagnosis of their disease. Serious infections were defined as infections necessitating admission to the hospital plus a positive culture and/or at least two of the following clinical criteria: fever, raised acute phase reaction in blood, focal complaints/abnormalities (e.g. leucocyturia or pulmonary infiltrate) and leucocytosis. Only if cultures showed S. pneumoniae was the episode considered a pneumococcal infection. An invasive pneumococcal infection was present if the (positive) culture was taken from a normally sterile focus (e.g. blood or liquor; not lung or sputum). We documented for the year preceding a serious infectious episode the use and dose of immunomodulating/immunosuppressive drugs. Laboratory parameters, namely levels of complement factors C3 (normal values 0.90–1.80 g/l), C4 (normal values 0.10–0.47 g/l), immunoglobulin G (IgG) (normal values 7.0–16.0 g/l) and the presence of leucopenia (leucocytes 30 mg. Statistical methods In the univariate and multivariate analysis, p values for clinical risk factors on infections were calculated, using chi-squares and logistic regression analysis, respectively. Results were considered significant with p values 30 mg) Cyclophosphamide year before No Yes a
Control patients
Serious infection episodes
Serious pneumococcal infections
invasive pneumococcal episodes
n ¼ 73a 33 (44.6%) 12 (16.4%) 5 (6.8%) 20 (27.4%) 3 (4.1%) n ¼ 74 72 (97.3%) 2 (2.7%)
n ¼ 126a 24 (19%) 17 (13.5%) 14 (11.1%) 46 (36.5%) 25 (19.8%) n ¼ 128a 109 (85.2%) 19 (14.8%)
n ¼ 10a 1 (10%) 4 (40%) 1 (10%) 2 (20%) 2 (20%) n ¼ 11 10 (90.9%) 1 (9.1%)
n ¼ 7a 1 (14.3%) 2 (28.6%) 1 (14.3%) 2 (28.6%) 1 (14.3%) n¼8 8 (100%) 0 (0%)
Missing data on medication use in some patients.
suggest that vaccination for S. pneumoniae could be of benefit in all SLE patients, which is in concordance with the opinions of others.4,11,13 An estimate of the costs of admissions for one invasive pneumococcal infections is E10.657,50 (E490 a day multiplied by 21.75 days admission per episode).14 The 23-valent pneumococcal vaccine costs on average E29.50, which covers five years of protection. Given an antibody response of 80%,15 one needs 120 vaccinations to prevent one invasive pneumococcal disease episode; total costs E3540. This rough calculation suggests that vaccination of all SLE patients is cost saving. One weakness of our study is the retrospective design which, among others, hampers proper evaluation of disease activity in relation to infection episodes. However, despite these drawbacks this study gives insight into serious infections in our SLE cohort and points to the need for vaccination against S. Pneumoniae.
Conclusion Because pneumococcal disease is 13 times more frequent in SLE patients, irrespective of their immunomodulatory treatment, than in the normal population, we would advise vaccinating all SLE patients irrespective of the use of immunomodulating-suppressive drugs.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgement The authors thank M.S. Jurgens contribution in the statistical analysis.
for
her
References 1 Goldblatt F, Chambers S, Rahman A, Isenberg DA. Serious infections in British patients with systemic lupus erythematosus: Hospitalisations and mortality. Lupus 2009; 18: 682–689. 2 Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82: 299–308. 3 Petri M. Infection in systemic lupus erythematosus. Rheum Dis Clin North Am 1998; 24: 423–456. 4 Millet A, Decaux O, Perlat A, Grosbois B, Jego P. Systemic lupus erythematosus and vaccination. Eur J Intern Med 2009; 20: 236–241. 5 Hill MD, Karsh J. Invasive soft tissue infections with Streptococcus pneumoniae in patients with systemic lupus erythematosus: Case report and review of the literature. Arthritis Rheum 1997; 40: 1716–1719. 6 Al-Rayes H, Al-Swailem R, Arfin M, Sobki S, Rizvi S, Tariq M. Systemic lupus erythematosus and infections: A retrospective study in Saudis. Lupus 2007; 16: 755–763. 7 Bosch X, Guilabert A, Pallares L, et al. Infections in systemic lupus erythematosus: A prospective and controlled study of 110 patients. Lupus 2006; 15: 584–589. 8 Noel V, Lortholary O, Casassus P, et al. Risk factors and prognostic influence of infection in a single cohort of 87 adults with systemic lupus erythematosus. Ann Rheum Dis 2001; 60: 1141–1144. 9 Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, MartinezBerriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009; 11: R109. 10 Jansen AG, Rodenburg GD, de Greeff SC, et al. Invasive pneumococcal disease in the Netherlands: Syndromes, outcome and potential vaccine benefits. Vaccine 2009; 27: 2394–2401. Lupus
Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
Serious infections in SLE with a focus on pneumococcal infections RKMAC Luijten et al.
1516 11 Kamen DL. How can we reduce the risk of serious infection for patients with systemic lupus erythematosus? Arthritis Res Ther 2009; 11: 129. 12 Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010; 69: 1269–1274. 13 Barber C, Gold WL, Fortin PR. Infections in the lupus patient: Perspectives on prevention. Curr Opin Rheumatol 2011; 23: 358–365.
14 Hakkaart-van Roijen L TSBC. Handleiding voor kostenonderzoek. Methoden en standaard kostprijzen voor economische evaluaties in de gezondheidszorg. College voor Zorgverzekeringen. College voor Zorgverzekeringen, 2010. 15 Elkayam O, Paran D, Caspi D, et al. Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus. Clin Infect Dis 2002; 34: 147–153.
Lupus Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
CONCISE REPORT
Serious infections in systemic lupus erythematosus with a focus on pneumococcal infections RKMAC Luijten, BVJ Cuppen, JWJ Bijlsma and RHWM Derksen Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, The Netherlands
Background: Infections are important denominators of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Pneumococcus pneumoniae has been identified as a relatively frequent cause of serious infections in SLE and vaccination against this pathogen is possible. We analysed the incidence of serious infections in a cohort of SLE patients, focussing on Streptococcus pneumoniae. Methods: We retrospectively screened the medical records of all SLE patients who were regularly seen in the outpatient clinic of our department between January 2010 and December 2012. We registered all infections that necessitated admission to the hospital (serious infection) and compared relevant clinical and laboratory parameters and immunomodulating/immunosuppressive treatment in patients with and without serious infections. Results: In the total cohort of 260 patients, there were 132 episodes of serious infection in 70 patients, with a median follow-up per patient of 11.4 years (range 0 to 50.2 years). S. pneumoniae accounted for 11/132 (8.3%) serious infection episodes and eight of 11 episodes were invasive. With a follow-up of 3970.6 years for the total cohort, this leads to an incidence of 201/100.000 patient-years. In the multivariate analysis neither clinical parameters nor use of immunosuppressive drugs correlated with occurrence of serious infections. Conclusions: Compared to the incidence of invasive pneumococcal infections in the Dutch population (15.6/100.000 patient years), the incidence in SLE patients is 13 times higher. This, in combination with the absence of a relation to use of immunosuppressive drugs, is a strong argument to recommend vaccination against S. pneumoniae in all SLE patients. Lupus (2014) 23, 1512–1516. Key words: Systemic lupus erythematosus; infections; vaccination
Introduction Infections are common in systemic lupus erythematous (SLE) patients and have major impact on morbidity and mortality.1 Infections account for approximately a quarter of overall mortality in this disease,2 and up to half of all patients suffer from at least one severe infection (defined as infection leading to hospital admission) during the course of their disease.3 Apart from intrinsic abnormalities in the adaptive and innate immune system in patients with SLE, such as complement deficiency, decreased phagocytosis by polynuclear neutrophils and macrophages and functional asplenia,4 immunosuppressive treatment predisposes to Correspondence to: Remco Luijten, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands. Email: [email protected] Received 13 February 2014; accepted 30 May 2014
infections. Streptococcus pneumoniae is a common pathogen in SLE patients.5 In our unit we advise yearly vaccination against influenza virus for all SLE patients. However, in contrast to recent recommendations we prevailingly vaccinated for S. pneumoniae in relation to splenectomy. The discrepancy between daily practice over the last 25 years and the recent recommendations was the reason for this retrospective study on serious infections in SLE patients followed in our unit.
Patients and methods Included in the study were all SLE patients with at least one regular visit between November 2010 and June 2012 in the outpatient clinic of the Department of Rheumatology and Clinical Immunology of the University Medical Center Utrecht, The Netherlands.
! The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav
Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
10.1177/0961203314543918
Serious infections in SLE with a focus on pneumococcal infections RKMAC Luijten et al.
1513
100 90 80 70 60 50 40 30 20 10 0
Total Study cohort With serious infecnos Without serious infecons
Figure 1 Cumulative American College of Rheumatology criteria per patient category.
Baseline characteristics included age, sex, year of diagnosis, years of follow-up and the American College of Rheumatology (ACR) criteria for the classification of SLE fulfilled cumulatively (Figure 1) and prednisone and cyclophosphamide use ever. The medical records of all SLE patients were screened for the occurrence of serious infections since the diagnosis of their disease. Serious infections were defined as infections necessitating admission to the hospital plus a positive culture and/or at least two of the following clinical criteria: fever, raised acute phase reaction in blood, focal complaints/abnormalities (e.g. leucocyturia or pulmonary infiltrate) and leucocytosis. Only if cultures showed S. pneumoniae was the episode considered a pneumococcal infection. An invasive pneumococcal infection was present if the (positive) culture was taken from a normally sterile focus (e.g. blood or liquor; not lung or sputum). We documented for the year preceding a serious infectious episode the use and dose of immunomodulating/immunosuppressive drugs. Laboratory parameters, namely levels of complement factors C3 (normal values 0.90–1.80 g/l), C4 (normal values 0.10–0.47 g/l), immunoglobulin G (IgG) (normal values 7.0–16.0 g/l) and the presence of leucopenia (leucocytes 30 mg. Statistical methods In the univariate and multivariate analysis, p values for clinical risk factors on infections were calculated, using chi-squares and logistic regression analysis, respectively. Results were considered significant with p values 30 mg) Cyclophosphamide year before No Yes a
Control patients
Serious infection episodes
Serious pneumococcal infections
invasive pneumococcal episodes
n ¼ 73a 33 (44.6%) 12 (16.4%) 5 (6.8%) 20 (27.4%) 3 (4.1%) n ¼ 74 72 (97.3%) 2 (2.7%)
n ¼ 126a 24 (19%) 17 (13.5%) 14 (11.1%) 46 (36.5%) 25 (19.8%) n ¼ 128a 109 (85.2%) 19 (14.8%)
n ¼ 10a 1 (10%) 4 (40%) 1 (10%) 2 (20%) 2 (20%) n ¼ 11 10 (90.9%) 1 (9.1%)
n ¼ 7a 1 (14.3%) 2 (28.6%) 1 (14.3%) 2 (28.6%) 1 (14.3%) n¼8 8 (100%) 0 (0%)
Missing data on medication use in some patients.
suggest that vaccination for S. pneumoniae could be of benefit in all SLE patients, which is in concordance with the opinions of others.4,11,13 An estimate of the costs of admissions for one invasive pneumococcal infections is E10.657,50 (E490 a day multiplied by 21.75 days admission per episode).14 The 23-valent pneumococcal vaccine costs on average E29.50, which covers five years of protection. Given an antibody response of 80%,15 one needs 120 vaccinations to prevent one invasive pneumococcal disease episode; total costs E3540. This rough calculation suggests that vaccination of all SLE patients is cost saving. One weakness of our study is the retrospective design which, among others, hampers proper evaluation of disease activity in relation to infection episodes. However, despite these drawbacks this study gives insight into serious infections in our SLE cohort and points to the need for vaccination against S. Pneumoniae.
Conclusion Because pneumococcal disease is 13 times more frequent in SLE patients, irrespective of their immunomodulatory treatment, than in the normal population, we would advise vaccinating all SLE patients irrespective of the use of immunomodulating-suppressive drugs.
Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.
Conflict of interest statement The authors have no conflicts of interest to declare.
Acknowledgement The authors thank M.S. Jurgens contribution in the statistical analysis.
for
her
References 1 Goldblatt F, Chambers S, Rahman A, Isenberg DA. Serious infections in British patients with systemic lupus erythematosus: Hospitalisations and mortality. Lupus 2009; 18: 682–689. 2 Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003; 82: 299–308. 3 Petri M. Infection in systemic lupus erythematosus. Rheum Dis Clin North Am 1998; 24: 423–456. 4 Millet A, Decaux O, Perlat A, Grosbois B, Jego P. Systemic lupus erythematosus and vaccination. Eur J Intern Med 2009; 20: 236–241. 5 Hill MD, Karsh J. Invasive soft tissue infections with Streptococcus pneumoniae in patients with systemic lupus erythematosus: Case report and review of the literature. Arthritis Rheum 1997; 40: 1716–1719. 6 Al-Rayes H, Al-Swailem R, Arfin M, Sobki S, Rizvi S, Tariq M. Systemic lupus erythematosus and infections: A retrospective study in Saudis. Lupus 2007; 16: 755–763. 7 Bosch X, Guilabert A, Pallares L, et al. Infections in systemic lupus erythematosus: A prospective and controlled study of 110 patients. Lupus 2006; 15: 584–589. 8 Noel V, Lortholary O, Casassus P, et al. Risk factors and prognostic influence of infection in a single cohort of 87 adults with systemic lupus erythematosus. Ann Rheum Dis 2001; 60: 1141–1144. 9 Ruiz-Irastorza G, Olivares N, Ruiz-Arruza I, MartinezBerriotxoa A, Egurbide MV, Aguirre C. Predictors of major infections in systemic lupus erythematosus. Arthritis Res Ther 2009; 11: R109. 10 Jansen AG, Rodenburg GD, de Greeff SC, et al. Invasive pneumococcal disease in the Netherlands: Syndromes, outcome and potential vaccine benefits. Vaccine 2009; 27: 2394–2401. Lupus
Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
Serious infections in SLE with a focus on pneumococcal infections RKMAC Luijten et al.
1516 11 Kamen DL. How can we reduce the risk of serious infection for patients with systemic lupus erythematosus? Arthritis Res Ther 2009; 11: 129. 12 Mosca M, Tani C, Aringer M, et al. European League Against Rheumatism recommendations for monitoring patients with systemic lupus erythematosus in clinical practice and in observational studies. Ann Rheum Dis 2010; 69: 1269–1274. 13 Barber C, Gold WL, Fortin PR. Infections in the lupus patient: Perspectives on prevention. Curr Opin Rheumatol 2011; 23: 358–365.
14 Hakkaart-van Roijen L TSBC. Handleiding voor kostenonderzoek. Methoden en standaard kostprijzen voor economische evaluaties in de gezondheidszorg. College voor Zorgverzekeringen. College voor Zorgverzekeringen, 2010. 15 Elkayam O, Paran D, Caspi D, et al. Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus. Clin Infect Dis 2002; 34: 147–153.
Lupus Downloaded from lup.sagepub.com at GEORGE WASHINGTON UNIVERSITY on February 20, 2015
