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Connective tissue diseases: The burden of serious infections in SLE

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Jessica Widdifield at Sunnybrook Health Sciences Centre
Jessica Widdifield
Sasha Bernatsky
Sasha Bernatsky
Sasha Bernatsky
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Abstract

Is the risk of hospitalization and death due to serious infections on the rise in patients with systemic lupus erythematosus (SLE)? A population-based study provides insights into these trends and highlights the need for safe, effective treatment strategies in SLE.
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NATURE REVIEWS
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RHEUMATOLOGY ADVANCE ONLINE PUBLICATION
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1
NEWS & VIEWS
CONNECTIVE TISSUE DISEASES
The burden of serious infections
inSLE
Jessica Widdifield and Sasha Bernatsky
Refers to Tektonidou, M.G. etal. Burden of serious infections in adults with systemic lupus erythematosus. A national
population‑based study, 1996–2011. Arthritis Care Res. (Hoboken) http://dx.doi.org/10.1002/acr.22575
Is the risk of hospitalization and death due to serious infections on the
rise in patients with systemic lupus erythematosus (SLE)? A population-
based study provides insights into these trends and highlights the need
for safe, effective treatment strategies in SLE.
Understanding the burden of serious com-
plications and excess mortality in chronic
diseases is imperative to improve patient
outcomes. Despite improvements in sur-
vival among patients with systemic lupus
erythematosus (SLE) in recent years, infec-
tions remain one of the leading causes
of morbidity and mortality,1 making the
management and prevention of infections
a top priority for physicians caring for these
patients. Research over the past decade has
identified many factors that contribute
to the increased susceptibility of patients
with SLE to infections, such as immune
abnormalities, organ-system manifesta-
tions associated with the disease, genetic
predisposition and the immunosuppressive
and cytotoxic effects of treatments. A US
population-based study has now explored
the morbidity and mortality associated with
serious infections in this group of patients.2
In the general population, hospitalizations
for infections have increased over time,3
probably reflecting the ageing of the popu-
lation and the corresponding accumulation
of comorbidities and increased frequencyof
medical interventions. Fortunately, in-
hospital deaths from serious infections have
decreased, which could reflect improve-
ments in overall health care. Tektonidou
etal.2 investigated whether similar trends
have occurred in adults with SLE by assess-
ing hospitalizations for serious infections in
relation to the general population, and com-
paring infection-related mortality among
inpatients with and without SLE. The authors
found a high burden of hospitalizations for
serious infections among patients with SLE,
which increased substantially over the study
period (1996–2011).
For each of the five types of serious infec-
tions studied (pneumonia, sepsis, urinary
tract infection, skin and soft tissue infec-
tions, and opportunistic infections), the risk
of hospitalization was more than 12-fold
higher among patients with SLE than in the
general population in 2011. Pneumonia was
the most common serious infection requir-
ing hospitalization. In-hospital mortality
was highest for patients with SLE who had
opportunistic infections or sepsis; however,
when compared with patients without SLE,
only those with opportunistic infections were
clearly shown to be at increased risk of mor-
tality (adjusted OR 1.52; 95%CI 1.12–2.07).
Similar to patterns in the general population,
in-hospital mortality generally decreased for
all types of infections in more recent years.
The study’s authors analysed data from the
US Nationwide Inpatient Sample, identifying
adults whose discharge diagnoses included
both SLE and infection.2 Along with poten-
tial misclassification due to coding errors and
missing data inherent to the data source (for
example, deaths after discharge from hospi-
tal), another potential limitation of the study
could arise from difficulties in differentiating
between infections and SLE flares (or identi-
fying their coexistence), as infections can
mimic exacerbations of SLE.4 Moreover, the
reasons for the observed increased number of
hospitalizations for infections among patients
with SLE in this study warrant further investi-
gation, being possibly related to a greater
recognition and diagnosis of SLE, a lower
threshold for admitting these patients or the
use of more aggressive treatment s trategies
with immunosuppressive medications.
Although the study did not include infor-
mation about use of specific medications
amongst the SLE population, and despite
the aforementioned limitations, the results
underscore the increasing burden of serious
infections and the elevated mortality in SLE.
Furthermore, the analyses were limited to
data on hospitalizations, whereas many bur-
densome infections (such as herpes zoster)
are managed outside the hospital; thus,the
study almost certainly underestimates
thefull burden of infections in SLE.
Under-recognition of the potentially ‘fatal’
nature of rheumatic diseases is recognized
as a serious problem for the rheumatology
community.5 The changing epidemiology
of serious infections in a rapidly growing
population of immunocompromised
patients presents a real challenge to physi-
cians. It is estimated that at least 50% of SLE
patients will experience a serious infection
during the course of their disease.6 As well,
the incidence of infections in patients with
SLE seems to be highest in the first 5years
after disease onset.7 One reason for this
increase might be the need of many patients,
particularly early in the disease course, for
high-dose corticosteroids, which can greatly
heighten infection risk.
The 2008 EULAR recommendations for
the management of SLE advise careful titra-
tion of corticosteroids and other immuno-
suppressive agents against disease activity,
prompt evaluation for infections, prophy lactic
use of antibiotics for patients at high risk of
certain infections (such as subacute bacterial
endocarditis in patients with valvular abnor-
malities and Pneumocystis jirovecii in patients
receiving intensive immuno suppressive treat-
ment), and immunizations similar to those
advised for the general population.8 However,
no randomized studies support the effective-
ness of this approach in SLE. EULAR has also
published, in 2011, specific recommenda-
tions related to vaccination in adult patients
with autoimmune inflammatory rheumatic
diseases.9 Vaccines against influenza and
pneumococcus seem to be safe and immuno-
genic in patients with SLE and their routine
administration should be encouraged;
‘‘
…infections remain one of
the leading causes of morbidity
andmortality
’’
© 2015 Macmillan Publishers Limited. All rights reserved
2
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ADVANCE ONLINE PUBLICATION www.nature.com/nrrheum
NEWS & VIEWS
however, many patients with SLE do not
receive these vaccinations, the most common
reason being the failure of their health-care
provider to recommendthem.10
Last, but not least, the article by
Tektonidou etal.2 raises yet again the issue
of the need for safe, effective treatment
strategies in SLE. Optimal prevention and
management of infections, and further
understanding of the risk of infection among
patients with SLE receiving active anti-
rheumatic treatment is necessary to improve
their care and outcomes. Perhaps the best
approach to counter serious infections is the
development of less-damaging methods of
immune suppression.
Division of Clinical Epidemiology, Research
Institute of the McGill University Health Centre,
687 Pine Avenue West, V‑Building, Montreal,
QCH3A1A1, Canada (J.W., S.B.).
Correspondence to: S.B.
sasha.bernatsky@mcgill.ca
doi:10.1038/nrrheum.2015.55
Published online 21 April 2015
Acknowledgements
S.B. holds a career award from the Fonds de la
recherche en santé du Québec (FRSQ). J.W. is
supported by fellowship awards from The Arthritis
Society and the Canadian Institutes of Health
Research (Banting).
Competing interests
The authors declare no competing interests.
1. Yurkovich, M., Vostretsova, K., Chen, W.
&Avina-Zubieta, J.A. Overall and cause-specific
mortality in patients with systemic lupus
erythematosus: a meta-analysis of
observational studies. Arthritis Care Res.
(Hoboken) 66, 608–616 (2014).
2. Tektonidou, M.G., Wang, Z., Dasgupta, A.
&Ward, M.M. Burden of serious infections
inadults with systemic lupus erythematosus.
Anational population-based study, 1996–
2011. Arthritis Care Res. (Hoboken) http://
dx.doi.org/10.1002/acr.22575.
3. Curns, A.T., Holman, R.C., Sejvar, J.J.,
Owings,M.F. & Schonberger, L.B. Infectious
disease hospitalizations among older adults
inthe United States from 1990 through 2002.
Arch. Intern. Med. 165, 2514–2520 (2005).
4. Sciascia, S. etal. Systemic lupus erythematosus
and infections: clinical importance of
conventional and upcoming biomarkers.
Autoimmun. Rev. 12, 157–163 (2012).
5. Pincus, T., Gibson, K.A. & Block, J.A.
Mortality—the neglected outcome in rheumatic
diseases? Arthritis Care Res. (Hoboken) http://
dx.doi.org/10.1002/acr.22554.
6. Bouza, E., Moya, J.G. & Muñoz P. Infections in
systemic lupus erythematosus and rheumatoid
arthritis. Infect. Dis. Clin. Nor th Am. 15, 335–361
(2001).
7. Kamen, D.L. How can we reduce the risk of
serious infection for patients with systemic
lupus erythematosus? Arthritis Res. Ther. 11,
129 (2009).
8. Bertsias, G. etal. EULAR recommendations
forthe management of systemic lupus
erythematosus. Report of a Task Force
oftheEULAR Standing Committee for
International Clinical Studies Including
Therapeutics. Ann.Rheum. Dis. 67, 195–205
(2008).
9. van Assen, S. etal. EULAR recommendations
for vaccination in adult patients with
autoimmune inflammatory rheumatic
diseases.Ann. Rheum. Dis. 70, 414–422
(2011).
10. Lawson, E.F., Trupin, L., Yelin, E.H.
&Yazdany,J. Reasons for failure to receive
pneumococcal and influenza vaccinations
among immunosuppressed patients with
systemic lupus erythematosus. Semin.
ArthritisRheum. http://dx.doi.org/10.1016/
j.semarthrit.2015.01.002.
© 2015 Macmillan Publishers Limited. All rights reserved
... Two severity indices of RA like high erythrocyte sedimentation rate (ESR) and rheumatoid factor positivity tend to be predictive of the advancement of severe infection in RA patients. The risk of severe infection in patients with systemic lupus erythematosus (SLE) was also assessed and it was discovered that in SLE, 20-30% of deaths are induced by infection [13]. In a study, the risk of serious infections in SLE was roughly five times higher than in RA patients. ...
Aetiologies of Acute Complications in Autoimmune Rheumatologic Diseases: A Hospital-Based Cross-Sectional Study
Article
Full-text available
  • Mar 2023
Background: Autoimmune rheumatic diseases (ARD) present unique challenges in clinical practice. Many of them present in medical emergencies in an unstable state and need immediate evaluation for further plans of action. The clinical conundrum is to distinguish between sepsis, disease flare, or Addisonian crisis (AC) (secondary to steroid withdrawal). This may be further complicated by overlapping clinical features like shock/fever and the coexistence of a combination of the above pathophysiologic mechanisms (e.g. AC with sepsis or AC with disease flare). The known biomarkers may not perform optimally to distinguish them and additional supportive investigations like imaging, cultures, autoimmune serological markers, etc. are needed. Ultimately the boundaries between "the art of medicine" and "the science of medicine" may get blurred, as the established literature evidence falls short and the expert opinion is needed in a time-sensitive manner. In this pragmatic study, researchers have attempted to explore the presentation of rheumatologic emergencies on the above three differentials (sepsis, disease flare, and AC). Materials and methods: In this hospital-based cross-sectional study, adult patients (age >18 years) with ARD who had unplanned hospital admission due to acute worsening were enrolled. This study was conducted over one year, after getting the Institutional Human Ethics Committee's approval. All relevant hematological, immunological, and hormonal parameters (specifically morning cortisol) were collected and analyzed. The aim was to find the individual and combined prevalence of sepsis, disease flare, or AC in this study group. Results: Forty-one patients were analyzed, with females in the majority (95%) and the dominant age group being 26-49 years (56.1%). A majority had a diagnosis of rheumatoid arthritis (RA) (56.1%) or systemic lupus erythematosus (SLE) (31.7%); the rest were other connective tissue diseases (12.2%). High-risk Quick Sequential Organ Failure Assessment score (qSOFA) score 2-3 was present in 29.3% while the rest had low-risk scores (qSOFA score 0-1). Thirty-two percent had severe disease activity, 46% had mild to moderate disease activity, and 22% of patients had no disease activity. While 78% of patients had low procalcitonin (PCT) values <0.5 microgm/L (low risk of sepsis), 15% had <20 microgm/L, and 7% percentage of patients had serum levels >20 microgm/L (high risk of sepsis). A total of 73.2% of patients had no evidence of infection while 26.8% had either microbiological/radiological evidence of infection. Only 7% of all patients had the presence of an AC. qSOFA scores didn't statistically correlate with a diagnosis of infection or AC but positively correlated with PCT and C-reactive protein (CRP) values. Serum PCT didn't correlate with the presence of infection with statistically significance (p-value 0.217). Conclusion: Infections and sepsis are the most important considerations in the emergency presentations of ARDs. Disease flare and AC are also important differentials. Current inflammatory biomarkers like serum CRP and PCT may be less valuable for discriminating between infectious and non-infectious sepsis, especially in chronic inflammatory diseases like ARDs. qSOFA scores may have a prognostic role with less discriminant value. Management of ARD emergencies needs better biomarkers and more research is warranted.
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... Some cases of flares have been described after vaccination against Table 5 Encephalitis related to major Abs a to neuronal cell surface antigens and their clinical characteristics (adapted from Refs. [3,107,109,148e151] [126]. In addition to adapted strategies of vaccination described above, there is an urgent need to replace immunosuppressive drugs by molecules that will modulate the autoimmune response without affecting the whole immune system [127,128]. ...
View
... The risk of serious infections in cases of SLE was reviewed recently. [29] In SLE, 20 -30% of deaths are caused by infections. In a US study, the rate of serious infections in SLE was ~10.8/100 patient-years, which is approximately 5 times higher than in RA patients. ...
Infections in the management of rheumatic diseases: An update
Article
Full-text available
  • Nov 2015
Patients with inflammatory rheumatic conditions have an increased risk of infection. While this could be the result of the underlying disease, it may also be caused by the use of immunosuppressive therapies, which are needed to treat these disorders. An increasing number of patients with rheumatoid arthritis or other rheumatic diseases are using biologic therapies (biologics) in addition to the synthetic diseasemodifying anti-rheumatic drugs. The side-effects and complications of these relatively new agents are unknown to many specialists (outside of rheumatology) and general practitioners. This article highlights updates on the most important infections encountered in the daily management of patients with rheumatic diseases and discusses how these may be prevented. © 2015, South African Medical Association. All rights reserved.
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Burden of Serious Infections in Adults With Systemic Lupus Erythematosus: A National Population-Based Study, 1996-2011
Article
Full-text available
  • Feb 2015
Objective. To compare rates of hospitalizations for serious infections, trends in rates from 1996 to 2011, and in-hospital mortality between patients with systemic lupus erythematosus (SLE) and those without SLE in a national sample. Methods. We analyzed hospitalizations for pneumonia, bacteremia/sepsis, urinary tract infections, skin infections, and opportunistic infections among adults in the Nationwide Inpatient Sample. We compared rates of hospitalizations yearly among patients with SLE and the general population. We also computed odds ratios for in-hospital mortality. Results. In 1996, the estimated number of hospitalizations for pneumonia in patients with SLE was 4382, followed by sepsis (2305), skin infections (1422), urinary tract infections (643), and opportunistic infections (370). Rates were much higher in SLE than those without SLE, with age-adjusted relative risks ranging from 5.7 (95% confidence interval (CI) 5.5, 6.0) for pneumonia to 9.8 (95% CI 9.1, 10.7) for urinary tract infection in 1996. Risks increased over time, so that by 2011, all relative risks exceeded 12.0. Overall risk of in-hospital mortality was higher in SLE only for opportunistic infections (adjusted odds ratio 1.52; 95% CI 1.12, 2.07). However, in pneumonia and sepsis, mortality risks were higher in SLE among those that required mechanical ventilation. Conclusion. Hospitalization rates for serious infections in SLE increased substantially between 1996 and 2011, reaching over 12 times higher than in patients without SLE in 2011. Reasons for this acceleration are unclear. In-hospital mortality was higher among patients with SLE and opportunistic infections, and those with pneumonia or sepsis who required mechanical ventilation. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
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EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases
Article
Full-text available
  • Mar 2011
  • ANN RHEUM DIS
To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune inflammatory rheumatic diseases (AIIRD). A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defined in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I-IV, the strength of recommendations was graded in categories A-D and Delphi voting was applied to determine the level of agreement between the experts of the task force. Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.
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How can we reduce the risk of serious infection for patients with systemic lupus erythematosus?
Article
Full-text available
  • Oct 2009
  • ARTHRITIS RES THER
Infection is responsible for approximately 25% of all deaths in patients with systemic lupus erythematosus (SLE), making it a leading cause of mortality among patients. Ruiz-Irastorza and colleagues, in a recent issue of Arthritis Research & Therapy, report the clinical predictors of major infections found in a prospective study of patients with SLE. Similar patterns of infection and pathogens as reported in previous studies were seen; what is striking, however, was the protective effect seen with anti-malarial use. Many infections in patients with SLE could be prevented with timely vaccinations, reducing exposure to contagious contacts, screening for latent infections, minimizing exposure to corticosteroids, targeted prophylaxis for high risk patients, and, unless contraindicated, anti-malarial therapy as standard of care.
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Reasons for Failure to Receive Pneumococcal and Influenza Vaccinations Among Immunosuppressed Patients with Systemic Lupus Erythematosus
Article
  • Jan 2015
  • SEMIN ARTHRITIS RHEU
To better understand why immunosuppressed individuals with systemic lupus erythematosus (SLE) fail to receive influenza and pneumococcal vaccines. These cross-sectional data were derived from the 2009 cycle of the Lupus Outcomes Study (LOS), an annual longitudinal telephone survey of individuals with confirmed SLE. Respondents were included in the analysis if they had taken immunosuppressive medications in the past year. We assessed any prior receipt of pneumococcal vaccine and influenza vaccine in the past year, and then elicited reasons for not receiving vaccination. We used bivariate statistics and multivariate logistic regression to assess frequency and predictors of reported reasons for not obtaining influenza or pneumococcal vaccines. Among 508 respondents who received immunosuppressants, 485 reported whether they had received vaccines. Among the 175 respondents who did not receive an influenza vaccine, the most common reason was lack of doctor recommendation (55%), followed by efficacy or safety concerns (21%), and lack of time (19%). Reasons for not receiving pneumococcal vaccine (N = 159) were similar: lack of recommendation (87%), lack of time (7%), and efficacy or safety concerns (4%). Younger, less-educated, non-white patients with shorter disease duration, as well as those immunosuppressed with steroids alone, were at the greatest risk for not receiving indicated vaccine recommendations. The most common reason why individuals with SLE did not receive pneumococcal and influenza vaccines was that physicians failed to recommend them. Data suggest that increasing vaccination rates in SLE will require improved process quality at the provider level, as well as addressing patient concerns and barriers. Copyright © 2015 Elsevier Inc. All rights reserved.
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Overall and Cause-Specific Mortality in Patients With Systemic Lupus Erythematosus: A Meta-Analysis of Observational Studies
Article
  • Apr 2014
Objective To determine the magnitude of risk from all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) compared to the general population through a meta-analysis of observational studies. Methods We searched the Medline and Embase databases from their inception to October 2011. Observational studies that met the following criteria were assessed: 1) a prespecified SLE definition; 2) overall and/or cause-specific deaths, including cardiovascular disease (CVD), infections, malignancy, and renal disease; and 3) reported standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs). We calculated weighted-pooled summary estimates of SMRs (meta-SMRs) for all-cause and cause-specific mortality using the random-effects model and tested for heterogeneity using the I-2 statistic by using Stata/IC statistical software. ResultsWe identified 12 studies comprising 27,123 patients with SLE (4,993 observed deaths) that met the inclusion criteria. Overall, there was a 3-fold increased risk of death in patients with SLE (meta-SMR 2.98, 95% CI 2.32-3.83) when compared with the general population. The risks of death due to CVD (meta-SMR 2.72, 95% CI 1.83-4.04), infection (meta-SMR 4.98, 95% CI 3.92-6.32), and renal disease (SMR 7.90, 95% CI 5.50-11.00) were significantly increased. Mortality due to malignancy was the only cause-specific entity not increased in SLE (meta-SMR 1.19, 95% CI 0.89-1.59). Conclusion The published data indicated a 3-fold increase in all-cause mortality in patients with SLE compared to the general population. Additionally, all cause-specific mortality rates were increased except for malignancy, with renal disease having the highest mortality risk.
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Immunization of patients with autoimmune inflammatory rheumatic diseases (the EULAR recommendations)
Article
  • Feb 2012
  • LUPUS
The European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) have been recently published. These evidence-based recommendations were based on existing literature in combination with expert opinion. Although patients with AIIRD are at increased risk of suffering from (complicated) infectious diseases--and vaccination seems a tool to reduce this risk--still many questions and controversies remain for the individual patient. In this overview, taking influenza as an example, the background of the recommendations, their clinical implications, and the direction of future research are discussed. The increase in knowledge on vaccine-preventable infections will allow us to further improve vaccination strategies.
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Infections in systemic lupus erythematosus and rheumatoid arthritis
Article
  • Jul 2001
  • INFECT DIS CLIN N AM
Patients with systemic lupus erythematosus have a higher infection rate than the general population. It is estimated that at least 50% of them will suffer a severe infectious episode during the course of the disease. Improvements in the control of the disease are discussed in this article.
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Infectious Disease Hospitalizations Among Older Adults in the United States From 1990 Through 2002
Article
  • Nov 2005
  • ARCH INTERN MED
To understand conditions associated with substantial morbidity among older adults (aged > or = 65 years), we describe hospitalization rates and trends for overall infectious disease (ID) and for specific ID groups among older adults in the United States from January 1, 1990, through December 31, 2002. The National Hospital Discharge Survey was used to generate hospitalization estimates from 1990 through 2002 for the US population of older adults. By using a comprehensive list of International Classification of Diseases, Ninth Revision, Clinical Modification codes associated with IDs, we identified and analyzed hospitalizations associated with specific ID and ID-related categories. There were approximately 21.4 million (SE, 636 000) ID hospitalizations among older adults from 1990 through 2002, and between 1990 through 1992 and 2000 through 2002, the ID hospitalization rate increased 13% from 449.4 to 507.9 hospitalizations per 10 000 older adults (P = .01). This increase was caused in part by the increasing relative contributions of patients aged 75 through 84 years and 85 years or older to the older adult ID hospitalization rate. Almost half of ID hospitalizations (46% [SE, 0.7%]) and ID-related hospital deaths (48% [SE, 1.6%]) among older adults were associated with lower respiratory tract infections from 2000 through 2002. The hospitalization rate for IDs increased slightly among the older adult US population during the 13-year study and was associated with the aging of the older adult population. The reduction of ID hospitalization rates among older adults could help attenuate the anticipated increase in the number of hospitalizations among older adults and should be a high priority given the projected population growth among older adults in the United States.
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