CLINICAL LITERATURE REVIEWS
L. Nandini Moorthy, MD MS
Assistant Professor of Pediatric Rheumatology
Robert Wood Johnson Medical School-UMDNJ,
Cardiovascular
disease is a major cause of morbidity and mortality in adults, and myocardial
infarction is more common in SLE patients than in the general population. As
the risk of cardiovascular disease increases with disease duration, early diagnosis and aggressive treatment of children
with SLE may be crucial in preventing and/or minimizing risk of atherosclerotic
heart disease. The following two adult
studies raise important questions of whether there may be early lesions in the
coronary arteries in the pediatric age group and what might be the best method
of stratifying risk, preventing, detecting, monitoring and managing symptomatic
and asymptomatic atherosclerotic cardiovascular disease in children with SLE.
1. Prevalence and correlates of accelerated
atherosclerosis in systemic lupus erythematosus.
Authors: Roman MJ.
Shanker BA.
Davis A.
Lockshin MD.
Sammaritano L.
Simantov R.
Crow MK.
Schwartz JE.
Paget SA.
Devereux RB.
Salmon JE.
Institution:
Division of Cardiology, Weill Medical College of Cornell University, the
Hospital for Special Surgery, New York, NY 10021, USA.
REVIEW
This article substantiates
the hypothesis that systemic lupus erythematosus (SLE) has atherogenic
potential because of chronic immune activation that is independent of
traditional risk factors. This novel
case-controlled study examines the prevalence of atherosclerosis and risk
factors in SLE patients, and determines if disease-related factors, treatment,
and immune and inflammatory mediators are separately related to the development
of atherosclerosis in SLE.
Salmon et al enrolled 197 SLE patients greater than 18
years of age over a 30-month period.
Each patient fulfilled the ACR criteria and was matched to a control based
on age, sex, race and blood pressure.
Each variable has been strictly operationalized as evidenced by the
following brief account of the methodology.
The presence of
atherosclerotic plaque was determined by ultrasonography of extracranial
carotid arteries, and was defined as a “focal protrusion of more than 50
percent of the surrounding wall.”
Echocardiography on all subjects included determination for the presence
of pulmonary hypertension, Libman-Sacks lesions, pericardial thickening and
effusion. The following traditional risk
factors were examined: presence or absence of family history of premature
myocardial infarction (prior to 55 years in first degree male relatives or
before 65 years in female relatives); hypertension; (blood pressure of at least
140/90 mm Hg or the use of antihypertensive medication); diabetes mellitus;
smoking status; fasting cholesterol level.
SLE Disease Activity
Index (SLEDAI), Systemic Lupus International Collaborating Clinics/American
College of Rheumatology damage index (SLICC), and medication use, including
corticosteroid therapy (current, former or none), were assessed. Average daily corticosteroid dose over 5
years was calculated. The following
laboratory analyses were performed: complete blood count, complements,
anti-ds-DNA, Sm, RNP and antiphospholipid antibody, C-reactive protein, CD40
ligand, and Lp (a) lipoprotein by cholesterol content, IL-6, TNF p55 and p75
receptors, soluble intracellular adhesion molecule 1 and vascular cell adhesion
molecule 1.
Mann-Whitney U and
chi-square tests were performed for comparison of groups. Stepwise,
forward-selection logistic-regression was used to determine the independence of
the association with atherosclerosis. As
elucidated above, the study design and variables chosen render adequate depth
to the analysis.
Salmon et al found that the patients and controls were
comparable in terms of demographic and risk factors for cardiovascular disease,
except that the controls had a higher blood pressure as compared to patients at
the time of the study. Atherosclerosis
(plaque) was more prevalent in SLE patients than the controls in all age groups
(37.1 percent vs. 15.2 percent, P<0.001).
In patients less than 40 years of age, the prevalence was 5.6 times
higher than in matched controls.
Multivariate analysis revealed that older age, the presence of SLE (odds
ratio, 4.8; 95 percent confidence interval, 2.6 to 8.7), and a higher serum
cholesterol level were the only factors that were separately associated with
the presence of atherosclerosis.
Repeating analysis after excluding patients with clinical cardiovascular
disease did not affect the results.
The authors found that as compared to patients without
plaque, SLE patients with plaque were older, had a greater disease duration,
higher disease-related damage score and more disease-related damage (as opposed
to medication-related damage). They were less likely to have multiple
autoantibodies (Ro, La, Sm, RNP, anticardiolipin antibodies) or to have
received prednisone, cyclophosphamide, or hydroxychloroquine. Inflammatory
mediators were increased in SLE patients as compared to controls, but a
statistically significant difference was not found between patients with and
without atherosclerosis.
Finally, in multivariate analyses,
Salmon et al found several independent predictors of atherosclerosis: older age
of diagnosis, longer disease duration, higher damage score, a lower use of
cyclophosphamide, and the absence of anti-Smith or anticardiolipin antibodies. Limiting the analysis to SLE patients who
developed the disease when they were younger than 35 years of age, the authors substantiated the relationship of
atherosclerosis with increased disease duration, high damage score, and lack of immunosuppressive medication. These
results led the authors to conclude that SLE is an independent risk
factor for atherosclerosis.
This study implicates disease-related factors, including
chronic inflammation, as playing a significant role in atherogenesis and
emphasizes the importance of future studies characterizing the role of
inflammatory markers, autoantibodies, and effect of medications. The significant association of increased
disease duration and cumulative damage with premature atherosclerosis strongly
suggests that early and aggressive intervention by pediatric rheumatologists
may be crucial in preventing premature coronary artery disease in young adults
with SLE.
2.
Premature coronary-artery atherosclerosis in systemic lupus erythematosus.
Authors:
Asanuma Y.
Oeser A.
Shintani AK. Turner E. Olsen N. Fazio S. Linton MF. Raggi P. Stein CM.
Institution:
Division of Clinical Pharmacology,
REVIEW
In this case-control study, Stein et al has examined the prevalence
and the extent of coronary artery atherosclerosis in patients with systemic
lupus erythematosus (SLE) using electron beam computed tomography.
Over a 34 month
period 64 SLE patients and 69 age-, sex- and race-matched controls older than
18 years were enrolled. Subjects with a
history of cardiovascular disease were excluded. Electron beam computed tomography was
conducted on all subjects and all sites of coronary artery calcification were
measured. Coronary artery
atherosclerosis was defined as a calcified plaque which was the measurement of
at least 3 consecutive pixels. Subsequently, the degree of
coronary-artery calcification was estimated.
The following
additional data were collected: current and cumulative medication dosage,
medical history, family history of coronary artery disease (defined as a
first-degree relative who had had a myocardial infarction or stroke prior to 55
years in first degree males or before 65 years in females), body-mass index,
blood pressure (hypertension was defined as systolic blood pressure of at least
140 or diastolic blood pressure of at least
90 mm Hg or the use of antihypertensive medication), disease activity
(SLE Disease Activity Index -SLEDAI), damage (Systemic Lupus International
Collaborating Clinics/American College of Rheumatology damage index -SLICC),
complete blood count, creatinine, total cholesterol, low-density lipoprotein
cholesterol, triglycerides, Lp(a) lipoprotein by cholesterol content and
homocysteine. In SLE patients,
C-reactive protein, erythrocyte sedimentation rate, and total hemolytic
complement were also measured. Results
of ANA, anti-ds-DNA, anticardiolipin antibodies, and lupus anticoagulant were
obtained from the medical records.
Mann-Whitney U tests and Fisher’s exact tests were used
to determine the distribution of coronary risk factors and calcium scores.
Logistic regression model estimated independent associations between
coronary–artery calcium and disease status after controlling for covariates.
Stein et al found that the patients and controls were
comparable in terms of baseline characteristics including cardiovascular risk
factors, except that hypertension, current smoking behavior, triglycerides, and
homocysteine levels
were significantly
increased in SLE patients. Coronary
artery calcification was much more prevalent in SLE patients (adjusted odds
ration 9.8, P=0.001). Three SLE patients had extensive coronary artery
calcification as defined as score >400, while none of the controls did. As compared to control subjects, SLE patients
developed coronary artery calcification at younger age, and the prevalence
increased with age. Calcification was
present in 7% of SLE patients under 40 years of age, 35% of SLE patients and
15% of controls between ages 40-49 years, 78% of SLE patients and 21% of
controls between ages 50-59 and 100% of patients with SLE and no controls in
age group over 60 years. The absence of
calcification in the >60 years age group is likely due to the small sample
in that subgroup and repeating the analysis after excluding the subgroup did
not change the results.
Stein et al found
that SLE patients with and without coronary artery calcification were similar
in most respects, including SLEDAI and SLICC scores, except that older age
(P<0.001) and male gender (P=0.008) were more common in those with
calcification. Additionally, patients
with calcification had higher average creatinine, and a lower frequency of
anticardiolipin and anti-ds-DNA antibodies. However, the significance
disappeared after adjustment for age and sex.
The authors found no significant association between the presence of
coronary artery calcification and the use of corticosteroid and/or
hydroxychloroquine. Other
immunosuppressive therapies were not considered.
Stein et al suggest that SLE patients have a higher
prevalence of coronary atherosclerosis and develop it at a younger age. The
study stresses the need for further research in young adults with SLE, early
detection and close monitoring for development of coronary artery disease. Additionally, a larger sample may be needed
to conduct exploratory analyses to examine the relationship of coronary artery
atherosclerosis as demonstrated by this computer tomography with medication
use, disease activity and damage.