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Patients with systemic lupus erythematosus (SLE) remain at risk for accelerated atherosclerosis, and important questions have yet to be answered, British investigators reported.
In a cohort of 124 patients with SLE followed for almost 6 years, 26% of those who had no carotid plaque at baseline had detectable plaque at follow-up, and 41% had evidence of plaque progression, according to Ian N. Bruce, MD, of the University of Manchester, and colleagues.
In addition, among those who had no clinical cardiovascular disease (CVD) at baseline, 7.2% developed CVD during the follow-up period, compared with a Framingham predicted 5-year risk of 1% (P<0.001), the researchers reported online in Lupus Science & Medicine.
"The impact of accelerated atherosclerosis on morbidity and mortality in SLE has been well documented over the past four decades," Bruce and colleagues wrote.
And while traditional CV risk factors contribute, disease-specific factors such as inflammation, renal disease, and immunosuppressive treatment also are likely to play a role. It has remained unclear, however, how rapid the rate of progression and which factors most strongly predict atherosclerosis.
To explore this, the researchers used high-resolution B-mode Doppler ultrasound to measure carotid intima-media thickness (CIMT) and carotid plaque in an SLE cohort that was enrolled from 2002 to 2005. The cohort initially included 200 patients, but only 124 were able to be reached for a follow-up visit 5.8 years later, at which time the patients' mean age was 49 and disease duration was 11 years. All the participants were white, as the study was originally intended to look at genetic factors.
Median SLE Disease Activity Index was 1, and SLE Damage Index (SDI) also was 1. For autoantibodies, 32% were positive for anticardiolipin (aCL), 37.1% for Ro antibody, and 17.7% for La antibody. Treatment had included antimalarials for 86% of the group and cyclophosphamide for 10%.
At baseline, 27% of patients had one or more detectable plaques, while at follow-up, the number had risen to 50%.
Of the 34 patients whose plaque was already present at baseline, the plaque index (summary score of number and size of plaques) had increased in 20, remained stable in nine, and decreased in the remainder.
Change in CIMT was 0.002 cm/year, which is approximately twice that reported for the general population.
In a univariate analysis adjusted for age and disease duration, factors that were negatively associated with plaque progression were positive Ro and La antibodies (OR 0.27, 95% CI 0.10-0.75 and OR 0.31, 95% CI 0.11-0.86, respectively), while aCL antibody positivity was associated with progression (OR 3.64, 95% CI 1.27-10.40).
Ro positivity may be characteristic of a lower-risk phenotype, the authors noted.
In a multivariate analysis, a positive aCL was independently associated with progression of plaque (OR 3.14, 95% CI 1.10-9.01).
Factors that were independently associated with CIMT progression on a univariate analysis included total cholesterol, metabolic syndrome, and SDI, while on a multivariate analysis independent predictors were lower systolic blood pressure, lower triglycerides, and metabolic syndrome.
As far as clinical outcomes, 13 CVD events were reported in 12 patients. On a univariate analysis, neither the presence of carotid plaque nor CIMT at baseline predicted clinical events, but on multivariate analysis, factors that were predictive were:
- Higher triglycerides, OR 3.61 (95% CI 1.23-10.56)
- Ever exposure to cyclophosphamide, OR 16.7 (95% CI 1.46-63.5)
- SDI score >0, OR 9.62 (95% CI 1.46-123)
The finding that SDI was negatively associated with progression was "paradoxical," according to the authors, who suggested that this might be an artifact, considering the wide confidence intervals, or a surviving cohort effect, meaning that patients with greater damage may have left the cohort. Other factors that were negatively associated with CIMT progression such as triglycerides and systolic blood pressure also may be explained by the small sample size and a surviving cohort effect.
Moreover, the association between clinical events and cyclophosphamide exposure should be interpreted with caution because of the small number of patients and wide confidence intervals, the researchers advised.
Longitudinal studies such as this may help improve risk stratification among SLE patients and identify potentially modifiable risk factors.
"A higher risk population also may be identified from patients who require potent immunosuppression as well as those with anticardiolipin antibodies. Such factors may be a useful adjunct to routine CVD screening approaches and may result in improved CVD risk in this high-risk population," Bruce and colleagues concluded.
Limitations of the study, they said, included its small sample size and relatively short duration. The team suggested that further studies should include larger numbers of patients, greater diversity, and more extensive follow-up.
The study was supported by Arthritis Research UK.
The authors reported having no conflicts of interest.