This study revealed substantial changes in TC, SBP, and DBP level over time among patients with SLE. Multivariate regression analysis using GEE showed an association of TC, SBP, and DBP, not only with lipid-lowering and antihypertensive therapy, but also with lupus activity and medications and other cardiovascular risk factors.
This study of variability and correlates of TC and BP was based on numerous (on average, 20) and frequent (on average, every 5.6 months) measurements of these variables in 1,260 patients with SLE, followed up on average for 9.3 years. In total, a large dataset of 26,267 individual data points was used in analysis of variability and correlates for TC, SBP, and DBP.
We chose to report 'variability' in serial measurements taken over time in two ways. First, TC, SBP, and DBP each were dichotomized into 'normal' and 'elevated' values based on conventional cut points, and over time, the proportion of patients in whom values fluctuated from one category to another was determined. Second, with TC, SBP, and DBP treated as continuous variables, total variance in each variable was quantified and dissected into within- and between-patient variance by using ANOVA modeling. The latter approach eliminates the need to dichotomize TC and BP values according to cut points, which, although based on evidence, are somewhat arbitrary. Common to both methods is the assessment of change in mean or average values over time. However, it must be borne in mind that this approach does not capture the trajectory taken by each variable measured serially in each patient.
In this study, over a mean and median follow-up period of 9.3 and 6.5 years, respectively, 8.8% of patients had persistent hypercholesterolemia, whereas almost two thirds (64.7%) had variable hypercholesterolemia. This is even greater variability over time than previously reported in SLE patients in the first 3 years of disease, wherein one third of patients had persistent hypercholesterolemia, whereas one third had variable hypercholesterolemia [8
]. The greater variability and fewer cases of persistent elevation in cholesterol may be due to fluctuations in disease activity over time and the effect of changes to therapy, including the use of corticosteroids and lipid-lowering agents. Furthermore, the longer follow-up in the present study means greater potential for the recording of change over time, irrespective of cause. Certainly the variation in cholesterol over time among patients with SLE far exceeds that reported for the general population, in whom, in the absence of treatment, cholesterol levels tend to be relatively stable over time [18
Likewise, almost half (46.4%) of all patients in this study had varying hypertension over the duration of the study, whereas only 1.7% had persistent hypertension. Although no previous studies exist with which to compare the proportion of SLE patients who have persistent and variable hypertension, the findings of this study support our original hypothesis that BP likely takes a variable course in patients with SLE.
The absolute total variance in TC and BP is reported in Table . The magnitude of total variance for TC is much smaller than that for SBP and DBP, reflecting the smaller range of possible values for the former. In addition, TC measurements may be inherently less variable over time for physiological reasons and also because TC is measured in a laboratory by using standardized assays that have small interassay variation [20
]. Conversely, blood pressure measurements are subject to measurement error by physicians and volatility because of the phenomenon of 'white-coat hypertension.' Sequential studies in the general population have shown that BP can decrease by an average of 10 to 15 mm Hg between clinic visits [9
]. Thus, many patients considered to be hypertensive at initial visits to a clinic turn out to be normotensive. To date, no studies have directly compared blood-pressure variability over time in SLE patients with healthy population controls.
Previous studies evaluated the role of TC and BP as predictors of atherosclerotic coronary events in SLE; this is the first study to look at these risk factors as 'outcome' variables and to seek to determine their independent correlates. The importance of this approach is twofold. First, this type of analysis provides insight into the reasons for the pronounced variability over time of these cardiac risk factors in SLE. Second, identifying correlates of TC and BP in SLE aids in the selection of covariates and interaction terms for inclusion in multivariate models when the outcome of interest is atherosclerotic coronary events.
In our analyses, we used GEE to allow adjustment for the expected correlation between repeated measures over time within individuals ('fixed effects'). These models have shown significant associations between increasing age and each of TC, SBP, and DBP. The association between older age and elevation in lipid levels and blood pressure is well described in the general population [21
]. Our models have also shown that greater disease activity at the time of measurement is independently associated with higher TC, SBP, and DBP. This is a very important observation. Borba et al.
] previously noted a significant correlation between SLEDAI scores and all lipid subfractions, including TC, as well as an 'active lupus pattern' of dyslipidemia in times of disease activity.
Although we found that use of immunosuppressives was significantly and independently associated with elevated TC, it is unlikely that hypercholesterolemia is a direct effect of treatment with these agents. Rather, immunosuppressive use is likely a surrogate for persistent low-grade disease activity that may not be adequately captured by the SLEDAI-2K scoring system. Notably, coincident use of immunosuppressives was negatively associated with both SBP and DBP, indicating that although greater disease activity is associated with higher BP, control of disease activity is associated with a reduction in BP.
The findings of this study support the long-suspected independent association between hypercholesterolemia and hypertension in SLE [24
]. In this study, hypertension and treatment with antihypertensives were significantly associated with TC, whereas hypercholesterolemia and lipid-lowering therapy were significantly correlated with both SBP and DBP. This association highlights the phenomenon of 'clustering' of traditional cardiac risk factors within individuals with SLE and stresses the need for screening for additional cardiac risk factors when one or more risk factors are present.
As shown in previous studies, concomitant use of antimalarials was associated with lower levels of TC. Reduction in plasma cholesterol level is one of the direct pharmacologic effects of antimalarials in patients with SLE [25
]. In this study, antimalarial use was also associated with lower levels of both SBP and DBP. However, a reduction in BP is not known to be a direct pharmacologic effect of this class of drugs. More likely, this association again points to the link between hypercholesterolemia and hypertension in SLE. Further support for this link was manifest in the association between lipid-lowering therapy and both reduced TC and BP. This observation also suggests that lipid-lowering therapy may have beneficial effects in patients with SLE, independent of a reduction in cholesterol level. However, the role of lipid-lowering therapy in prevention of atherosclerotic events in SLE can be definitively assessed only in an intervention study.
Among women with SLE, other independent correlates of TC and BP were current smoking and hormone-replacement therapy. However, our analyses were limited by lack of data on pack-years of smoking [28
]. The association between smoking and hypercholesterolemia has been well described in the general population, and now, in this study, it also has been demonstrated in women with SLE [29
]. In the general population, smoking also is associated with hypertension, in particular, with elevated SBP, an association that also was found in this study of patients with SLE [30
]. Although among postmenopausal women, estrogen has been shown to have a beneficial effect on serum lipid concentrations, progestin contained in most standard HRT regimens partly negates this effect [28
]. The net result of these opposing effects is dependent on the patient's age and overall cardiovascular risk profile. The association between diabetes and BP seen here in women with SLE has been well described in the general population [33
The link between longer disease duration and higher TC and DBP suggests that the accrual of cardiac risk factors occurs over the course of disease and is consistent with the concept that chronic inflammation contributes to cardiac risk through association with traditional risk factors and other as-yet-undefined mechanisms.
Finally, this study has confirmed the well-known association between corticosteroid use and hypercholesterolemia [34
]. This highlights the need for vigilant monitoring of lipid levels in times of active disease and during treatment with corticosteroids.
Future studies must be done to quantify the CAD risk associated with corticosteroid dose. Future studies will also need to determine the relation between various lipids and lipoproteins, such as high- and low-density lipoprotein cholesterol (HDL-C and LDL-C) over time in SLE. Lack of a large number of serial measurements of these lipid and lipoprotein fractions among our patients precluded us from doing such an analysis in the present study.
The contributions of this study to the field of SLE-related CAD are both conceptual and practical. First, this study has illustrated a very important concept: the marked variability of TC and BP over time in patients with SLE. The dynamic nature of these variables, in patients with SLE, makes a strong case for deriving summary measures that better capture cumulative exposure to these risk factors over time, than a single-point-in-time or 'snap-shot' measurement. Use of such cumulative measures would allow more-accurate quantification of risk for CAD in SLE. Second, this study has provided some insights into the complex relation between various risk factors for CAD in SLE. However, these interactions merit further investigation in longitudinal studies.