Abstract
Objective. Despite the high prevalence of cardiovascular (CV) disease among patients with systemic lupus erythematosus (SLE), the relationship between age, blood pressure (BP), and BP variability (BPV) is not well understood. We studied visit-to-visit BPV, its relationship to age, clinical, and demographic characteristics, and its potential role as a CV risk factor in patients with SLE.
Methods. We analyzed systolic (SBP) and diastolic BP (DBP) measures in our cohort using mixed-effects regression models. From these models, we then obtained estimates of the mean BP, the visit-to-visit SD, and the between-person SD. The estimated means were compared to the general population using data from the National Health Statistics Reports from 2001 to 2008. In addition, we examined the relationship between BP (means, variances), patient demographic and clinical characteristics, and subsequent CV events.
Results. The mean SBP in SLE increased with age and was significantly higher in younger patients compared to the general population. BPV in SLE was elevated across all ages. BPV was significantly higher in African Americans, in patients with traditional CV risk factors, those with high disease activity, and in patients taking prednisone. Hydroxychloroquine was associated with significantly lower BPV. Within-person variability in DBP of ≥ 9 mmHg was highly associated with CV events in a multivariate analysis.
Conclusion. Age-related BP patterns in SLE differ from the general population. Increased visit-to-visit BPV is affected by many disease-specific and traditional CV factors. Increased DBP variability is highly associated with CV events in SLE.
Based on 2007 to 2010 data, 33% of US adults over 20 years of age had hypertension (HTN). This represented 78 million US adults with HTN1. It is estimated that the implementation of the new 2017 American College of Cardiology and American Heart Association definition of HTN (> 130/80 mmHg) will result in nearly half (46%) of the US adult population being classified as hypertensive2. The National Health and Nutritional Examination Survey (NHANES)3 and the Framingham Study4 demonstrated that aging in the general population is accompanied by steady increases in systolic blood pressure (SBP) and gradual declines in diastolic blood pressure (DBP). Elderly hypertensive patients tend to exhibit isolated systolic HTN and an elevated pulse pressure as a result of reduced arterial compliance, while hypertensive individuals younger than 50 years usually exhibit systolic and diastolic HTN and a narrowed pulse pressure, reflecting increased peripheral vascular resistance5.
Mean BP is widely considered of primary importance as a risk factor for cardiovascular (CV) disease6 and in diagnosis and treatment of HTN7. Visit-to-visit variability in BP was previously considered an obstacle to the reliable estimation of usual BP8,9. Visit-to-visit variability in measured clinic BP is common10,11,12 and guidelines recommend continued monitoring or 24-h ambulatory BP monitoring in patients with episodic HTN13,14 with treatment decisions based on mean BP.
Rothwell, et al, however, demonstrated that visit-to-visit BP variability (BPV) is increased in cohorts at high risk of stroke11,15, and that visit-to-visit variability in SBP is a powerful predictor of stroke and coronary events independent of mean SBP16. Increased visit-to-visit BPV has been shown to be a predictor of all-cause mortality and CV mortality17, and has been associated with decreased endothelial function18, albuminuria and microalbuminuria19, left ventricular diastolic dysfunction20, and cognitive impairment21.
Patients with systemic lupus erythematosus (SLE) have a significantly increased risk of CV events due to atherosclerosis. The latest data from the Hopkins Lupus Cohort estimates the risk of CV events among patients with SLE to be 2.66 times higher compared to the general population22. Traditional Framingham CV risk factors do not account for the entire risk in patients with SLE23. In the Hopkins Lupus Cohort, 74% of patients are hypertensive24. Over the first 3 years of followup the percentage of hypertensive SLE patients in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort increased from 39.2% to 58.3%25. Despite the high prevalence of CV events in SLE, it is not known whether BP patterns are similar to the general population and differ with age, whether BPV is increased in patients with SLE, and whether it plays a role in the highly elevated CV risk in patients with SLE. We thus hypothesized that the BP patterns differ in SLE compared to the general population, that visit-to-visit BPV is increased, and that it is an independent CV risk marker.
MATERIALS AND METHODS
Patients and activity indices
As previously described26, the Hopkins Lupus Cohort is a prospective cohort study of predictors of lupus flare, atherosclerosis, and health status in SLE. The study cohort includes all patients at the Hopkins Lupus Center who have a clinical diagnosis of SLE and give informed consent to participate in the study. Subjects enrolled in the cohort are followed quarterly or more frequently if clinically necessary. The clinical features, laboratory testing, and damage accrual data are recorded at the time of entry into the cohort and are updated at subsequent visits. The Hopkins Lupus Cohort has been approved by the Johns Hopkins University School of Medicine Institutional Review Board (NA_00039294) and complies with the Health Insurance Portability and Accountability Act. All patients gave written informed consent.
Ninety-five percent of patients fulfilled 4 or more of the American College of Rheumatology 1982 revised classification criteria for SLE27,28 and the SLICC classification criteria for SLE29. Disease activity was measured with the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) revision of the SELENA–Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) instrument score30 and the physician’s global assessment31.
BP was measured at each visit using a Carescape Dinamap V100 monitor, which was calibrated once every 12 months according to manufacturer guidelines. Patients were in a seated position with the arm supported at heart level. Cuff sizes used included adult small (23–33 cm) and adult large (31–40 cm).
The analyses were based on different subsets of patients from the cohort. Each subset was about 92% female. Most (60%) were under 40 years of age at cohort entry while a small proportion (6%) were 60 years or older. Most were either white (55%) or African American (38%).
Statistical methods for estimating means and variances of BP in patients with SLE
The mean SBP and DBP measures in this cohort were estimated using random intercept models, fit by restricted maximum likelihood. Using this approach, we obtained estimates of the mean BP, the within-person SD (i.e., the SD of individual’s BP around their personal mean), and the between-person SD (i.e., the SD of the person-specific mean BP).
To compare means with national data from 2001 to 2008, we analyzed data from 22,672 clinic visits of 1509 cohort members that took place between 2001 and 2008. Of the 1509 patients, 661 (44%) contributed < 10 visits, 329 (22%) contributed 10–19 visits, and 520 (34%) contributed 20 or more visits. The estimated means were compared to the mean SBP and DBP in the general population using data from the National Health Statistics Reports (19,921 adults aged 18 yrs and over with BP estimates calculated using the mean of up to 3 measurements)32. To obtain more precise estimates of the means and variances of BP by age, we used a larger sample, including data from 52,791 cohort visits of 2128 patients seen from 1987 to 2013.
Statistical methods for the analysis of the relationship between clinical and demographic characteristics and BPV
This analysis was based on 63,890 clinic visits of 2525 cohort members from 1987 to 2018. Within and between-patient BPV was estimated using random intercept models. The statistical significance of differences between clinical subgroups regarding BPV was determined using likelihood ratio tests.
Statistical methods for the analysis of the relationship between BP variables and CV events
This analysis was based on 1340 cohort members who had at least 8 clinical assessments of BP in the cohort between 1987 and 2013. They were 92% female (n = 1235). The average duration of followup per patient was 74 months (6.2 yrs). Four hundred fifty-nine (34%) were followed for less than 3 years, 331 (25%) were followed for 3–6 years, 210 (16%) were followed for 6–9 years, and 340 (25%) were followed for 10 or more years.
CV events were defined as either stroke, myocardial infarction, incident angina, a coronary procedure (coronary artery bypass graft surgery or percutaneous coronary intervention), or claudication. Considering only the first CV event for each person, there were 105 events. This is a rate of 12.7 per thousand person-years. Of these, 60 were strokes, 23 were myocardial infarctions, 24 were angina or coronary procedures, 14 were claudications, and 3 were mixed.
For each month of followup for a patient in the cohort, the previous 8 BP measurements were included in the analysis. The following variables were calculated based on those most recent 8 measures: mean prior SBP and DBP, SD of prior SBP and DBP, and coefficient of variation of prior SBP and DBP. This information was then linked with whether the patient had a CV event in that month. Person-months were aggregated, and the risks of a CV event by monthly characteristics were calculated. Person-months after a previous CV event were excluded. In addition to adjusting for age, race, and sex, the rate ratios are also adjusted for diabetes, cholesterol ≥ 240 mg/dl, body mass index (BMI) > 25 kg/m2, most recent prednisone dose, and past or current smoking.
RESULTS
Table 1 compares the mean BP in the Hopkins Lupus Cohort to the NHANES mean BP in broad age groups from 2001 to 200832. The SBP in SLE follows the trend of increase with age seen in the general population. SBP was significantly higher among young patients with SLE, regardless of ethnicity or sex. With age, this difference narrowed, only to be reversed in women older than 60 years of age (p < 0.001), but not in men.
Comparison of the Hopkins Lupus Cohort with the NHANES sample regarding mean systolic (SBP) and mean diastolic blood pressure (DBP) from 2001 to 2008 by age and ethnicity.
Table 2 provides estimates of the mean and SD of SBP and DBP in patients with SLE in each decade of life. There are 2 components of SD: (1) SD within a person around his/her personal mean BP; and (2) SD between people regarding personal mean BP. The total SD is determined by the component SD. BPV in SLE is elevated across all age groups. Within-person SD of SBP increased with age and ranged between 12.5 mmHg among 20-year-olds and 16.0 mmHg among 80-year-olds, while DBP variability remained stable through all age groups and ranged between 8.6 mmHg and 11.8 mmHg. These values are substantially higher than the within-person BPV reported by NHANES (i.e., 7.7 mmHg for SBP and 5.8 mmHg for DBP)33 but are comparable to previously published data in stroke cohorts34,35,36.
Mean and variance of systolic (SBP) and diastolic blood pressure (DBP) by decade of life in SLE.
Table 3 shows the relationship between BPV and clinical and demographic characteristics. BPV was statistically significantly higher (p < 0.0001) in African American patients. High disease activity (SLEDAI > 4), positive anti-dsDNA, hypocomplementemia, and antiphospholipid antibodies were all significantly (p < 0.0001) associated with higher BPV. Hypercholesterolemia, diabetes, and smoking were also associated with higher BPV (p < 0.0001). Patients taking hydroxychloroquine (HCQ) had significantly (p < 0.0001) lower BPV, while BPV increased with prednisone dose and was significantly higher (p < 0.0001) in patients taking prednisone > 12.5 mg/day.
Variability of blood pressure in subgroups of clinic visits defined by patient or clinical characteristics.
Table 4 shows the relationship between SBP and DBP summary measures (based on the prior 8 BP assessments) and rates of CV events in the Hopkins Lupus Cohort. Visit-to-visit SBP variability of ≥ 14 mmHg [relative risk (RR) 1.9, 95% CI 1.0–3.3, p < 0.05] and DBP variability of ≥ 9 mmHg (RR 2.5, 95% CI 1.3–4.9, p < 0.01) were predictive of future CV events in a univariate analysis. After adjustment for age, ethnicity, sex, diabetes, hypercholesterolemia, BMI > 25 kg/m2, most recent prednisone use, and smoking, DBP variability of > 9 mmHg (RR 2.1, 95% CI 1.0–4.1, p < 0.05) remained significantly associated with cardiovascular events.
Relationship between systolic (SBP) and diastolic blood pressure (DBP) summary measures and rates of CV events in the Hopkins Lupus Cohort.
The mean SBP in the previous 8 visits was a stronger predictor of CV events than any other BP measurement. Table 5 shows the association between the other measures of recent BP and CV events after adjustment for age, race, sex, and mean SBP in the past 8 visits. None of the measurements were significantly associated with events after these adjustments. In contrast, for every model shown in the table, mean SBP was a significant predictor of CV events, with OR ranging from 1.5 to 1.7 per SD increase.
Association between various recent blood pressure measurements and risk of a CVE after adjusting for age, race, sex, and the mean value of the 8 most recent systolic blood pressures.1
DISCUSSION
Accelerated atherosclerosis remains a major cause of morbidity and mortality in patients with SLE and other autoimmune diseases37. Traditional Framingham CV risk factors do not account for the entire risk in SLE and the search for disease-specific factors that elevate this risk has been ongoing for decades.
Compared to general population data from the National Health Statistics Reports, SBP in SLE follows a similar trend of increase with age with substantially higher mean SBP among the young (aged 18–39 yrs) regardless of ethnicity. With age, we observe sex-specific patterns among SLE patients, with elderly females (age 60+ yrs), regardless of ethnicity, having statistically significantly lower mean SBP compared to their non-SLE counterparts. This trend of reversal is not seen among men, where patients with SLE have higher mean SBP among all age groups, although the difference loses its statistical significance among the elderly.
In contrast to mean SBP, the mean DBP is higher in patients with SLE among all age groups regardless of ethnicity or sex, except for middle-aged white women (aged 40–59 yrs), who had a statistically significantly lower mean DBP. In contrast to women, where all age groups had statistically significant differences in DBP compared to the general population, only elderly white men had significantly higher mean DBP compared to their counterparts in NHANES.
SBP variability in SLE expressed as within-person SD and between-person SD rises with age in contrast to the DBP variability, which remains unchanged. The average intra-individual SD for SBP were 14.1 mmHg in our cohort, comparable to data from stroke cohorts: 13.6 in UK-TIA trial34, 15.0 in the Dutch TIA trial38, and 13.9 mmHg in the European Carotid Surgery Trial39. These values are substantially higher than the reported SD for SBP in the general population from the NHANES survey, which was 7.7 mmHg33. For DBP, the average intraindividual SD was 8.8, compared to 7.6, 7.8, and 7.4 mmHg, respectively, in stroke cohorts. These values are also higher than the within-person DBP variability reported by NHANES of 5.8 mmHg. It should be noted, however, that in NHANES, BPV was based on measures relatively close in time (median of 17 days apart) and based on averages of 2 measures at each visit.
BPV in SLE is affected by both traditional CV risk factors and disease-specific factors. Among traditional CV risk factors, diabetes, hypercholesterolemia, and smoking were associated with higher BPV. Surprisingly, patients with a BMI < 20 kg/m2 had higher BPV than those with normal weight or obese patients, possibly related to higher disease activity in this subgroup. A SLEDAI > 4, anti-dsDNA positivity, and hypocomplementemia were also associated with higher BPV. BPV increased with higher prednisone doses and was highest in patients taking > 12.5 mg/day. BPV was significantly higher among African Americans. HCQ use was protective and was associated with significantly lower BPV.
Visit-to-visit variability in SBP ≥ 14 mmHg and DBP ≥ 9 mmHg were highly associated with CV events (p < 0.05) in a univariate analysis. After adjustments, only visit-to-visit DBP variability remained significantly (p < 0.05) associated with CV events.
In contrast to the stroke populations, BPV in patients with SLE was not an independent CV risk factor; after adjusting for mean SBP, none of the studied measures were significantly associated with CV events.
There is no evidence that longterm BPV directly causes CV outcomes, but the current approach in patients with a history of stroke or coronary artery disease is to consider correctable causes when unexpected BP changes occur40. Similarly, when faced with a patient with SLE who has high BPV, one should consider correctable underlying causes, for example, high-dose prednisone or noncompliance with HCQ. There is evidence of an antihypertensive drug class effect on BPV in stroke patients, i.e., that calcium channel blockers and thiazide diuretics decrease longterm variability, while beta blockers, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors increase the BPV41. It is intriguing to consider the future possibility of pharmacologically modifying BPV in patients with SLE and the effect it could have on CV outcomes.
Age-related BP patterns differ in patients with SLE with significantly higher mean SBP and DBP in younger patients, a difference that diminishes with age and reverses in women over 60 years of age. Visit-to-visit SBP and DBP variability in SLE rises with age and is comparable to the one described in stroke cohorts. BPV in SLE is higher in patients with traditional CV risk factors, such as diabetes, hypercholesterolemia, and smoking, but also in patients with high disease activity, those taking prednisone, and in patients of African American ethnicity. HCQ use is associated with significantly lower BPV. Increased visit-to-visit DBP variability is highly associated with CV events in SLE, but mean BP remains the dominant CV risk factor in this population.
Footnotes
The Hopkins Lupus Cohort is supported by a grant from the US National Institutes of Health (NIH; AR 43727 and 69572). This publication was also made possible by grant number UL1 RR 025005 from the National Center for Research Resources, a component of the NIH, and the NIH Roadmap for Medical Research. Dr. G. Stojan was supported by NIH grant T32 AR048522 and now by AR 69572.
- Accepted for publication June 4, 2019.
