Age-Related Blood Pressue Patterns in Lupus

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Rheumatologists should not be falsely reassured by a normal mean blood pressure in lupus patients, according to a study from Johns Hopkins University that found age-related blood pressure patterns in systemic lupus erythematosus (SLE) differ from the general population and that increased diastolic blood pressure variability (BPV) is highly associated with cardiovascular events in SLE.¹

“Patients with a high blood pressure variability should be more carefully assessed in order to minimize all potential secondary factors that might be driving [variability], like prednisone use, and to optimize blood pressure control in the long run,” says lead author of the study, George Stojan, MD, assistant professor of medicine in the Division of Rheuma­tology at the Johns Hopkins University School of Medicine, Baltimore, and co-director of the Johns Hopkins Lupus Center.

As a rheumatology fellow, when Dr. Stojan began seeing patients in the Hopkins Lupus Center, he was struck by the high BPV he saw in patients from visit to visit. He was aware of articles in The Lancet, by neurologist Peter Rothwell, that established blood pressure variability as an independent cardio­vascular risk factor in patients with stroke, and
became interested in assessing the importance of this finding in patients with SLE. Increased atherosclerosis continues to be a major cause of illness and death in patients with lupus and other autoimmune diseases.²

“Accelerated atherosclerosis and its long-term sequelae are a major cause of late mortality among patients with systemic lupus erythematosus,” says Dr. Stojan. “The importance of mean blood pressure as a cardiovascular risk factor in this population has been well described.”

The Study

Dr. Stojan

Dr. Stojan’s study looked at BPV from visit to visit and its relationship to age, demographics and clinical characteristics, as well as its potential for use as a cardiovascular risk factor in patients with SLE. The researchers used mixed-effects regression models to analyze systolic and diastolic blood pressure measures. From the models, they obtained estimates of the mean blood pressure, the visit-to-visit standard deviation and between-person standard deviation.

The researchers used data from National Health Statistics Reports from 2001–2008 to compare the general population to the estimated patient means and also examined the relationship between blood pressure, patient demographics, clinical characteristics and subsequent cardiovascular events.

The Hopkins Lupus Cohort is a prospective cohort study of predictors of lupus flare, atherosclerosis and health status in SLE. Ninety-five percent of patients in this cohort fulfilled four or more of the ACR’s 1982 revised classification criteria for SLE and the SLICC classification criteria for SLE.^3-6 The patients were followed quarterly, or more if clinically needed, and patient data (including laboratory testing, clinical features and damage accrual) were recorded at the time of entry into the cohort and updated at each visit.

Patients on hydroxychloroquine had significantly lower blood pressure variability.

The investigators measured disease activity with the SELENA revision of the Safety of Estrogens in Lupus Erythema­tosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index instrument score and the Physician Global Assessment. At each visit, they measured blood pressure using a Carescape Dinamap V100 monitor calibrated once every 12 months according to manufacturer guidelines with patients seated and the arm supported at heart level.

The cohort was divided into subsets of patients, with each subset approximately 92% female. Most (60%) were younger than age 40 at entry to the cohort, although a small proportion (6%) was 60 or older. Most were Caucasian (55%) or African American (38%).

Mean systolic and diastolic blood pressure measures were estimated using random intercept models, fit by restricted maximum likelihood. Using this approach, the investigators got estimates of the mean blood pressure, the within-person standard deviation (i.e., the standard deviation of an individual’s blood pressure around their personal mean) and the between-person standard deviation (i.e., the standard deviation of the person-specific mean blood pressures). They compared means with national data collected from 2001–2008 by analyzing data from 22,672 clinic visits of 1,509 cohort members between 2001 and 2008.

The researchers used data from the National Health Statistics Reports (19,921 adults aged 18 and over with blood pressure estimates calculated using the mean of up to three measurements) to compare the estimated means to the mean systolic and diastolic pressures in the general population.⁷ They used a larger sample, including data from 52,791 cohort visits of 2,128 patients seen from 1987 to 2013, to obtain more precise estimates of the means and variances of blood pressure by age.

To analyze the relationship between clinical and demographic characteristics and blood pressure variability, the researchers used random intercept models to estimate within-patient and between-patient BPV. They used likelihood ratio tests to determine the statistical significance of differences between clinical subgroups with respect to BPV. The analysis was based on 63,890 clinic visits of 2,525 cohort members from 1987 to 2018.

The researchers analyzed the relationship between blood pressure parameters and cardiovascular events based on 1,340 cohort members who had at least eight clinical assessments of blood pressure in the cohort between 1987 and 2013. Ninety-two percent of the cohort members were women, and the average duration of follow-up was 6.2 years. The researchers defined cardiovascular events as stroke, myocardial infarction, incident angina, a coronary procedure (coronary artery bypass graft surgery or percutaneous coronary intervention) or claudication. Considering only the first cardiovascular event for each person, 105 events occurred.

The researchers aggregated person-months and calculated the risks of a cardiovascular event by monthly characteristics. They excluded person-months after a previous cardiovascular event. For each month of follow-up for a patient, the previous eight blood pressure measurements were included in the analysis. The following variables were calculated based on those most recent past eight measures, and the information was later linked to whether the patient experienced a cardiovascular event that month:

• Mean prior systolic blood pressure and diastolic blood pressure;
• Standard deviation of prior systolic and diastolic blood pressure; and
• Coefficient of variation of prior systolic and diastolic blood pressure.

The Findings

The researchers found the mean systolic blood pressure in SLE was significantly higher in younger patients (18–39 years old) than in the general population, and it increased with age. BPV in SLE was elevated across all ages and was significantly higher in African Americans, in those with high disease activity, in those taking prednisone and in patients with traditional cardiovascular risk factors. Hydroxychloroquine was associated with significantly lower BPV.

In a multivariate analysis, a within-person variability in diastolic blood pressure of ≥9 mmHg was highly associated with cardiovascular events.

According to Dr. Stojan, the fact that visit-to-visit BPV in patients with lupus was similar to the one seen in stroke cohorts was unexpected. “Its association with multiple factors, such as ethnicity, disease activity, prednisone use, anti-dsDNA positivity, hypocomplementemia and antiphospholipid antibodies, was surprising,” he says. “Patients on hydroxychloroquine had significantly lower blood pressure variability.”

As for the role stress may play in BPV among lupus patients, Dr. Stojan says both basic and clinical data have shown increased blood pressure variability with emotional stress, especially in patients who already have underlying hypertension. “The effect, if any, in lupus would be difficult to discern because the variability is affected by many disease-specific factors, such as disease activity, prednisone use and serologies, as well as patient-specific factors, such as ethnicity, body mass index, etc.,” he says.

What’s Next

Given the relatively small number of cardio­vascular events in the patients studied, Dr. Stojan says he would like to see the question of whether blood pressure variability is an independent cardiovascular risk marker in lupus revisited.

“The most important question in my mind is whether we could decrease the cardio­vascular risk in lupus by using anti­hypertensives known to decrease blood pressure variability, such as calcium channel blockers and thiazides,” he says. “We generally use ACE inhibitors as our first choice in lupus due to their benefits in lupus nephritis, but this drug class has been shown not to decrease blood pressure variability in other populations, such as stroke patients.”

Renée Bacher is a frequent contributor to The Rheumatologist and other medical magazines. She is based in Baton Rouge, La.

References

1. Stojan G, Magder LS, Petri M. Blood pressure variability and age-related blood pressure patterns in systemic lupus erythematosus. J Rheumatol. 2020 Mar;47(3):387–393.
2. Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J Cardiovasc Pharmacol. 2013 Sep;62(3):255–262.
3. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725.
4. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–1277.
5. Petri M, Orbai A-M, Alarcón GS, et al. Derivation and validation of the systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677–2686.
6. Petri M. Hopkins Lupus Cohort. 1999 update. Rheum Dis Clin North Am. 2000 May;26(2):199–213, v.
7. Wright JD, Hughes JP, Ostchega Y, et al. Mean systolic and diastolic blood pressure in adults aged 18 and over in the United States, 2001–2008. Natl Health Stat Rep. 2011Mar 25;(35)1–22, 24.