Research ArticleArticle

Prevalence of and Factors Associated with Hypertension in Young and Old Women with Systemic Lupus Erythematosus

JOSÉ MARIO SABIO, JOSÉ ANTONIO VARGAS-HITOS, NURIA NAVARRETE-NAVARRETE, JUAN DIEGO MEDIAVILLA, JUAN JIMÉNEZ-JÁIMEZ, ANTONIO DÍAZ-CHAMORRO and JUAN JIMÉNEZ-ALONSO for the Grupo Lupus Virgen de las Nieves
The Journal of Rheumatology June 2011, 38 (6) 1026-1032; DOI: https://doi.org/10.3899/jrheum.101132

Abstract

Objective. Hypertension (HT) is more prevalent in patients with systemic lupus erythematosus (SLE) than among the general population and it has been associated with atherosclerotic cardiovascular diseases in these patients. We examined the proportion of HT and factors associated with it in young and old women with SLE.

Methods. Participants (112 women with SLE and 223 healthy age-matched women) were categorized as young (age ≤ 40 years) or old (age > 40 years). We compared cardiovascular and specific SLE-related variables and inflammatory markers in hypertensive and normotensive women with SLE for each age range. We also assessed the factors independently associated with HT in the entire cohort and in each age range by means of a multivariate regression analysis.

Results. The prevalence of HT was higher in women with SLE than in controls (56% vs 29%; p < 0.001), and was proportionally higher in younger women with SLE (40% vs 11%; p < 0.001) than in older women with SLE (74% vs 47%; p = 0.001). After adjustment for potential confounders, HT was associated with renal involvement and higher nonobesity-related insulin levels in younger women with SLE. In older patients, HT was associated with age, renal involvement, and obesity. Finally, in the entire cohort, HT was associated with age, insulin, renal involvement, and the Systemic Lupus Erythematosus Disease Activity Index score.

Conclusion. An association between HT and insulin has been identified in women with SLE, particularly younger ones. Factors associated with HT in women with SLE differed depending on their age. HT was more prevalent in women with SLE than in control subjects, being proportionally higher in young women with SLE.

Key Indexing Terms:

Cardiovascular diseases (CVD) are a major cause of morbidity and mortality in systemic lupus erythematosus (SLE)1, which involves an underlying process of accelerated arteriosclerosis. The factors behind this phenomenon are not yet fully understood, but it is believed that a complex interaction among SLE-related factors, medication, and traditional cardiovascular risk factors could be implicated2,3,4. Hypertension (HT), which is one of the most important modifiable risk factors for the development of CVD among the general population, is known to be more prevalent in patients with SLE than in control subjects5,6. The association between HT and clinical or subclinical cardiovascular diseases in patients with SLE has also been documented6,7,8,9. Although the pathogenesis of HT in patients with SLE has not been fully elucidated10, a combination of traditional (age, sex, ethnicity, and obesity) and SLE-related factors (inflammation, renal impairment, disease duration, and use of corticosteroids) have been found to be associated with HT11,12. In addition, we recently found differences in the prevalence of metabolic syndrome (MetS), in which HT was the most prevalent component in patients with SLE, when compared with sex and age-matched controls, depending on the age range considered. The frequency of MetS was almost 4 times higher in the group of patients with SLE below the age of 40 than in controls of the same age, but there were no differences between patients with SLE and controls above the age of 405. In addition, it is well known that SLE activity and complications vary throughout the disease course13. Therefore, we postulated that the proportion of HT and the factors associated with its presence might differ in younger and older women with SLE. If true, these findings could have implications for the management of HT in patients with SLE and could improve our understanding of the pathogenic mechanisms involved in the development of premature arteriosclerosis in these patients.

MATERIALS AND METHODS

One hundred twelve women with SLE with ≥ 4 American College of Rheumatology criteria for SLE classification were consecutively recruited. We used as a control group a published historic cohort5 consisting of 223 women matched for age who did not have a history of connective tissue disorders. All participants were white, reflecting the local demographic situation. They gave their informed consent to participate in our study, which was approved by the local ethics committee.

Ours was a cross-sectional study conducted over a 4-month period. Patients attending a scheduled visit over the period of study were assessed for sociodemographic, anthropometric and clinical data, traditional cardiovascular risk factors, and current medications. Additional information necessary for the study was obtained from medical records in a computerized database. Fasting blood samples for biochemical and immunological tests were collected and routinely processed by the hospital laboratory. They included full blood cell count, erythrocyte sedimentation rate (ESR; Westergren method), C-reactive protein (CRP; immunoturbidimetric method), fibrinogen (von Clauss assay), homocysteine (AxSYM Homocysteine, Abbott Laboratories, Abbott Park, IL, USA), insulin (BioRad, France), anticardiolipin antibodies (ELISA), serum C3 and C4 levels (nephelometry), anti-dsDNA antibodies (ELISA), interleukin 6 (IL-6; immunoradiometric assay, BioSource Europe, Nivelles, Belgium), and a routine biochemistry profile. The homeostasis model of assessment (HOMA index) was calculated using baseline glucose and insulin levels14. Blood pressure (BP) was measured twice on the dominant arm with a 5-min interval between readings and while the patient was in a seated position, using a validated automatic oscillometric device (HEM-705IT; Omron Health Care, Kyoto, Japan). Patients were diagnosed as having HT when they had systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg or when they were receiving drugs specifically to treat HT at the time of our study. Baseline kidney function was estimated using creatinine clearance calculated with the Cockcroft-Gault formula: creatinine clearance=[140−age (years)]×weight (kg)×0.85/72×plasma creatinine (mg/dl) Renal involvement was defined as a history of lupus nephritis confirmed by a kidney biopsy, history of persistent proteinuria ≥ 0.5 g/day, or worsening of creatinine clearance (< 90 ml/min), when a renal biopsy could not be performed. Definitions of obesity, dyslipidemia, diabetes, smoking and alcohol status, and sedentary lifestyle have been described in detail5. Disease activity and accumulated organ damage were measured using the SLE Disease Activity Index (SLEDAI)15 and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)16, respectively.

Statistical analysis

Patients were categorized as young (age ≤ 40 years) or old (age > 40 years). This age (40 years) corresponded to the median age of the cohort. This cutoff was also used to define young and old patients in a previous study5. Data were presented as the median (interquartile range) for continuous variables and as a percentage for categorical variables. Differences between continuous variables were tested for significance using the Mann-Whitney U test or Student’s t test as appropriate. Categorical data were analyzed with a 2-tailed Fisher’s exact test and OR and 95% CI were calculated. A multiple backward stepwise linear regression model was used to identify factors independently associated with HT (dependent variables) in women with SLE according to the age categories. Independent variables included in the models were age, obesity, renal involvement, SLEDAI score, SDI score, insulin, homocysteine, duration of the disease, and the use of prednisone. All analyses used a 5% 2-sided significance level. Statistical analyses were carried out using SPSS software for Windows (version 15.0., SPSS Inc., Chicago, IL, USA).

RESULTS

Differences between women with SLE and control subjects

The main characteristics of the participants are shown in Table 1. HT was present in 56% of the women with SLE and in 29% of the control subjects (OR 3.1, 95% CI 1.9–5.0, p < 0.001). The difference in the prevalence of HT was more pronounced in the age group under age 40 (40% vs 11%; OR 5.4, 95% CI 2.4–12.0, p < 0.001) than in the older group (74% vs 47%; OR 3.2, 95% CI 1.6–6.5, p = 0.001; Figure 1).

Figure 1.
Figure 1.

Frequency of hypertension (HT) in women with systemic lupus erythematosus (SLE) and controls according to age. *40% vs 11% (OR 5.4, 95% CI 2.4–12.0). **74% vs 47% (OR 3.2, 95% CI 1.6–6.5). ***56% vs 29% (OR 3.1, 95% CI 1.9–5.0).

View this table:
Table 1.

Main characteristics of women with systemic lupus erythematosus (SLE) and age-matched control subjects. Data are expressed as median (interquartile range) or percentage.

Differences according to hypertensive status

The main differences between the 2 groups are shown in Table 2. As expected, hypertensive women with SLE were older and more likely to have obesity, dyslipidemia, and renal impairment. In accord with this finding, hypertensive patients had higher HOMA index values, reflecting increased insulin resistance in the group of patients with HT. In contrast, they were less likely to be smokers or consumers of alcohol. No differences in the frequency of sedentary lifestyle and diabetes were found, although all women with diabetes and SLE also had HT. With regard to SLE-related factors and treatments, women with SLE who had HT had higher SLEDAI and SDI scores and higher levels of ESR, IL-6, homocysteine, and fibrinogen. In addition, the duration of disease was longer in women with SLE who had HT, and they tended to be more likely to have anti-dsDNA antibodies (p = 0.054). No differences were found in the presence of antiphospholipid antibodies or in the levels of CRP (although the median was 2-fold greater in the group of patients with HT). The use of prednisone, hydroxychloroquine (HCQ), nonsteroidal antiinflammatory drugs (NSAID), and immunosuppressive therapy was similar in both groups.

View this table:
Table 2.

Main characteristics of women with systemic lupus erythematosus with and without hypertension. Mann-Whitney U test was used for continuous variables and Pearson’s chi-square test for categorical variables.

Differences between women with SLE with and without HT for each age range

In patients under age 40, those with and without HT were comparable in age, body mass index (BMI), and other traditional risk factors such as diabetes, smoking, alcohol consumption, and sedentary lifestyle (data not shown). In contrast, hypertensive patients had higher levels of uric acid and insulin and higher HOMA index values, as well as higher total cholesterol, low-density lipoprotein cholesterol, and triglycerides. Although renal impairment was more frequent among hypertensive patients, no differences were found in median creatinine levels and median creatinine clearance. Of note, hypertensive women under age 40 with SLE had more disease activity-related markers than normotensive patients of the same age. They also had a higher SLEDAI score, greater presence of anti-dsDNA antibodies, and higher levels of ESR (but not CRP) and fibrinogen, a higher platelet count, and lower levels of albumin and hemoglobin. The hypertensive patients also took higher doses of prednisone, immunosuppressive agents, and NSAID. In addition, SDI and levels of homocysteine were higher in hypertensive patients. Interestingly, the duration of SLE was shorter in hypertensive patients in comparison with normotensive subjects (Table 3).

View this table:
Table 3.

Comparison of demographic data, biochemical measurements, and therapies between women with systemic lupus erythematosus (SLE) with and without hypertension, categorized by age. Mann-Whitney U test was used for continuous variables and Pearson’s chi-square test for categorical variables. Data are expressed as the median (interquartile range) or a percentage.

In contrast, in the older group, hypertensive patients had a higher BMI, greater renal impairment, and worse renal function, and the duration of disease was longer in comparison with normotensive patients. Similarly, they also had higher levels of uric acid and homocysteine. However, in contrast with the younger group, no differences were found in disease activity-related markers and in treatment for SLE (Table 3).

Differences between hypertensive women with SLE according to age

Those older than age 40 had longer disease duration, higher BMI, and were more likely than the younger group to be obese and to have renal impairment with lower creatinine clearance and serum albumin levels. In contrast, younger hypertensive women had higher levels of insulin and more disease activity-related markers such as a higher SLEDAI score, anti-dsDNA antibodies, anemia, and higher platelet counts. They also took more prednisone and immunosuppressive therapy (Table 3).

Multivariate analysis

In younger women with SLE, variables independently associated with HT were renal impairment and insulin levels. In the older group, the associated variables were age, obesity, and renal impairment. Finally, when all women with SLE were considered, the variables that retained significance were age, insulin levels, renal involvement, and SLEDAI score (Table 4).

View this table:
Table 4.

Variables associated with the presence of hypertension in women with systemic lupus erythematosus (SLE), using logistic regression. Models correctly classified 84.0%, 81.1%, and 84.9% with a cutoff value of 0.5, for the entire cohort, younger, and older women, respectively.

DISCUSSION

The overall prevalence of HT was almost 2-fold higher in women with SLE in relation to control subjects, but proportionally it was significantly higher in women with SLE who were aged ≤ 40 years (3.6-fold) than in those above age 40 (1.5-fold). In our cohort of women with SLE, the presence of HT was independently associated with age, renal involvement, insulin levels, and SLEDAI score. However, factors associated with HT in women with SLE were different according to the age range considered. In SLE women under age 40, it was independently associated with renal involvement and insulin levels. In contrast, in those older than 40, it was associated to a greater extent with traditional cardiovascular risk factors (age, obesity, and renal involvement).

A growing body of literature supports a role for the immune system and chronic inflammation in the development of HT among the general population17,18,19,20. Moreover, it has been demonstrated that immunosuppressive therapy with mycophenolate mofetil reduced BP in patients with psoriasis and rheumatoid arthritis21. Since SLE is a chronic inflammatory autoimmune disorder, it is likely that inflammation plays a central role in the pathogenesis of HT in these patients. Our findings seem to support this hypothesis. Women with SLE who had HT had a higher SLEDAI score, higher levels of ESR, IL-6 and fibrinogen, and they tended to be more likely to have anti-dsDNA antibodies (p = 0.054) compared to normotensive patients. In addition, in the younger group, the disease activity was greater in hypertensive than in normotensive patients, as indicated by a higher SLEDAI score and higher levels of inflammatory markers. In contrast, no differences were found in disease activity markers between hypertensive and normotensive patients older than 40 years. Finally, disease activity was also greater in younger hypertensive patients compared with older hypertensive patients, as indicated by a higher SLEDAI score and greater use of prednisone and immunosuppressive agents. In view of these findings, we hypothesize that in younger women with SLE, HT is associated to a greater extent with inflammation, while in older patients, who present SLE activity to a lesser degree, HT is mainly associated with traditional cardiovascular factors such as age, obesity, and chronic renal involvement, as indicated by the multivariable analysis. Therefore, as the disease becomes less active over time, SLE-related factors as contributors to HT could be replaced by the traditional risk factors associated with age, as occurs among the general population.

However, a possible confounding factor may exist: patients who had higher disease activity also received a higher prednisone dose, which has been found to trigger an increase in BP. Therefore, HT could be associated to a greater extent with prednisone use rather than with the inflammation itself. However, as discussed, the median dose used in both hypertensive and normotensive groups was very low (only 4 patients in the cohort received > 10 mg/day), and it is likely that these doses of prednisone were not high enough to have a significant effect on BP. In this regard, it has been reported that a 10-mg increase in the prednisone dose given to patients with SLE in the last 90 days produced a change in mean arterial BP of 1.1 mm Hg22, and the same increase in the dose of prednisone in the preceding year led to a 1.6 mm Hg rise in systolic BP3.

It is very likely that much of the inflammation observed in hypertensive patients is due to the presence of lupus nephritis, especially among younger patients. In this regard, we found that the SLEDAI score was independently associated with HT when the entire cohort was considered. However, in a large cohort study (LUMINA) this association was not documented, probably because, unlike in our study, scores from the renal domain were excluded in the Systemic Lupus Activity Measure-Revised12. This may also explain why the SLEDAI score was not independently associated with HT in the younger group, in which a high disease activity was observed. In other words, it is likely that the SLEDAI score and renal involvement are not completely independent variables in this group.

In accord with the findings of other authors12, a strong association between renal involvement and HT was identified in both the younger and older subgroups. The definition of renal involvement used in our study includes different settings ranging from active lupus nephritis to chronic renal failure without inflammation. Unfortunately, these alternatives were not taken into account at the time of patient inclusion. However, when only patients with renal involvement were considered, younger women with SLE received a higher prednisone dose (p = 0.001) and they were more likely to use prednisone (p = 0.026), immunosuppressive therapy (p = 0.049), and HCQ (p = 0.009) than older patients (data not shown). In addition, they had higher SLEDAI scores (p = 0.047), higher levels of anti-dsDNA antibodies (p = 0.024), and lower levels of C4 (p = 0.045) and hemoglobin (p = 0.015; data not shown). These data suggest that renal involvement in women with SLE aged ≤ 40 years consists of a more active renal disease, while in older women with SLE it corresponds to a more inactive chronic renal impairment.

To our knowledge, ours is the first study in which insulin levels have been independently associated with the presence of HT in women with SLE, especially in those under age 40. In keeping with this finding, it has been recently established that insulin levels strongly affect the risk of HT in young women among the general population23. The presence of hyperinsulinemia and increased insulin resistance has been identified in patients with SLE4,24,25,26. It has been demonstrated that NZBWF1 mice (a murine model of SLE) present many characteristics associated with metabolic syndrome, including HT and insulin resistance27. Several theories have been proposed that explain how insulin may promote HT. Placebo-controlled studies in healthy subjects have demonstrated that insulin perfusion is associated with an increase in plasma catecholamine levels, heart rate, and systolic BP28,29. Euglycemic clamp studies have shown that insulin infusion increases plasma-renin activity and angiotensin II levels and modifies the renal handling of sodium30,31,32. Finally, it has been demonstrated that modest increases in insulin in healthy subjects impair endothelium function33. There are several mechanisms that could potentially contribute to the presence of higher insulin levels in younger women with SLE who have HT in relation to those without HT, such as obesity, prednisone use, and systemic inflammation. A study has shown that the major contributing factor to insulin resistance in SLE was BMI34. However, no differences were observed in BMI between the 2 groups in our study, suggesting that the increased insulin levels observed in the group of younger hypertensive women do not appear to be generally associated with the presence of obesity. With regard to prednisone use, Posadas-Romero, et al24 reported a significant independent association between prednisone dosage and insulin levels in a pediatric cohort. In our study, young hypertensive women with SLE received a higher prednisone dose than normotensives [median 6.3 mg/day (range 3.8–10) vs 2.5 mg/day (range 0–5)], but these doses were considerably lower than those included in Posadas-Romero, et al. In keeping with this, no association has been found between the use of prednisone at low doses and insulin levels20,21. In addition, we recently found that the percentage of patients with SLE who have insulin resistance was similar among those who took an average of ≤ 7.5 mg/day of prednisone and those who were taking none35.

Therefore, collectively these results suggest that the hyperinsulinemia observed in these patients could be largely due to inflammation. Thus, in younger patients with a more active disease, inflammation could drive insulin resistance and hyperinsulinemia, and in turn, increased insulin levels could lead to HT by means of these mechanisms, ultimately contributing to the development of premature arteriosclerosis. However, given that this was a cross-sectional study, conclusions can only be used for hypothesis generation, and do not provide proof of causality or directionality, for which further appropriate investigations are required. Another possible limitation is that the ethnic background of the study population (white) might restrict the generalization of the results to other SLE cohorts.

The factors associated with HT in women with SLE differed depending on their age. HT seems to be associated with SLE-related factors such as a more active renal disease and inflammatory nonobesity-related hyperinsulinemia in younger women, while in older women it may be associated to a greater extent with traditional cardiovascular risk factors (age, obesity, and noninflammatory renal disease). Moreover, HT was found to be more prevalent in women with SLE than in control subjects, being proportionally higher in women with SLE aged ≤ 40 years than in women with SLE who were older than 40 years (3.6-fold and 1.6-fold, respectively). These data may be useful in improving our understanding of the pathogenesis of HT in SLE and in the early identification of patients who may need to be specifically targeted for screening and intervention in a routine clinical setting.

Acknowledgment

We thank Ana Rosales for her invaluable assistance in organizing the clinical records. We also thank all our patients for their cooperation and interest in our study.

  • Accepted for publication January 25, 2011.

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