Abstract
Objectives
To determine the association between the occurrence of hypertension and damage accrual in patients with systemic lupus erythematosus (SLE).
Materials and methods
From January 2012 to January 2020, we evaluated 314 SLE patients, all members of the Almenara Lupus Cohort. We applied the American College of Cardiology/American Heart Association (ACC/AHA) guidelines to define hypertension, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to determine organ damage, and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) to assess disease activity. We performed univariable and multivariable analysis using generalized estimating equations, adjusting for potential confounders (demographic factors, disease-related factors and treatment).
Results
314 patients and 1695 visits were included; 93% of the patients were women. Their mean disease duration was of 6.8 years (SD: 6.4), and their age at diagnosis of 35.7 (SD: 13.4) years. Baseline damage was 0.8 (SD: 1.2) at the first visit, increasing by 0.15 points at the subsequent follow-up visit (SD: 0.46). The prevalence of hypertension in these patients was 56.4% at least once during their follow-up. In the multivariable analysis, hypertension remained associated with damage accrual (IRR: 1.645, 95% CI: 1.187–2.280, p = 0.003) after adjusting for confounders. In the analyses performed per domain, hypertension was associated with renal damage in the multivariable model (OR: 4.331, 95% CI 1.547–12.126, p = 0.005).
Conclusion
Hypertension was associated with subsequent greater damage in our SLE patients. Thus, providers involved on the care of these patients should monitor their blood pressure at all clinic visits.
Introduction
Hypertension is an important risk factor for cardiovascular diseases (CVD) and it is very common in patients with systemic lupus erythematosus (SLE) with its prevalence ranging from 9.4% to 77.0%.1–3 The World Health Organization (WHO) has reported that the effects of hypertension on target organs such as the heart, kidneys, and brain, among others, are the leading cause of death in the world. 4 SLE patients have a five to six fold increase in the risk of CVD 5 and women between the ages of 35 and 44 have a 50-fold greater risk of myocardial infarction when compared to the age-matched general population. 6 Therefore, the evaluation and management of hypertension should be a priority for all SLE patients.
Both, hypertension and SLE, are multifactorial conditions. Therefore, it may not be surprising that there is an overlap between the genetic and environmental risk factors for the development of both. 1 The underlying pathophysiologic mechanisms of hypertension are not completely understood, but they include endothelial dysfunction and glomerular damage. Endothelial progenitor cells are quantitatively and functionally lower and reduced, respectively in SLE patients, and these cells are relevant for vascular repair, neovascularization and endothelial function. 7 Furthermore, endothelin-1 and angiotensin II have been reported to be increased in SLE patients, 8 and angiotensin-converting enzyme (ACE) polymorphisms have been associated with SLE risk. 9 Additionally, the immune system is involved in the pathogenesis of hypertension and cardiovascular disease by the expression of proinflammatory cytokines such as interleukin-6 (IL-6), IL-8, type-I interferon,10,11 among others, and these cytokines are also related to the pathogenesis of SLE. Finally, renal involvement would also increase the risk of hypertension due to impairment of the glomerular filtration rate and renal plasma flow. 8 Therefore, a combination of traditional (age, gender, obesity, ethnicity, etc.) and disease-related (immune system dysfunction, inflammation, kidney disease, treatment side effects, among others) factors can contribute to hypertension in patients with SLE. 12
Hypertension has been found to predict a twofold risk of stroke in patients with SLE. 13 In addition, hypertension has been associated with cognitive dysfunction, which is a common and debilitating manifestation in these patients (OR: 2.06, 95% CI 1.19–3.56). 4 On the other hand, lupus nephritis is present in 50%–70% of patients with SLE and it has a strong relationship with hypertension 6 ; additionally, hypertension is a predictor of renal damage. 14 Furthermore, hypertension has been reported to be a predictor of damage accrual in the Hopkins Lupus Cohort 15 (OR 1.3, 95% CI 1.1–1.6) but not in others. 16 Nevertheless, there is limited information about the association between hypertension and damage in Latin American SLE patients; therefore, the objective of this study is to determine if hypertension is associated with damage accrual in patients with SLE from a Peruvian lupus cohort.
Methods
The Almenara Lupus Cohort has been previously described. 17 In short, this cohort was started in 2012 at the Rheumatology Department of the Hospital Guillermo Almenara Irigoyen in Lima, Peru. The protocol had been approved by the hospital’s Institutional Review Board. Patients who signed the informed consent were recruited and followed every 6 months. Evaluations included an interview, medical records review, physical examination, and laboratory tests. For these analyses, we have included those patients who had at least two visits between January 2012 and February 2020.
SLE was defined using the 1997 revised American College of Rheumatology (ACR) criteria
Damage was ascertained with the Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (SDI) 14 ; treatment-related variables included current prednisone dose, antimalarials and immunosuppressive drugs use (current, past or never)
Hypertension was defined as a systolic blood pressure equal or higher than 130 mmHg and the diastolic blood pressure equal or higher than 80 mmHg based on the 2017 guidelines of the American College of Cardiology/American Heart Association (ACC/AHA). 20
Statistical analyses
Categorical variables are reported as frequencies and percentages. Numerical variables are reported as means and standard deviations (SD). Univariable and multivariable generalized estimation equations (GEE) negative binomial models were performed to determine the association between hypertension and the increase in the SDI, including follow-up as an offset variable, adjusted for age at diagnosis, socioeconomic status, disease duration, SLEDAI-2K, SDI, prednisone (daily dose), antimalarial (current, past or never) and immunosuppressive drug use (current, past or never). Confounders were determined at one visit whereas the outcome was determined at the subsequent visit.
As alternative models, to determine the impact on the increase of damage within each organ/domain, univariable and multivariable GEE logistic regression models were performed. In these cases, the outcome was the increase (or not) per organ/domain damage, and visits were included until the maximum score per organ was achieved. Additionally, for premature gonadal failure, only women aged younger than 40 at diagnosis were included. Multivariable models were adjusted for age at diagnosis, socioeconomic status, disease duration, follow-up time, SLEDAI-2K, SDI, prednisone (daily dose), antimalarial (current, past or never) and immunosuppressive drug use (current, past or never). Confounders were determined at one visit whereas the outcome was determined at the subsequent visit.
A p < 0.05 was considered statistical significant in all analyses. All analyses were performed with the SPSS v.28.0 (IBM, Chicago, IL).
Results
Characteristics of SLE patients at the baseline visit.
N: Number. SD: Standard deviation. SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2K. SDI: Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index. *Socioeconomic status ascertained with the Graffar index.
In total, 1695 visits were included. During the follow-up, the SDI increased in 192 (11.3%) of the visits. One hundred and 76 patients (56.4%) presented hypertension at least once during their follow-up and it was present in 686 of the visits (40.5%). Among the 686 visits in which hypertension was present, the SDI increased in 97 (14.1%) of the subsequent visits, while in the 914 visits in which hypertension was not present, the SDI increased in 95 (9.4%) of the subsequent visits (p = 0.003).
Association between hypertension and damage accrual. Univariable and multivariable models.
OR: Odds ratio. CI: Confidence interval *Adjusted for age at diagnosis, socioeconomic status, disease duration, follow-up time, SLEDAI-2K, SDI, prednisone (daily dose), antimalarial (current, past or never) and immunosuppressive drug use (current, past or never).
When the analyses were done per organ/domain, hypertension was associated with renal damage in the univariable model OR: 4.703, 95% CI 1.930–11.464, p < 0.001 and this association remained significant in the multivariable model: OR: 4.331, 95% CI 1.547–12.126, p = 0.005.
Discussion
In this primarily Mestizo prevalent lupus cohort, hypertension was associated with a higher probability of damage accrual and of renal damage, even after adjusting for possible confounders.
The prevalence of hypertension in SLE is highly variable; in a recent review, it ranged between 9.4 and 77.0%; however, the majority of the studies included in the review reported a prevalence between 30 and 50%. 3 A review on the immunological mechanisms of hypertension shows that hypertension, once the immune system is activated, can cause significant endothelial dysfunction which partially explains the higher incidence of CVD and atherosclerosis in SLE patients. 21
Previously, the Hopkins and the SLICC cohorts have reported hypertension as a predictor of damage accrual15,22; similarly was the case for a Portuguese 23 and an Italian 24 cohort; they reported hypertension as a predictor of damage accrual in a mainly White population. However, it is important to point out that these cohorts do not include South American patients, and only the SLICC cohort included Hispanics patients (from Mexico or the US). The only South American study reporting the possible association between hypertension and damage was done in Colombia. In this study, however, no association between hypertension and damage accrual was found in the multivariable model 16 ; it should be noted, that the ethnic/ancestral composition of these populations differ significantly; the Peruvian population being predominantly Mestizo (i.e., of European and Native American ancestry) whereas the Colombian population has a large African ancestry.
When we examined the impact of hypertension on the different domains of the SDI, we found that hypertension predicted renal damage; this is consistent with previous reports like the one from the GLADEL 14 or the PROFILE 25 cohorts. However, it is important to point out that these cohorts reported hypertension only at baseline and not during the patients’ follow-up.
Our study has some limitations; firstly, as this is a prevalent cohort, we cannot exclude the impact of disease characteristics present before the baseline visit. Secondly, due to the relatively small sample size, we were not able to find and association between hypertension and damage accrual in other than the renal domain. Thirdly, as this is a single center cohort, these results cannot possibly be directly extrapolated to other populations. However, it is important to highlight that this is the first study that includes a predominantly Mestizo population and that we have ascertained hypertension at each visit and not just at baseline and examined its impact on damage accrual in SLE.
In conclusion, hypertension was significantly associated with damage accrual in SLE patients; this was particularly the case for the renal domain. These results reinforce the relevance of monitoring and managing hypertension in SLE patients to prevent damage accrual.
Footnotes
Author contributions
All authors were involved in drafting or revising this article critically for important intellectual content, and all authors approved the final version to be published. Dr Manuel F. Ugarte-Gil has full access to all the data from the study and takes responsibility for their integrity and the accuracy of the analyses performed.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MFU-G has grant support from Janssen and Pfizer, he has been speaker for GSK and Aztra-Zeneca and he has been part of advisory boards for Aztra-Zeneca, GSK, Tecnofarma and Ferrer; RVG-C has grant support from Pfizer; CR-S and VP-Q have grant support from Janssen. All other authors declare to have no conflicts of interest.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: These analyses were supported by a grant from the Universidad Científica del Sur. Additionally, the Almenara Lupus Cohort has been partially supported by Institutional grants from EsSalud (1483-GCGP-ESSALUD-2013, 1733-GCGP-ESSALUD-2014 and the 2015 Kaelin Prize 04-IETSI-ESALUD-2016), from the Pan American League of Associations for Rheumatology (PANLAR) (2015 PANLAR Prize and the 2018 H. Ralph Schumacher MD/JCR/PANLAR Prize), from the Fundación Instituto Hipólito Unanue, Lima, Perú and Janssen Pharmaceutical.
