Systemic Lupus Erythematosus and Arterial Hypertension: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Juan Duarte.

Systemic lupus erythematosus (SLE) is a multifactorial disorder with contributions from hormones, genetics, and the environment, predominantly affecting young women. Cardiovascular disease is the primary cause of mortality in SLE, and hypertension is more prevalent among SLE patients.

  • systemic lupus erythematosus
  • endothelial dysfunction
  • hypertension

1. Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystemic inflammation and organ damage manifestations that affect the skin, joints, kidneys, heart, lungs, blood, and the central nervous system [1]. Autoantibodies targeting the cell nucleus are present in 99% of SLE patients, and autoantibodies specific to double-stranded DNA (anti-dsDNA) have been identified in more than 70% of patients [2]. Even though the presence of anti-dsDNA is predictive in 95% of SLE cases, a more extensive immune dysregulation is involved in the etiopathogenesis of SLE, although the exact cause of SLE remains unclear [3]. In a study by Wang et al., mitochondrial DNA (mtDNA) was detected in neutrophils with extracellular traps (NETs) [4]. The researchers observed elevated levels of anti-mtDNA antibodies in SLE patients compared to control subjects, which were significantly correlated with disease activity. Moreover, the presence of anti-mtDNA antibodies was disproportionately associated with lupus nephritis and showed a stronger correlation with the lupus nephritis activity index compared to anti-dsDNA levels [4].
SLE is a complex disorder influenced by a combination of hormonal, genetic, and environmental factors, primarily affecting young women (with a female-to-male ratio of 9 to 1) and typically manifesting during the reproductive years. The leading cause of mortality in SLE is cardiovascular disease (CVD), which can be attributed to a combination of risk factors such as hypertension, dyslipidemia, and a prothrombotic state. Increased atherosclerosis has already been demonstrated in SLE [5]. SLE has been linked to a proatherogenic lipid profile that includes elevated total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) [6]. The most common abnormality seen in SLE patients is a decrease in HDL-C. The prevalence of dyslipidemia was 36% at the time of diagnosis and 60% at 3-year follow-up in a cohort of 918 SLE patients [7,8][7][8]. In this study, the prevalence of other traditional risk factors, such current smoking and diabetes, at enrollment was 13.7% and 3.4%, respectively, which was also increased through the follow-up [7,8][7][8]. Furthermore, metabolic syndrome is recognized as a proinflammatory state that may contribute to premature atherosclerosis and diabetes development in SLE patients, increasing their CVD risk. Metabolic syndrome is more common in SLE patients [9]. A recent systematic review and meta-analysis looked at the risk of CV events and CV risk factors in adult SLE patients. When compared to adults without SLE, the relative risk (RR) of hypertension was higher at 2.7, whereas the RRs of diabetes and metabolic syndrome were elevated but not statistically significant [10]. However, while traditional Framingham risk factors may contribute to CVD pathogenesis in SLE patients, they cannot fully explain the increased CVD risk in SLE patients [11]. Indeed, certain SLE-specific factors may play a role in CVD onset and progression in SLE patients. Additionally, another contributing factor to cardiovascular disease in SLE is the presence of elevated antiphospholipid antibodies, which can directly induce pro-inflammatory and prothrombotic effects on the endothelium and disrupt coagulation by inhibiting annexin A5, thereby negating its antithrombotic and protective effects [12].
Zhao M et al. reported that 71.9% of SLE patients had hypertension, and a significant portion of them, specifically 74.4%, were either undertreated or not treated at all [13]. Despite the high prevalence of hypertension among SLE patients, current hypertension management guidelines do not address the specific needs of individuals with autoimmune disorders like SLE. This has led healthcare providers to rely on recommendations designed for the general population, lacking data from comprehensive clinical trials within the SLE patient group [14]. Consequently, many patients with this autoimmune disease do not receive the appropriate antihypertensive medications they may require [15].

2. Systemic Lupus Erythematosus and Arterial Hypertension

Hypertension stands as the leading risk factor for the progression of renal, vascular, and cardiac diseases in the general population [19][16], which is exacerbated by immune-mediated mechanisms in SLE patients. Multiple studies highlight the elevated prevalence of hypertension in women with SLE. Women aged 35 to 44 with SLE are 50 times more likely to experience a cardiac event, such as infarction or angina, than individuals of the same age without the condition [12,20][12][17]. Nonetheless, there is a scarcity of mechanistic studies on hypertension in SLE, and the precise underlying mechanisms remain unknown [21][18]. The renal pathological mechanisms related to autoimmune-induced hypertension remain incompletely understood. It is established that a loss of self-tolerance results in the production of autoantibodies. These autoantibodies form complexes, which deposit into tissues such as the kidneys, leading to the activation of other immune cells and the complement system. This, in turn, triggers the local secretion of inflammatory mediators, promoting chronic renal inflammation and oxidative stress [22][19]. These processes can potentially disrupt fluid and electrolyte balance in the kidneys or lead to renal vascular dysfunction, subsequently causing hypertension [23][20]. Various animal models of SLE have been employed to investigate the genetic and immunological mechanisms contributing to this autoimmune disorder. The NZBWF1 mouse model, utilized for over four decades, closely resembles human lupus nephritis. These mice exhibit features like immunocomplex deposition in glomeruli, high plasma levels of anti-dsDNA, albuminuria, and hypertension between 25–30 weeks of age [24][21]. In both female humans with SLE and the NZBWF1 mouse model, lupus nephritis precedes hypertension. This provides an opportunity to study the contributing factors to hypertension in the context of chronic renal inflammation [25][22]. However, like humans, it exists a disparity between nephritis and blood pressure in animal models of SLE. For instance, MRL/lpr, BXSB, and NZBWF1 mice develop glomerulonephritis, but only the NZBWF1 mouse model develops hypertension [26][23]. Hence, the NZBWF1 model is especially valuable for understanding the pathophysiology of hypertension in SLE. Several factors contribute to hypertension in this model, including altered renal hemodynamics, endothelial dysfunction, changes in the inflammatory cytokine profile, oxidative stress, dysfunction in the adaptive immune system, and sex hormones [21][18]. However, it is important to note that hypertension in this lupus mouse model is not salt-sensitive [27][24]. This precludes the use of diuretics as a treatment option. Nevertheless, angiotensin-converting enzyme inhibitor drugs (ACEIs) like captopril and enalapril delay the onset of renal damage and reduce blood pressure, while cyclophosphamide treatment does not have effect in blood pressure [28,29][25][26]. Moreover, captopril reduced chronic renal lesions by reducing TGF-beta expression in the kidneys but had no effect on autoantibody production [30][27]. Recently, a murine model of lupus induced by topical administration of imiquimod, a toll-like receptor (TLR) 7 agonist, in the ears of BALB/c mice has been established [31][28]. These mice develop splenomegaly, autoantibody production, and glomerulonephritis with immunocomplex deposition within 4–6 weeks. Furthermore, they exhibit elevated levels of type I interferon, a result of TLR7 activation. It is worth noting that gain-of-function variants of TLR7 have been linked to lupus nephritis [32][29]. This model has also shown signs of endothelial dysfunction [33][30] and hypertension [18][31], indicating that TLR7 endosomal receptor activation, triggered by self-antigens (ds-DNA and ssRNA), may contribute to lupus-associated vasculopathy. Additionally, wresearchers have observed an approximately 2.5-fold increase in TLR7 expression in the vascular wall (unpublished data) in hypertensive NZBWF1 mice. However, the relevance of this finding to the occurrence of endothelial dysfunction in this model remains unknown. In another murine model induced by pristane to mimic SLE, which is widely used to evaluate potential therapeutic agents resembling human idiopathic lupus syndrome [34][32], hypertension, chronic inflammation, and endothelial dysfunction were also observed [35][33]. There is limited evidence regarding the impact of first line SLE therapies on blood pressure. Corticosteroids, the most commonly used agents for all autoimmune diseases, have been associated with hypertension in SLE patients. Furthermore, women who had used prednisone for a longer period and had a higher cumulative dose of prednisone, as well as those who had previously had a coronary event, were more likely to have plaque [36][34]. On the other hand, mycophenolate mofetil (MMF) and hydroxychloroquine have demonstrated beneficial effects on blood pressure, independently of additional antihypertensive treatments and existing renal disease [37][35]. Several mechanisms by which hydroxychloroquine may protect against vascular injury have been proposed in mouse studies, including the reduction of vascular oxidative stress via antioxidant action in a mouse model of SLE [17,38][36][37] and the regulation of endothelial nitric oxide synthase in a mouse model of antiphospholipid syndrome [39][38]. Novel immunomodulatory drugs like belimumab and anifrolumab offer promising options for regulating immune system activation in SLE, but their effects on renal inflammation and hypertension in SLE have received limited investigation. Other new immunomodulatory drugs include JAK inhibitors (jakinibs), which inhibit the downstream cellular effects of various cytokines, including type I IFNs and cytokines involved in neutrophil development and function. Jakinib tofacitinib was shown to be effective in reversing lupus symptoms and vascular dysfunction in mice, as well as inhibiting netosis [40][39]. Short-term use of tofacitinib in SLE patients with mild–moderate disease activity was safe and improved arterial stiffness [41][40]; however, long-term clinical studies are needed to determine whether this treatment confers benefits for SLE patients addressing CV morbidity and mortality, especially given a reported link between thrombosis and JAK inhibition [42][41].

2.1. Role of Endothelial Function in SLE Hypertension

A substantial number of individuals with SLE exhibit signs of subclinical vascular disease that precede the onset of atherosclerosis. These subclinical changes include the development of endothelial dysfunction (with preserved vascular smooth muscle function) [43][42], arterial wall thickening, and coronary perfusion abnormalities [44][43]. Multiple studies emphasize the prominent impact on the endothelium in SLE. A meta-analysis of 25 case-control studies encompassing 1313 SLE patients and 1012 healthy controls, utilizing a random effects model, revealed that SLE patients exhibited lower brachial artery endothelium-dependent flow-mediated dilation compared to healthy controls [45][44]. Notably, diabetes mellitus, renal disease, and diastolic hypertension are significant contributors to endothelial dysfunction in SLE patients [45][44]. However, whether endothelial dysfunction plays a causal role in SLE-associated hypertension or is merely an associated condition remains uncertain. Possible mechanisms underlying endothelial dysfunction in SLE encompass netosis, endotoxemia, and an imbalance between pro-inflammatory and anti-inflammatory cytokines, leading to reduced nitric oxide (NO) bioavailability, endothelial leakage, and impaired endothelial repair (Figure 1). The decreased vasodilator response to acetylcholine in NZBWF1 mice is observed before the onset of proteinuria and elevated blood pressure, suggesting that these early vascular function changes may contribute to the development of hypertension in SLE [46][45]. The specific causes of endothelial dysfunction in the NZBWF1 model are not yet completely understood. Oxidative stress and proinflammatory cytokines have been proposed as potential factors contributing to hypertensive endothelial dysfunction in SLE.
Figure 1. Mechanisms potentially underlying pathogenesis of hypertension in SLE. Several SLE-specific factors, such as impairment of endothelial repair, endothelial dysfunction and arterial stiffness influence vascular health, contributing to development of hypertension. eNOS, endothelial nitric oxide synthase; ECs, endothelial cells; EPCs, endothelial progenitor cells; ER, endoplasmic reticulum; FcRs, Fc receptors; IFN, interferon; IL, interleukin; NETs, neutrophil extracellular traps; NO, nitric oxide; LPS, lipopolysaccharide; TLR, Toll-like receptors; VSMCs, vascular smooth muscle cells.
OurThe research has indicated that endothelial nitric oxide synthase (eNOS) expression in the aorta of NZBWF1 mice remains unaltered [17][36]. However, wresearchers have observed a reduction in the phosphorylation of its activation site, Ser-1177, and no changes in the NO- cyclic guanosine monophosphate (cGMP) pathway signaling [47][46]. Additionally, wresearchers have identified an increased production of oxygen free radicals (ROS), mediated by the activation of the NADPH oxidase (NOX) system, which appears to be responsible not only for endothelial dysfunction but also for the development of hypertension. The administration of antioxidants (tempol + apocynin) restored endothelial function and reduced blood pressure in lupus mice [17][36]. Similarly, in pristane-induced SLE mice, endothelial dysfunction was associated with eNOS uncoupling and overexpression of NOX-1 [48][47]. The alterations in endothelial function observed in the NZBWF1 model may be linked to the vascular proinflammatory state triggered by circulating autoantibodies and proinflammatory cytokines (tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-17, and IL21), or the infiltration of immune cells, particularly Th17 lymphocytes, into the vascular wall [47,49][46][48]. The proinflammatory cytokine IL-17 is known to induce endothelial dysfunction in the vasculature through Rho-kinase-mediated mechanisms [50][49], possibly due in part to increased ROS generation via NOX activation [51][50]. In contrast, IL-10, the primary cytokine released by Tregs, is known to attenuate NOX activity [52][51]. In SLE mice, elevated levels of plasma endotoxins were observed. Activation of TLR-4 in vessels with bacterial products such as lipopolysaccharide (LPS) can lead to increased NOX-dependent O2− production and inflammation [53][52]. The endothelial dysfunction identified in human umbilical vein endothelial cells (HUVECs) acutely induced (within 24 h) by plasma from lupus patients with active nephritis is associated with ROS production generated sequentially by endoplasmic reticulum stress and NOX activation [54][53]. The innate immune system’s role in SLE pathogenesis is of special interest, with current research identifying neutrophils, neutrophil extracellular traps (NETs), and IFN signaling as disease progression and endothelial dysfunction drivers. By cleaving vascular endothelial cadherin with neutrophil elastase present within NETs, NETs can promote vascular leakage and endothelial-to-mesenchymal transition, increasing beta-catenin signaling, which may have profibrotic effects in SLE patients [55][54]. Furthermore, endothelial progenitor cell loss and dysfunction have been linked to elevated serum levels of type I IFNs in SLE patients [56][55] and in mouse models of lupus [57,58][56][57], suggesting a role for SLE-specific immune dysregulation in contributing to an imbalance of increased endothelial damage and reduced vascular repair/angiogenesis. In addition, IFN-α has been shown to alter NO signaling via transcriptional control of eNOS expression, resulting in decreased NO generation in insulin-stimulated HUVECs, which contribute to endothelial dysfunction [59][58]. Large artery stiffness is caused by the deterioration of the anatomical features of the arterial wall, which results in a decrease in the elastin-to-collagen ratio. Vascular stiffness is an outcome of hypertension rather than its cause. When compared to controls, SLE patients had higher arterial stiffness [60,61][59][60]. Arterial stiffness, as well as associated features of reflected pulse waves in the artery, may contribute to systolic blood pressure and pulse pressure rises. Endothelial dysfunction and collagen deposition in the extracellular matrix are both important factors in arterial stiffness. Moreover, in young patients with SLE, there was a significant positive correlation of arterial stiffness with triglyceride-rich lipoproteins, although the cause–effect relationship of this link was not established [62][61].

2.2. Immune System and Hypertension in SLE

It is now commonly accepted that aberrant immune system activation is linked to the development of hypertension, both in humans and experimental models. In fact, there have been numerous genetic polymorphisms associated with hypertension described that exert effects on the immune response [63][62]. Non-specific immunosuppressive therapies, such as cyclophosphamide, have been proven in experimental models of spontaneous non-autoimmune hypertension to not only prevent the development of hypertension but also to lower blood pressure in animals with established hypertension [64][63]. Similarly, MMF, an immunosuppressive therapy frequently used in SLE patients to suppress T and B lymphocyte proliferation, has been effective in attenuating the development of hypertension in various experimental models and in humans [65,66,67][64][65][66]. Several studies have found a link between circulating autoantibodies, which are seen in systemic autoimmune diseases, and essential hypertension in humans. SLE is a chronic autoimmune disorder characterized by the hyperreactivity of B and T lymphocytes due to a loss of tolerance to self-antigens, resulting in the production of pathogenic autoantibodies, particularly against nuclear components. However, it remains unclear whether the autoantibodies produced in SLE contribute mechanistically to the development of hypertension in these patients. The immunization process leading to the abnormal production of autoantibodies in SLE is partly attributed to the delayed clearance of apoptotic cells. OurThe research has demonstrated that the activation of peroxisome proliferator-activated receptors β/δ (PPARβ/δ) plays a crucial role in the proper clearance of deceased cells by macrophages in the NZBWF1 model, which has been associated with a reduction in elevated blood pressure [47][46]. Animal models of SLE are critical in understanding the relationship between autoantibodies and hypertension. As previously stated, the NZBWF1 mouse model closely resembles key characteristics of clinical SLE, including autoantibody generation, immune-complex-mediated kidney damage, and hypertension. Recent studies have shown that long-term B cell depletion using anti-CD20 successfully reduced autoantibody synthesis and prevented the onset of hypertension in SLE mice [68][67]. Furthermore, continuous administration of the immunosuppressive medication MMF selectively lowered B cells while preventing the development of hypertension [69][68]. These data unequivocally indicate a relationship between B cells, autoantibodies, and the onset of hypertension. However, it is important to highlight that these treatments were only beneficial when started before the commencement of the disease. Similarly, treatment efforts targeting B cells in humans, such as anti-CD20 (rituximab), have had minimal effectiveness in large controlled clinical studies [70][69]. It has been suggested that the low efficacy is due in part to the persistence of plasma cells, which are not the target of B cell treatments. Plasma cells take up residence in the bone marrow and spleen for extended periods, ranging from months to years, and are primarily responsible for producing serum immunoglobulins, including SLE autoantibodies. The depletion of plasma cells using the proteasome inhibitor bortezomib has been demonstrated to diminish autoantibody production and alleviate hypertension in female NZBWF1 mice. Collectively, these findings indicate that the mechanistic link between autoantibody production and autoimmune-associated hypertension involves plasma cells [71][70]. Autoantibody production and the clinical severity of lupus in NZBWF1 mice prone to the disease are contingent on the assistance of CD4+ T cells [72][71]. Activated B cells migrate to areas rich in T cells within secondary lymphoid organs, where they recruit antigen-bound T cells. Subsequently, B cell differentiation occurs, either extrafollicularly into plasmablasts, with limited antibody production capacity, or by transitioning along the follicular pathway, forming germinal centers (GCs). Within GCs, follicular T-helper (Tfh) cells facilitate somatic hypermutation and isotype switching of B cells, culminating in the generation of long-lived plasma cells capable of producing high-affinity antibodies [73,74][72][73]. In a murine model of SLE, a connection between increased Tfh cell numbers and the development of autoimmunity has been established [75[74][75],76], suggesting that anomalies in the positive selection of Tfh cells could lead to systemic autoimmunity. Tregs also play a role in regulating the production of lupus-associated antibodies, including anti-dsDNA [77][76]. A substantial inverse correlation has been observed between Tregs and anti-dsDNA levels [78][77]. Although the precise role of Tregs in the pathogenesis of SLE remains to be fully elucidated, expanding Tregs could pose a potential challenge in the treatment of SLE, especially in terms of inducing B cell tolerance. Additionally, it has been postulated that Th17 cells, a subset of T cells, might be responsible for the abnormal selection of autoreactive B cells in GCs and the humoral response in vivo [79][78]. Collectively, inhibiting the differentiation of Tfh cells into Th17 cells and B cells into long-lived plasma cells, alongside expanding Tregs, could emerge as novel treatment options for SLE, centered on diminishing autoantibody production. Furthermore, the expansion of Treg cells through low-dose IL-2 has been shown to alleviate hypertension in NZBWF1 mice [80][79], while the neutralization of IL-17, the primary proinflammatory cytokine produced by Th17 cells, has been found to ameliorate endothelial dysfunction and reduce high blood pressure in SLE mice induced by TLR7 activation [18][31].

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