Elucidating the Intriguing Association Between Systemic Lupus Erythematosus and Cardiovascular Disease

Systemic lupus erythematosus (SLE) patients have demonstrated a higher risk of developing cardiovascular disease (CVD), resulting in it being one of the leading causes of death in SLE patients. SLE itself acts as a sole risk factor influencing the prevalence and progression of CVD. However, conventional risk factors, such as age, hypertension, smoking, and obesity, play a crucial role as well. Therefore, this systematic review attempts to unravel the association of CVD in SLE patients while evaluating the role of conventional risk factors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to search the PubMed database starting from March 2021 systematically. Original studies that evaluated the prevalence and progression of CVD in SLE patients were extracted by two reviewers independently. Quality in Prognostic Studies (QUIPS) tool was used to assess the risk of bias. Most studies have a moderate to low risk of bias. Among 3,653 studies identified by our search, 10 studies were included in the review. Strong epidemiologic evidence of SLE patients having an increased relative risk of CVD compared to controls was found. Traditional CVD risk factors, such as age, hypertension, obesity, and smoking, influence the prevalence of CVD among SLE patients. Several SLE-specific factors such disease activity, duration, and certain medications also acted as influencing factors. However, the relative risk of CVD was still higher in SLE patients after adjustment of certain risk factors. One study found that the odds of having a Coronary Artery Calcification (CAC) score greater than zero in women with SLE aged less than or equal to 45 years was 12.6 times higher than women in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort (95% CI 5.2 to 30.7) (participants of CARDIA cohort acted as control). This finding was made after age, hypertension, total cholesterol levels, and aspirin use were adjusted, and the study was restricted to women. Although conventional risk factors increase CVD prevalence, SLE itself also dramatically increases the prevalence of CVD. Therefore, we recommend that SLE should be treated as a "CVD risk equivalent." SLE patients should be managed more extensively with greater emphasis given to cardiac health for better clinical outcomes.


Introduction And Background
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality, both in developed and developing countries. The underlying pathological change in CVD is atherosclerosis. Endothelial cell injury initiates atherosclerosis with deposition of oxidized low-density lipoprotein (oxLDL) in the arterial wall resulting in the activation of monocytes, which then get attracted to the subendothelial space and become activated macrophages. Macrophages then internalize oxLDL from the circulation and arterial smooth muscle cells, forming a lipid-rich cell called "foam cells." A variety of cytokines are produced by macrophages which accelerate smooth muscle cell and fibroblast migration. As a result, a plaque inside the vascular wall, also known as an atheroma, is formed [1].
Systemic lupus erythematosus (SLE) is a chronic, autoimmune disorder with a variable clinical course involving multiple body organs. SLE affects 20-150 per 100,000 individuals, with most cases (70%-90%) occurring in women [2]. Common complications of SLE that result in significant morbidity and mortality include infection, nephritis, stroke, peripheral artery disease (PAD), and CVD [3,4]. In 1976, Urowitz et al. described the bimodal mortality pattern in SLE patients, which stated that death within the first three years after diagnosis was usually due to active disease, infections, and glomerulonephritis. Death later in the disease course, almost four to 20 years after SLE diagnosis, was usually due to CVD [5]. This hypothesis resulted in a growing interest in both the epidemiology and pathophysiology of CVD among SLE patients.
Multiple risk factors, such as hypertension, hyperlipidemia, and smoking, have been shown to predict and influence CVD onset in patients with SLE. However, multiple pathophysiological processes in SLE itself are an independent risk factor for CVD [6]. Mechanisms by which SLE itself promotes arterial wall injury include renal disease, hypertension, antiphospholipid antibodies, thrombosis, treatment with corticosteroids, and the endothelial response immune-complex mediated inflammation [7].
With advances in treatment and a better understanding of disease mechanisms, overall mortality for patients with SLE has improved in the last 30 years. However, deaths due to CVD in SLE patients have remained the same [8]. Therefore, for better clinical outcomes, we must determine the prevalence and progression of CVD in SLE patients and ways to predict the risk of developing CVD in SLE patients to identify patients who would require a more aggressive treatment approach.
In this review, we look at the connection between SLE and CVD. We aim to highlight the prevalence of CVD and understand CVD progression in SLE patients with respect to other CVD risk factors.

Search Strategy and Selection Criteria
The following medical topic heading terms and keywords were used to search the PubMed database: SLE, autoantibodies, autoimmune vasculitis, atherosclerosis, CVD, and SLE. The search protocol for our systematic review was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Group Guidelines, starting from March 2021 [9]. Only original studies on human subjects published in the English language were included in the search. Two reviewers independently performed the screening process to acknowledge all citations of possible acceptability, including searching the reference list of pertinent articles for additional sources. We excluded review articles, nonhuman studies, case reports, letters, conference abstracts, and editorials. Basic science studies concerning the mechanism of atherosclerotic disease and studies related to non-atherosclerotic CVD, such as pericarditis, myocarditis, conduction system disease, and valvular disease, were also excluded. Articles that targeted only the antiphospholipid antibody syndrome without concomitant SLE were in the exclusion criteria as well. Our search was limited to studies that examined the prevalence and progression of CVD in SLE patients. Kappa statistics were used to evaluate the inter-rater reliability of the two reviewers [10].

Data Extraction
All abstracts were screened, and eligibility criteria were applied to identify studies that were appropriate for inclusion. Data were then extracted independently using predetermined criteria, including date of publication, population, language, study design, duration, participant data, outcome definition, results, and risk of bias.

Methodological Quality Assessment
Two independent investigators evaluated the possibility of bias in the included studies using the Quality in Prognosis Studies (QUIPS) method developed by Hayden et al. [10] to evaluate each article. The QUIPS tool employs 30 parameters divided into six domains (patient selection, study attrition, prognostic factor calculation, result measurement, confounding measurement and account, and statistical analysis and reporting). Each criterion is scored as "yes," "no," or "unclear." Therefore, each domain is evaluated as being of "low," "moderate," or "high" risk of bias according to the scoring system. A study was considered high quality when the bias was scored as low or moderate concerning almost all domains. Conversely, a study was deemed low quality when the bias was rated high in most of the bias domains. Any disputes were resolved by consensus.

Study Design
No.   Figure 2 demonstrates the risk of bias assessment of the review. Most studies showed to have a low to moderate risk of bias. Five out of 10 studies showed a high risk of bias in at least one domain [11][12][13][14]16]. Moderate to high risk of bias in confounding measurement was found in five out of 10 studies [11][12][13][14]16]. One study did not mention confounders [13]. All 10 studies used statistical models to evaluate prognostic relationships in which five out of 10 studies showed a moderate risk of bias [10,13,[16][17][18].  [20].

Prevalence and Progression of CVD in SLE patients
Eight out of 10 studies evaluated the prevalence of CVD in SLE patients [11][12][13][14][15][16]18,19]. Two studies assessed the progression of CVD in SLE patients [17,20]. Gartshteyn [13]. Patients with SLE have a significantly more significant LANCP burden (p<0.001), although the control group predominantly included the male population. A substantially more significant LANCP burden was noticed in middle-aged women with SLE (age 45-59) compared with controls. There was no statistically significant variation between patients aged 60 and over. The control group included women older than 45, and the number of male patients with SLE was small.
Ishimori et al. included 20 cases and 10 controls (without evidence of CVD) and used CCTA to assess CAC and CMR to assess MRPI [14]. Only two SLE patients had mild coronary atherosclerosis (isolated noncalcified plaque with 25% to 49% stenosis in the left anterior descending coronary artery in one patient and a CAC score of 5.9 in another patient, consistent with minimal calcification), but no patient had obstructive CVD. On CMR, stress-induced hypoperfusion was found in eight of 18 (44%; 95% confidence interval: 21.5% to 67.4%) SLE patients compared to zero of ten of the reference control group (Fisher exact test p-value = 0.014) by semiquantitative visual analysis.  [20]. CAC progression at follow-up was found in 27 cases (18.1%) compared with 16 controls (12.9%). Progression in AC at follow-up was found in 32 cases (28.3%) compared with 22 controls (18.0%). In 112 SLE cases, where both AC and CAC were measured at baseline and at followup, 13 (11.6%) had progression in both compared to AC and CAC progression in 13 (10.7%) out of 122 controls.

Other Risk Factors That Affect the Prevalence of CVD in SLE
(i) Age: Seven out of ten studies evaluated the role of age affecting the prevalence and progression of CVD in SLE patients [11][12][13]15,16,19,20].
Young patients with SLE had higher prevalence of chronic kidney disease (29.9% vs. 5.1%; SMD = 0.7), hypertension (45.9% vs. 13.2%; SMD = 0.8) and hypercoagulability (7.6% vs. 0.5%; SMD = 0.4) compared to controls which was observed by Levinson et al. [12]. As the population aged, the difference in the prevalence of these risk factors became less prominent. On the contrary, diabetes mellitus (DM) was less frequent in SLE versus controls in all age groups. Hyperlipidemia was less frequent in younger SLE patients with CVD than controls (SLE 21.6% vs. control 37.2% SMD = 0.4). It remained lower in older age groups with a moderate effect size.
Kaul et al. found that patients with SLE were significantly younger compared to controls (median age 49 years vs. 70 years, p<0.001) at the time of cardiac catheterization [15]. SLE had the greatest adjusted odds of ASCVD compared to matched control patients in younger women, according to Katz et al. [16]. cardiolipin (aCL) IgG and anti-β2-glycoprotein I (aβ2GPI) IgG levels were found in patients with atherosclerotic plaques in coronary vessels or with myocardial perfusion defects. Moreover, a significantly higher level of antinuclear antibodies and higher frequency of lupus anticoagulant (LA) incidence were observed in patients with coronary calcifications. Elevated levels of aCL IgG >20 RU/mL or antiβ2GPI IgG >3 RU/mL were associated with the relative risk of coronary calcification formation by 4.1 compared to patients with normal values. Consistently, the relative risk of coronary calcification formation in LA positive patients was 4.4 compared to LA-negative patients.
Lertratanakul et al. found that a higher modified ACR/SLECC-DI score is associated with CAC progression in univariate models [20].

Discussion
The data collected in our review strongly supported that in patients with SLE, the prevalence of CVD is significantly higher, occurs in a younger age group, and is impacted by both conventional risk factors and the burden of immune-mediated inflammation [4,8,[21][22][23]. The most significant relative risk was found in younger patients with SLE compared to their healthy counterparts. However, the absolute risk of CVD among SLE patients increased with advancing age.
In our review, eight out of 10 studies evaluated the prevalence of CVD in SLE patients. Two out of 10 studies assessed the progression of CVD in SLE patients. All the studies found a positive correlation between SLE and CVD. Furthermore, as most of the studies (six out of 10) were prospective cohorts, it helped understand the CVD clinical course in SLE patients better.
Traditional CVD risk factors, like hyperlipidemia, obesity, cigarette smoking, advancing age, hypertension, male sex, renal disease, DM, and elevated C-reactive protein, were all associated with increased CVD risk among SLE patients according to the collected epidemiological data. All of these risk factors were not examined simultaneously in the same populations. Therefore, the relative risk associated with each was not possible to evaluate, although we found the relative risk of CVD in SLE to be higher, even after adjusting certain risk factors. Gartshteyn et al. discovered that the chances of developing CAC>0 in women with SLE aged 45 years were 12.6 times higher than in women in the CARDIA cohort (95% CI 5.2 to 30.7) after age, hypertension, overall cholesterol levels, and aspirin usage were modified [11].
Several SLE-associated factors have also been predictive of CVD risk in the reviewed cohort studies in addition to conventional risk factors. These SLE-related factors include SLE disease duration, medications used, particular antibodies such as aCL IgG, antiβ2GPI IgG, and ACR/SLECC-DI score. The differences between the relative importance of risk factors for CVD among SLE patients in the reviewed studies is most probably due to differences in design methods and differences in patient and comparison groups. Moreover, the variability among these risk factors is considered simultaneously in multivariate models, making it challenging to separate inherently related elements. Sadly, certain SLE-related factors, such as disease activity, organ damage, and antiphospholipid antibodies, were not included in administrative data.
We also know that traditional stress tests can only detect flow-limiting stenosis and may miss early coronary atherosclerosis. Noninvasive imaging of coronary plaques is much more promising and superior resulting in significant advances in our understanding of atherosclerosis and its pathogenesis. Moreover, most of the studies we reviewed (eight out of 10) relied on noninvasive imaging techniques to detect the prevalence and progression of CVD in SLE patients, our understanding of the relation between CVD and SLE became more elaborate [11,[13][14][15][17][18][19][20].
We must recognize shortcomings in our study, including the exclusion of non-translated non-English articles, inconsistency in the accuracy of primary research due to the presence of confounding variables, and the use of various methodological approaches by different studies in determining outcomes -these issues rendered incorporating findings in the analysis of results challenging.

Conclusions
In conclusion, SLE is associated with higher prevalence and faster progression of CVD, making SLE patients particularly vulnerable, requiring more extensive coronary health management. Therefore, it can be proposed that SLE be treated as a "CVD equivalent" such as DM, with lower lipid goals, more aggressive aspirin use, and potentially more aggressive monitoring. However, we must conduct more randomized clinical trials to evaluate the effect of aggressive coronary care in patients with SLE.

CAC Scoring
CAC scoring ranges from 0 to 400. A Higher score correlates with a greater chance of an annual CVD event like myocardial infarction (MI). A score closer to 0 indicates lower chances of CVD.

LANCP
A LANCP score of <30 Hounsfield Units (HU) contains necrotic cores characterized by endothelial dysfunction, oxidative stress, and inflammation. They are a better predictor of future cardiovascular events than traditional cardiovascular risk factors in the general population.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.