Accelerated atherosclerosis in patients with systemic lupus erythematosus (SLE): a case–control study

doi:10.21203/rs.3.rs-4307586/v1

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Accelerated atherosclerosis in patients with systemic lupus erythematosus (SLE): a case–control study

https://doi.org/10.21203/rs.3.rs-4307586/v1

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Introduction: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that can lead to cardiovascular disease (CVD) and increased mortality. Identifying accelerated atherosclerosis, preventing risk factor propagation, and intervening during the preclinical stage of atherogenesis is crucial. This study aimed to evaluate accelerated atherosclerosis in SLE patients and explore related factors.

Methods: This study included 86 patients and 45 age- and sex–matched individuals in the control group. The intima-media thickness (IMT) of the common carotid arteries (CCA) and internal carotid arteries (ICA) was measured using color Doppler ultrasound. The following laboratory parameters, were evaluated: CBC, total cholesterol, HDL, LDL, Cr, ESR, CRP, anti-DNA, and urine. The patients completed a questionnaire that included the Lupus Disease Activity Index (SLEDAI) and demographic information.

Results: The average IMT in both the CCA and ICA was significantly greater in patients with lupus (CCA: 0.57 ± 0.09 mm, ICA: 0.49 ± 0.11 mm) than in controls (CCA: 0.37 ± 0.06 mm, ICA: 0.27 ± 0.07 mm); (P < 0.0001). A significant and positive correlation was found between the IMT of the ICA and CCA and age, disease duration, and ESR in the SLE group.

Conclusion: The IMT of the CCA and ICA can predict the risk of accelerated atherosclerosis in SLE patients; and is correlated with age, disease duration, and the ESR.

SLE

Systemic lupus erythematosus

IMT

Atherosclerosis

Carotid arteries

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that can affect multiple organs throughout the body. The root cause of SLE is inflammation triggered by immune complexes, which can lead to a range of complications over time (1). Although kidney disease and infections are the most common causes of death in SLE patients, it is important to note that cardiovascular disease (CVD) is also a significant risk factor that should not be overlooked (2). Accelerated atherosclerosis is a condition in which the artery wall develops lesions that can cause the narrowing of the artery due to the accumulation of atheromatous plaque. At first, there may be no noticeable symptoms. However, in severe cases, depending on the affected vessels, it can lead to conditions such as coronary artery disease, stroke, peripheral vascular disease, or kidney problems (3, 4).

Research suggests that inflammatory and autoimmune processes at the local level may contribute to the development of atherosclerosis in individuals with SLE (5). Although the high prevalence of atherosclerosis in this population cannot be solely attributed to Framingham risk factors, it is thought to be the result of complex interactions between genetic background, traditional risk factors, and SLE–related risk factors such as systemic inflammation and endothelial apoptosis (6–8). Even with increased awareness of CVD and advancements in clinical diagnosis, atherogenesis in most patients usually remains clinically undetectable until cardiovascular complications emerge. Therefore, assessing and managing the modifiable risk factors is of utmost importance in the prevention of ischemic heart disease (IHD) and cerebrovascular accidents (CVAs).

Ultrasound assessment of the intima–media thickness (IMT) is a reliable method for evaluating atherosclerosis and assessing the risk of CVD (9). Therefore, we conducted a study to evaluate accelerated atherosclerosis in patients with SLE and explore the related factors.

For this case–control study, we selected 86 patients (82 women, 4 men; average age 39.14 ± 7.71 years) from Golestan Province, Iran, who had been diagnosed with SLE and referred to Sayad Shirazi Hospital in Gorgan. The diagnosis was established through the application of the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for SLE (10).

The study had specific criteria for patient inclusion: individuals between the ages of 18 and 63 who were willing to participate and did not have a medical history of diabetes, hypertension, angina, ischemic heart disease, stroke, or smoking were eligible. Patients with a family history of ischemic heart disease before the age of 50 or who had taken aspirin or statins for more than a month were not included. The control group consisted of 45 healthy individuals (43 women, 2 men) of similar age (mean age 38.27 ± 8.51 years) who were not taking medication and who showed no signs of inflammatory or atherosclerotic disease. The study was approved by the Ethics Committee of Golestan University of Medical Sciences in Gorgan, Golestan Province, Iran, with the ethics code IR.GOUMS.REC.1401.364. After providing informed consent, the subjects were evaluated for atherosclerosis at the radiology center of Sayad Shirazi Hospital in Gorgan. For the US measurements, a Philips Affiniti 50 US system with a linear transducer (L4-12 MHz) was used. The IMT of the bilateral common carotid arteries (CCA) and internal carotid arteries (ICA) was measured using color Doppler ultrasound. The method was validated with two repeated measurements, and a pathological cutoff value of IMT ≥ 0.9 mm was selected based on the latest guidelines from the European Society of Hypertension/European Society of Cardiology (ESH/ESC) for hypertension (11). Plaques were defined as focal areas in the vessel wall in which the IMT showed an increase of 0.5 mm or 50% relative to the IMT in the adjacent wall. All ultrasound examinations were performed by the same radiologist who was blinded for diagnosis. Laboratory parameters, including complete blood count (CBC), total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), creatinine (Cr), the erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), were assessed in all participants after a 12-hour overnight fasting period. In the case group, urine analysis (U/A), C3, C4, CH50, and anti-double-stranded DNA (anti–dsDNA) were also evaluated. Following the laboratory evaluations, the patients were referred to a rheumatologist for examination and evaluation of the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) (12), as detailed in supplementary file 1. The patients were then managed based on their laboratory tests and sonography results.

Statistical methods

According to a study by Christina Svensson et al. in Sweden (13), the sample size for each group was determined based on the mean and standard deviation of the ICA, with a confidence level of 0.95 and a test power of 0.80. Initially, 59 individuals were planned for each group. However, due to the difference in standard deviation, the modified sample size was set at 86 patients and 45 controls. Quantitative traits were described using the mean and standard deviation, while frequency distribution tables were used for qualitative traits. To compare the means of quantitative variables between the two groups, the normality of the data distribution was checked using the Shapiro–Wilk test, and the homogeneity of variance was assessed using Levene's test. If nonhomogeneity was found, Welch's t–test was used. In cases of nonnormality, the Mann–Whitney test was employed to compare the two groups. To adjust for intervening variables, the ANCOVA method was used, and nonparametric tests were used for categorical data. The significance level for all tests was set at 0.05. A linear regression model with a significance level of 0.001 was used to investigate the effect of each variable on the IMT of the vessels. Data analysis was performed using R software version 3.5.1.

The basic demographic and laboratory data of the patients in the studied group are shown in Table 1.

Among the variables measured, the mean ESR in the patient group (22.04 ± 10.21 mm/hour) and the control group (14.11 ± 7.01 mm/hour) significantly differed (P < 0.0001). Additionally, the results indicate that 75.6% of patients and 24.2% of controls had positive CRP. Based on Fisher's exact test, the relationship between CRP and SLE was found to be statistically significant.

Table 2 presents the results of the study on the IMT of the right and left sides of the CCA and ICA in the SLE group and the control group. The study revealed that the mean IMT in the SLE group was significantly greater than that in the control group. Among the 86 patients diagnosed with SLE, a pathological thickness (IMT ≥ 0.9 mm) was observed on the left side of the ICA in one of the patients. Similarly, two of the 86 patients with SLE had atherosclerotic plaques in the same area.

The demographic details and IMT measurements for these individuals are presented in Table 3.

Table 4 displays the correlations between the IMT and demographic information, traditional and SLE-related risk factors in linear regression models among SLE patients. The findings suggest that age, duration of disease, and inflammatory factors are positively and significantly associated with IMT in SLE patients. However, no clear relationships were detected between IMT and body mass index (BMI), cumulative daily dose of prednisolone, SLEDAI-2K, or laboratory factors including anti–dsDNA, total cholesterol, HDL, LDL, and Cr, in the patient group.

These results provide valuable insights into the factors that contribute to IMT in SLE patients. The positive correlation between age, duration of disease, and inflammatory factors and IMT highlights the importance of managing these factors in the treatment of SLE patients. However, the lack of correlation between IMT and other risk factors suggests that further research is needed to better understand the underlying mechanisms of IMT in SLE patients. Overall, these findings have important implications for the management and treatment of SLE patients, and can inform the development of targeted interventions to improve patient outcomes.

Table 5 shows that there was a significant positive correlation between the IMT and laboratory factors, such as the ESR, total cholesterol, and LDL, in the control group.

This study aimed to measure IMT in the CCA and ICA to evaluate accelerated atherosclerosis in patients with SLE and healthy controls. The results showed a statistically significant difference between the patients and the controls. Additionally, the evaluation of other variables revealed a significantly greater inflammatory factor ESR in the SLE group. Furthermore, according to the linear regression model, there was a significant positive correlation between age, disease duration, and the ESR and IMT in the ICA and CCA. In the control group, there was a significant and positive relationship between total cholesterol, LDL, and ESR and IMT in the CCA and ICA. Moreover, in this study, 1% of the patients in the case group had an IMT ≥ 0.9 mm, and two patients (2%) had plaque on the left side of the ICA.

Several previous studies have been conducted on the IMT in the CCA and ICA, but only a few have evaluated the benefits of ultrasound in other vessels.

In the review of previous similar studies, a case–control study conducted by Christina Svensson et al. (13) in Linköping was performed, aiming to use high–frequency ultrasound to determine the increase in IMT in several arterial areas among 60 patients with SLE and a healthy control group of 60 individuals. The study reported a significant difference in IMT in the ICA (0.52 ± 0.17 vs. 0.45 ± 0.09 mm, p = 0.004), while no significant differences were detected in the CCA.

Andrea Smrzova et al. (14) conducted a study in Moravia to evaluate the clinical significance of ultrasound examination of the common carotid artery in diagnosing subclinical atherosclerosis. The present study included 63 SLE patients with SLE and 24 controls, and reported significant differences in the intima-media thickness (IMT) (P ≤ 0.03) between patients with lupus (0.569 ± 0.11) and healthy controls (0.495 ± 0.05).

In their 7-year follow-up study, Nikolaos Papazoglou et al. (15) retorted new plaque development in 32 out of 86 patients with SLE compared to 8 out of 42 controls (P = 0.037). Multivariate analysis revealed a significant 50% reduction in atherosclerotic plaque progression for each additional modifiable risk factor (e.g., cholesterol, blood pressure) that met the target set by the European Society of Cardiology.

Sofia Ajeganova et al. (16) conducted a study comparing the progression of subclinical atherosclerosis and its contributing factors in patients with SLE and controls. A 7-year follow-up was completed for 77 patients with SLE and 74 controls (68% and 61% of the original cohort, respectively). The study revealed comparable changes in carotid intima-media thickness (cIMT) between patients with mild SLE and controls. Traditional cardiovascular risk factors, a history of lupus nephritis, and increased corticosteroid usage were identified as promoting cIMT progression in SLE patients.

In a similar case–control study involving 60 SLE patients conducted by Zahra Rezaieyazdi et al. (17) in Iran, no increase in the prevalence of atherosclerosis was reported in the case group.

In the present study, as shown in Table 2, there was a significant difference in the mean IMT in the CCA and ICA between the two groups (P < 0.0001).

Previous studies evaluating factors related to IMT and atherosclerosis, as reported by Christina Svensson et al. (13), revealed a significant positive correlation between IMT of carotid arteries and age, disease duration, and cholesterol, as well as a significant negative correlation with CRP, in the SLE group. According to the report by Zahra Rezaieyazdi et al. (17), the mean IMT in the case group was directly related to the serum levels of cholesterol (p < 0.009) and LDL (p < 0.001).

In the study by Andrea Smrzova et al. (14), a clear relationship was found between IMT and disease duration, age, and serum creatinine. However, no correlation was found between lupus activity parameters, such as the SLEDAI and anti-dsDNA, and lipid metabolism parameters.

In the present study, age, disease duration, and the ESR in all vessels were significantly positively correlated with IMT in the SLE group. However, there was no clear relationship between IMT and BMI, SLEDAI-2K, the cumulative daily dose of prednisolone, anti–dsDNA, total cholesterol, HDL, LDL, or serum creatinine. In the control group, laboratory factors, including the ESR, total cholesterol, and LDL in all vessels, had a positive and significant relationship with IMT.

The differences in the results of the reviewed articles may be attributed to the limited number of studies conducted in this field and the variations in their statistical populations. Therefore, systematic review studies are recommended to obtain more accurate results. Additionally, considering that the average SLEDAI-2K score of the patients was reported to be 2.29 and that only 26 out of 86 patients (30%) were in the active phase of the disease, the lack of correlation between the SLE disease activity index and atherosclerosis in this study may be due to the absence of screening for patients in the active phase of SLE. However, despite the limited number of related articles in this field, the present study confidently demonstrated a statistically significant difference in the IMT of the carotid artery between SLE patients and nondiseased individuals, which may be related to SLE.

The limitations of the present study include its cross–sectional design, the lack of screening for patients in the active phase of lupus, and the noncooperation of patients in undergoing further diagnostic measures to assess atherosclerosis, such as measuring the ankle-brachial index (ABI).

On the other hand, the strengths of the present study include the use of well age- and sex-matched patient and control groups, universal and free access to healthcare, and screening individuals for criteria related to atherosclerosis to prevent cardiovascular complications.

It should be noted that changes in the vessel wall and atherosclerosis in inflammatory diseases can be evaluated using different imaging methods, such as computed tomography, arterial angiography, magnetic resonance imaging (MRI), positron emission tomography (PET), and combined MRI–PET (18). However, compared to the ultrasound, these alternative methods are less accessible, more expensive, and expose patients to more radiation. For future studies, measuring the ABI as a complement to the examinations performed in this study, as well as conducting systematic review studies and studies at the cellular-molecular and histological level, may yield further results.

The IMT can be utilized as a clinical predictor of the risk of accelerated atherosclerosis in patients with systemic lupus erythematosus, and it is associated with age, disease duration, and the ESR.

Ethics approval and consent to participate: The whole research was approved by the Ethics Committee of Golestan University of Medical Sciences in Gorgan, Golestan Province, Iran, with the ethics code IR.GOUMS.REC.1401.364 and written informed consent was obtained from all participants.

Consent for publication: Not applicable

Availability of data and materials: The datasets analysed during the current study are available from the corresponding author on reasonable request.

Competing interests: The authors declare that they have no competing interests.

Funding: No funding

Authors' contributions: Z.N. Conducted interviews with the study subjects and performed data collection. Z.N., N.A. and N.B. interpreted and analyzed the data and wrote the main manuscript text and prepared the tables. N.A. is corresponding author, visited SLE patients. M.M. and F.H. measured the IMT of vessels using color Doppler ultrasound and substantively revised the drafted work. All authors reviewed the manuscript and approved the submitted version.

Acknowledgements: Not applicable

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No competing interests reported.

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Accelerated atherosclerosis in patients with systemic lupus erythematosus (SLE): a case–control study

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Abstract

Introduction

Methods

Statistical methods

Results

Discussion

Conclusion

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