Systemic lupus erythematosus (SLE) is known as a quiet rare autoimmune disease. It is characterized by the presence of antinuclear antibodies, immune complex deposition, chronic inflammation and organ damage. SLE may affect any organ in human body, but it specifically affects the skin, joints, and kidneys. SLE has been reported to affect more than 3•4 million people worldwide [1]. The global SLE prevalence is estimated to be 43.7 (15.87 to 108.92) per 100 000 persons [1]. The disease is highly prevalent in North America (241/100000 population [1]. The majority of the population affected are women with a ratio of about 9 women to 1 man. When coming to ethnicities, variation is also noted, interestingly SLE is reported to be more common in African and Arabic populations [2, 3]. The United Arab Emirates, Barbados and Brazil had the highest SLE prevalence [1]. In the OMAN-LUPUS Study, the mean prevalence of SLE in Oman was 38.8 per 100,000 inhabitants, which is high in an Omani population of approximately 4 million [4]. In comparison to general population, it’s found that mortality is higher in SLE patients, with infection and cardiovascular diseases (CVD) being the most common causes of death [2, 3]. The clinical cardiac conditions associated with SLE include pericarditis, myocarditis, valve diseases including Libman-sacks endocarditis, coronary artery disease (CAD) due to premature atherosclerosis, stroke and heart failure, which carries a high rate of mortality when compared to non-SLE patients [5, 6]. The pathophysiology of cardiac involvement in SLE includes higher prevalence of endothelial cell dysfunction leading to increased chemokines and endothelial adhesion molecules recruiting increased monocytes/macrophages that engulf oxidized-LDL making foam cells and premature atheroma [1]. In addition, this disease involves dysregulation of both innate (i.e. neutrophils) and adaptive immune responses (B/T lymphocytes and antiphospholipid autoantibodies) leading to blood vessel inflammation, unstable coronary plaque, and thrombus formation in both arterial and venous systems [1]. Furthermore, use of corticosteroids and other immunosuppressive medications can accelerate atherosclerosis. In a study, SLE patients were found to suffer myocardial infarction (MI) and stroke two to three times higher than the general population [7]. Results from number of studies that looked at the cardiovascular (CV) risk factors in SLE patients have shown an increased prevalence of hypertension, diabetes, dyslipidemia, metabolic syndrome, end-stage renal disease, high C-reactive protein levels compared with age and gender matched controls [1, 8-13]. Both European and American guidelines recommend that the patients with SLE disease require evaluation for development of CV risk factors and to apply preventive measures to avoid the risk in developing CV complications [14, 15]. Even though SLE is common in Oman, no studies are done in Oman to know CV risk factors prevalence and complications in SLE in this population. Hence, we aimed primarily to establish the common CV complications in patients diagnosed with SLE which includes coronary artery diseases, hemorrhagic and ischemic strokes and transient ischemic attacks. As secondary objective we also looked at the association between SLE and risk factors to develop CVD and the association between the SLE disease severity using established risk score Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index (SLICC/ACR DI) and the risk to develop cardiovascular events (CVEs).

Study Design and Setting             

We conducted a single center cross-sectional retrospective cohort study for all the patients who attended Rheumatology clinic, Royal Hospital, Muscat, Sultanate of Oman with the diagnosis of SLE according to European League against Rheumatism (EULAR) and the American College of Rheumatology (ACR) (EULAR/ACR) criteria. All patients from the period of January 2006 to December 2020 were evaluated. Inclusion criteria was defined as adult patients > 18 years, diagnosis of SLE, following up with Royal Hospital, Rheumatology clinic. Following patients were excluded: those who didn’t meet the inclusion criteria, lost to follow up or death before 2020, other diagnosis than SLE or following up with other health institutes. Ethical approval was obtained from the Scientific Research Committee, at Royal hospital, Muscat, Oman (SRC#37/2021).

Patients’ data was obtained from (Al Shifa 3+) electronic health system and recorded including, demographic data, including patient’s age, sex, weight and height. The date of first SLE manifestations, the date of diagnosis and SLICC/ACR DI score was documented. CV risk factors including hypertension (HTN), type II diabetes mellitus (TII DM), dyslipidemia (DL) with the lipid profile after SLE disease diagnosis were also recorded. Navigating through the electronic health care system, we identified development of CVEs after the diagnosis of SLE disease as mentioned in the records by physicians. Medications profile, including the use of steroids with the dosage, using hydroxychloroquine and the doses as well using of lipid lowering agents were also gathered from the electronic health care system. Patients’ details were entered in a pre-designed data entry chart using EpiData client entry Program.

Definitions

• SLE: diagnosis was made using EULAR/ACR criteria [16].
• The SLICC/ ACR DI score: a valid damage index for SLE, it records damage occurring in patients with SLE regardless of its cause [17].
• CV risk factors were defined as follows:

1. HTN: blood pressure ≥140/90 mm/Hg, documented diagnosis of hypertension after SLE diagnosis or use of antihypertensive medication.
2. DL: LDL cholesterol level as 2.6mmol/ in non-diabetic or 1.8mmol/ in diabetic patients or the use of lipid lowering agents

• Diabetes mellitus: as glycosylated hemoglobin (HbA1c) of ≥6.5%, self-reported physician diagnosis or pharmacologic treatment.
• CVEs are defined as: acute coronary syndrome (including ST-elevation MI, Non-ST-elevation MI and unstable angina), stable angina, ischemic stroke, hemorrhagic stroke and transient ischemic attack (TIA).

Statistical Analysis

Statistical calculations were performed using IBM SPSS Statistics 29.0 software. Patients were divided into two groups. First group with established CVE after SLE diagnosis and second group with no established CVE. Continuous variables are presented as means ± standard deviations or medians and inter-quartile ranges depending on whether the data were normally distributed or not. Chi-square test or Fisher’s exact were used to assess the association between categorical variables as appropriate. The Independent Samples t Test was used to compares the association of means of two independent groups. To evaluate the independence of the association between the diagnosis and CVS risk factors we used binary logistic regression analysis. Two-sided p-values< 0.05 were considered to be statistically significant.

A total of 672 patients were initially identified from January 2006 to June 2020, and 577 patients were included in the data analysis after applying inclusion criteria with 95 patients were excluded from the study. Calculated Sample Size using 95% Confidence level was 452. The clinical characteristics of the patients are summarized in Table1. 89.4% of the patients were females and 10.6% were males. Among patients with CVEs, 10.7% males (n=3) and 89.3% females (n=25). Mean age among study population was 37-years, with maximum age of 85-yrs and minimum of 14-yrs. Mean age among patients with CVEs was 44-yrs while the mean age for those no CVEs was 37-years. Association between developing CVDs and the age was calculated using Independent Sample t Test was statistically significant (P value 0.006). Out of 577 patients, we could find documented body mass index (BMI) in the electronic data for 462 patients. Median BMI was 26.00. The minimum BMI was 13 and the maximum was 56. Median BMI among those who developed CVEs was 28.00. The minimum BMI was 18 and the maximum was 46. Association between high BMI and development of CVEs was calculated using Independent Samples t Test, which resulted in P value of 0.087 which not statistically significant.

Table.1: Baseline characteristics, risk factors, cardiovascular events and treatment of the SLE patients with CV events.

Legend: SLE: systemic lupus erythematosus; CV: cardiovascular; BMI: body mass index; LDL: low density lipoprotein; DL: dyslipidemia; SLICC/ACR DI: Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index; HCQ: hydroxychloroquine; HTN: hypertension; DM: diabetes mellitus; TIA: transient ischemic attack; ACS: acute coronary syndrome For the Cardiovascular risk factors, which are illustrated in Figure 1 2.9% of our study population developed Type II DM after SLE diagnosis (n=17). 97.1% had no DM after SLE diagnosis (n=560). 3.6% of those with CVEs had Type II DM (n= 1). 96.4% of those with CVEs had no evidence Type II DM (n= 27). Association between diagnosis of DM and developing CVEs was calculated using Fisher's Exact Test which was not statistically significant (P value 0.576. We could find documented lipid profile for 392 patients among the 577 patients diagnosed with SLE. 51.5% of patients developed DL after SLE diagnosis (n=202). 48.5% of SLE patient has no evidence of DL (n=190). Among patients with CVEs 63% had DL (n=17) and 37% had no DL (n=10). 1 patient who had CVE had missing lipid profile data. The prevalence of CVEs among patients who are labelled as DL is 8.4%. Association between DL and developing CVEs using Fisher's Exact Test is not statistically significant (P value 0.237). 6.1% of patients developed Hypertension after SLE diagnosis (n=35). 93.9% of patients had no evidence of HTN after SLE diagnosis (n=542). 17.9 % of those with CVEs had HTN (n= 5). 82.1 % of those with CVEs had no evidence of HTN (n=23). Association between diagnosis of HTN and developing CVEs was calculated using Fisher's Exact Test which was statistically significant (P value 0.022).

Figure1: Prevalence of HTN, DM and DL in SLE patients.

Legend: HTN: hypertension; DM: diabetes mellitus; DL: dyslipidemia; SLE: systemic lupus erythematosus.

Among the study population, 4.9% developed CVEs (n=28). 21.4% of patients with CVEs developed more than 1 events. (n=6). Total number of CVEs were 34. The details of CVEs in Figure 2. 39.3% of patients developed ischemic stroke (n=11), 32.1% of patients developed acute coronary syndromes (ACS) (n=9), 17.9% of patients developed Transient ischemic attacks (n=5), 7.1% of patients developed Hemorrhagic strokes (n=2), and 3.6 % of patients developed stable angina (n=1). Among the patients who developed CVEs (n=28), 57.1% had documented CRP at the time of event (n=16). Maximum CRP value was 140 in a patient who developed ischemic stroke and minimum CRP value was 1 in a patient developed acute coronary syndrome. Among the patients who developed CVEs, 89.3% had documentations regarding being on steroids before or during the event (n=25). 64% of patients who developed CVEs were off steroids (n=16) and 36% patients were on steroids (n=9). The mean dose of steroids was 3.42 mg of oral Prednisolone. 44.4% of patients were on the dose of 5 mg of oral prednisolone (n=4), 22.2% patients were on the dose of 7.5 mg of oral prednisolone (n=2), 11.1% patients were on the dose of 10 mg of oral prednisolone (n=1), 11.1% patients were on the dose of 10 mg of oral prednisolone (n=1), 11.1% patients were on the dose of 15 mg of oral prednisolone (n=1) and 11.1% patients were on the dose of 30 mg of oral prednisolone (n=1). 86.1% patients of the study population were on Hydroxychloroquine (n=497). 74.1% of patients with CVEs were on Hydroxychloroquine (n=20). Association between use of hydroxychloroquine and developing CVEs using Fisher's Exact Test is not statistically significant (P value 0.168).

Figure 2: Distribution of cardiovascular events.

Legend: TIA: transient ischemic attack; ACS: acute coronary syndrome; S. Angina: stable angina; I. Stroke: ischemic stroke; H. Stroke: hemorrhagic stroke.

Among the study population, majority of patients had SLICC/ACR DI of 0 with percentage of 46.4%. With details as shown on Table 2. Among patient with CVEs, 21 patients out of 28 patients had SLICC score <=4 and 7 patients out of 28 patients had SLICC score >=5. Among patients with no CVEs, 527 patients out of 550 patients had SLICC score <=4 and 23 patients out of 550 patients had SLICC score >=5. Association between development of CVEs and SLICC/ACR DI score using Fisher's Exact Test is statistically significant (P value 0.001).

Table 2: SLICC/ACR D1 Score of the total cohort of SLE patients.

Legend: SLICC/ACR DI: Systemic Lupus International Collaborating Clinics/ American College of Rheumatology Damage Index; SLE: systemic lupus erythematosus.

The predominant findings from this study are:

1. Among the Omani patients who were diagnosed with SLE and followed-up, 51.5% developed dyslipidemia, which is high, 6.1% developed hypertension and 2.9% developed diabetes mellitus after SLE diagnosis which are low when compared to other studies.
2. Overall, 4.9% developed CVEs which is low when compared to Western countries.
3. Patients with higher SLICC/ACR DI The predominant findings from this study are: score were more vulnerable to develop CVEs which is similar as another studies.
4. Among 577 patients with diagnosis of SLE, the majority of were female, with female: male ratio of 9:1, which is similar to reported international data.
5. This study showed that advanced age and hypertension in SLE patients is associated with development of CVEs and was statistically significant.

When looking to traditional CV risk factors: The prevalence of DL in SLE ranges from 36% at diagnosis to 60% or even higher after 3 years, depending on definition [18, 19]. In one of the studies, the prevalence of DL was 34% when compared to controls (36%) [20]. In another study, SLE patients received lipid-lowering treatment more frequently when compared to patients with rheumatoid arthritis (RA) of matched age group (39% vs 20.4%) [21]. In studies from Formiga et al., from KSA and from Iran, the prevalence of dyslipidemia was 55%, 52.1% and 62% respectively, which is similar to the current study in which 51.5% of SLE patients had dyslipidemia [22, 23, 24]. The difference in the percentages of the lipid profile may be due to genetic and dietary factors among these populations. In addition, it can be explained by having a number of 185 patients with no documented lipid profile status in our study. Among those patients who develop CVEs, 63% had dyslipidemia after SLE diagnosis. We didn’t find statistically significant association between DL and developing CVEs. With regard to HTN, in the Toronto Risk Factor Study, HTN was noted in 33% of SLE patient’s vs 13% in the controls [20]. Sabio et. al. in another study found that HTN was more prevalent in SLE patients when compared to healthy controls (56% vs 29%) [25]. In the current study, HTN was low at 6.1% which may be due to ethnic differences conferring increased susceptibility for HTN in some ethnicities. 17.9 % of those with CVEs had HTN which was statistically significant association. In a recent large study of 6159 SLE patients, 3.34% of patients developed DM [26]. In the Toronto Risk Factor Study DM was noted in 5% of SLE patients [20]. In the current study, DM developed in 2.9% of SLE patients. In a large metaanalysis of 37 studies, there was no increased risk of DM in SLE patients [27]. However, several cohort studies have demonstrated a reduced risk of DM in SLE patients taking antimalarials, which was used in 86% of patients in the current study and low number of patients taking steroids as noted in this study [27]. This is in line with current European League Against Rheumatism (EULAR) guidelines recommendation of minimizing the daily dose or discontinuing steroids as noted in our study [28]. It is well documented in the literature that SLE patients have a higher risk of developing CVD as compared to the general population [29], which are MI [30] and stroke [31]. The risk to develop MI and stroke in SLE patients was found to be two to three times higher than general population according to one systematic review and meta-analysis done by Yazdany et al. in 2020 based on 26 cohort and cross-sectional studies [32]. The overall prevalence of clinical CAD in SLE patients has ranged from 6 to 10% in various cohorts [33]. In another study the incidence of CVEs was high 25.4% among patients with SLE, including acute MI (4.1%) and stroke (7.3%) [34]. In this study, we have found low occurrence of CVEs (4.9%). The event with highest number of patients was in ischemic stroke (1.9%) and a low percentage of MI (1.5%). In a long term study over 8.5 years of 3,411 SLE patients ischemic stroke occurrence was 3.75% for SLE patients vs 1.92% for control subjects; myocardial infarction was 2.17% for SLE patient’s vs 1.49% for control subjects which is similar as in this current study [6]. The low number of CVEs in this cohort could be attributed to low prevalence of HTN, DM, high use of hydroxychloroquine, low use of steroids, majority had low SLICC/ACR DI score and most on antilipidemic drugs though history of DL was high. SLE also have been identified as a major cause to increase the risk to develop other risk factors for CAD, including obesity which are noted in conjugation with the use of corticosteroid [35]. However, in this study median BMI was 26 probably due to low use of steroids in this cohort. We evaluated the association between development of CVEs and C-reactive Protein (C-RP) value, and we have found that the highest (C-RP) value was 140 in a patient who developed ischemic stroke and 1 in a patient developed acute coronary syndrome, we didn’t assess the association between (C-RP) value and development of CVEs due to low number of patients with documented (C-RP) value during the event. When evaluating the medications chart: 64% of patients who developed CVEs were not on steroids. Majority of patients in our study were on Hydroxychloroquine with percentage of 86.1%, which is expected as it is Grade A recommendation in SLE patients with no contraindications to use it. Our study didn’t find association between development CVEs and the use of hydroxychloroquine as noted in the large metaanalysis [27]. In addition, hydroxychloroquine use is known to improve glucose metabolism, lipid profile by blocking toll-like receptors, inhibiting the production of interferon-α which all lead to improvements in pancreatic beta cell function, insulin sensitivity and glucose metabolism in addition to its immunomodulatory benefits which might be the reason for low occurrence of hypertension, diabetes and low CVEs in this cohort of patients [27, 36-38]. Among the study population, majority of patients had SLICC/ACR DI of 0 with percentage of 46.4%. Those who developed CVEs there was statistically significant correlation with SLICC/ACR DI score >=5. We suggest that a higher SLICC/ACR DI score is related to development of CVEs as our study showed that the association between development of CVEs and high SLICC/ACR DI score was statistically significant. The limitations of this study include the following: First, given the small number of cases with CVEs, we could not perform comprehensive validation studies. Further studies in a larger population for longer duration are needed. Second, the current research targeted a cross-sectional study and did not include follow-up data. Finally, this was a single-center study, and some multi-center studies are still needed to validate and further explore.

In this study, we have found that among the Omani patients who were diagnosed with SLE and followed-up, about 50% of them developed dyslipidemia, which is high, but comparable to few studies and very low percentage developed hypertension and diabetes mellitus. Overall, < 5% e developed CVEs which is low when compared to Western countries. In addition, patients with higher SLICC/ACR DI score were more vulnerable to develop CVEs which is similar as in other studies and so we suggest to closely follow up and screen SLE patients with high SLICC/ACR DI score ≥ 5 for CV risk factors and events.

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