https://orcid.org/0000-0002-8519-5382
ABSTRACT
Background
Subclinical atherosclerosis may be seen at an early age of ankylosing spondylitis (AS). Syndecan 1 (S1) expression is increased in response to proinflammatory cytokine and inflammation. High S1 may reduce carotid atherosclerosis progression. We aimed to investigate the relationship between S1 levels and subclinical atherosclerosis in patients with AS.
Methods
Fifty-eight patients diagnosed with AS and 58 age-, sex-, and body mass index-matched controls were included in the study. S1 level and carotid intima-media thickness (cIMT) were evaluated using appropriate methods.
Results
AS patients’ cIMT (0.53 ± 0.1 vs 0.45 ± 0.1 mm, p = .008), S1 (6.0 [1.7–149.2] vs 5.5 [1.0–29.8] ng/ml, p = .020), CRP (C-reactive protein) (2.1 [0.1–19.7] vs 1.1 [0.3–9.6] mg/dl, p = .012), fibrinogen (330.2 ± 87.0 vs 278.0 ± 54.5 mg/dl, p < .001) values were significantly higher than the values of the control group. There was a negative correlation between cIMT and CRP (p = .034), age (p < .001), disease duration (p = .005), BASDAI (p = .048) and fibrinogen (p = .009) in AS patients. There was a negative correlation between cIMT and S1 (p = .029). In multivariate analysis, an independent relationship was found between cIMT and age (β = 0.611, p < .001) and syndecan (β = −0.196, p = .046).
Conclusion
S1 level may rise in AS patients to suppress the inverse effects of proinflammatory cytokines and inflammation. A negative relationship between the cIMT values of AS patients and S1 level may reveal that S1 has a protective effect on the development of atherosclerosis in AS patients, independent of disease activity.
Introduction
Ankylosing spondylitis (AS) is a chronic, progressive, and inflammatory disease of the spine and sacroiliac joints, which is in the spondyloarthropathy class and causes articular problems such as chronic inflammatory, axial back pain, oligoarthritis, and enthesitis (Citation1,Citation2). By disease progresses, causing ossification of the vertebral ligaments, a fusion of the vertebral bodies, and loss of spinal flexibility. It usually occurs in men between 20–40 ages (Citation3). AS’s prevalence is 1.74–15.0/100000 in western societies and around 0.9% in the global population (Citation4,Citation5). Its prevalence decreases with age. The human leukocyte antigen, HLA-B27, is positive in 75–90% of patients with AS (Citation6).
The etiology of AS has not yet been clarified, and discussions continue on whether AS is an autoimmune or an autoinflammatory disease (Citation7). Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-17, and IL-23 play a role in the progression of the disease (Citation8). In the disease’s course, extra-articular findings such as uveitis, bone, kidney, and skin involvements, and intestinal, heart, and lung diseases are common (Citation9). The prevalence of cardiac involvement in patients with AS is 2–10% (Citation10). Even without classical risk factors, patients with AS have an increased risk of cardiovascular disease (Citation11). AS can also cause atherosclerotic heart disease, aortic regurgitation, aortitis of ascending aorta section, conduction disorders, and left ventricular diastolic dysfunction (Citation12). Atherosclerotic heart diseases can be detected with carotid intima-media thickness (cIMT) while still in the subclinical stage (Citation13). Subclinical atherosclerosis may occur in AS patients even at an early age, and the cIMT value of these patients was higher than healthy individuals in studies (Citation14).
Syndecan 1 (S1) is a protein-structured member of the syndecan proteoglycan family encoded by the S1 gene (Citation15). A transmembrane domain of S1 contains heparan sulfate and chondroitin sulfate, which interact with extracellular matrix proteins through the heparan sulfate receptor and are involved in cell proliferation and migration (Citation16). At low S1 levels, increased intercellular adhesion molecule-1 (ICAM-1) and increased leukocyte uptake by heparan sulfate result in enhanced inflammation (Citation17). Increased S1 levels are protective against inflammation (Citation18). S1 expression was found in the synovial sampling of patients with rheumatoid arthritis and psoriatic arthritis (Citation19). This condition suggests that S1 may play a role in the pathophysiology of arthritis, such as migration and recruitment of leukocytes and angiogenesis in the chronically inflamed synovium. In the absence of S1 expressed from M2 macrophages, leukocyte infiltration due to impaired migration and increased adhesion occurs, and the atherosclerotic process accelerates (Citation20).
To date, the S1 level has not been studied in AS patients. In this study, we aimed to determine whether the S1 level in AS patients is different from healthy controls and whether there is a relationship between S1 level and subclinical atherosclerosis.
Methods
Patients
Fifty-eight AS patients over 18 were diagnosed with AS according to the Modified New York and American College of Rheumatology criteria (Citation21) who applied to the Rheumatology and Internal Medicine outpatient clinics of Necmettin Erbakan University Meram Medical Faculty Hospital were included in the study. 58 age- and sex-matched healthy volunteers were taken as the control group. Pregnant women, patients under 18 age and cardiovascular disease (coronary artery disease, hypertension, heart valve disease, and heart failure), thyroid disease, diabetes mellitus, hyperlipidemia, acute or chronic renal failure, neurological disease (cerebrovascular disease and demyelinating diseases), other rheumatological and autoimmune diseases, malignancy were not included. Written informed consent was obtained from all individuals included in the study. The study protocol was evaluated and approved by the Necmettin Erbakan University Ethics Committee (Ethics committee approval number: 2022/3919). Disease activity indices [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI)] of the patients were calculated. The sociodemographic characteristics of all individuals were recorded.
Laboratory
Venous blood samples were taken from all patients after 10–12 hours of fasting. The blood samples taken were centrifuged at 4000 rpm for 5 minutes, and the serums were stored at −80°C. On the study day, thawed serum samples of all individuals were studied. Biochemical tests were analyzed with the photometric method of the Abbott Architect C16000 analyzer. Hematological parameters were studied by the Abbott Cell Dyn Ruby analyzer. C-reactive protein (CRP) was evaluated with the nephelometric method of the Coulter Immage 800 device. The erythrocyte sedimentation rate (ESR) was evaluated with the automated device Westerr (Eventus vacuplus ES 100). The study was completed in 3 months. Blood samples were stored at −30°C until the study was completed.
Syndecan 1 measurement
Serum S1 levels were analyzed by Enzyme-linked Immunosorbent Assay (ELISA) using a commercial kit (Human Syndecan-1 CD138 ELISA Kit, Bioassay Technology Laboratory, China) according to the manufacturer’s instructions.
cIMT measurement
The cIMT for all patients in the patient and control groups was measured blindly by a same radiologist experienced in vascular imaging with a Siemens Acuson S3000 ultrasound device using a 9L4 (4.0–9.0 MHz) linear transducer. The Carotid system of the patients was evaluated in B-mode, pulsed Doppler mode, and color mode by turning the patient in the supine position, with the neck slightly extended, in the opposite direction of the side to be examined. A standard was established by measuring the distance between the first echogenic line adjacent to the vessel lumen and the second echogenic line, the intima-media thickness 3 cm proximal to the common carotid artery bifurcation level. cIMT measurements were always made from the non-plaque arterial segment by a blind radiologist.
Statistical analysis
Whether the AS group and the control group showed homogeneous distribution was analyzed with the Kolmogorov-Smirnov test. Homogeneous data were analyzed by Student’s t-test, nonhomogeneous data were analyzed by Mann Whitney U test, and categorical data were analyzed by chi-square test. Pearson correlation test was used for correlation analysis. In the multivariate regression analysis; independent variables associated with the cIMT dependent variable were detected.
Results
Sociodemographic data and drug treatments of AS patients are shown in .
Table 1. General characteristics of the patients with ankylosing spondylitis (n = 58).
AS patients’ cIMT (0.53 ± 0.1 vs 0.45 ± 0.1 mm, p = .008), S1 (6.0 [1.7–149.2] vs 5.5 [1.0–29.8] ng/ml, p = .020), CRP (2.1 [0.1–19.7] vs 1.1 [0.3–9.6] mg/dl, p = .012), fibrinogen (330.2 ± 87.0 vs 278.0 ± 54.5 mg/dl, p < .001) values were significantly higher than the values of the control group. The albumin value of AS patients (45.1 ± 4.0 vs. 47.0 ± 2.3 g/dl, p = .003) was significantly lower than those of the control group. All biochemical values of AS patients and the control group are shown in .
Table 2. Sociodemographic characteristics and laboratory results of the patient and control group.
In the correlation analysis, there was a negative correlation between cIMT and CRP (p = .034), age (p < .001), disease duration (p = .005), BASDAI (p = .048), and fibrinogen (p = .009) in AS patients. There was a negative correlation between cIMT and S1 (p = .029). There was no correlation between cIMT and S1 and other parameters (all p > .05). The results of the correlation analysis are shown in .
Table 3. Correlation analysis results of patients with ankylosing spondylitis.
Variables associated with cIMT were detected by univariate analysis. In this analysis, age (beta [β] = 0.702, p < .001), disease duration (β = 0.364, p = .005), BASDAI (β = 0.261, 0.048), S1 (β = 0.288, p = .029), CRP (β = 0.279, p = .034), fibrinogen (β = 0.339, p = .009). In multivariate analysis, an independent relationship was found between cIMT and age (β = 0.611, p < .001) and S1 (β = 0.196, p = .046). All regression analysis results are given in .
Table 4. Predictive markers for cIMT in patients with ankylosing spondylitis.
Discussion
We found a higher S1 level in AS patients than in healthy controls. There was no relationship between AS disease activities (BASDAI and BASFI) and S1. The cIMT values of AS patients were significantly higher than healthy controls. There was a negative relationship between cIMT and S1 in the correlation analysis. In multivariate regression analysis, we detected an independent association between cIMT and S1.
An increase in the incidence of subclinical atherosclerosis and coronary heart disease, which can not be explained by traditional risk factors, has been found in AS patients (Citation22). In these patients, subclinical atherosclerosis has been detected even in the early stages of the disease (Citation23). The continued release of proinflammatory cytokines such as TNF-α, IL-1, IL-6, IL-17, and IL-23 in AS plays a crucial role in the disease’s etiology (Citation24). Proinflammatory cytokines cause endothelial dysfunction and also accelerate atherosclerosis. In addition, increased ICAM-1 and vascular cell adhesion molecule-1 levels in AS patients are responsible for endothelial dysfunction and accelerated atherosclerosis (Citation25). cIMT in AS patients is a safe and inexpensive marker for the early detection of subclinical atherosclerosis (Citation23,Citation26). In many studies, the cIMT value was higher in AS patients than in healthy controls. There is a strong correlation between cIMT and CRP, age, and disease duration in AS patients (Citation27). However, Gupta et al. reported that cIMT was not associated with disease activities (BASFI and BASDAI) in AS patients, and cIMT was associated with age and disease duration in these patients (Citation28). In our study, there was a weak correlation between BASDAI and cIMT.
S1, a core component of endothelial glycocalyx, released from simple and stratified epithelia, protects the vascular endothelium against proinflammatory cytokines (Citation29). S1 is a biomarker of endothelial glycocalyx degradation (Citation30). During myocardial infarction, a previous study reported that the release of S1 in the infarct area and serum of rats increased (Citation31). S1 alleviated the increased inflammatory response during myocardial infarction and reduced post-MI cardiac dilatation and ventricular dysfunction (Citation18). Nemoto et al. reported that there was no relationship between angiographic disease severity and S1 level in patients with coronary artery disease, but low serum S1 levels were associated with a high prevalence of vulnerable lipid-rich plaques(Citation32) (). It was observed that S1 levels increased up to the first 12 hours of patients with the acute coronary syndrome (Citation33). In addition, S1 level was determined to be high in patients with stress-related cardiomyopathy (Citation34). The S1 level in patients with myocardial infarction was sixfold higher than in healthy controls (Citation35). We found the S1 level to be higher in AS patients compared to healthy controls. However, the elevation of S1 level in AS patients compared to healthy controls was not as exaggerated as in myocardial infarction. We hypothesize that S1 level may elevate independent of disease activity to reduce an increase in inflammation in AS patients.
Proinflammatory cytokines such as TNF-α and IL-1β and increased reactive oxygen species play a key role in endothelial glycocalyx disruption (Citation36), which is one of the initial steps of atherosclerosis. The middle carotid region with abundant endothelial glycocalyx is exposed to laminar blood flow and is resistant to atherosclerosis (Citation37). On the contrary, the blood flow is turbulent in the internal carotid sinus region and endothelial glycocalyx is very low in this region, and lipid accumulation occurs effortlessly (Citation37). S1 level was found to be higher in patients with anti-phospholipids and lupus than in healthy controls. Increased S1 may reflect an increase in inflammation and oxidative stress (Citation38,Citation39). S1, released into the circulatory system, shows an anti-atherosclerotic effect by protecting endothelial cells against atherogenic agents (Citation38). He G et al. has found a negative relationship between wall shear stress measured from the radial artery after coronary bypass and S1 (Citation40). Also, Miranda S et al. found a correlation between high S1 levels and increased cIMT and impaired endothelial glycocalyx in patients with anti-phospholipid syndrome (Citation38). In their study, the S1 level of the patients was 2-fold that of the healthy controls. S1 level may be elevated to prevent high inflammation. That is, a high S1 level may reflect increased inflammation. In our study, the S1 level in AS patients was higher in healthy individuals, but not as much as the results of Miranda et al.’s studies. The low disease activities of our AS patients may have affected our finding of the S1 level as such in them. S1 can inhibit leukocyte adhesion in endothelial cells (Citation41). It prevents carotid hyperplasia by inhibiting the smooth muscle cell response to factors that cause intimal hyperplasia, such as platelet-derived growth factor-BB, fibroblast growth factor 2, and epidermal growth factor (Citation42). S1 levels may increase moderately to suppress this inflammation in patients with AS with low inflammation. The negative correlation between the S1 level and cIMT in AS patients suggests that S1 protects against atherosclerosis by reducing inflammation and protecting the endothelial glycocalyx in AS patients. S1 may prevent carotid artery thickening in AS patients independent of disease activity.
Nemoto et al. found no relationship between S1 level and serum cholesterol and high sensitive (hs)-CRP (Citation32). We could not find any relation between S1 and the lipid panel and CRP. If CRP values are not high, there may be no relation between cIMT and CRP values (Citation27). In our study, despite the low CRP level of our patients, we found a positive association in contrast to the S1-CRP unrelatedness. Although S1 levels were reported high in patients with active lupus (Citation38) in the literature, we could not find a relationship between S1 and disease activity in patients with AS. The small number of subjects in our study and the relatively low disease activity of the patients included in the study may have affected our results.
Limitation
The major limiting factor in our study is the small number of subjects. The lower disease activity of the patients included in the study may have affected the results. The fact that hs-CRP was not studied in our study is another limiting factor. The presence of subclinical atherosclerosis in AS patients was demonstrated by a single marker. The relationship between S1 and proinflammatory cytokines was not studied in this study. Detailed studies are needed.
Conclusion
The S1 level of AS patients is higher than healthy controls. S1 level may rise in AS patients to suppress the inverse effects of proinflammatory cytokines and inflammation. A negative relationship between the cIMT values of AS patients and S1 level may reveal that S1 has a protective effect on the development of atherosclerosis in AS patients, independent of disease activity.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
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