Abstract
Background/Aim: Low levels of vitamin D play a role progression of cardiovascular diseases. Knowledge lacks whether a relationship exists between vitamin D levels and subclinical carotid atherosclerosis in patients with primary Sjögren's syndrome (pSS). Patients and Methods: We evaluated vitamin D levels and subclinical carotid atherosclerosis in 25 patients with pSS compared to 22 mild ostheoarthritic control patients (OCp). Results: Intima-media thickness (IMT) and levels of vitamin D were significantly increased and decreased in pSS, respectively. No correlation was observed between low levels of vitamin D and IMT in pSS. Significant positive correlation between disease duration and IMT and negative between vitamin D levels and increased Sjögren syndrome disease activity index (SSDAI) and syndrome disease damage index (SSDDI) were also found in pSS. Conclusion: IMT of pSS with long disease duration is significantly increased with respect to that of OCp. Vitamin D deficiency does not play a role on IMT of pSS, whereas it plays a role in disease damage and activity. A long disease duration is associated with subclinical atherosclerosis in pSS.
Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease generally affecting the exocrine glands with extra glandular manifestations in up to about half of patients (1). Pathophysiology of pSS is not fully understood, although it has been suggested that low levels of vitamin D might favor initiation and propagation of this syndrome, as well as of other autoimmune diseases (2, 3). Indeed, vitamin D is an important pro-hormone able to modify mineral homeostasis and to have multiple immunosuppressive properties (3). Interestingly, for several years it has been reported that the progression of atherosclerosis is major in chronic inflammatory rheumatic diseases than in control-matched subjects (4-11). However, in pSS, the cardiovascular risk has been frequently studied less than in other connective tissue diseases and conflicting results have emerged (12, 13); according to some authors, a higher subclinical atherosclerosis is present in the early stages of pSS (12), whereas, according to others, it is present in pSS patients with a longer disease duration (13). A previous study of ours failed to find a higher subclinical atherosclerosis in middle elderly pSS (14).
Recently, in a very large cohort of pSS that grouped patients aged 35 to 74 years, an increased risk of cerebrovascular events and myocardial infarction was observed (15).
Since vitamin D insufficiency has been associated with the development of connective tissue disease and cardiovascular diseases (2, 3, 16), the aim of this study is to evaluate whether there is an association between serum levels of vitamin D, presence of subclinical carotid atherosclerosis and disease activity, comparing long duration pSS disease patients with a control-matched group.
Patients and Methods
Twenty-five female patients with pSS (diagnosed according to the revised international classification criteria for Sjögren's syndrome (17) (median disease duration of 8.2 years) (mean age=68±6.5) and 22 age- and gender-matched mild ostheoarthritic control patients (OCp) (mean age=66±7.3) with no history of autoimmune diseases were enrolled from the outpatient Rheumatology Department of ‘’Campus Bio-Medico” University of Rome, Rome, Italy, over a period of nine months. Both pSS and OCp were steadily visiting our University for a regular check-up; only these patients were selected due to the strict adherence to the inclusion criteria.
Inclusion criteria of pSS and OCP were: not to have secondary inflammatory disease, fever, lymphadenopathy, diabetes, hypertension, neoplasm, cardiovascular diseases and renal insufficiency.
Both for pSS and OCp, disease-related clinical and laboratory data (anti-Ro, anti-La, complete blood count, C-reactive protein (CRP), erythrosedimentation rate (ESR) lipid profile, glycemia) and those of the traditional cardiovascular disease risk factors were present in the medical archive of our Department. None of the enrolled patients received vitamin D supplementation at the time of this study.
Anthropometric measurements were also taken in pSS and control patients.
Body mass index (BMI) was calculated according to the following formula:
Blood pressure was measured in all pSS and control patients three times in 30 min.
Scoring systems for the assessment of disease damage (SSDDI) and disease activity (SSDAI) in Sjogren's syndrome were also obtained in accordance with previous accepted indices for disease damage and disease activity (18).
This study was approved by the ethics committee of Campus Bio-Medico University and, therefore, performed in accordance with the ethical standards set in the last version of the 1964 Declaration of Helsinki. Written informed consent was obtained from each patient prior to performing any study-specific procedures.
Duplex Doppler sonographic examination. Both pSS patients and OCp underwent Duplex Doppler sonography of common and internal carotid; during the examination, performed in both sides of the neck, the patient was laying in the supine decubitus position maintaining a quiet respiration. Always, the same experienced sonographer, unaware of the patient's diagnosis, clinical and laboratory characteristics, performed the color Doppler examination, using a high resolution ultrasonographic machine (LOGIQ E9 general electric; GE healthcare, Little Chalfont, UK) equipped with a linear 6-15 MHz transducer.
In all patients (pSS and OCp), the probe was perpendicular to the carotid; the B mode settings of gain, depth, focal zone were optimized and a mild focal compression was made to obtain a higher quality of the carotid wall image.
In online mode, multiple measurements were performed scanning the interface lumen-intima where it was regular and parallel to adventitia; here, using an electronic caliper, the distance between the two echogenic lines that mark the interfaces of the carotid wall was measured. This space, defined as “carotid intima-media thickness” (IMT), is the combined thickness of the intimal and medial layers.
Three regions of interest, on the near and the far wall, were viewed: the distal portion of common carotid (1 cm before the carotid bulb), the carotid bulb and the first portion of the internal carotid (1 cm after carotid bulb).
The average of mean IMT and the maximum IMT (max-IMT determined as the greatest thickness measured) from the three regions of interest, from the right and left side, were used for data analysis (19). The intraobserver coefficient of variation was 2% (n=20).
Values of IMT greater than 1.5 millimeters defined the presence of atherosclerotic plaques (20, 21) and were excluded.
Doppler sonographic parameters were obtained after placing the sample volume of the ultrasound beam in the middle of the common and internal carotid, on the left and right side, using an angle of insonation of 60°. Resistivity index (RI) and pulsatility index (PI) were automatically calculated by the ultrasound machine, according to the following formulas:
where sV =peak systolic velocity; dV =end diastolic velocity and mV=mean velocity.
The mean value of three measurements from the right and left side was used for statistical evaluation.
Stiffness parameters were also calculated due to the close interrelationship with the endothelial function (22). Stiffness parameters were assessed evaluating the diameter changes of the common carotid during an entire cardiac cycle. Both common carotids were scanned with the least possible pressure to avoid compression of the overlying jugular vein and allow expansion of the carotid artery in all directions, on the middle segment of the vessel, at a plaque-free site, in M-mode sonographic approach; the maximum and the minimum diameters were measured, at systole (sDIA) and diastole (dDIA) detected by a synchronous electrocardiogram (ECG) by means of a caliper as the distance between the trailing edge of the anterior wall and the leading edge of the posterior wall. Stiffness parameters (common carotid vascular strain (VS), vascular distensibility (VD), vascular stiffness (VSf) and pressure–strain elastic modulus (PSEM)) were calculated applying the following equations:
where sBP is the systolic blood pressure; dBP the diastolic blood pressure; and k the conversion factor from mmHg to Pa (k=7×10−3).
All data are expressed as mean value of three right and left carotid measurements for each subject.
Statistical analysis. Statistical analysis was performed by suitable software (Prism 6.0, Inc., San Diego, CA, USA). Comparisons of continuous variables among groups were performed by Student's t-test. The categorical variables were assessed using the Pearson's χ2 test. Two-sided p-values <0.05 were considered statistically significant.
Results
The median disease duration of pSS was 8.2 years, the median values of SSDAI and SSDDI were 2.92 and 2.68, respectively; none of the patients was taking steroids or disease-modifying immunorheumatic drugs (DMARDs). PSS and OCp were not affected by renal or hepatic failure, bleeding disorders, diabetes, hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections. Prevalence of traditional cardiovascular (CV) disease risk factors was compared between pSS and OCp and no significant difference was found (Table I).
Color Doppler evaluation of RI, PI and VSf in carotid vessels did not show any significant differences between pSS and OCp (Table II). Atherosclerotic plaques were found in 12 patients and 7 controls (p=0.05).
A significant increase of IMT (p=0.001) (Table III) and a significant decrease of vitamin D levels (p=0.005) were observed in pSS compared to OCp. No correlation was observed between low levels of vitamin D and IMT in pSS patients (r=0.06). A positive correlation between disease duration and IMT (r=0.12) and negative correlation between low levels of vitamin D and increased SSDAI (r=−0.18) and SSDDI (r=−0.35) was found in pSS.
Clinical features of pSS and control patients.
Discussion
An increased prevalence of atherosclerosis has been ascertained in connective tissue diseases (4-11), with several causes being implicated in increased cardiovascular risk, such as chronic inflammation, immunologic alterations and the use of steroids (23). Recently, vitamin D insufficiency has also been proposed as a possible risk factor of increased atherosclerosis in several connective tissue diseases (24). Due to the lack of information on the role of vitamin D in pSS, the aim of this study was to evaluate vitamin D levels and disease activity in pSS with long disease duration and to compare carotid IMT between pSS and OCp patients. Our results demonstrated that pSS with long disease duration had a lower level of vitamin D and a significant increase of carotid IMT compared to OCp; however, no correlation between increased IMT and low levels of vitamin D was found; on the contrary, a significant correlation between disease duration and increase of carotid IMT in pSS was recorded. Our previous study on pSS with shorter disease duration failed to demonstrate increased carotid IMT values in comparison to those of controls (14); conversely, this result is in accordance with previous studies performed on pSS with long disease duration (>7.5 years) (9, 25).
Vascular stiffness in pSS and control patients.
Mean intima-media thickness (IMT) on both sides in primary Sjögren's syndrome (pSS) and control patients.
Interestingly, a negative correlation was found between SSDDI, SSDAI and levels of vitamin D in pSS with long disease duration. In the past, conflicting results emerged about the role of vitamin D in disease damage and activity of Sjögren's syndrome (25-28). Some authors demonstrated lower levels of vitamin D in pSS in comparison to controls, thus hypothesizing that this might favor the development of this syndrome (2, 25, 26). In contrast, other authors did not find significant difference in vitamin D levels between pSS and controls (27, 28), thus excluding a role of vitamin D insufficiency in the pathogenesis of Sjögren's syndrome. According to our results, the role of vitamin D insufficiency in the pathogenesis of Sjögren's syndrome cannot be excluded, whereas, a direct effect of this vitamin on the development of atherosclerosis can be excluded.
A possible synergism between vitamin D and glucocorticoids has been demonstrated showing additive effects of this vitamin on the steroid-mediated inhibition of human lymphocyte and monocyte proliferation. Indeed, increasing autoantibody production by B cells and flares in connective tissue disease have been demonstrated in the presence of vitamin D deficiency and seasonal vitamin D decrease (29).
Moreover, experimental autoimmunity and autoimmune diseases may be exacerbated when there is vitamin D insufficiency, whereas may be reduced after vitamin D administration.
Conclusion
Taken these considerations together, it is evident that vitamin D has no direct role in subclinical atherosclerosis in pSS with long disease duration compared to OCp; however, an indirect role, through triggering of chronic inflammation and immunologic alterations, that seem to be the truly responsible for the increased signs of subclinical atherosclerosis in pSS, cannot be ruled out. Chronic inflammation and immunologic alterations seem to be able to induce subclinical atherosclerosis in pSS with long disease duration.
Finally, the presented results are in accordance with previous findings on the role of vitamin D supplementation on different rheumatic patients (30); it is, therefore, believed that, also in pSS, vitamin D prophylactic supplementation might be recommended. More studies are necessary to confirm these data.
Footnotes
Conflicts of Interest
The Authors declare that there is no conflict of interest.
Funding
None.
- Received April 27, 2016.
- Revision received May 5, 2016.
- Accepted June 5, 2016.
- Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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