Summary
Background
It takes years for atherosclerosis to manifest symptoms. However, it needs to be identified earlier because of the premature cardiovascular risk factors in patients with rheumatoid arthritis (RA). In this study, we aimed to investigate the effect of atherosclerosis on the ankle brachial pressure index (ABPI) and carotis intima media thickness (CIMT) in patients with RA.
Methods
RA patients attending the rheumatology clinic were examined retrospectively; then we called them for the measurements of ABPI and CIMT prospectively. Subjects were divided into four groups, as follows (Table 1): group 1 comprised RA patients with an ABPI less than 0.9; group 2 included RA patients with an ABPI between 0.9 and 1.2; group 3 was made up of RA patients with an ABPI greater than 1.2; and group 4 included patients without RA with an ABPI between 0.9 and 1.2 as a control group. Patients’ demographic data were recorded. Hypertension (HT), diabetes mellitus, ABPI and CIMT measurements were taken by specialists. Duration of RA and disease scores (disease activity score-28, health assessment questionnaire score and visual assessment score) were recorded.
Results
The prevalence of peripheral vascular disease in patients with RA was twice as high as that in the normal population of equivalent age. Patients in group 2, with RA and normal ABPI, exhibited a significant higher mean in CIMT (mm) compared with the control group (p < 0.01), despite having normal ABPI. This confirms that these patients have a higher risk of stroke compared with the control group. Group 1’s newly diagnosed HT (p < 0.01) and systolic blood pressure (SBP) values (p < 0.01) were higher and statistically significant when compared with the group 4 (control group); in addition, significant plaque levels were observed in the carotid arteries (p < 0.01). Group 3 patients had a similar history of HT and increased SBP compared with patients in group 4 (p < 0.01), and had similar characteristics to with group 1. No statistically significant differences were found between the groups in terms of inflammatory markers such as C-reactive protein and rheumatoid factor, anti-cyclic citrullinated peptide and white blood cell counts.
Conclusion
Based on the present findings, patients with RA need to be evaluated in the early stage of the disease for subclinical peripheral artery disease using the ABPI, as well as CIMT, which is also a non-invasive technique, in terms of cerebrovascular events. Inflammatory markers exhibited no statistically significant difference. We think that the atherosclerotic process stems not only from the inflammatory effects of RA, but also perhaps from its immunological nature.
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Introduction
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that causes morbidities due to synovial inflammation and joint destruction. Relatively high mortality has been found in patients with RA compared with the general population; this is frequently due to premature cardiovascular diseases. The most common of these mortalities are cerebrovascular and coronary artery disease, whose occurrence is 59 % higher in the RA population [1, 2]. Moreover, cardiovascular diseases are seen 10 years earlier in RA compared with the normal population, and RA is defined as a risk factor equivalent for cardiovascular risk, like diabetes mellitus (DM) [3]. Atherosclerosis develops subclinically over many years, and needs to be identified according to modified cardiovascular risk factors in patients with RA. The comorbidity between RA and atherosclerotic disease is not yet exactly understood. Genetic factors, inflammation and immunological factors have all been implicated. Inflammatory and immunological mechanisms exhibit a parallel with atherosclerotic plaque formation and rheumatoid synovitis [4, 5]. Detection of atherosclerosis at an early stage can help to reduce the effects of cardiovascular diseases.
In this context, measuring the ankle brachial pressure index (ABPI) may be regarded as a simple, reliable and inexpensive but effective method of detecting subclinical atherosclerosis in peripheral artery disease. Decreased arterial flow indicates systemic atherosclerosis, and is regarded as an independent cardiovascular risk factor, together with an increase in carotid intima media thickness (CIMT) [6, 7]. CIMT measurement is an approved test that is simple, reliable and non-invasive in terms of determining subclinical atherosclerosis. CIMT has also been recommended by the American Heart Association, American Society of Echocardiography and Society for Vascular Medicine as a screening test for heart disease in healthy individuals [8, 9].
A high ABPI is a marker of systemic calcification-related arterial stiffness and shows an increase in cardiovascular mortality [10]. Arterial stiffness in patients with RA is thought to be associated with glucocorticoid use [11]. The use of CIMT and ABPI may help to identify high-risk RA patients who may benefit from active therapy to prevent clinical disease and presence of plaques. We think that ABPI measurements, which are easily used in clinical practice and should be employed routinely, will be beneficial in patients with RA [12].
Methods
The study protocol was cleared by the University Ethical Committee. Written informed consent was obtained from all of the RA patients and control patients. Ninety patients with RA meeting the 1987 American College of Rheumatology criteria [13] and attending our rheumatology clinic between January 2012 and November 2013 were examined retrospectively; we then called them in prospectively for ABPI and CIMT measurements. Eighty patients without RA or peripheral disease (ABPI between 0.9 and 1.2) were regarded as the control group. Patients aged under 18 were excluded. In all the subjects, a detailed history was taken and a brief physical examination and laboratory investigations were carried out. Subjects with systemic inflammatory disease other than RA, active infectious disease, severe anaemia (haemoglobulin ≤ 9.0 g/dl for women and ≤ 10 g/dl for men), severe renal dysfunction (receiving dialysis and/or with a glomerular filtration rate ≤ 30 ml/min/m2) or unsuitable for ABPI and CIMT measurement were also excluded.
Hypertension (HT) had to be newly diagnosed, and/or patients had to be receiving hypertensive therapy or to have been diagnosed by a doctor during assessment (systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg at three measurements at intervals of 3–5 min). For DM, patients who were newly diagnosed and/or receiving antidiabetic therapy were included (fasting plasma glucose ≥ 126 mg/dl or blood glucose ≥ 200 mg/dl at any time). The ABPI was measured routinely by the same cardiovascular surgeon. Patients underwent comprehensive examination.
Following selection, patients were divided into four groups, as follows: RA patients with an ABPI less than 0.9 (group 1); RA patients with an ABPI between 0.9 and 1.2 (group 2); RA patients with an ABPI greater than 1.2 (group 3); and a control group of patients without RA, with an ABPI between 0.9 and 1.2 (group 4; Table 1). Patients’ age, gender, body mass index (kg/m2), smoking status, HT, diabetes and any history of cerebrovascular disease were recorded. Duration of RA and disease scores (disease activity score-28 (DAS28), health assessment questionnaire (HAQ) score, visual assessment score (VAS)), C-reactive protein (CRP), erythrocyte sedimentation rate and rheumatoid factor levels were recorded. Lipid profile, haemogram values and creatinine levels were also recorded.
Patients’ ABPI measurements were taken after a resting time of 15 min. The ankle pressure was measured in the dorsalis pedis and tibialis posterior artery bilaterally. The brachial pressure was measured in both arms. The ABPI for each lower extremity was calculated by dividing the higher of the recorded ankle pressures (dorsalis pedis and tibialis posterior artery). After this measurement, the patients underwent comprehensive CIMT examination on the same day.
CIMT was measured using Vivid 7 (GE Vingmend Ultrasound AS, Horten, Norway) with a linear array of 10 mHz probes. Every patient was lying in the supine position. The transducer probe was manipulated so that the near and far walls of the carotid artery were parallel, and the lumen diameter was maximised in the longitudinal plane. The section 10 mm proximal to the carotid bifurcation was identified, and the CIMT of the far wall was evaluated as the distance between the lumen intima interface and the media intima interface. The CIMT was measured on a frozen frame of suitable longitudinal image, with the image magnified to achieve a higher resolution of detail.
Statistical analysis
Statistical analysis was performed using SPSS (version 15.0, SPSS, Chicago, Illinois, USA). Quantitative variables were expressed as mean value ± SD or median (minimum–maximum) and qualitative variables as percentages (%). The four groups were compared using the Kolmogorov–Smirnov test. Comparison of parametric values between the four groups was performed using the Mann–Whitney U test. Categorical variables were compared using the χ2 test, and p < 0.01 was considered statistically significant.
Results
A total of 178 patients were included in the study, although 8 were subsequently excluded for various reasons, active infection being present in 4 patients (2 from the control group, 2 from other groups), severe anaemia in 3 (2 from the control group, 1 from another group) and RA accompanied by ankylosing spondylitis in one (non-control group). The demographic data are shown in Table 2. Group 1 RA patients exhibited a statistically significant increase in CIMT and ABPI values compared with the control group (p < 0.01). Group 1 patients with ABPI < 0.9 represented an older population compared with the group 2 patients with normal ABPI (p < 0.01). There was also a significant degree of HT in their histories (p < 0.01), and a statistically significant increase in their SBP (p < 0.01) compared with the control group (Table 3). Group 3 patients, with ABPI ≥ 1.2, had a similar history of HT and higher SBP compared with the control group (p < 0.01), and similar characteristics to those of group 1 patients. Group 2 RA patients with normal ABPI had significantly higher CIMT and ABPI compared with the control group (p < 0.01), although they had normal ABPI values. This confirms that these patients have a higher risk of stroke and peripheral artery compared with the control group.
Groups 1 and 3 also had significantly raised CIMT and ABPI values (p < 0.01). Eight patients had ABPIs lower than 0.9. More stiff plaque was present in the carotid arteries of patients in group 1 (p < 0.01; Table 2). A comparison of the mean serum blood tests values (anti-cyclic citrullinated peptide, CRP, RF, erythrocyte sedimentation rate, fasting plasma glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, haemoglobulin, white blood cells) and disease scores (DAS, HAQ, swollen joint count, tender joint count, VAS) among patients with RA (established on the basis of ABPI values) and he control group are shown in Tables 4 and 5. There were no significant differences in the mean serum blood values and disease scores amongst the four groups.
Discussion
Routine measurement of ABPI in patients with RA is used as a simple, reliable, inexpensive, non-invasive marker for the purpose of diagnosing subjects with both decreased arterial flow and arterial stiffness. CIMT is relatively comfortable for the patient, as it is a non-invasive investigation. It also offers the advantage of low cost and wide availability in developing countries. The age of the patients was significantly higher in group 1 (p < 0.01). HT and SBP in both patient groups were significantly increased compared with the control group (p < 0.01). ABPI measurements are vitally important in elderly patients at risk of ventricular dysfunction and coronary artery disease. There are significant differences in terms of cardiovascular risks in patients with RA, such as ventricular dysfunction and arterial HT, due to the association with accelerated atherogenesis [14–16]. The presence of atherosclerosis among patients with RA assessed using CIMT as a marker appears to be a reflection of subclinical atherosclerosis. Higher CIMT values have been described in RA patients with no classic cardiovascular risk factors or clinically evident cardiovascular disease [17].
The prevalence of peripheral arterial disease in the normal population in the same age range as our control group is 4 % [18]. Peripheral arterial diseases were twice as high in patients with RA in our study than in the general population. This confirms that all patients with RA have a greater risk for peripheral arterial diseases than the normal population.
In this study, mean (mm) CIMT levels in patients in groups 1 and 3 were significantly higher than those in group 4 (p < 0.01), although no peripheral arterial disease or cerebrovascular events were identified in patients in groups 1 and 3. Group 2 RA patients with normal ABPI had significantly higher CIMT and ABPI levels than the control group (p < 0.01), although they had normal ABPIs. This confirms that these patients are at a higher risk for peripheral arterial diseases, cerebrovascular events and vascular complications compared with the control group. It is important to monitor these patients for the risk of cerebrovascular events and peripheral arterial diseases [19]. Monitoring CIMT levels also has been recommended for heart disease in healthy individuals and has been suggested for evaluating the regression and/or progression of atherosclerotic cardiovascular disease and as a predictor of the presence of coronary atherosclerosis and its clinical outcomes [8, 20]. CIMT levels were also observed to be higher in adult Indian patients with RA [21].
No statistical significance was determined between the groups in terms of inflammatory markers such as CRP and white blood cell counts. These findings show that the atherosclerotic process derives not only from the inflammatory effects of RA, but maybe also from its immunological nature [7, 14]. In a study of 502 patients with RA, Lopez-Mejias et al. [22] reported that ZC3HC1 rs11556924 polymorphism is associated with subclinical atherosclerosis. This may also derive from PON 1 gene polymorphism [23].
The absence of any difference between the groups in terms of the RA markers disease duration, DAS28 score, HAQ score, VAS score, RF and anti-citrullinated cyclic peptide levels supports the idea of RA being a natural characteristic in the development of peripheral artery disease [24]. As the mean duration of disease in our study was 70 months, we do not think that this led to a significant change in the above parameters.
Guellec et al. [25] determined low ABPI values in 10 % of patients presenting to hospital with RA. They also reported a greater history of coronary artery disease in the patient group with an ABPI below 0.9 and of diabetes in the patient group with ABPI above 1.2. They concluded that routinely measured ABPI can assist with revealing low arterial flow in elderly patients with RA and patients with RA and diabetes. In our study, however, we observed more advanced age and elevated SBP in patients with ABPI below 0.9. Similar to those of Guellec et al., our study results suggest that ABPI may be useful in showing low arterial flow in patients with RA with advanced age and HT. We think that the measurement of the ABPI in RA patients with cardiovascular and cerebrovascular risk factors may assist in the identification of high-risk patients, in addition to routine cardiovascular and cerebrovascular monitoring [25]. Approximately 10 % of our patients exhibited a decreased ABPI level, similar to the rate reported in the literature. These patients were evaluated and monitored for peripheral vascular disease by the cardiovascular surgery department.
Mean CIMT values among patients with RA were significantly higher when compared with the control group in the present study. Similar observations were reported in other studies from Eastern Europe, the Far East and North America [26–28]. CIMT and the ABPI emerged as significant markers in terms of atherosclerosis development and complications of potential future cerebrovascular diseases; these may be useful tools to assess cardiovascular risk even in early RA patients [29].
Study limitations
The study group was small. The duration of disease in our study was 70 months, and further prospective studies with larger patient numbers and longer follow-up may be needed in the future.
Conclusion
Peripheral artery diseases may be seen in approximately 10 % of patients with RA. All patients with RA should be evaluated with the ABPI in terms of subclinical peripheral artery disease and with CIMT in terms of subclinical cerebrovascular events. Side effects that may develop due to these diseases can be reduced with appropriate treatment. ABPI and CIMT measurements are cheap, non-invasive, easily applicable and important techniques that should be employed in the early detection of disease in these patient groups.
Conflict of interest
T. Kurt, A. Temiz, F. Gokmen, G. Adam, S. Ozcan, E. Ozbudak, and M. Sacar declare that that there are no actual or potential conflicts of interest in relation to this article.
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Kurt, T., Temiz, A., Gokmen, F. et al. Can the ankle brachial pressure index (ABPI) and carotis intima media thickness (CIMT) be new early stage markers of subclinical atherosclerosis in patients with rheumatoid arthritis?. Wien Klin Wochenschr 127, 529–534 (2015). https://doi.org/10.1007/s00508-015-0767-x
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DOI: https://doi.org/10.1007/s00508-015-0767-x