Objective: to Evaluate Subclinical Atherosclerosis by Ankle Brachial Index (ABI) Measurement

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ABSTRACT

Objective: To evaluate subclinical atherosclerosis by ankle brachial index (ABI) measurement in patient with early rheumatoid arthritis (RA) compared with age-, sex-, body mass index (BMI)-, and atherosclerosis-associated underlying diseases matched healthy persons.

Method: Forty-five patients with early RA who met the 2010 EULAR/ACR classification criteria for the classification of RA and disease duration of ≤ 3 years were included in this study. Smokers, patients with diabetes mellitus and previous cardiovascular events were excluded. Forty-five age-, sex-, BMI- and atherosclerotic-associated underlying diseases-matched volunteers were selected as controls. ABI were measured by a skilled staff unawared of the persons studied.

Results: Patients with RA had similar traditional risk factors to those of controls, such as proportion of previous smokers, exercise < 3 times/week, and menopausal state. No significant difference in the mean BMI, waist circumference, blood pressure, fasting blood sugar, and lipid profiles. Mean ABI was 1.06±0.07 for RA patients and mean ABI was 1.06±0.07 for controls, (p = 0.96). Nobody has definite abnormal range ABI (ABI ≤ 0.9). In addition, both groups have similar proportion of persons with borderline and low normal ABI, which may indicate an increase risk of subclinical atherosclerosis.

Conclusions: No diferrence in ABI between patients with early RA and matched controls. A significant abnormal ABI in RA patients was no demonstrated.

Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease with unknown etiology,which predominantly characterized by chronic arthritis, joint damage, and disability. In Thailand, the incidence of RA was approximately 0.12 – 0.3% (1, 2). Theoverall mortality rate of patients with RAwas 2 times higher than that of normal population (3,4). The major cause of death in patient with RA was cardiovascular events such as coronary arterial disease, myocardial infarction, heart failure, cerebrovascular disease and peripheral arterial disease. Interestingly, the recent researcheshave shown that patients with RA had increased the risk of cardiovascular mortality by 50 – 60% and the risk of atherosclerosiswas 1.3 – 3 times higher than healthy people (5, 6).The risk of cardiovascular events in patients with RA approximated that of normal populationof whom age 10 years older (7). Moreover, another study also found that patients with RA had a risk of cardiovascular mortality equivalent to patients with DM type 2 , which was 2.16 times of that for normal population (8, 9).

Atherosclerosis in patients with RAcan be caused by several factors including traditional risk factors and RA-related risk factors such as disease activity, disease severity and the effect of RA therapy (10-13).

A number of evidence showed that the causes of cardiovascular diseases in patients with RA cannot be explained by traditional risk factorsonly but also influenced by the RA-related risk factors. For example, a prospective study comparing traditional risk factors andRA-related risk factors for predicting future cardiovascular events. The results shown that when using RA-related risk factors combined with traditional risk factors, they could predict cardiovascular events better than using traditional risk factors alone (c-statistic 0.66 and 0.57, respectively) (14). The incidence of atherosclerosis in patients with RArose to 3.17 times when adjusted for the traditional risk factors (13).

The patients with RA were more likely to develop accelerated atherosclerosis than general population due to the systemic inflammatory processes caused by pro-inflammatory cytokines in the blood circulation and multiples organs such as liver, adipose tissue, and endothelial cells. These pro-inflammatory cytokines, especially tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1, IL-8 result in endothelial activation, endothelial dysfunction and finally widespread atherosclerosis. Thus, the inflammatory processes in RA and atherosclerosis are similar, but the level of inflammation inRAwere intense. Endothelial activation can increase the expression of adhesion molecules including vascular cellular adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), P-selectin, and E-selectin. Also, it could convey leukocyte diapedesis into blood vessel wall and release many pro-inflammatory cytokines such asTNF, IL-1, IL-6 and inflammatory mediators such as C-reactive protein (CRP), prostaglandins. These inflammatorymediators continuously stimulate endothelial cellsand lead to endothelial dysfunction. Finally, it could cause the atherosclerosis throughout the body (15-20).

Besides the chronic inflammatory processes in RA that may directly affected the initiation and progression of atherosclerosis. Evidence also shows that patients with RA have ahigher the prevalence of traditional risk factors than normal population such ashypertension, insulin resistance and dyslipidemia through inflammatory processes. For instance, a low level of HDL could reflect high disease activity (21-24) of which it could increase the traditional risk factors of atherosclerosis as well.

For RA-related factors, there are many factors that associate with the atherosclerosis such as longer disease duration, higher disease activity, increased inflammatory markers, extra-articular features, positivity of rheumatoid factor, and positivity of anti-citrullinated peptide (anti-CCP) (25-27).

Likewise, drug therapy for RA also affects atherosclerotic risk. There was evidence showing that disease modifying anti-rheumatic drugs (DMARDs) could decrease atherosclerotic risk, especiallymethotrexate (MTx), the main drug for RA therapy, not only it helps reduce the inflammation of arthritis, slows radiographic progression, but also reducesoverall mortality rate and cardiovascular events (28). For antimalarial drugs, there was evidenceof their effectiveness in improving lipid profiles, decreasing insulin resistance and antiplatelet effect (29, 30). However, there was insufficient dataon the direct effect of atherosclerosis for these agents. However, ciclosporine and leflunomide have negative effect on cardiovascular events asthey increasethe risk of hypertension. In addition, ciclosporine could result in renal dysfunction. For glucocorticoids, more carotid atherosclerosis and cardiovascular events were observed in RA patients taking this agent than general population (31,32). Nonsteroidal anti-inflammatory drugs were found to associate with an increased risk of cardiovascular events (33).

To minimize the cardiovascular mortality in patients with RA, it was found that not only the tightly control of traditional risk factors, but also the control of inflammation in rheumatoid arthritis was also important. Likewise, there were evidences that the adequate use of DMARDs could decrease the formation and progression of atherosclerosis (34).

To identify subclinical atherosclerosis, several methods have been progressed. They lude coronary CT to qualify coronary arterial calcification, carotid intima media thickness (c-IMT), and ankle brachial index(ABI).

ABI has shown to have positive relationship with subclinical atherosclerosis (35), and can predict the risk of cardiovascular events and cardiovascular mortality rate in the future (36-38). ABI valuescorrelated with other indicators of subclinical atherosclerosis examined by other methodsfor example coronary arterial calcification level by using coronary CT, c-IMT. In addition, ABI could predict the risk of atherosclerosis similar to c-IMT(39-42). In addition, ABI measurement is an easy and noninvasive method which does not require specially trained personals and not costly.Thismethod also provides reproducibility and reliability results (43).

Subclinical atherosclerosis can occur early in the case of RA. The prevalence of subclinical atherosclerosis in RA patients is higher than that in general population.These previous studies had several methodological weaknesses, such as no control of traditional atherosclerotic risk factors. Moreover, these studies were conducted in Western countries.Differences in ethnic races, cultures and lifestyle may involve the results not applicable in Thai RA patients.

Therefore, this study was aimed to investigate the prevalence of subclinical atherosclerosis in RA patients with that ofmatched controls for age, gender, traditional atherosclerosis-related underlying diseases and body mass index (BMI).

Methodology

We studied in RA patients,with symptom duration of less than 3 years and at outpatient clinics at King Chulalongkorn Memorial Hospital (KCMH). The patients were included into the study if they were 20-60 years of age and were diagnosed of RA according to ACR/EULAR (American College of Rheumatology/ European League Against Rheumatism) 2010 classification criteria (44).The participants for the control group were selected from normal people who annual check-up at KCMH. They werematched for age, gender, traditional atherosclerosis-related underlying disease and BMI with RA patients.Exclusion criteria included diabetes mellitus; previous history of cardiovascular diseases such as coronary arterial disease, cerebrovascular disease, and peripheral arterial disease; premature menopause and chronic systemic inflammatory disorder other than RA.

Sample size calculation was based on the study by Alkaabi JK,et al. (45).This study investigatedsubclinical atherosclerosis in 40RA patientsand 40 age-, sex- matched normal persons using ABI. This study found that 10 RA patients had ABI <1.0, which accounted for 25%. Whereas only 1 person for the control group had ABI <1.0 (2.5%). The difference was statistically significant (p = 0.007). alpha was 0.05 and the power was 95%. the calculated sample size was at least 45 participants for each group.

For procedures, the research h were conducted as follows: participants in the group of RA patients were asked about their previous history of RA symptom such as age of onset, arthritis period since the onset until time to diagnosis, period of time to treatment with DMARDs, duration of treatment, duration of morning stiffness, distribution of arthritis, extra-articular symptoms and functional capacity as functional class according to ACR (46), and assessment of functional capacity evaluated by using questionnaire Thai HAQ (47), drug therapy of RA, as well astraditional atherosclerotic risk factors in both two groups such as age, gender, smoking history, life style activity, underlying disease including hypertension, dyslipidemia and diabetes mellitus, menstruation history, menopausal status, hormonal usage, current medication usage and family history of premature coronary artery disease. Also, history of cardiovascular events such as myocardial ischemia, heart failure, cerebrovascular disease, peripheral arterial disease was evaluated. In addition, participants were asked to do physical examination in term of weight, height, waist circumferences, blood pressure, cardiovascular examination as well as joint examination including swollen joint count, tender joint count and extra-articular symptoms evaluation. Thereafter review all the outpatient data from medical record included laboratory results such as fasting blood sugar, lipid profiles, liver and kidney function test, complete blood count, ESR within the past 6 months. If not available, the participants were requested to do the test again. Furthermore, participants were asked to do electrocardiogram, review radiograph (if available) and evaluate metabolic syndrome according to the diagnosis of The National Cholesterol Education Program (NCEP) 2001 (48). For the disease activity of RA, this study applied DAS 28 scores in which it can classify as follows: disease remission (DAS 28 < 2.6), low disease activity (DAS 28≤3.2), moderate disease activity (3.2 < DAS 28 ≤5.1) and high disease activity (DAS 28 > 5.1).

The measurement of ABI was done by a trained staff unaware of the persons studiedby using Vasera 1000 which equipped with continuous wave doppler ultrasonic sensor and blood pressure cuff. The test was started from covering blood pressure cuff at brachial artery which far 2.54 cm.above elbow to measure the systolic blood pressure at brachial artery and then attached the blood pressure cuff 1 cm. above the medial malleolus to measure systolic blood pressure at posterior tibial and dorsalis pedis artery of each leg in order to calculating the ABI value. The result was indicated the ratio of systolic blood pressure at posterior tibial and dorsalis pedis arteries to systolic blood pressure at brachial artery. If the ABI in either of the two less than 0.9, it was obviously considered as outliers in which it indicated peripheral arterial disease and definite abnormal value which associated with subclinical atherosclerosis, cardiovascular events and cardiovascular mortality. Also, researcher classify of ABI into subgroup according to the study by McDermont MM, et al.(35).All participants in this research was received and signed the consent form and this study has been completely approved by the research committee board of KCMH.

Statistical analysis

Continuous data were presented asmean±SD (standard deviation), median and range.Categorical data were presented as percentage or proportion. The comparison between continuous data was calculated by Student’s t-test or Mann-Whitney U-test. The comparison between categorical data was calculated by Chi-square or Fisher’s exact test. The relationship between other factors towards ABI in rheumatoid arthritis patients were calculated in odd ratio using binary logistic regression. All data were analyzed using SPSS version 16.

Results

In total of 49 patients with RA were initially included in this study. FourRA patients were excluded due totwo patients could not certainly specify the disease duration of hypertension and one patient had a previous cerebrovascular disease and current smoking.

Basic characteristics of RA patients and general population are shown in Table 1. Both groups were not significantly different in terms of the traditional atherosclerotic risk factors including age, gender, body mass index, waist circumferences, family history of premature coronary arterial disease, proportion of ex-smokers, menopausal women, exercise less than 3 times per week, as well as level of blood pressure, fasting blood sugar, total cholesterol, triglyceride, HDL, LDL and the ratio of TC to HDL except rheumatoid arthritis groups that had the proportion of low economic persons 73.3% and low level of education 53.3% compared to general population that had a proportion of 46.7% and 22.2% respectively. The different was statistically significant (p = 0.02).

Rheumatoid arthritis group and general population group in this research had a characteristics as follows; the mean±SD age was 46.0±9.0 years old, 91.1% were female in which the risk factors of atherosclerosis were relatively similar such as the proportion of exercise less than 3 times per week in both two groups was 83.3%, the proportion of postmenopausal women was 35.4%, the mean±SDof systolic blood pressure was equal to 118.3±11.3 mm.Hg, the mean±SDof diastolic blood pressure was 73.1±8.3 mm.Hg, the mean±SDof mean arterial pressure (MAP) was 88.2±8.8 mm.Hg, the mean±SDof body mass index was 22.6±3.1 kg./m2 and the mean±SD of waist circumferences was 75.9±9.2 cms. The mean of all these parameters of this population study was in the normal range.

However, one RA patient had hypertension after two years of RA which had been matched to normal person who have similar hypertension about same one year. Also, the hypertension had been well controlled within the normal range in both. Furthermore, all participants in this research had no previous history of cardiovascular disease and denied to have history of its symptom such as angina chest pain, dyspnea on exertion, weakness, facial palsy or dysarthria and vascular claudication. In addition, none of participant in both groups had not taking medicine of lipid lowering agent, antiplatelet agent and antihypertensive drugs in angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blockers (ARB).

For the laboratory test, the results of both groups in this research were as follows: the mean±SDof fasting blood sugar was 86.6±6.9 mg/dL, total cholesterol was 195.9±34.9 mg/dL, triglyceride was 86.5±36 mg/dL., HDL was 69.1±21.6 mg/dL., LDL was 109.5±32.5 mg/dL. and the ratio of TC/HDL was 3.0±0.9 in which all of them were within the normal range and no one in this study had metabolic syndrome.

The baseline characteristics of RA patients was shown in Table 2. The mean±SDof disease duration since the onset of symptom was 19.7±12.4 months which the lowest duration of 3 months and highest duration 36 months. The mean±SDof period of time to treatment with DMARDs was 6.9±6.8 months in which the shortest time to treatment period was one months until the longest period of 26 months. Moreover, the mean±SDof treatment duration with DMARDswas equal to 12.2±11.5 months ranging from not receiving DMARDs until the maximum treatment period of 34 months. In non-DMARDs patients, there were total 4 participants who have not been taken DMARDs in first diagnosis of rheumatoid arthritis and there was one participant who stopped DMARDs for more than 4 months. For the mean±SDof age of disease onset was 44±9.1 years old which the youngest age was 18 years old and the oldest was 50 years olds. Likewise, the mean±SDof age of participants during enrolling in this study was 46.0±9.0 years old which the youngest age of 21 years old and the oldest of 60 years old.

For disease activity, it could be evaluated by many parameters including the amount of tender joint count based on American Rheumatism Association (ARA) (49) which included the total number of 68 joints in which this study showed the mean±SDof number of tender joint counts was 3.0±3.7 joints with the range of 0-19 joints. The measurement of swollen joint counts was also followed ARA which included total number of 66 joints. The mean±SDof swollen joint counts was 8.9±5.5 joints with the range of 0 – 23 joints. For pain, it was measured by visual analog scale (VAS) in which the patients was asked to rate severity of pain during the past one weeks, with ranged from 0 which mean no pain to 100 which mean the maximum of pain. In this study, the mean±SDof VAS was 17.1±18.8 with the minimum score was 0 and the maximum score was 70. For period of morning stiffness, the mean±SD was 27.1±63.8 minutes which the range between 0 – 300 minutes. The mean±SD of ESR was equal to 32.4±22.7 mm/ hr which the lowest point of 6 and the highest point was 107 mm/hr. The mean±SD of DAS 28 score was equal to 3.96±1.34 in which it considered as moderate disease activity. If classified orderly, it was found that the proportion of disease remission equal to 20%, the proportion of low disease activity was equal to13.3%, the proportion of moderate disease activity was equal to 40% andthe proportion of high disease activity was equal to 26.7%. For the functional capacity, every patient was able to do all activities (functional class I). The functional capacity of patients was shown by the mean of Thai HAQ which was equal to 0.24.