Rheumatoid arthritis and macrovascular disease

J. K. Alkaabi, M. Ho1, R. Levison, T. Pullar2 and J. J. F. Belch

University Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY,
1 Department of Rheumatology, Northampton General Hospital, Northampton NN1 5BD and
2 Rheumatology Unit, Ninewells Hospital NHS Trust, Dundee DD1 9SY, UK


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To measure the extent of subclinical atherosclerosis in patients with rheumatoid arthritis (RA) compared with controls, and to evaluate any potential vascular risk factors.

Methods. Forty RA patients were compared with an age- and sex-matched control group. Non-invasive vascular tests, i.e. carotid duplex scanning [measuring common carotid artery intima–media thickness (IMT)], ankle–brachial blood pressure index (ABPI) and QT dispersion on ECG (QTD), were performed. Traditional risk factors such as high blood pressure, blood sugar, lipids and steroid usage were assessed.

Results. The average IMT (S.E.) in RA patients was 0.73 (0.03) mm, compared with 0.62 (0.03) mm in the control group (P=0.01, Mann–Whitney). Ten out of 40 RA patients (25%) had an ABPI < 1.0 compared with 1/40 (2.5%) in the control group (P=0.007, Fisher's). QTD was higher in RA patients; mean (S.E.) 55 (2.70) ms compared with 40 (2.50) ms in the control group (P < 0.001, t-test). There were no significant differences in the prevalence of high blood pressure, diabetes or lipid profiles. However, patients on steroids had a higher mean QTD (S.E.): 63.5 (4) compared with 48 (2.7) ms in those patients who had not received long-term steroids (P=0.003, t-test).

Conclusion. RA patients have an increased risk of subclinical vascular disease as was shown by a higher prevalence of carotid disease, peripheral arterial disease and increased QTD. Among traditional risk factors we found a history of steroid usage to be one of the potential risk factors.

KEY WORDS: Rheumatoid arthritis, Cardiovascular risk.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
It is almost 50 yr since Cobb et al. [1] published their article on rheumatoid arthritis (RA) mortality. They found that mortality in RA was increased by approximately 30%, compared with the general population. The majority of subsequent studies have also shown this increased mortality in patients with RA, with a standardized mortality ratio (SMR) ranging from 1.13 to 2.98 [2]. Several hospital- and community-based studies have shown an increase in deaths due to cardiovascular diseases (CVD) [3, 4]. Surprisingly the extent of atherosclerosis in RA is not known, nor have standard CVD risk factors been fully evaluated.

The carotid artery intima–media thickness (IMT), as measured non-invasively using B-mode ultrasound, has been proposed as an early manifestation of atherosclerosis [5]. It corresponds to the width of the vessel intima and media, which consists of endothelial cells, connective tissue and smooth muscle. It is the site of lipid deposition in plaque formation [6]. Increased IMT may pre-date the clinical manifestations of atherosclerosis by many years in subjects at risk of atherosclerosis [7] and because of the non-invasive character and easy applicability of the technique, it has been widely used in the assessment of atherosclerosis.

In this study we have attempted to determine: (i) the extent of subclinical atherosclerosis in patients with no previous history of CVD, using non-invasive techniques [IMT, ankle–brachial blood pressure index (ABPI), and QT dispersion on ECG (QTD)] and (ii) we have evaluated potential risk factors for accelerated macrovascular disease in RA.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Participants
Forty consecutive RA patients (20 males and 20 females), with no previous history of CVD, were recruited from the rheumatology out-patient clinics in Ninewells Hospital (Dundee). The patient pool from which these consecutive patients were recruited contains the majority of RA cases in the Tayside area (population catchment 450 000). All patients fulfilled the 1987 American Rheumatism Association criteria for RA, and were diagnosed by a consultant rheumatologist (Dr T. Pullar). All patients had a disease duration of at least 5 yr at inclusion into the study. Patients with other connective tissue diseases were excluded from the study. The following information was recorded for all patients: RA disease duration, oral steroid treatment (current or past), current antirheumatic drug treatment, RA functional class (Steinbrocker) and all history of cardiovascular events [i.e. myocardial infarction (MI), stroke (cerebrovascular accident), transient ischaemic attack, etc]. In addition, the subjects' smoking habit (current, past, never smoked), weight and height were recorded. Patients were asked to complete the Stanford Health Assessment Questionnaire (HAQ) to measure their functional capacity. All subjects were asked to complete the Edinburgh Artery Study claudication questionnaire, and World Health Organization chest pain questionnaire. Forty volunteers (20 males and 20 females) with no history of inflammatory arthritis or vascular disease, matched for age, sex and postal code (for area of residence), were recruited from the community as controls. These controls were derived from the general population in the area who were registered with general practitioners. All participants gave informed written consent for inclusion, and the local committee on medical ethics (Tayside Committee on Medical Research Ethics) approved the study.

Blood sample collection
All subjects fasted overnight and attended between 9.00 and 9.30 am to minimize diurnal variation in levels of biochemical, haemostatic and rheological factors. Samples were obtained from an antecubital fossa vein for measurement of serum lipids [total cholesterol, high-density lipoprotein (HDL), triglycerides (TG)] and blood glucose. Disease activity was assessed by measurement of plasma viscosity (PV), and a swollen and tender joint count.

Non-invasive vascular assessment
Carotid duplex scanning
Measurements were made by an experienced vascular technologist whose Duplex results have previously been validated by angiography. High-resolution B-mode carotid ultrasonography was performed with a Hewlett Packard Sono 2500 duplex scanner. A 7.5-MHz linear array transducer was used. The subject lay supine with the neck extended and the chin turned contralateral to the side being examined. Scanning involved examination of the carotid arteries in transverse and longitudinal planes. Measurement of common carotid artery intima–media thickness (IMTcca) was made 1 cm distal to the carotid bifurcation in the posterior wall. If an area of significantly increased IMT was observed, the maximum thickness at that site was also recorded. Measurements were made over both right and left carotid arteries. Abnormalities were recorded according to the severity of stenosis: normal, minimal disease (< 20% lumen stenosis), moderate (20–49%), severe (50–74%) and critical stenosis (>= 75%). Carotid plaques were classified morphologically according to B-mode appearance and based on the degree of echolucency, i.e. type I–V [8]. This is the standard technique used in Ninewells Hospital on approximately 5000 patients/yr [9, 10].

ABPI measurement
This was measured using a Doppler ultrasound velocity detector (Model 811–13 Parks Medical Electronics, INC, Aloha, Oregon, USA). A suitably sized sphygmomanometer cuff was placed around the ankle, 3 cm proximal to the malleolus. The subject rested for approximately 15 min, then the cuff was inflated above the systolic pressure and allowed to deflate at a rate of 2 mmHg/s. The pressure was noted at the reappearance of the blood velocity signal. Measurements were made for each extremity. The normal ABPI is 1.0, and any value < 1.0 is considered to indicate the presence of peripheral arterial obstructive disease (PAOD) [11].

Resting ECG and QT dispersion
Electrocardiograms were recorded as a standard resting 12-lead ECG at 25 mm/s. The QTD was measured using a digitizing pad (Calcomp). QT dispersion, defined as the difference between maximum and minimum QT value, was calculated using computerized software (in-house package).

Statistical methods
Fisher's test was used to analyse the differences between the group for incidence of carotid disease and PAOD. In addition, a {chi}2-test was used where appropriate. Differences between variables that assumed normal distribution were investigated by means of an unpaired t-test, variables that did not assume a normal distribution were investigated using the non-parametric Mann–Whitney U-test (MW). To investigate the correlations between variables, Pearson's correlation was used for data with normal distribution and the Spearman's rank correlation for data that were not normally distributed. For all tests, values of P < 0.05 (two-tailed) were considered statistically significant. All the data were analysed using SPSS for Windows (release 10).


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Demographic details
Demographic details for both groups were similar, with no statistically significant differences between the two groups (Table 1Go). The rheumatoid characteristics of the RA group are shown in Table 2Go.


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TABLE 1. Demographic details of the study group

 

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TABLE 2. Rheumatoid characteristics of the patients

 

Risk factors
There were no significant differences seen in the risk factors measured between the groups (Table 3Go), including family history of vascular disease. The systolic blood pressure was significantly higher in RA patients when compared with control subjects; mean (S.E.) 137 (3) vs 126 (3) mmHg (P=0.01, Mann–Whitney test)]. Despite this the formal diagnosis of hypertension was equal between groups. Five patients (12.5%) and four control subjects (10%) had a systolic blood pressure >= 160 mmHg; in addition, two patients (5%) and two controls (5%) had a past history of hypertension and were receiving anti-hypertensive treatment. This was not statistically significant (P=0.56, {chi}2-test). Twelve patients (30%) were currently on long-term steroids (i.e. for >= 6 months) and a further four patients (10%) had a history of long-term steroids. When patients who were taking, or had taken, long-term steroids were analysed for the presence of PAOD, five patients (12.5%) had an ABPI <= 1.0, but this was not statistically significant (P=0.48, Fisher's test) when compared with patients who had not taken steroids. Two RA patients (5%) had diabetes, but none of the control subjects was diabetic (P=0.50, Fisher's test).


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TABLE 3. Risk factor profile

 

Carotid artery disease
The average intima–media thickness [(right+left)/2] was greater in the RA group; mean (S.E.) 0.73 (0.03) mm vs 0.62 (0.03) mm in the control group. This difference was significant at P=0.01 (MW test). Furthermore, three patients (7.5%) had moderate internal carotid artery stenosis compared with one subject (2.5%) in the control group. Severe internal carotid disease occurred in three patients (7.5%), whereas none of the control subjects showed any evidence of significant stenosis (Table 4Go). However, none of these differences was statistically significant. Moderate common carotid artery disease occurred in equal numbers in both groups (one in each group). Within the RA group there were no differences in the measured IMT between the sexes. There were no significant differences between patients with or without evidence of erosions or extra-articular disease in respect of the presence or absence of carotid disease.


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TABLE 4. Non-invasive vascular assessment results

 
Carotid plaques were present in 11 patients and nine controls (type IV plaque in seven patients and six controls and type III in four patients and three controls). Neither of these was statistically significant.

Correlations of intima–-media thickness (IMT)
In both groups IMT correlated positively with age (for RA, r=0.60, P=0.001, n=39, and for control, r=0.53, P=0.001, n=39, Spearman's) and systolic blood pressure (r=0.38, P=0.01, n=39; r=0.47, P=0.003, n=39, Spearman's, respectively). The average IMT correlated positively with QTD in the RA group (r=0.41, P=0.01, n=34, Pearson's correlation) but not in the control group. Furthermore, IMT correlated positively with total cholesterol in the control group (r=0.33, P=0.04, n=40, Spearman's correlation), but not in the RA group. In the RA group there was no correlation between IMT, inflammatory markers, disease duration or the HAQ score.

Ankle–brachial blood pressure (ABPI) results
Ten patients (25%) had an ABPI < 1.0 compared with one (2.5%) control subject (P=0.007, Fisher's test). Of these, six patients (15%) had an ABPI <= 0.90 compared with no control subjects (P=0.026, Fisher's test) (Table 4Go). In total, three patients out of these 10 patients with an ABPI < 1.0 had a positive (7.5%) Edinburgh Claudication Questionnaire (ECQ) indicating clinical symptoms of claudication. Patients with an ABPI < 1.0 had a higher HAQ score compared with patients with a normal ABPI; mean (S.E.) 1.7 (0.2) vs 0.78 (0.14), (P=0.01, MW), respectively.

QT-dispersion results
There was a significant difference in the QTD in the measured ECGs. RA patients had a higher QTD compared with controls; mean (S.E.) 55 (2.7) ms vs 40 (2.5) ms (P < 0.001, t-test), respectively. There were no significant correlations between QTD, disease duration, HAQ score or risk factor profiles for RA or controls. However, RA patients who were on, or had a history of, long-term steroids (i.e. >= 6 months) had a higher mean QTD than those patients who had not received long-term steroids; mean (S.E.) 63.5 (4) vs 48 (2.7) ms (P=0.003, t-test), respectively. Furthermore, patients with evidence of extra-articular disease had a higher mean QTD compared with patients with no evidence of extra-articular disease; mean (S.E.) 63 (5) ms vs 49 (3), (P=0.01, t-test), respectively. In addition, patients with evidence of erosions had a higher QTD compared with patients without any evidence of erosions; mean QTD (S.E.) 57 (3) ms vs 44 (3), (P=0.054, t-test), respectively.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our study shows that these RA patients have a high prevalence of macrovascular disease in the form of carotid artery disease, peripheral arterial obstructive disease (PAOD) and subclinical heart disease. Whilst the study population all attended hospital clinics, in general the numbers of such patients are likely to be significant and contribute to the majority of the workload in RA for the rheumatologist. The measure of carotid IMT has also been linked to MI and stroke [12]. It has been shown that the relative risk of MI or stroke for subjects with the highest IMT is 3.87 [95% confidence interval (CI): 2.72–5.51] compared with subjects with the lowest IMT. Our patients also have a higher prevalence of carotid disease and such findings suggest that these patients have an increased risk of stroke. The role of ABPI in predicting cardiovascular mortality is also well established and previous studies in selected groups of patients have demonstrated that a low ABPI is associated with reduced survival. Among subjects with both symptomatic and asymptomatic peripheral arterial disease, with an ABPI <= 0.90, the relative risk of non-fatal MI is 1.38 (95% CI: 0.88–2.16), for stroke 1.98 (1.05–3.77), for cardiovascular death 1.85 (1.15–2.97) and for all-cause mortality 1.58 (1.14–2.18) [13]. Our findings of increased PAOD in this RA population support this and provide evidence for the first time of generalized atherosclerosis in this RA population.

Another interesting finding in our patients is the significant difference in QTD on ECG between RA patients and controls. QT dispersion has been shown as an important predictor of cardiac mortality and the risk of sudden cardiac death. Subjects with the highest QTD had a 2-fold risk for cardiac death and a 40% increased risk of total mortality [14]. Those with extra-articular manifestations and erosions appear to be most at risk.

We know the RA population has an increased cardiovascular mortality and premature death rate, but why do these patients have a higher incidence of atherosclerosis? The reason for this is not clear, but there are several factors which are known risks in the development of atherosclerosis. Steroids may play a role in the increased mortality from vascular disease. Some reports have suggested that prolonged treatment with steroids accelerates the development of atherosclerosis [15]. Steroids have atherogenic properties that are known to enhance the development of atherosclerosis, such as hypertension, hyperlipidaemia and diabetes, and they induce vascular injury. In addition, they produce a state of hypercoagulability. In our present study, we have found an increased atherosclerotic burden in those patients who were on long-term steroids. This suggests that steroid treatment may be a contributor to the higher rate of atherosclerosis seen in this group of patients. However, steroids are generally prescribed in severe and intractable cases of RA and thus steroid usage itself may be a marker for more severe RA, which in itself could be a risk factor. Mortality studies have indicated that mortality in RA is related to disease duration. Cobb et al. [1] observed that the younger the onset of RA, the more disparate the life expectancy compared with controls. Our data did not show any direct relationship between the extent of atherosclerosis and disease duration, but with extra-articular manifestation and erosion. Disease duration does not necessarily reflect the overall disease intensity or severity and other markers such as the functional class, HAQ score or the presence of extra-articular disease or erosions may reflect the severity of the disease better. In fact our data have shown that patients with evidence of PAOD had a higher HAQ score than those without. Furthermore, patients with extra-articular disease and erosions had a higher mean QTD than those with no evidence of extra-articular disease. This may explain why the presence of extra-articular disease reduces life expectancy, a finding noted earlier by Gordon et al. [16]

Serum lipids are strong predictors of CVD risk, but in our study we found no significant difference in the lipid profile between the groups. This finding is in line with other studies [17]. Patients with active disease are known to have global reduction of all lipid subsets. Furthermore, reduction in disease activity tends to normalize lipid parameters (our RA patients had a relatively normal plasma viscosity). The effects of antirheumatic drugs should also be taken into account as certain second-line agents may lead to normalization of the lipid profile [18]. Nevertheless, both groups had a significant number of subjects with cholesterol above the recommended level of 5.0 mM/l (53% in the case of RA patients). Furthermore, in a disease like RA characterized by disturbed antioxidant mechanisms (oxidative stress) [19], a high proportion of low-density lipoprotein (LDL) is oxidized, even at a lower ambient lipid concentration, thus placing RA patients at an even higher cardiovascular risk.

Diabetes is a major risk factor for the development of atherosclerosis, but the blood sugar results in our patients were no different from the controls, and excluding diabetic patients from the analysis did not alter the overall prevalence of vascular disease in the RA group. Abnormal plasma fibrinolysis in RA patients has been documented previously by our group. Previously we have shown impaired plasma fibrinolysis in RA [20], which is inversely proportional to disease activity. We have also shown that RA patients who have evidence of vascular damage in the form of vasculitis have a very marked decrease in fibrinolysis [21]. Furthermore, they also have increased levels of factor VIII von Willebrand factor antigen (a marker of vascular damage) [22]. This coagulation factor promotes thrombosis and platelet aggregation and may also contribute to the cardiovascular mortality in RA. Hypertension is another established cardiovascular risk factor. The mean systolic blood pressure was increased in our patients over controls, but the prevalence of hypertension (i.e. systolic blood pressure >= 160 mmHg, or receiving anti-hypertensive treatment) was not different from the controls and this is in agreement with some other studies [23].

In conclusion, this study shows the increased risk of vascular disease in RA patients. Multiple risk factors are likely to influence the risk of developing cardiovascular events in this patient group. Among traditional risk factors we found a history of steroid usage to be one of the potential risk factors. Further studies are needed to elucidate other non-traditional factors such as endothelial dysfunction, immune activation and impaired fibrinolysis in addition to oxidative stress.


    Acknowledgments
 
The study was supported by Tenovus, Tayside and the Chest, Heart and Stroke Association Scotland.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 3 September 2001; Accepted 2 August 2002