Increased Prevalence of Severe Subclinical Atherosclerotic Findings in Long-Term Treated Rheumatoid Arthritis Patients Without Clinically Evident Atherosclerotic Disease : Medicine

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Increased Prevalence of Severe Subclinical Atherosclerotic Findings in Long-Term Treated Rheumatoid Arthritis Patients Without Clinically Evident Atherosclerotic Disease

Gonzalez-Juanatey, Carlos MD; Llorca, Javier MD, PhD; Testa, Ana MD; Revuelta, Javier MD; Garcia-Porrua, Carlos MD, PhD; Gonzalez-Gay, Miguel A. MD, PhD

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doi: 10.1097/01.md.0000101572.76273.60
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Abstract

INTRODUCTION

Cardiovascular disease is the most common cause of mortality in patients with rheumatoid arthritis (RA), with a relative risk of about 2 compared with age-matched controls 5,21,26. We recently confirmed the presence of endothelial dysfunction in long-term actively treated RA patients 8. Since vascular endothelial dysfunction is closely linked to the development of atherosclerosis, this condition may be an early step in the development of atherosclerosis in RA patients.

Macrovascular disease is generally observed in patients with atherosclerosis. Case-control studies have shown that increased intima-media thickness (IMT) of the common carotid artery is an indicator of generalized atherosclerosis 3,10. It may precede the development of atherosclerosis by many years. Thus, determining the carotid IMT using ultrasound techniques provides useful and early information of atherosclerosis in subclinical stages of the disease in individuals at risk 14,19. The IMT corresponds to the width of the vessel intima and media, which consists of endothelium, connective tissue, and smooth muscle 19. This is also the site of lipid deposition and plaque formation 24. The close correlation between the common carotid artery IMT measured by B-mode ultrasound and the presence of coronary artery disease 13,25 supports the use of this noninvasive technique in the study of individuals with increased risk of cardiovascular mortality.

An increase in thrombotic markers in RA patients compared with controls has been described 15. Besides increased mortality due to cardiovascular disease 16, high morbidity due to cardiovascular and cerebrovascular complications is also present in RA patients 5,28. Japanese and Korean investigators have described an increased carotid IMT in RA patients compared with ethnically matched controls 11,17. However, these studies included some patients with cardiovascular risk factors such as hypertension, diabetes, or smoking. Also, the mean disease duration for the whole group of Korean RA patients was only 4 years 17.

Information on carotid IMT as an early marker of atherosclerosis in white populations is limited 1. In a recent report, investigators from the United Kingdom described increased carotid IMT in a series of 20 men and 20 women with RA compared with matched controls. However, as with the former studies, smokers and patients with hypertension and diabetes were not excluded from the analysis 1.

To further investigate the presence of subclinical atherosclerosis in a western population, we assessed the carotid IMT and the presence of carotid plaques in a series of long-term treated, white RA patients from a defined population without clinically evident atherosclerosis or its complications.

PATIENTS AND METHODS

Patients

Patients who met the 1987 American College of Rheumatology classification criteria for RA 2 and were treated by the same group of rheumatologists (MAG-G and CG-P) were recruited from Hospital Xeral-Calde, Lugo, in northwest Spain. The cohort constituted a series of patients attending hospital outpatient clinics seen over 1 month (May 2001). RA patients were considered seropositive if the rheumatoid factor (by nephelometry) was positive at least twice during the course of the disease. At the time of this study only 10 of the 47 patients had clinical criteria of active disease (disease activity score 28 greater than 3.2) 20.

Inclusion Criteria

Patients

Since the purpose of this study was to examine whether there were subclinical morphologic atherosclerotic changes in RA patients who had been treated chronically, only those treated for at least 5 years and currently being treated with 1 or more disease-modifying antirheumatic drugs (DMARDs) at the time of the study were included. Patients had to be nonsmokers or ex-smokers for at least 5 years. Also, RA patients seen during the period of recruitment who had hypertension (systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 90 mm Hg), diabetes mellitus (fasting overnight venous plasma glucose concentration in all RA patients included in this study was less than 110 mg/dL) or renal insufficiency, had suffered cardiovascular or cerebrovascular events, had evidence of cardiovascular disease, or used estrogen or drugs affecting the cardiovascular system were excluded. During the period of recruitment only 47 patients fulfilled the inclusion criteria described above. All had been treated with nonsteroidal antiinflammatory drugs (indomethacin: 100 mg/day, naproxen: 500–1000 mg/day, or diclofenac: 100–150 mg/day) and all but 1 had received treatment with low doses of prednisone immediately after disease diagnosis. Most patients had started treatment with prednisone 5 mg bid. All of them have been treated and were in treatment with 1 or more DMARDs, including chloroquine, sulphasalazine, gold, methotrexate (median dose, 15 mg/week) and cyclosporine A (median dose, 3 mg/kg per day). Treatment with DMARDs was initiated as soon as a diagnosis of RA was made. When the ultrasonographic study was undertaken, 46 patients were being treated with methotrexate, generally in combination with chloroquine. Ten were on combined therapy with MTX and cyclosporine A. Five patients who had been treated with methotrexate plus cyclosporine A were switched to methotrexate plus antitumor necrosis factor-α monoclonal antibody-infliximab because of the severity of the disease.

Control Group

Age- (±3 yr) and sex-matched controls from the Lugo region were also studied. All (n = 47) were ethnically matched (white), and could trace their ancestry in the region for at least 3 generations. None had a history of hypertension, diabetes mellitus, renal insufficiency, or cardiovascular or cerebrovascular events or had smoked within the 5 years before the study. None of the controls had used estrogen or drugs affecting the cardiovascular system. Informed consent was obtained from all cases and controls.

Ultrasonographic Study

Carotid IMT and carotid plaques were measured in the right common carotid artery. The study was performed using high-resolution B-mode ultrasound (Hewlett Packard SONOS 5500), with a 10-MHz linear transducer.

Patients and controls were examined in supine position with the neck extended and the chin turned contralateral to the side being examined. Measurement of IMT was assessed in the common carotid artery 1 cm distal to the carotid bifurcation in the posterior wall 22. Scanning involved examination of the right common carotid artery in longitudinal and transverse planes. All measurements were made manually on digitized still images that were obtained during ultrasound scanning. They were calculated as the average of measurement during 3 cardiac cycles at end-diastole. Measurements of IMT were performed by 2 cardiologists (CG-J, AT). In all cases the cardiologists were blinded to clinical information of the subjects and both agreed on the results. The reproducibility of the IMT measurements was evaluated in 10 patients and 10 controls within 1 week of the first examination. The correlation coefficient for IMT was 0.986. Atherosclerotic plaques were evaluated by ultrasound scanning in the common carotid artery as described above. Atherosclerotic plaque was defined as a distinct protrusion, greater than 1.5 mm, into the vessel lumen.

Radiographic Assessment

As recently described 7, 26 joints of hands and feet (wrists; 2, 3, 4, and 5 metacarpophalangeal; 2, 3, 4, and 5 proximal interphalangeal; and 2, 3, 4, and 5 metatarsophalangeal joints) were assessed according to the method reported by Larsen et al 12.

Statistical Analysis

Continuous data were described as mean and standard déviation (mean ± SD), and categorical variables as percentage. Comparisons between 2 categories were made using the Student t test (2-tailed) for continuous variables. To analyze categorical data we performed the chi-square test. When the minimum expected value was less than 5, the Fisher exact test was used. Statistical significance was accepted at p < 0.05. Relationships between 2 continuous variables were assessed by linear correlation coefficient. Multivariable analysis using backward stepwise logistic regression was performed to determine the best model for predicting increased carotid IMT and carotid plaques. All statistical analyses were performed with the package Stata 8/SE (Stata Corporation, College Station, TX).

RESULTS

Clinical Characteristics of RA Patients

The main demographic, clinical, and laboratory features of the 47 RA patients without clinical evidence of cardiovascular disease, atherosclerosis, or its complications are shown in Table 1. The mean age at the time of diagnosis was 43 years. During the course of the disease, extraarticular manifestation were observed in 18 (38%) patients. Rheumatoid nodules were found in 10 (21%) patients. Most RA patients who fulfilled the inclusion criteria for this study were rheumatoid factor positive (see Table 1).

T1-4
TABLE 1:
Demographic, Clinical, and Laboratory Features of the 47 Patients With Rheumatoid Arthritis Included in This Study

Clinical and Ultrasonographic Differences Between RA Patients and Controls

The main clinical and ultrasonographic differences between patients and controls without clinical evidence of cardiovascular disease, atherosclerosis, or its complications are summarized in Table 2. RA patients exhibited greater carotid IMT than did matched controls (0.779 ± 0.164 mm in patients compared with 0.699 ± 0.129 mm in matched controls; p = 0.010). In addition, 16 (34%) of the 47 RA patients showed carotid plaques compared with only 7 (15%) of the 47 controls (p = 0.031).

T2-4
TABLE 2:
Main Clinical and Ultrasonographic Differences Between Rheumatoid Arthritis Patients and Controls

Effects of Clinical Features of RA Patients on Carotid IMT

A strong positive correlation between the age at the time of the study and the carotid IMT in RA patients was observed (Table 3). There was no correlation between carotid IMT and disease duration. It was also the case for cumulative dose of prednisone, radiographic Larsen score in the hands and feet, C-reactive protein values, HDL and LDL cholesterol, and systolic and diastolic blood pressure measurements at the time of this study (see Table 3). Likewise, carotid IMT was not associated with sex, previous history of smoking, or rheumatoid factor status (Table 4). However, RA patients who exhibited extraarticular manifestations had a statistically significant greater carotid IMT than the remaining patients (0.843 ± 0.187 mm in patients with extraarticular manifestations compared with 0.740 ± 0.136 in the others; p = 0.033). Patients with nodular disease also had greater carotid IMT, but the difference did not achieve statistical significance (see Table 4).

T3-4
TABLE 3:
Correlation Between Selected Measures of Disease in 47 Rheumatoid Arthritis Patients and Carotid Intima-Media Thickness
T4-4
TABLE 4:
Association Between Clinical Features of Rheumatoid Arthritis and Carotid Intima-Media Thickness (IMT)

Differences Between RA Patients With and Without Carotid Plaques

To investigate further the macrovascular atherosclerotic disease in RA patients without clinically evident atherosclerosis or its complications, we assessed whether RA patients with carotid plaques had some clinical or ultrasonographic peculiarities that might help identify these RA patients before the occurrence of clinical manifestations related to the atherosclerotic disease. As expected, patients with carotid plaques had significantly greater carotid IMT (0.859 ± 0.116 mm) than did RA patients without plaques (0.739 ± 0.171 mm) (p = 0.014). At the time of this study RA patients with carotid plaques were older (65.5 ± 6.1 yr versus 55.9 ± 13.7 yr in RA patients without plaques; p = 0.011) and had a significantly longer disease duration (mean, 21.0 yr) and more extraarticular manifestations (63%) than those without plaques (mean, 12.7 yr of disease duration and 26% of extraarticular manifestations in patients without plaques) (Table 5). No differences between RA patients with or without plaques according to sex, previous history of smoking, HDL and LDL cholesterol and systolic and diastolic blood pressure measurements at the time of this study, rheumatoid factor, Larsen radiographic score in hands and feet, and cumulative dose of prednisone were observed (see Table 5).

T5-4
TABLE 5:
Main Clinical and Ultrasonographic Differences Between Rheumatoid Arthritis Patients With and Without Carotid Plaques

Predictive Model for Increased Carotid IMT in RA Patients

An important issue in our series of long-term actively treated RA patients without clinically evident atherosclerosis was to assess whether demographic or clinical features might predict the increased carotid IMT as a morphologic marker of subclinical atherosclerotic disease. However, by logistic regression analysis only an age at the time of study greater than 60 years was associated with an increased risk of abnormal carotid IMT (Table 6). Figure 1 shows a receiver operating characteristic (ROC) curve that describes the relationship between age older than 60 years and increased carotid IMT in RA patients.

T6-4
TABLE 6:
Best Predictive Model for Increased Carotid Intima-Media Thickness in Long-Term Treated Rheumatoid Arthritis Patients
F1-4
FIGURE 1:
Receiver operating characteristic (ROC) curve on the relationship between age greater than 60 years old and increased carotid intima-media thickness (area under ROC curve = 0.715).

Predictive Model for Carotid Plaques in RA Patients

Since carotid plaques constitute the morphologic expression of severe macrovascular atherosclerotic disease, the search for predictive factors for plaques in RA patients without clinical evidence of cardiovascular disease, atherosclerosis, or its complications was even more important than that of increased carotid IMT. When demographic, clinical, and ultrasonographic variables were examined, the age at the time of the study again was found be a predictive factor for severe macrovascular atherosclerotic disease (Table 7). It was somehow expected, since this variable was also a predictive factor for increased IMT. In addition, in RA patients the duration of the disease was also a predictive factor for the development of carotid plaques (see Table 7). Thus, an older age in longstanding RA patients can predict the development of a severe morphologic expression of atherosclerotic disease. Figure 2 shows the ROC curve for the best predictive model for the presence of carotid plaques in RA patients.

F2-4
FIGURE 2:
Receiver operating characteristic (ROC) curve for the best predictive model for the presence of carotid plaques in RA patients (area under ROC curve = 0.823).
T7-4
TABLE 7:
Best Predictive Model for the Presence of Carotid Plaques in Long-term Treated Rheumatoid Arthritis Patients

DISCUSSION

Our study constitutes the first attempt, to our knowledge, to assess the potential risk factors for developing carotid plaques, as expression of severe atherosclerotic disease, in patients with RA. It also confirms a high frequency of macrovascular disease, in the form of increased carotid IMT, in long-term actively treated white patients with RA without a history of atherosclerosis or its complications.

Increased carotid IMT was also observed in Japanese and Korean RA patients 11,17. However, genetic differences, as shown for HLA-DRB1 association, between RA patients from these populations and our white population may account for a different expression of RA severity and its complications 6. In addition, the lower background incidence of atherosclerosis in Koreans 17 may account for differences between Koreans and whites in terms of severe macrovascular findings of atherosclerotic disease, such as the presence of carotid plaques. However, regardless of the ethnic background in both Asian patients 11,17 and white patients from the United Kingdom 1 or northwest Spain, (current study), the presence of abnormally increased carotid IMT remains constant in RA patients.

In our series a strong correlation between the age at the time of the study and the carotid IMT was observed; this was also the case for Japanese patients 11. In that series common carotid IMT was positively associated with disease duration and the metacarpophalangeal joint Larsen score 11. In our series there was no association between IMT and disease duration, sex, cumulative dose of prednisone, Larsen scores in hands and feet, rheumatoid factor, HDL and LDL cholesterol, and C-reactive protein at the time of the study. These observations are in keeping with the data reported in the United Kingdom and Korean studies 1,17. However, when the presence of carotid plaques was assessed, in RA patients from northwestern Spain, the disease duration was found to be an additional variable required for the development of carotid plaques. Thus, it is possible that a longstanding severe disease, manifested by the positive association between carotid IMT and the presence of extraarticular manifestations in RA, might also be required for the presence of carotid plaques, as the morphologic expression of severe atherosclerotic disease. This may explain differences in the prevalence of carotid plaques between RA patients from the Lugo region of northwest Spain and their ethnically matched controls. In this regard, although in controls the age at the time of study also yielded a significant positive correlation with the carotid IMT (p = 0.001), Lugo RA patients had a significantly increased frequency of carotid plaques compared with controls (p = 0.031).

A question still unanswered is why RA patients have a higher incidence of atherosclerosis than the control population. Endothelial dysfunction plays a key role in early atherosclerosis 4,23 and contributes to the development of clinical features in the later stages of the vascular disease 27.

Atherosclerosis and RA share similar inflammatory mechanisms that include involvement of cytokines such as tumor necrosis factor-α and interleukin-6 18. Inflammatory mechanisms implicated in the development of synovial lesions in RA might also involve the vessel walls and promote the development of atherosclerotic lesions in RA patients. An impaired endothelial function has proved to be useful in predicting the development of subsequent cardiovascular events 9. In RA patients, inflammation may lead to endothelial dysfunction, subsequent atherosclerosis, and cardiovascular events. Thus, the presence of a low-grade, protracted inflammatory response in actively treated RA patients who have some kind of genetic predisposition might promote atherogenesis mechanisms that lead to arterial wall changes, the presence of plaques being the most severe expression.

In conclusion, our results confirm an increased frequency of severe subclinical atherosclerotic findings in long-term actively treated RA patients from northwest Spain. An early recognition of these findings before the occurrence of atherosclerotic complications may reduce the high prevalence of cardiovascular events observed in patients with RA.

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