Objective To determine if the use of carotid ultrasonography (US) may improve the stratification of the cardiovascular (CV) risk in rheumatoid arthritis (RA).
Methods A set of 370 consecutive patients without history of CV events were studied to assess carotid intima-media thickness (cIMT) and plaques. As previously proposed, CV risk was calculated according to the modified EULAR systematic coronary risk evaluation (mSCORE) for RA that was adapted by the application of a multiplier factor of 1.5 in those patients fulfilling ≥2 of 3 specific criteria.
Results The mean disease duration was 9.8 years, 250 (68%) had rheumatoid factor/anticyclic citrullinated peptide positivity and 61 (17%) extra-articular manifestations. 43 were excluded because they had type 2 diabetes mellitus or severe chronic kidney disease. CV risk was categorised in the remaining 327 RA patients according to the mSCORE: mild (96 cases; 29.3%), moderate (201; 61.5%) and high/very high risk (30; 9.2%). Only five patients were reclassified as having high/very high CV risk when the mSCORE was applied. Severe carotid US abnormalities (cIMT >0.90 mm and/or plaques) were uncommon in patients with low mSCORE (13%). Nevertheless, in patients with moderate mSCORE, severe carotid US abnormalities were observed in 63% of cases. A model that included a chart mSCORE risk ≥5% plus the presence of severe carotid US findings in patients with moderate mSCORE risk (≥1% and <5%) yielded high sensitivity for high/very high CV risk (93 (95% CI 88 to 96)).
Conclusions Our results support the use of carotid US in the assessment of CV risk in patients with RA.
- Rheumatoid Arthritis
- Cardiovascular Disease
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Accelerated atherogenesis leading to increased incidence of cardiovascular (CV) mortality has been reported in patients with rheumatoid arthritis (RA).1 ,2 Traditional and non-traditional CV risk factors are associated with atherosclerosis in RA.3 However, this high incidence of CV events in patients with RA cannot only be explained by the presence of traditional CV risk factors.4 Besides a genetic component,5 the presence of chronic inflammation is a key factor implicated in the atherogenesis process observed in RA.6
Adequate stratification of the CV risk is an issue of major importance in patients with RA. Based on a pool of datasets from 12 European cohort studies, mainly carried out in general population settings, European experts performed the systematic coronary risk evaluation (SCORE) project to develop a risk scoring system for use in the clinical management of CV risk in European clinical practice.7 The SCORE risk estimation system offers direct estimation of fatal CV risk in a format suited to the constraints of clinical practice.7 A task force of the European League Against Rheumatism (EULAR) has proposed to adapt the CV risk management calculated in RA patients according to the SCORE function by the application of a multiplier factor of 1.5 in those patients with two of the following three criteria: disease duration >10 years, rheumatoid factor (RF) or anticyclic citrullinated peptide (anti-CCP) antibody positivity, and presence of certain extra-articular manifestations.8 However, concern about the use of the modified EULAR SCORE (mSCORE) to fully establish the CV risk of RA patients is still present. Reports describing patients who did not reach values to be considered as having high CV risk according to the mSCORE who suffered CV complications, mainly ischaemic heart disease, have been reported.9 Because of that, the search for additional tools that may identify high risk RA patients who may benefit from active therapy to prevent CV events is required. It may be of major importance in RA patients who are not included in the categories of high or very high CV risk according to the mSCORE.
Several validated non-invasive imaging techniques are currently available to determine subclinical atherosclerosis in patients with rheumatic diseases. They can offer a unique opportunity to study the relation of surrogate markers to the development of atherosclerosis.10 Among them, by the assessment of carotid intima-media thickness (cIMT) and the presence of plaques, carotid ultrasonography (US) has become an affordable efficient technique to measure the presence of subclinical atherosclerosis.10 ,11 Both cIMT and carotid plaques were found to be good predictors of CV events in low and intermediate risk groups of non-rheumatic individuals.12 Also, cIMT has proved to provide additional value to the Framingham risk score when predicting CV events.13 In addition, both cIMT >0.90 mm and the presence of carotid plaques are considered expression of subclinical organ damage and factors influencing the CV prognosis in the general population.14 Individuals with carotid plaques should be considered as having very high CV risk.15 Increased cIMT and higher incidence of plaques have been found in patients with RA, even in selected patients without classic CV risk factors.16 ,17 In keeping with results observed in the general population, cIMT was found to predict the development of CV events in RA.18 RA patients without classic CV risk factors at the time of the US assessment who had cIMT values greater than 0.90 mm had increased risk of suffering CV events over a 5-year follow-up period. 18 Evans et al19 also confirmed the implication of carotid plaques as predictors of future CV events in RA. They found a 2.5 increased risk of CV complications among RA patients with unilateral plaques, and 4.3 among those with bilateral plaques.19
Taking together all these considerations, we previously suggested the possibility of performing carotid US when the mSCORE does not yield results of high CV risk in RA patients.20 To further investigate this issue, in the present study we aimed to determine if the use of carotid US may improve the stratification of the CV risk of RA patients. For this purpose, we studied a series of RA patients seen at the reference hospital for a defined population of Northern Spain.
Patients and methods
A set of 370 consecutive Spanish patients with a diagnosis of RA recruited from Hospital Universitario Marqués de Valdecilla (Santander, Spain) who were seen over 1-year period were included in the present study. All the patients who were assessed for carotid US fulfilled the 1987 American College of Rheumatology classification criteria for RA and also fulfilled the 2010 classification criteria for RA.21–23
Patients with a history of CV events (ischaemic heart disease, cerebrovascular accident, peripheral arterial disease or heart failure that were defined as previously reported) were not recruited in this study.5 ,18 Then, clinical records of all patients were again reviewed in an attempt to fully establish comorbidities. Patients with type 1 diabetes with target organ damage, type 2 diabetes mellitus (if before disease diagnosis they had been diagnosed as having diabetes mellitus by their family physicians or if two fasting plasma glucose levels on different days at the time of disease diagnosis or over the extended follow-up were greater than 125 mg/dl) or those who had severe chronic kidney disease (if glomerular filtration rate <60 ml/min/1.73 m2) are considered as having very high CV risk according to current guidelines and, because of that, they were excluded from the analysis.6 ,15
Patients were considered as having extra-articular manifestations as previously reported.6 The SCORE system estimates the 10-year risk of a first fatal atherosclerotic event, whether heart attack, stroke or other occlusive arterial disease, including sudden cardiac death. Risk estimates have been produced as charts for high and low risk regions in Europe.15 Spain was included in the low risk region in Europe. Therefore, both SCORE and mSCORE according to the EULAR recommendations were calculated to determine the 10-year risk of fatal CV disease in a population at low CV disease risk (as it was considered for the Spanish population).15 ,24 SCORE chart assessment was based on the following risk factors: age, gender, smoking, systolic blood pressure, total cholesterol and High-density lipoprotein (HDL)-cholesterol.15 ,24 A subject's written consent was obtained in all the cases. The study was approved by the local Ethical Committee.
Carotid US examination
Carotid US examination included the measurement of cIMT in the common carotid artery and the detection of focal plaques in the extracranial carotid tree. A commercially available scanner, Mylab 70, Esaote (Genoa, Italy) equipped with 7–12 MHz linear transducer and the automated software guided technique radiofrequency—Quality Intima Media Thickness in real-time (QIMT, Esaote, Maastricht, Holland)—was used.25–29 Carotid plaques were counted in each territory and defined as no plaque, unilateral plaque or bilateral plaques26 ,27 ,30 (see online supplementary text).
Results were expressed as number (percentage) or mean±SD. Equality of percentages was tested using the Fisher exact test (two tailed). To estimate the sensitivity, we considered patients having mSCORE ≥5% or the presence of cIMT >0.90 mm and/or carotid plaques as the gold standard for high or very high CV risk; 95% CIs for sensitivity were estimated assuming a binomial distribution. All statistical tests were performed with the package Stata V.12/SE (Stata Corp, College Station, Texas, USA).
Most patients from this series of 370 patients without CV events were women (298; 80%). The age at the time of the study and disease duration (mean±SD) was 58.9±13.7 and 9.8±8.3 years, respectively. RF and/or anti-CCP positivity were found in 250 (68%) cases. A total of 61 subjects (17%) had extra-articular manifestations. They included the presence of nodular disease in 24 patients, secondary Sjögren's syndrome in 21, pleuritis/pericarditis in eight, pulmonary fibrosis in seven, rheumatoid vasculitis in two, scleritis/episcleritis in two, Raynaud's phenomenon in three, sclerosing cholangitis in one case and Felty's syndrome in one case.
The SCORE (mean±SD) was 1.83±2.03 and the mSCORE calculated according to the EULAR task force recommendations was 2.16±2.49. Regarding US results, cIMT >0.90 mm was observed in 46 (12%) patients and carotid plaques in 195 (53%). In all, 45 of the 46 patients with cIMT>0.90 also had carotid plaques. Other characteristics of this series of patients are shown in table 1.
SCORE risk, mSCORE risk, cIMT >0.90 mm and carotid plaques in patients with RA
Patients were stratified according to the results derived from the SCORE analysis. For this purpose, we calculated the SCORE for each patient using information related to sex, age, smoking, systolic blood pressure and atherogenic index (total cholesterol/HDL-cholesterol). Therefore, each patient had a potential risk that could range from 0% to 10%. Patients with SCORE <1% were included in the category of low risk. Those with a SCORE ≥1% and <5% were in the category of moderate risk. When the chart SCORE result was ≥5% and <10% they were classified as having high risk. Finally, those patients with SCORE results ≥10% were in the category of very high CV risk.
As shown in table 2, when the risk model was adapted using the multiplication factor indicated by the EULAR recommendations to establish the mSCORE, only 7 (3%) of the 237 patients initially categorised as having moderate CV risk (≥1% and <5%) fulfilled definitions for high and/or very high CV risk (mSCORE≥5%). The frequency of severe US abnormalities manifested by cIMT>0.90 mm and/or carotid plaques was lower in patients with low CV risk (<1%) than in the other categories.
None of the patients from this series had type 1 diabetes with target organ damage. However, 31 fulfilled definitions for type 2 diabetes mellitus and 12 had severe chronic kidney disease. Therefore, these 43 patients were excluded from further analyses and SCORE, mSCORE and US data were assessed in the remaining 327 cases.
Table 3 shows SCORE, mSCORE and frequency of cIMT >0.90 mm and carotid plaques in these 327 patients. As discussed before, only 5 (2.4%) of the 206 categorised as having moderate CV risk according to the SCORE were reclassified as having high or very high CV risk when the mSCORE was applied. However, in patients classified as having moderate CV risk according to the mSCORE, the frequency of cIMT >0.90 mm and/or plaques was higher than 60% (table 3).
Moderate mSCORE risk and severe US abnormalities
From 327 patients without diabetes or severe chronic kidney disease, 201 had moderate CV risk after applying the mSCORE. They were also stratified according to the presence of one or more of the multiplication factors proposed by the EULAR task force and the presence of severe US findings. As shown in table 4, the frequency of severe US abnormalities in patients with moderate mSCORE was high regardless of the presence of multiplication factors or not. In this regard, although severe US abnormalities were more commonly observed in those with 2 or 3 multiplication factors (42 of 60 patients; 70%) than in those without any of the 3 factors (23 of the 40 patients; 58%), no statistically significant differences were found (table 4).
Low mSCORE risk and severe US abnormalities
Unlike patients with moderate mSCORE, those with low mSCORE had lower incidence of severe carotid US abnormalities (table 5). In this category, the stratification of patients according to the presence of multiplication factors did not show differences in the percentage of patients with cIMT>0.90 mm and/or carotid plaques (p=0.80) (table 5).
The frequency of severe US abnormalities in patients with low mSCORE without any multiplication factor was 16% (three of 19 patients) while it was 14% in those with 2 or 3 multiplication factors (4 of 28).
Model to establish the presence of high or very high CV risk in patients with RA
In assessing data from tables 3, 4 and 5, we observed that 168 of 327 RA patients had high or very high CV risk (30 with high or very high risk according to mSCORE plus 138 with low or moderate mSCORE but severe findings in carotid US).
The sensitivity to detect high or very high CV risk using only the mSCORE was very low (18 (95% CI 12 to 25)) as the charts only detected 30 of these 168 patients.
Using a chart mSCORE risk ≥5% (n=30) plus the presence of severe carotid US findings in patients with moderate mSCORE risk (≥1% and <5%) who had 2 or 3 of the multiplication factor variables indicated by the EULAR task force (n=42), we disclosed a higher sensitivity as 72 RA patients were detected as having high or very high CV risk (43 (95% CI 35 to 51)). More importantly, the inclusion in the model of patients with mSCORE risk ≥5% (n=30) plus all the patients with moderate mSCORE risk (≥1% and <5%) who had severe carotid US abnormalities (n=126), regardless of the presence or absence of any multiplication factor, yielded a very high sensitivity. In this regard, following this procedure 156 patients fulfilled definitions for high or very high CV risk (sensitivity 93 (95% CI 88 to 96)).
However, when we assessed the sensitivity of carotid US to detect high or very high CV risk in the patients with low mSCORE we observed that it was low, regardless of the assessment of US in patients who had multiplication factors proposed by the EULAR task force or not. In this regard, only 12 of the 96 (13%) patients with low mSCORE had cIMT>0.90 mm and/or carotid plaques.
In accord with previous reports, patients with a cIMT <0.60 mm and no plaque can be considered as being free of atherosclerosis.3 ,31 In contrast, a cIMT≥0.60 mm may be considered as a marker of atherosclerosis and the presence of plaque is strongly indicative of advanced atherosclerosis.3 ,31 Therefore, we recalculated the study using a cIMT≥0.60 mm instead of >0.90 mm as a marker of high or very high CV risk. As expected, following this procedure the percentage of patients who were categorised as having high or very high CV risk was higher in the group of patients with moderate mSCORE (table 4) than in the group of patients with low mSCORE (table 5). However, there is consensus on the use of a cIMT value >0.90 mm rather than >0.60 mm as the value strongly indicative of the presence of atherosclerosis and increased risk of CV disease.
The results found in this study support the use of carotid US in the stratification of the CV risk of RA patients with moderate mSCORE. As observed in the general population, the yield of carotid US to establish the CV risk in patients with low mSCORE was reduced. Therefore, this non-invasive technique should be restricted to RA patients with moderate CV risk according to SCORE charts.
In the general population, the ACCF/AHA 2010 guidelines emphasised that carotid US including measurement of cIMT is a useful technique for CV risk assessment in asymptomatic adults at intermediate risk.32 In this regard, cIMT was independently associated with future risk for ischaemic coronary events and stroke in middle-aged and older individuals. Furthermore, the finding of atherosclerotic plaque increased the predicted coronary artery disease risk at any level of cIMT.33 These data reported in the general population are in line with our present findings in RA and emphasise even more the ability of cIMT/plaques to reclassify individuals from moderate risk group into high risk group.
The analysis of our data confirmed that the multiplying factor of the SCORE does not increase substantially the number of patients that change from moderate to high or very high CV risk.34 Another result of particular relevance of our study was that more than 60% of the RA patients with moderate risk according to the mSCORE had carotid plaques and/or cIMT>0.90 mm.
Carotid plaques have been associated with extra-articular manifestations and long disease duration, even in selected RA patients without traditional CV risk factors.17 Also, progression of cIMT has been observed in long-standing patients with severe RA undergoing anti-TNF-α therapy,35 and the evidence indicates that the rate at which the cIMT increases per unit of age steepens in proportion to the RA duration.36 Electron-beam CT studies have also confirmed that coronary-artery calcification occurs more frequently in patients with established RA than in patients with early RA and controls.37 Also, anti-CCP positivity was reported to predict the risk of CV events in RA.38 These observations emphasise the need of careful assessment of CV risk in RA patients with severe and long-standing disease. However, we also found a high frequency of severe US abnormalities in RA patients with moderate mSCORE and disease duration less than 10 years, RF and anti-CCP negative and absence of extra-articular manifestations. With respect to this, some studies have described an increased incidence of CV events at the onset of RA.39 ,40 The presence of a chronic pro-inflammatory state, even in the early subclinical stages of the disease, may account for this elevated risk of CV disease in RA.
While parameters in the mSCORE can easily be assessed, cIMT assessment with the automated software used in the present study is not widely accessible.26 Nevertheless, in the clinical practice stratification of the risk may also be performed using US scans that are used for musculoskeletal studies. So, even without automated methods for analysis, the presence of carotid plaques can be determined easily, thereby facilitating CV risk stratification in patients with RA. Regrettably, many clinicians do not have access to even the most basic US technology. In these situations, further tools, such as the ankle-brachial index that enables the identification of asymptomatic patients with atherosclerotic disease in the general population, may also be used in the stratification of the CV risk of RA patients.
In conclusion, the mSCORE did not significantly improve the identification of RA patient with high risk as did US of the carotid arteries. Our results support the necessity of using carotid US in the assessment of CV risk in patients with RA.
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Files in this Data Supplement:
- Data supplement 1 - Online supplement
Handling editor Tore K Kvien
JL and MAG-G shared senior authorship in this study.
Contributors AC performed the US study, contributed to the elaboration of the protocol of study, helped in the interpretation of data and in the elaboration of the manuscript. CG-J contributed to the elaboration of the protocol of study, helped in the interpretation of data and the elaboration of the manuscript. MEP and RB recruited patients for the study and contributed to the elaboration of the manuscript. JL contributed to the elaboration of the protocol of study, helped in the interpretation of data and the elaboration of the manuscript and performed the statistical analysis. MAG-G recruited patients for the study, contributed to the elaboration of the protocol of study, helped in the interpretation of data and was responsible of the final drafting and elaboration of the manuscript.
Funding This study was supported by grants from ‘Fondo de Investigaciones Sanitarias’ PI06/0024, PS09/00748 and PI12/00060 (Spain). This work was also partially supported by RETICS Program, RD08/0075 and RD12/0009/0013 (RIER) from ‘Instituto de Salud Carlos III’ (ISCIII) (Spain).
Competing interests None.
Patient consent Obtained.
Ethics approval Cantabria (Spain) Ethical Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This study has not previously been submitted for publication to any other journal. Data are original.