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Carotid ultrasound in the cardiovascular risk stratification of patients with rheumatoid arthritis: when and for whom?
  1. Miguel A González-Gay1,
  2. Carlos González-Juanatey2,
  3. Javier Llorca3
  1. 1Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, IFIMAV, Santander, Spain
  2. 2Department of Rheumatology, Hospital Xeral-Calde, Lugo, Spain
  3. 3Department of Epidemiology and Computational Biology, School of Medicine, University of Cantabria, and CIBER Epidemiología y Salud Pública (CIBERESP), IFIMAV, Santander, Spain
  1. Correspondence to Miguel A González-Gay, Rheumatology Division, Hospital Universitario Marqués de Valdecilla, IFIMAV, Avenida de Valdecilla, S/N, 39008, Santander, Spain; miguelaggay{at}hotmail.com

Abstract

Adequate stratification of cardiovascular (CV) risk is one of the major points of interest in the management of patients with rheumatoid arthritis (RA). A task force of the European League Against Rheumatism has proposed to adapt CV risk management calculated in RA patients according to the systematic coronary risk evaluation (SCORE) function by 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 severe extra-articular manifestations. However, a major concern when using the modified SCORE is to know whether the effect of chronic inflammation on the CV risk of RA patients can be fully determined using this tool. As increased carotid intima–media thickness (IMT) and carotid plaques have been proved to predict the development of CV events in RA, the authors suggest performing carotid ultrasound when SCORE does not yield results indicating high CV risk in RA patients with extra-articular manifestations, RF or anti-CCP positivity as well as in patients with 10 years disease duration or longer. The presence of abnormal carotid IMT (>0.90 mm) or carotid plaques would lead to these patients being considered as having high CV risk regardless of the results derived from the modified SCORE.

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Rheumatoid arthritis (RA) is the prototype of chronic inflammatory disease associated with increased cardiovascular (CV) mortality.1 This is the result of accelerated atherosclerosis.2 Classic CV risk factors are important in the pathogenesis of atherosclerosis in patients with RA.3 However, they do not fully explain the increased risk of CV events observed in RA.4 Chronic inflammation has emerged as a pivotal factor in the atherogenesis process observed in this condition.5 Even during ‘quiescent’ phases of RA, systemic levels of cytokines or their regulatory components often remain dysregulated compared with in people without RA and as such will continue to promote vascular disease.6

Adequate stratification of CV risk is one of the major points of interest in the management of patients with RA. The systematic coronary risk evaluation (SCORE) project developed a risk scoring system for use in clinical management of CV risk in European clinical practice.7 The SCORE risk estimation system offers direct estimation of total 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 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 severe extra-articular manifestations.8 However, a major concern when using the modified SCORE in RA is to know whether we can fully determine the effect of chronic inflammation on CV risk using this tool. In this regard, we recently reported that, in long-standing patients with RA, there was no significant increase in SCORE when the multiplication factor was used for RA patients at high risk.9 In our hands, the final effect on the calculated CV risk was low, and clinically significant in only a few patients.9 Like Crowson and Gabriel,10 we have also seen RA patients who were not considered to have high CV risk according to the modified SCORE, but did have CV complications, mainly ischaemic heart disease. These patients had high levels of inflammation but few or sometimes no classic CV risk factors. Therefore, in our hands, the use of the modified SCORE does not increase our ability to discriminate patients at high risk of experiencing CV events. Therefore the reliability of the clinical CV risk assessment tools designed for the general population for accurately estimating CV risk in individual patients with RA needs to be re-evaluated.

All this evidence has prompted a search for additional tools that may identify high-risk RA patients who may benefit from active therapy to prevent clinical CV disease. It is particularly true for patients considered to have low CV risk according to the modified SCORE. For this purpose, we can use several non-invasive imaging techniques that offer a unique opportunity to study the relation of surrogate markers to the development of atherosclerosis. Among them, carotid ultrasound (US), based on assessment of intima–media thickness (IMT) (figure 1A) and presence of plaques (figure 1B), is considered a cheap and efficient way to measure subclinical atherosclerosis.11 Both carotid IMT and carotid plaques have proved to be good predictors of CV events in low- and intermediate-risk groups of non-rheumatic patients.12 A recent study showed that carotid IMT offers additional value to the Framingham risk score in the prediction of CV events.13 Interestingly, a recent meta-analysis confirmed the presence of increased carotid IMT in patients with RA compared with control subjects.14

Figure 1

(A) Carotid intima–media thickness and (B) carotid plaques.

In line with the above, it is known that a common carotid artery IMT ≥0.60 mm is a marker of atherosclerosis.15 16 Moreover, both carotid artery IMT >0.90 mm and the presence of carotid plaques are considered to be an expression of subclinical organ damage and factors influencing CV prognosis in the general population.17 Carotid IMT has been shown 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 IMT values >0.90 mm had an increased risk of CV events over a 5-year follow-up period.18 Evans et al confirmed the implication of carotid plaques as predictors of future CV events in RA.19 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

Although there is evidence that there is already an increased CV risk at disease onset,20 21 some studies did not show increased occurrence of ischaemic heart disease before the onset of RA.22 Several reports indicate that a clear excess risk in RA is only observed after about 10 years.1 A possible explanation for this apparent discrepancy is that, at disease onset, there is a limited increase in CV risk that is clearly amplified by RA itself, leading to an increased slope of atherogenic burden. Early or late detection of this increased CV burden in RA patients compared with the general population in different studies may have caused these apparent contradictory observations. Therefore, considering that RA is a chronic disease, we support the relevance of disease duration at the time of using additional tools different from the modified SCORE to establish the CV risk of RA. Del Rincon et al reported that, in patients with RA, the duration of this chronic inflammatory disease augmented the effect of age on atherosclerosis.23 They confirmed that, in patients with RA, the systemic inflammation amplifies the age-related risk of CV disease. They found that the rate at which carotid IMT increased per unit of age increased in proportion to RA duration: from 0.154 mm/10 years in patients with RA of duration ≤7 years to 0.295 mm/10 years in patients with RA of duration ≥20 years. In line with this, we found that RA patients with long disease duration (>14 years) often had abnormally high carotid IMT values.24 It was not the case for RA patients with disease duration ≤7 years.24 Also, we previously observed that RA patients with carotid plaques have significantly longer disease duration and more extra-articular manifestations than those without plaques.25 Besides age at the time of the study, disease duration was the best predictive factor for the development of severe morphological expression of atherosclerotic disease at the carotid level.25 This is in agreement with electron-beam CT studies, which also confirmed that coronary-artery calcification occurred more commonly in patients with established RA than in patients with early RA and controls.26

On the other hand, besides extra-articular manifestations, RF and anti-CCP positivity are well-established determinants of increased CV mortality in RA.27

Obviously, there could be a long debate about the best set of predictors for determining CV risk of patients with RA. Therefore a practical approach may be to follow the EULAR task force recommendation to use the modified SCORE to establish the CV risk of each patient with RA. However, we raise a concern in some cases where SCORE results do not yield data showing high CV risk. We therefore propose the use of US to determine carotid IMT and presence/absence of plaques in some situations. We suggest performing carotid US when the modified SCORE does not yield results showing high CV risk in patients with extra-articular manifestations, RF or anti-CCP positivity, as well as in patients with disease duration of 10 years or longer. The presence of abnormal carotid IMT (>0.90 mm) or carotid plaques would lead to consideration of high CV risk regardless of the results from the modified SCORE (figure 2).

Figure 2

Algorithm to stratify the cardiovascular risk (CV) by carotid ultrasound (US) in rheumatoid arthritis (RA). CCP, cyclic citrullinated peptide; IMT, intima–media thickness; RF, rheumatoid factor; SCORE, systematic coronary risk evaluation.

Limitations to the use of carotid US as a tool for accurately assessing the risk of CV disease in RA may exist. However, a recent study performed by rheumatologists with basic training in carotid US found that automated radiofrequency-based US measurement of carotid IMT has very low inter-observer variability. Therefore, although many doctors do not yet have access to ultrasonography, these observations indicate that carotid US may be a reliable method for assessing CV risk in RA patients.28 Finally, because of the need for accurate CV risk evaluation in RA, further tools, such as the arterial stiffness index, which has been shown to be associated with the development of CV disease in non-rheumatic patients, need to be assessed in patients with RA.

Acknowledgments

This study was supported by two grants from the Fondo de Investigaciones Sanitarias PI06-0024 and PS09/00748 (Spain). This work was partially supported by the RETICS Program, RD08/0075 (RIER) from the Instituto de Salud Carlos III (ISCIII).

References

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Footnotes

  • Funding ‘Fondo de Investigaciones Sanitarias’ (Spain).

  • Competing interests None.

  • Patient consent Obtained.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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