The increased cardiovascular risk in rheumatoid arthritis: when does it start?

Established rheumatoid arthritis (RA) is associated with a doubled cardiovascular risk. However, data about the cardiovascular risk in early RA are scarce. Preclinical atherosclerosis can be reliably assessed with the carotid intima media thickness (cIMT), and the cIMT is a well-validated predictor of cardiovascular events. The cIMT was therefore used in a recent controlled, prospective study in patients with early RA. Surprisingly, an increased cardiovascular risk at baseline could not be demonstrated whereas cIMT progression appeared to be comparable with the general population. Obviously, this study underscores the need for further large-scale investigations to solve the emerging discrepancy with the existing literature.

Nowadays it is well known that patients with established rheumatoid arthritis (RA) suff er from an increased cardio vascular risk in comparison with the general population, and both traditional cardiovascular risk factors as well as the underlying chronic infl ammatory process contribute to this excess cardiovascular risk. Little is known, however, about the cardiovascular risk in early RA patients -hence the recent article by Södergren and colleagues could be an important contribution to the fi eld [1].
Th e increased cardiovascular risk in RA is mainly due to atherosclerotic events. Until recently atherosclerosis was considered an accumulation of lipoproteins within the arterial wall. During the past decade, however, athero sclerosis has been recognized as a chronic infl ammatory process in the artery. Th e fi rst step in the process is endothelial dysfunction caused by traditional cardio vascular risk factors such as smoking. Th e endothelium becomes more permeable -to lipids, for example -and becomes procoagulant instead of anticoagulant. Th e infl ammatory response further results in an entry of infl ammatory cells and muscle cells. Foam cells are formed and result in fatty streaks. Th is lesion progresses and a fi brous cap is formed, consisting of smooth muscle cells and a collagen matrix that separates this atherosclerotic plaque from the arterial lumen. Ultimately, the plaque may rupture and the subsequent thrombosis causes a myocardial infarction.
In the study by Södergren and colleagues, the carotid intima media thickness (cIMT) (a marker of preclinical atherosclerosis) and fl ow-mediated dilatation of the brachial artery (a marker of endothelial dysfunction) were assessed in 79 early RA patients and in 44 agematched and sex-matched controls. In a subgroup of 27 RA patients (and controls), the assessments were repeated after 18 months. Carotid plaques, another feature of preclinical athero sclerosis that can be assessed during cIMT measurement, were not reported. Th e fl owmediated dilatation and the cIMT at baseline were not signifi cantly diff erent between the two groups. Th is observation is remarkable particu larly for the cIMT, as RA patients had signifi cantly more cardiovascular risk factors (hypertension, smoking and dyslipidemia)important determinants of the cIMT [2] -than the controls, and one would expect at least a tendency for an increased cIMT in RA patients, whereas an opposite trend was seen. Moreover, these results contradict fi ndings from other studies that indicate an increased rate of cardiovascular events as well as cardiovascular risk factors before the clinical onset of RA.
Th e cIMT thickness in both groups was, as expected, associated with the traditional cardiovascular risk factors, and no relationship with disease activity markers was found in the RA group. Th is latter fi nding is in line with the results of our recent meta-analysis of cIMT in established RA patients, where also no relationship with disease activity could be demonstrated [3]. Perhaps using a cumulative disease activity marker (for example, number of erosions) would have been more appropriate

Abstract
Established rheumatoid arthritis (RA) is associated with a doubled cardiovascular risk. However, data about the cardiovascular risk in early RA are scarce. Preclinical atherosclerosis can be reliably assessed with the carotid intima media thickness (cIMT), and the cIMT is a wellvalidated predictor of cardiovascular events. The cIMT was therefore used in a recent controlled, prospective study in patients with early RA. Surprisingly, an increased cardiovascular risk at baseline could not be demonstrated whereas cIMT progression appeared to be comparable with the general population. Obviously, this study underscores the need for further large-scale investigations to solve the emerging discrepancy with the existing literature.
in view of the observed relationships between disease duration/severity and cardiovascular risk. Moreover, this meta-analysis revealed a cIMT diff erence of 0.09 mm between RA patients and controls, indicating an approximately 15% increased cardiovascular risk [4]. Th is value is far less than expected in view of the 50 to 100% increased cardiovascular risk demonstrated in early RA and established RA patients [5,6]. Th e majority of the cardiovascular events are caused by plaque ruptures, which must imply that plaques rupture earlier in an infl ammatory situation than in a non-infl ammatory situation [7].
Th e observed increase in cIMT for RA patients in the study by Södergren and colleagues was 0.05 mm in 18 months, and was signifi cantly larger than that in the control group. Th is value fi ts within the increase observed in a much larger investi gation in the general population [8], however, so it is tempting to speculate that this normal cIMT progression in RA patients was due to eff ective antirheumatic treatment, nowadays aimed at remission, even though prospective data about disease activity were not provided.
Although there remain some methodological issues, the study by Södergren and colleagues clearly underscores two pivotal aspects about the cardiovascular risk in RA: an increased prevalence of cardiovascular risk factors in RA, and that eff ective antirheumatic treatment probably decreases the cardiovascular risk in RA. Th eir study therefore supports the recently published European League Against Rheumatism recommendations for cardiovascular risk management in infl ammatory arthritis patients, which advocate that cardiovascular risk management should be aimed at disease activity suppres sion as well as at cardiovascular risk factor screening and treatment [9].
As the present fi ndings are in contradiction with the existing literature, larger prospective, controlled investigations with a rigorous methodological design are necessary. Another challenging topic for future studies is how to identify the patients with a high risk for plaque rupture. Such studies may hopefully become redundant when it is demonstrated that eff ective antirheumatic therapy, aimed at disease remission, normalizes the change of plaque rupture.