| COMMENTARIES |
Carotid Intima-Media Thickness as a Predictor for Cardiovascular Events in Patients with Rheumatoid Arthritis
Jet J.C.S. Veldhuijzen van Zanten, Aamer Sandoo, and George D. Kitas, School of Sport and Exercise Sciences, University of Birmingham, Birmingham, B15 2TT, U.K.; Rheumatology Department, Dudley Group of Hospitals NHS Trust, Pensnett Road, Dudley, West Midlands, DY1 2HQ, U.K.
Please address correspondence to:
Dr. Jet Veldhuijzen van Zanten
School of Sport and Exercise Sciences
University of Birmingham
Birmingham
B15 2TT
United Kingdom
Email: veldhujj@bham.ac.uk
Rheumatoid arthritis (RA) is a chronic inflammatory musculoskeletal disease, with principal symptoms of pain, stiffness, and swelling of joints. Patients with RA are at increased risk for cardiovascular disease, with almost half of all deaths in RA due to cardiovascular disease [1]. Even though the underlying mechanisms for this increased risk remain to be determined, it is likely that the inflammation associated with RA not only affects the joints but also the blood vessels [2]. Indeed, patients with RA have been shown to have increased carotid intima-media thickness (cIMT), which is a measurement of the thickness of the carotid artery vessel wall. cIMT is a non-invasive vascular assessment and it is thought to reflect structural vessel changes at relatively advanced, yet sub-clinical, stages of atherosclerosis. It is a good predictor for cardiovascular events in the general population, especially in people with low-grade inflammation assessed with C-reactive protein [3].
The majority of the studies that examined cIMT in patients with RA have employed a cross-sectional design. The extent of cIMT has been related to disease duration, with patients with long disease duration (> 20 years) showing a higher cIMT compared to those with shorter disease duration (< 7 years) [4]. Moreover, increased cIMT was already evident in RA patients within 12 months of diagnosis and associated with levels of inflammation [5]. These findings have been suggested to provide evidence for accelerated atherosclerosis in RA. However, does an increased cIMT reflect structural damage to the vessel or is this reversible with a reduction in inflammation?
A recent longitudinal study showed that cIMT can be reduced following successful treatment of RA. Twelve months after starting anti-TNF treatment, Del Porto and colleagues [6] found a decrease in cIMT in those patients that responded adequately to anti-TNF treatment, whereas no changes in cIMT, disease activity, nor inflammation were reported for the control group (patients who did not consent to anti-TNF treatment). It is worth noting that the decrease in cIMT was associated with a disease activity score (DAS44), but not with the change in levels of inflammation [6]. To our knowledge, this is the first study to show a change in vessel wall structure following effective treatment on cIMT in RA patients. In patients with renal impairment, another disease population at increased risk for cardiovascular disease, the change in cIMT was already evident after 6 months of statin therapy and remained present for 18 months of continued treatment [7]. These studies provide evidence for fluctuations in vessel wall structure in response to control of the disease. However, these studies have examined only the long-term effect of treatment (> 6 months). Thus, it is unknown whether the cIMT response to effective treatment is rapid, or whether long-term treatment is needed before any reversible changes in cIMT are evident.
Several studies have examined the association between effective treatment and other surrogate markers of atherosclerosis in RA patients. These assessments involve vasodilatory responses to various stimuli (e.g. shear stress or chemicals) which are thought to reflect endothelial function alterations at the early stages of atherosclerosis [8]. Much like cIMT, this assessment is associated with increased risk for cardiovascular events in the general population [9]. Endothelial dysfunction is present in RA patients early after diagnosis [10] and has also been interpreted as indicative of accelerated atherosclerosis. A rapid improvement in endothelial function has been reported following inflammation-reducing treatment [11;12]; however, the improvement in endothelial function was also reported to be transient [13]. Further, in a group of healthy participants, an inflammatory response to a vaccination induced a prompt reversible impairment in endothelial function [14]. Thus, both in healthy participants as well as in RA patients, there is evidence for the rapid effect of changes in inflammation on endothelial function. However, it remains to be determined whether the changes in vessel wall structure do respond in the same timeframe.
The responsiveness of these markers to alterations in inflammation is of particular importance for their use as predictors for cardiovascular events in patients with RA. To our knowledge, only one study examined the association between cIMT and cardiovascular events in patients with RA [15]. In a cohort of 47 patients, the 8 patients who suffered a cardiovascular event during a 5-year follow-up period had significantly higher cIMT at the start of the 5-year period [15]. Interestingly, one of the patients that developed a cardiovascular event had a particularly high cIMT at the start of the study. Is this reflective of high inflammation at the time of assessment or of a stable structural high cIMT? Without measures of inflammation and cIMT at multiple time points throughout the follow-up period, this question cannot be answered.
In conclusion, patients with RA have been shown to display higher levels of cIMT and endothelial dysfunction, both markers for atherosclerosis. This has been interpreted as evidence for accelerated atherosclerosis in this patient population. However, the use of these markers as predictors for cardiovascular events has only been shown in one study, which did not take into account the levels of inflammation. This is particularly important given the reversibility of cIMT and endothelial dysfunction as a result of effective treatment of arthritis. Further investigation is needed to examine if a temporarily high value of cIMT is indeed a good predictor for future cardiovascular events in RA or merely a measurement of current active disease. In addition, the effect of intermittent, but reversible, insults to vascular structure as well as function on the risk for cardiovascular events needs to be established. This can only be explored with prospective, longitudinal studies which are specifically designed for this purpose.
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