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Abstract
Objective Rheumatoid arthritis (RA) is associated with increased coronary artery disease (CAD) and subclinical carotid atheromatosis, reportedly to equal diabetes mellitus (DM). The presence of atheromatic plaques in femoral arteries of RA patients without DM was compared with with DM patients.
Methods Femoral plaques were recorded in 30 (17 men, age 43.0±12 years, disease duration 9.9±7.1 years) and 60 older RA patients (27 men, age 63.0±7.1 years, disease duration 11.4±7.9 years) matched 1:1 for age, gender and disease duration with DM types 1 and 2 patients, respectively. All were asymptomatic and free of CAD.
Results The number of femoral plaques per patient in either RA subgroup was comparable with DM (0.64±0.82 vs 0.77±0.89 in total respective populations, p=0.340); percentages of patients with femoral plaques were also comparable (RA vs DM type 1 20% and 13%, respectively; RA vs DM type 2 58% and 66%, respectively). Hypertension and dyslipidaemia were significantly more frequent in both DM groups than RA groups.
Conclusions Subclinical femoral atheromatosis in RA is analogous to DM, further confirming the territorial unrestricted acceleration of the atheromatic process in these patients. Cardiovascular risk stratification based on both carotid and femoral plaque detection in RA should be addressed prospectively.
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Rheumatoid arthritis (RA) has been recognised as a novel cardiovascular disease (CVD) risk factor.1 Patients with RA have an approximately twofold higher risk of CVD compared with the general population,1 and RA is considered an ‘epidemiological equivalent’ of diabetes mellitus (DM) in terms of myocardial infarction risk.2,–,4 Accelerated atherosclerosis is proposed as the underlying pathophysiological mechanism leading to increased CVD in RA.1 RA-specific factors (systemic inflammation and type of drug treatment), as well as the aggregation of classic CVD risk factors in these patients, are considered to be responsible for that. The actual contribution of each factor has not been elucidated because a puzzling image is created by the interaction between vascular ageing, RA disease status (age of onset, activity, duration and treatment) and classic CVD risk factors.5
The detection of subclinical arterial disease is recommended for individuals free of established CVD but being at intermediate risk of developing it6 in order to improve risk stratification, to motivate lifestyle modifications, as well as to initiate earlier CVD drug treatment. Assessment of subclinical atheromatosis by high-resolution ultrasound in the carotid artery can provide such valuable information in RA because its prevalence is higher than that observed in matched non-RA individuals,7 being equivalent to that observed in matched patients with type 2 DM;7 importantly, it detects those RA patients at higher risk by 2.5 to 4.3 times for CVD.8
Atheromatosis is a systemic arterial disease with unpredictable focal preference. The identification of subclinical atheromatosis in arterial territories, beyond the carotid artery, is of potential importance because it might provide additional information regarding CVD risk stratification, as previously suggested in the case of the common femoral artery.9,–,11 Data on femoral subclinical atheromatosis are limited in both RA and non-RA populations. In our previous study we reported a higher prevalence of femoral plaques in these patients compared with non-RA matched controls. Moreover, we found significant differences regarding the predictors of carotid versus femoral atheromatic plaques, implying that different patients develop carotid and/or femoral plaques.12
In this study, we compared the prevalence of subclinical femoral atheromatosis between RA patients and carefully matched for age, gender and disease duration DM patients who are considered as per se having an increased risk of CVD.13
Methods
Since November 2009 any asymptomatic and free of coronary artery disease (CAD), consenting patient with RA or DM followed at the respective outpatient clinics of our department was referred to our cardiovascular research laboratory regardless of his/her CVD risk profile. In the present study candidate participants were all patients without DM but with RA14 and all DM patients assessed up to February 2012. Those patients who were successfully matched 1:1 for age (±3 years), gender and disease duration (±3 years) were analysed. In addition, all free of CAD patients with RA and concomitant DM type 2 are presented. The study was approved by the Ethical/Scientific Committee of Laikon Hospital (reference no 664) and all subjects provided informed consent according to the Declaration of Helsinki.
Femoral plaques were recorded by using a 14.0 MHz multi-frequency linear array probe attached to a high-resolution ultrasound machine (Vivid 7 Pro; GE Healthcare, Solingen, Germany), as previously described.10 All vascular tests were performed by the same skilled technician as previously described in detail.7 ,12
Continuous variables are expressed as means±SD and proportions were used for categorical variables. Paired t test, independent t test and χ2 two-sided tests were applied, as appropriate. Significance was defined as p<0.05.
Results
Sixty RA patients were matched with type 2 DM patients, whereas 30 other younger RA patients were matched with type 1 DM patients; disease duration did not differ significantly between the two RA subgroups (table 1). The traditional CVD risk factor profile was significantly worse in both type 1 and type 2 DM patients than RA patients (table 1).
Comparison of the characteristics between patients without DM with RA free of CVD matched 1:1 (for age, gender and disease duration) with subjects with DM type 1 (n=30) or type 2 (n=60)
We found that the prevalence of femoral plaques per subject was comparable between the RA patients without DM and their matched pairs with DM (table 1), being in total 0.64±0.82 versus 0.77±0.89, respectively, p=0.340. Moreover, the percentage of patients either with RA or DM who had at least one femoral plaque at the right or left common femoral artery was comparable (43% vs 47%, respectively, p=0.653). Notably, the prevalence of patients with at least one femoral plaque was 78% among those patients with concomitant RA and DM type 2 (four men and five women, age 64±10 years, RA disease duration 7.0±3.5 years, DM disease duration 4.4±3.8 years, 33% smokers, 33% with dyslipidaemia, 56% with hypertension).
As shown in figure 1 the number of patients with at least one femoral plaque (unilateral or bilateral) was comparable between the RA and DM type 1 subgroup (p=0.353), as well as between the RA and DM type 2 subgroup (p=0.550).
Comparison of the number of patients with femoral plaques (unilaterally or bilaterally) between patients without diabetes mellitus (DM) with rheumatoid arthritis (RA) free of cardiovascular disease matched 1:1 (for age, gender and disease duration) with subjects with DM type 1 (n=30, mean age 42 years) or type 2 (n=60, mean age 63 years).
Discussion
Our main finding is that the prevalence of femoral plaques in a free of CVD cohort of RA patients without DM (43%) was comparable with that of a matched cohort of DM patients (47%), despite the obvious higher burden of CVD risk in the latter group. This prevalence was 78% in RA patients with DM. The major limitation of the present study is that a relatively small sample size was available, probably resulting in insufficient statistical power to detect non-sizeable differences. However, we feel that this finding is rather convincing given the fact that the powerful independent predictors of CVD such as smoking, obesity, dyslipidaemia and hypertension were more prevalent in the two DM groups than the corresponding RA matched groups without DM.
As 1:1 matching for age, gender and disease duration was based solely on feasibility, younger RA patients were compared with type 1 DM subjects in order to fulfil the last matching criterion. Patients with types 1 and 2 DM belong to high CAD groups and the American Heart Association and the American Diabetes Association have suggested similar lipid and blood pressure goals for primary prevention in both groups.13 However, we acknowledge the fact that differences in macrovascular arterial disease (eg, coronary plaque morphology and burden) exist between the two DM types, as also verified recently.15 Head to head comparison regarding femoral plaques in these two groups is not available in the literature and will always be compromised on the basis of differences regarding age and DM disease duration.
Taken together with our previously published observations on the carotid subclinical atheromatosis process,12 the present results suggest that the acceleration of atheromatosis in RA in both the carotid and the femoral arterial beds is comparable to that observed in DM. The notion of this territorial unrestricted atheromatosis process in RA disease may be useful in order to develop ‘global’ risk scores from both arterial sites that will more efficiently detect RA patients at high risk for coronary heart disease. Indeed, previous studies in non-RA patients with CAD suggested that scores incorporating data from both arterial beds perform better than single site evidence regarding the detection of established CAD.9 ,10 Moreover, a recent study by Griffin et al 11 suggested that the presence of femoral plaques in the general population is more closely associated with the presence of CVD than the presence of carotid plaques.
Few issues related to the development of ‘global’ risk scores must be taken into consideration. First, evidence from non-RA populations suggests that plaque formation in the femoral and the carotid arteries may present substantial differences in terms of their morphology, pathology and biochemistry (ie, more frequently fibrous cap atheroma in carotid arteries and more fibrocalcific plaques and osteoid metaplasia in femoral arteries),16 as well as in terms of associations with CVD risk factors9 ,10 and response to treatment, as suggested by the effect of statins on intimal-medial thickening.17 Differences in the arterial wall composition, elasticity, morphology and flow patterns between femoral and carotid arteries may partly account for the above. Along these lines, there are limited data suggesting differences in the natural history of plaque formation and physiology between the two arterial sites.18 As reported recently, carotid plaque progression is associated with negative remodelling, whereas femoral plaque burden was compensated by positive remodelling.19 Such diversities between the femoral and carotid plaques seem to substantiate the hypothesis regarding the additional prognostic value of femoral plaque formation, which must be addressed in future studies.
To conclude, given the inherent limitations for such types of study, these findings suggest that the acceleration of femoral atheromatosis is analogous to DM. Future studies must address whether CVD stratification in RA can be improved on the basis of both subclinical carotid and femoral plaque detection.
References
Footnotes
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Competing interests None.
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Ethics approval The study was approved by the Ethical/Scientific Committee of Laikon Hospital (reference no 664).
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.