A CHD prevalence rate of 49% in RA patients as compared with 27% in OA patients [1
] and a fourfold increased incidence of cardiovascular events in RA patients as compared with the general population [2
] were recently reported. Raised total cholesterol and other traditional cardiovascular risk factors did not account for the respective findings [2
]. RA patients also experience a 1.3-fold to 2.4-fold increased mortality rate from CHD [4
In the present study, cardiovascular risk assessment revealed that RA patients exercised more frequently, but they had diabetes more often and their IS and HDL cholesterol concentrations were lower, as compared with OA patients. As expected, the CRP levels were also higher in RA patients as compared with OA patients. Inflammation, as reflected by the acute phase response, is implicated in CVD in its own right both in the general population [14
] and in RA patients [15
]. CRP may also directly contribute to atherosclerosis. CRP is localized in atheromatous lesions and stimulates macrophages to produce tissue factor, an important procoagulant found in atherosclerotic plaques [2
]. In the present study, the CRP was also significantly associated with decreased IS and HDL cholesterol concentrations. Although elevated CRP levels could explain the difference in IS between RA patients and OA patients, they could only partially account for the low HDL cholesterol concentrations.
These findings confirm our previous study [6
], suggest that RA may select for subjects with low HDL cholesterol, and suggest that RA and CVD may share a common predisposition as previously reported [6
]. Further genetic linkage studies may be worthwhile to confirm whether HDL cholesterol concentrations are intrinsically low in RA patients.
Both determination of the LDL cholesterol target in the individual patient as well as identification of metabolic syndrome features, particularly comprising the presence of abdominal obesity, low HDL cholesterol, elevated triglycerides and plasma glucose, and hypertension, are recommended in cardiovascular risk assessment [5
]. Insulin resistance constitutes an established pivotal pathogenetic mechanism in the metabolic syndrome [8
]. Although OA is associated with insulin resistance [19
] and dyslipidemia [19
], both IS and HDL cholesterol concentrations were still significantly lower in RA patients as compared with OA patients. Also, eight RA patients and one OA patient had type 2 diabetes. In a recent study, diabetes was identified in 38 out of 236 (16.1%) RA patients, as compared with 442 out of 4635 (9.5%) non-RA subjects (P
≤ 0.0001) [2
]. Also, type 2 diabetes is a late complication of the metabolic syndrome [8
] and its occurrence in our patients was not related to the use of glucocorticoids. The high frequency of diabetes in the present RA cohort may not be a chance finding.
In view of the high prevalence of insulin resistance in IA [6
], the pathogenetic role of insulin resistance in the metabolic syndrome and its relationship to the acute phase response in IA [6
], we analyzed the relationships among abdominal obesity, CRP, IS, HDL cholesterol and triglycerides in both OA patients and RA patients. In OA patients, the waist circumference contributed to the variance in IS but no other associations could be identified. By contrast, in RA patients, all of the respective risk factors were interdependent. Also, a high CRP was associated with the presence of hypertension.
In the present study, we found inflammation and abdominal obesity to be associated with decreased IS in RA patients. Insulin resistance and the other metabolic syndrome features also relate to psychosocial stress and other environmental factors' related abnormalities in cortisol, sex steroid and growth hormone secretion [21
]. The role of psychosocial stressors in decreased IS in RA patients requires further study.
The biochemical disturbances clustering in the metabolic syndrome may participate in the onset and persistence of IA [6
]. With regard to cardiovascular risk, our findings suggest that identification of the metabolic syndrome may be particularly important in this condition. RA patients in a recent study were found to have high levels of small, dense LDL particles, and this was related to the acute phase response [22
]. High circulating levels of small, dense LDL particles constitute another characteristic feature of the metabolic syndrome [5
]. Furthermore, the acute phase response may contribute to atherosclerosis through endothelial activation and interaction with procoagulant factors [3
]. The high prevalence of CVD in RA patients [1
] also implicates that this condition should be considered a CHD equivalent when determining the LDL cholesterol target (i.e. the latter may be as low as 2.6 mmol/l) [5
]. Indeed, mildly deranged LDL cholesterol concentrations, LDL/HDL ratios and triglyceride concentrations mediate the accelerated atherosclerosis in RA patients [3
]. In 58 (73%) of our RA patients, the LDL cholesterol was >2.6 mmol/l.
A limitation of the present study, as applies to other reports on CVD in RA patients [2
], is that most patients were on drug treatment. Only patients on lipid-lowering agents were excluded. However, excluding patients on drug treatment may have yielded results that do not represent the situation in the clinic. Also, patients on glucocorticoids and/or DMARDs experienced no differences in IS or lipid values as compared with those patients who were not on these agents. Of interest, in this regard, both glucocorticoids and DMARDs were shown to attenuate insulin resistance in IA, an effect that was attributed to acute phase response suppression [24