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(Circulation. 2003;108:2957.)
© 2003 American Heart Association, Inc.

Review: Current Perspective

Explaining How "High-Grade" Systemic Inflammation Accelerates Vascular Risk in Rheumatoid Arthritis

Naveed Sattar, MD; David W. McCarey, MD; Hilary Capell, MD; Iain B. McInnes, MD

From the Department of Pathological Biochemistry and Centre for Rheumatic Diseases, North Glasgow Hospitals University NHS Trust, Glasgow Royal Infirmary, Glasgow, Scotland.

Correspondence to Dr Naveed Sattar, Department of Pathological Biochemistry, Glasgow Royal Infirmary, Glasgow G31 2ER, Scotland, UK. E-mail nsattar{at}clinmed.gla.ac.uk

	Abstract

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
There is intense interest in mechanisms whereby low-grade inflammation could interact with conventional and novel vascular risk factors to promote the atheromatous lesion. Patients with rheumatoid arthritis (RA), who by definition manifest persistent high levels of inflammation, are at greater risk of developing cardiovascular disease. Mechanisms mediating this enhanced risk are ill defined. On the basis of available evidence, we argue here that the systemic inflammatory response in RA is critical to accelerated atherogenesis operating via accentuation of established and novel risk factor pathways. By implication, long-term suppression of the systemic inflammatory response in RA should be effective in reducing risk of coronary heart disease. Early epidemiological observational and clinical studies are commensurate with this hypothesis. By contrast, risk factor modulation with conventional agents, such as statins, may provide unpredictable clinical benefit in the context of uncontrolled systemic inflammatory parameters. Unraveling such complex relationships in which exaggerated inflammation–risk factor interactions are prevalent may elicit novel insights to effector mechanisms in vascular disease generally.

Key Words: immune system • risk factors • atherosclerosis

	Introduction

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Considerable evidence indicates that patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease (CHD).¹ Seventeen of 21 relevant observational studies show an increased standardized morality ratio in RA and that life expectancy is shortened by 3 to 18 years. Pooled analysis of these studies suggests a 70% increase in risk of death in RA patients. Life expectancy is especially shortened in RA patients treated in specialist referral centers, where the prognosis is comparable to that of triple-vessel CHD or stage 4 Hodgkin’s disease.¹ Cardiovascular disease accounts for 35% to 50% of excess mortality in RA patients, with cerebrovascular disease being the second leading cause of death. Intriguingly, most evidence suggests that classic risk factors do not explain excess vascular disease in RA. In an 8-year follow-up of 236 RA patients, a 3.96-fold (95% CI 1.86 to 8.43) higher incidence of cardiovascular events relative to a community-dwelling cohort was noted.² However, this risk ratio was only minimally attenuated (to 3.17 [95% CI 1.33 to 6.36]) by adjustment for conventional risk factors. These clinical epidemiological observations strongly suggest that mechanisms other than classic risk factors promote accelerated atherogenesis in RA, and responsible candidate pathways are explored in this review.

	Inflammation as a Candidate Pathway for CHD

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
It is firmly established that systemic markers of inflammation, albeit at considerably lower levels than those apparent in RA, independently predict CHD events in men and women with or without existing heart disease.^3,4 The levels of cytokines and other inflammatory mediators detected in CHD are such that high-sensitivity assays rather than conventional assays are required. This concept of inflammatory-driven atherogenesis is consistent with the plaque composition of unstable coronary lesions, with an abundance of inflammatory molecules and immune cells at the shoulder region that act to erode the collagen cap that separates the atheromatous material of the plaque from blood.⁴ This appearance is similar to that of inflammatory synovitis in RA.⁵ However, whereas in RA, C-reactive protein (CRP) is a powerful measure of synovial inflammation, and alteration in CRP is a useful predictor of clinical response to therapy,⁶ the same does not necessarily hold true for vascular risk. Indeed, in population studies, elevated systemic cytokine levels or acute-phase reactants are not as simply explained by the magnitude of diseased blood vessels per individual, detected at least by conventional techniques. Thus, measures of plaque thickness in carotid arteries do not account for observed elevations in inflammatory parameters.³ Rather, factors such as age, smoking, and in particular adiposity appear to correlate more closely to CRP and systemic cytokine concentrations.^3,4 Adiposity explains as much as 30% of the systemic inflammatory burden in population studies.^3,4 Thus, altered circulating cytokines (leading to altered acute-phase response as a surrogate for inflammatory mediators that operate on the liver) likely arise not only from vessel-wall inflammation (ie, the target organ) but also from other tissues. Crucially, they may also mediate pathophysiologically important effector function at such sites. Such pathways are often markedly exaggerated in RA, in which chronic cytokine release can also arise from the inflamed joint.

	Cytokines Have Extensive Metabolic Effects: Functional Pleiotropy

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
The foregoing prompts 2 critical questions, namely, how do cytokines operate to promote vascular disease at the molecular level, and in which tissues? The answer likely lies in the pleiotropic functions of cytokines, because in addition to their role in regulating immune responses, cytokines mediate numerous metabolic effects.⁷ One consequence of this functional pleiotropy is that the intensity of the metabolic adaptations parallels other cytokine effects. Cytokine-induced metabolic effects, which include transient alterations in lipids and peripheral insulin resistance, are favorable in the short term and function as part of the host response to infection and acute inflammation to target specific metabolic fuels to and from essential organs.⁷ However, chronic elevation in cytokine levels, irrespective of magnitude or cause, is deleterious and promotes accelerated atherogenesis via aggravation of several risk factor pathways, including lipoprotein metabolism and insulin resistance. Indeed, even a heightened level of the low-grade chronic inflammatory response in population studies correlates with many classic and novel risk factor pathways for CHD.^3,4 From a developmental standpoint, cytokines or cytokine-like molecules such as leptin⁸ or interleukin (IL)-6⁹ may have evolved to impart their systemic metabolic effects at very low levels, such that even minor degrees of chronic elevation, as seen in obese, insulin-resistant individuals, are damaging.

	From Synovitis to Accelerated Atherogenesis

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
In RA, the primary site of inflammation is the synovial tissue, from which cytokines can be released into the systemic circulation. Thus, measurable plasma levels of, for example, tumor necrosis factor (TNF)-, IL-1ß, and IL-6 are commonly present at several-fold higher levels than noted during the low-grade inflammation discussed above.⁶ These circulating cytokines are in a position to alter the function of distant tissues, including adipose, skeletal muscle, liver, and vascular endothelium, to generate a spectrum of proatherogenic changes that includes insulin resistance, a characteristic dyslipidemia, prothrombotic effects, pro-oxidative stress, and endothelial dysfunction. These individual pathway perturbances, linked at many sites, in turn converge to promote accelerated atherogenesis as depicted by Figure 1. Consistent with this pathogenic pathway, the magnitude of the systemic inflammatory response in RA correlates with the degree of alteration in all of the above risk factors (Table). Moreover, premature mortality in RA, largely due to cardiovascular disease, is related to the number of inflamed joints.¹⁰ It is likely that the magnitude and chronicity of systemic inflammation in RA is particularly deleterious. Thus, even during "quiescent" phases of the disease, systemic levels of cytokines or their regulatory components often remain dysregulated relative to non-RA subjects and as such will continue to promote vascular disease (Figure 2).

View larger version (41K): [in this window] [in a new window]   Figure 1. In RA, primary site of inflammation is synovial tissue, from which cytokines can be released into systemic circulation. These circulating cytokines alter function of distant tissues, including adipose, skeletal muscle, liver, and vascular endothelium, to generate a spectrum of proatherogenic changes that include insulin resistance, characteristic dyslipidemia, pro-oxidative effects, and endothelial dysfunction and damage. +ve indicates positive; P>C, peripheral greater than central; TG, triglyceride; vWF, von Willebrand factor; and tPA, tissue plasminogen activator.

View this table: [in this window] [in a new window]   Risk Factor Perturbances in RA, Their Association With the Inflammatory Response in Cross-Sectional Studies, and Documented Improvements Upon Inflammatory Suppression

View larger version (24K): [in this window] [in a new window]   Figure 2. Magnitude and chronicity of systemic inflammation in RA is particularly deleterious, such that even during quiescent phases of disease, systemic levels of cytokines remain high relative to non-RA subjects and thus may continue to promote vascular risk.

The evidence of perturbances in CHD risk factor pathways in RA patients, the extent of correlation of each individual pathway with the inflammatory response, and preliminary evidence indicating the favorable effect of dampening the inflammatory response are summarized in the Table and discussed in detail below.

	Insulin Resistance

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
More than a decade ago, Paolisso and colleagues¹¹ noted basal hyperinsulinemia and insulin resistance by the euglycemic clamp technique in RA patients, with both abnormalities correlating to the degree of inflammation. More significantly, a paradoxical and rapid improvement in insulin sensitivity with steroid (or sulfasalazine) therapy has been noted.¹² Because steroids worsen insulin sensitivity and promote glucose intolerance in healthy subjects, steroid-induced improvement in insulin sensitivity in RA patients implicates the inflammatory response as the predominant causal pathway; biologically plausible mechanisms exist to explain this link. Cytokines, particularly TNF-, can directly impede insulin-mediated glucose uptake in skeletal muscle.¹³ Moreover, IL-6 and TNF- can stimulate adipocyte lipolysis, leading to increased release of free fatty acids (FFAs) from peripheral tissues and an enhanced cycle of fatty acids between liver and adipose tissue beds.¹⁴ Elevations in fatty acid fluxes have long been considered important in the pathophysiology of insulin resistance. These observations predict a beneficial effect of TNF- blockade on insulin sensitivity in RA subjects, but relevant studies are currently lacking.

	Dyslipidemia in RA

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Numerous modest-sized studies have investigated lipid concentrations in RA patients. Some of these are prospective, determining the effects of antiinflammatory or disease-modifying therapies on lipids. Together, these studies demonstrate that the lipid pattern in RA is highly consistent with the pattern of lipid perturbance (low total and HDL cholesterol and high triglyceride) seen in several other inflammatory and infectious conditions.¹⁵ For example, RA patients demonstrate low total cholesterol driven mainly by low HDL cholesterol concentrations. Numerous studies report an inverse association between inflammatory markers (CRP or erythrocyte sedimentation rate [ESR]) and HDL cholesterol or its main protein, apolipoprotein AI.^16,17 Reduction in ESR after 14 days of treatment with an antiinflammatory agent has been correlated to elevations in total and HDL cholesterol.¹⁷ When examined, LDL cholesterol is often low in RA, whereas a majority of data indicate higher triglyceride concentrations,¹⁸ correlated positively with ESR level in 1 study.¹⁷ Fewer studies have shown no difference in lipid parameters between RA patients and control subjects. At the subfraction level, lower HDL₂ concentration and a higher mass of small, dense atherogenic LDL species have been noted¹⁹; of note, HDL₂ correlated negatively and small, dense LDL correlated positively with the degree of inflammatory activity, as indicated by plasma phospholipase A₂ (PLA₂) concentrations.

Despite lower total cholesterol concentration, an observation that helps explain a failure of cholesterol adjustment to account for any excess CHD risk in RA,² when taken as a whole, the dyslipidemic pattern observed is highly atherogenic. Low HDL cholesterol is a strong predictor of cardiovascular events, whereas small, dense LDL, triglyceride-rich particles, and elevations in FFAs are proatherogenic (reviewed in Sattar et al²⁰).

Mechanisms underlying the lipid pattern in RA include effects of cytokines at adipose tissue to increase FFA release, at the liver to increase FFA and triglyceride synthesis, and at the vascular endothelium to reduce lipoprotein lipase activity,¹⁵ the principal catabolic enzyme for triglyceride-rich lipids. High triglyceride levels reduce HDL cholesterol by virtue of neutral lipid exchange, and this same process promotes synthesis of small, dense LDL.¹⁵ Finally, high lipoprotein(a) is a consistent finding in RA¹⁶; again, such elevation may be secondary to inflammatory activity in RA.¹⁶ A meta-analysis of prospective studies supports a role of lipoprotein(a) in atherogenesis.²¹

	Oxidative Stress

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
The dyslipidemic pattern in RA is clearly pro-oxidative. This pattern, combined with evidence that cytokines can directly promote oxidative modification of LDL,²² perhaps by stimulating superoxide secretion from monocytes and endothelial cells, suggests potential for high levels of oxidized lipids in RA. In fact, global oxidative activity is enhanced in RA, in correlation with positive acute-phase reactants such as ceruloplasmin.²³ By contrast, vitamin A and E concentrations are low in RA in conjunction with negative acute-phase markers.²⁴ These observations emphasize the potential for feedback loops in RA whereby cytokines lead to a dyslipidemia that promotes oxidation, which in turn leads to further cytokine release at endothelial cells.

	Endothelial Dysfunction

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Endothelial dysfunction is a critical early step in the process of atherogenesis; recent studies support the predictive ability of endothelial function measures for subsequent CHD events.²⁵ Considerable indirect evidence supports systemic endothelial activation in RA.²⁶ For example, circulating concentrations of several cell adhesion molecules, such as intracellular adhesion molecule (ICAM), and E-selectin are elevated in RA patients, as are concentrations of von Willebrand factor and tissue plasminogen activator antigen.^27,28 sE-selectin, sL-selectin, and sICAM-1 concentrations have been correlated to markers of inflammation in RA patients,^27,28 and a fall in sICAM-1 has been correlated to a decrease in CRP after sulfasalazine introduction.²⁸ Microalbuminuria, considered in part to reflect endothelial injury, is also common in RA in correlation with elevated CRP levels; indeed, 1 in 4 patients with RA demonstrates an elevated urine albumin to creatinine ratio.²⁹ Finally, recent studies using "direct" measures of vascular function, such as pulse-wave analysis³⁰ and flow-mediated vasodilation,³¹ confirm significant endothelial dysfunction in RA patients, again correlating with markers of systemic inflammation. More importantly, the latter study demonstrated improved endothelial function after anti-TNF- therapy.³¹ These data directly implicate TNF- as a mediator of endothelial dysfunction in RA.

With respect to mechanisms, cytokines are potent upregulators of cellular adhesion molecule expression on endothelial cells, and thus their role in endothelial activation is unambiguous. TNF- could mediate endothelial dysfunction via diminished expression of endothelial nitric oxide synthase and cyclo-oxygenase-1.³² TNF- also impedes degradation of asymmetric dimethylarginine, the endogenous inhibitor of NOS.³³

Finally, many of the previously discussed perturbances linked to the systemic inflammation in RA—insulin resistance, dyslipidemia, and oxidation—can promote endothelial dysfunction (Figure 1). Therefore, numerous direct and indirect mechanisms link systemic inflammation to endothelial dysfunction in RA patients.

	Hemostatic Changes

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
There is ample evidence to suggest increased clotting potential in RA patients. Elevated fibrinogen, von Willebrand factor, fibrin D-dimer, and tissue plasminogen activator antigen concentrations are seen in RA patients, even in those with well-controlled RA (median ESR 22 mm/hr [interquartile range 12 to 40]; CRP 8 mg/L (interquartile range 6 to 22]).³⁴ Further contributing to a hypercoagulable state in RA is the thrombocytosis.¹ Many of these parameters are clearly associated with the extent of the inflammatory response, and explanatory mechanisms are evident. For example, TNF- causes the expression of tissue factor on monocytes and possibly endothelium, thereby initiating the coagulation cascade, whereas IL-6 can increase levels of fibrinogen, an acute-phase reactant.³⁵

Perturbation of T-cell subsets in RA, both phenotypic and functional, in part reflects systemic cytokine elevation.⁵ Of particular interest, expanded populations of CD4+/CD28- T cells, which have putative autoreactive properties, are evident in the peripheral circulation in RA. Such T cells are also seen in the circulation and plaques of patients with unstable angina.³⁶

	Blood Pressure

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Garnero et al³⁷ reported an increased prevalence of hypertension in 88 RA patients compared with 72 age- and sex-matched controls, whereas del Rincon et al² noted higher systolic blood pressure in RA patients than in population-based controls. Whether elevated blood pressure and inflammatory activity are linked in RA has not been examined, but a significant graded relationship between blood pressure and IL-6 levels has been noted in a study of 508 apparently healthy men.³⁸

	Homocysteine

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Interesting recent data also indicate a potential link between inflammatory activity in RA and the homocysteine pathway. Chiang et al³⁹ noted that plasma pyridoxal 5'-phosphate levels, a marker of vitamin B₆ status, correlated inversely with markers of inflammation (CRP, ESR) in 37 patients with RA, whereas the extent of increase in homocysteine levels after a methionine load correlated positively with such markers. More recently, Lazzerini and colleagues⁴⁰ noted a reduction in plasma homocysteine level in patients with RA given pulsed glucocorticoid treatment. Although non–cytokine-mediated effects may be relevant to the steroid-induced homocysteine lowering, the authors acknowledged that lower levels of inflammation-related humoral factors might be equally relevant.

	Evidence of Similar Metabolic Perturbances in Other Chronic Inflammatory Conditions

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
Other conditions associated with chronic systemic inflammation, such as lung cancer, exhibit a near-identical spectrum of metabolic defects as that described in RA, including insulin resistance, low HDL cholesterol, elevated soluble cell adhesion molecules, microalbuminuria, endothelial dysfunction, and oxidation.^41–45 Crucially, when examined, many such defects correlate with the degree of inflammatory activity in these disease processes. These observations support the notion that common mechanisms link immune dysregulation and metabolic dysfunction across a range of diseases that share common cellular and molecular effector pathways.

	Effects on CHD Risk of Dampening Inflammation

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
The information collated herein predicts that absolute and long-term suppression of the systemic inflammatory response in RA should lessen CHD risk by improving risk factors. Tantalizing epidemiological evidence suggests that this indeed may be the case. In an 18-year follow-up of 1240 patients with RA, Choi and colleagues⁴⁶ recently reported that methotrexate treatment, generally considered to be the most effective disease-modifying antirheumatoid drug (DMARD), reduced overall mortality by 60% (95% CI 20% to 80%), primarily by reducing CHD mortality by 70% (95% CI 30% to 80%). Non-CHD mortality was not significantly altered. Others have shown that using 1 DMARD reduced risk of death in RA. That methotrexate or other DMARD therapy, in spite of some potentially toxic effects, appears to lessen CHD risk in RA clearly suggests a dominant role of systemic inflammation in accelerating CHD in such patients.

	Future Research Questions and Trials

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
The foregoing review and hypotheses that arise make several predictions amenable to clinical study. Despite accumulating evidence of elevated CHD risk factors in RA from retrospective epidemiological studies, confirmatory data from prospective follow-up of a large number of RA patients are needed. Such studies should include better characterization of insulin sensitivity, endothelial function, aspects of large-vessel stiffness, and novel aspects of the dyslipidemia, such as activity of HDL- and LDL-related enzymes. Calculation of area under the curve of cumulative CRP may be useful. The evidence for the beneficial influence of antiinflammatory therapies on several risk factor pathways in RA collated herein comes mostly from small or inadequately controlled studies. Thus, more robust and comprehensive investigations of the metabolic effects of antiinflammatory therapy are required using, where possible, improved methodologies (for example, the effect of TNF- blockade on endothelial function in RA patients³¹). Such findings would help to underscore the importance of inflammatory activity in determining elevated CHD risk in RA (Figure 3) and may shed light on mechanisms of vascular disease more generally. Well-developed longitudinal studies with comprehensive baseline measures should help establish which markers independently predict occurrence of CHD events in RA and therefore allow better risk stratification. Clearly, measuring cholesterol alone and other simple measures such as systolic blood pressure measurement are likely to be relatively uninformative, as noted previously.²

View larger version (22K): [in this window] [in a new window]   Figure 3. Before onset of RA, classic risk factors predict risk of event. However, after onset of disease, severity of systemic inflammation secondary to RA joint disease is critical in acceleration of atherogenesis, and thus risk factors influenced by systemic inflammation will predict risk of future events.

Finally, there is major interest in determining whether established therapies for CHD risk reduction, such as statins or ACE inhibitors, offer similar or conceivably greater protection for RA patients. These drugs may proffer multiple beneficial "pleiotropic" effects and could therefore favorably affect several sites (Figure 1). The antiinflammatory properties of statins may offer particular advantages to RA patients. For example, statins inhibit interferon-–inducible macrophage major histocompatibility complex class II expression via class II transactivator suppression, activate peroxisome proliferator-activated receptor- (PPAR-) via inhibition of Rho-dependent pathways, and dampen nuclear factor-B activity, and may modulate T-cell costimulation through direct effects on leukocyte function-associated antigen-1/ICAM-1 interactions.⁴⁷ These properties indicate that statins might modulate functional maturation of T lymphocytes. Consistent with such effects, we noted a significant disease-modifying effect of statin treatment in an animal model of arthritis; critically, a parallel reduction in systemic cytokine levels was also noted.⁴⁸

The new class of insulin-sensitizing agents, thiazolidinediones, which function as PPAR- agonists, would also be a potential option in RA, because not only do they exhibit antiinflammatory properties,⁴⁹ but insulin resistance is a feature of RA. Moreover, some insulin-resistant populations appear to have a greater incidence of RA (eg, PIMA Indians).⁵⁰

	Concluding Remarks

Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
This review has collated evidence to suggest that the systemic inflammatory response in RA is central to the accelerated atherogenesis in this condition by its accentuation of established and novel risk factor pathways. From this model, we predict that long-term suppression of the systemic inflammatory response in RA should lessen CHD risk, and available evidence favors this likelihood. Likewise, a paradoxical improvement in insulin sensitivity with steroid treatment in RA strongly supports our suggestion. We also suggest that classic and novel risk factors that can be significantly influenced by the systemic inflammation in RA (for example, HDL cholesterol, von Willebrand factor, and markers of insulin resistance), rather than cholesterol or blood pressure alone, will better predict CHD risk in RA. Future prospective studies are required to confirm this proposal. Finally, because some existing cardioprotective therapies exhibit antiinflammatory properties, which appear beneficial, at least in the context of the low-grade chronic inflammatory response of CHD, we predict that the relative magnitude of benefit accrued from such therapies may be greater in RA than in noninflamed controls. Clinical trials are urgently required to test this proposal.

	Acknowledgments

 
The authors acknowledge support from the Arthritis Research Campaign and the Scottish Council for Postgraduate Medical and Dental Education.

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Top Abstract Introduction Inflammation as a Candidate... Cytokines Have Extensive... From Synovitis to Accelerated... Insulin Resistance Dyslipidemia in RA Oxidative Stress Endothelial Dysfunction Hemostatic Changes Blood Pressure Homocysteine Evidence of Similar Metabolic... Effects on CHD Risk... Future Research Questions and... Concluding Remarks References

 
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