Circulation. 2003;108:2957-2963
doi: 10.1161/01.CIR.0000099844.31524.05
(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
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Abstract
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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
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Introduction
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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.
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Inflammation as a Candidate Pathway for CHD
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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.
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Cytokines Have Extensive Metabolic Effects: Functional Pleiotropy
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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 leptin
8 or interleukin (IL)-6
9 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.
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From Synovitis to Accelerated Atherogenesis
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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).
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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.
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Risk Factor Perturbances in RA, Their Association With the Inflammatory Response in Cross-Sectional Studies, and Documented Improvements Upon Inflammatory Suppression
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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.
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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.
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Insulin Resistance
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More than a decade ago, Paolisso and colleagues
11 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.
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Dyslipidemia in RA
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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 HDL
2 concentration
and a higher mass of small, dense atherogenic LDL species have
been noted
19; of note, HDL
2 correlated negatively and small,
dense LDL correlated positively with the degree of inflammatory
activity, as indicated by plasma phospholipase A
2 (PLA
2) 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
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Oxidative Stress
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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.
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Endothelial Dysfunction
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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 analysis
30 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.
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Hemostatic Changes
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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
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Blood Pressure
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Garnero et al
37 reported an increased prevalence of hypertension
in 88 RA patients compared with 72 age- and sex-matched controls,
whereas del Rincon et al
2 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
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Homocysteine
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Interesting recent data also indicate a potential link between
inflammatory activity in RA and the homocysteine pathway. Chiang
et al
39 noted that plasma pyridoxal 5'-phosphate levels, a marker
of vitamin B
6 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 colleagues
40 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.
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Evidence of Similar Metabolic Perturbances in Other Chronic Inflammatory Conditions
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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.
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Effects on CHD Risk of Dampening Inflammation
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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 colleagues
46 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.
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Future Research Questions and Trials
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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 patients
31).
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
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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.
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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
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Concluding Remarks
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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.
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Acknowledgments
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The authors acknowledge support from the Arthritis Research
Campaign and the Scottish Council for Postgraduate Medical and
Dental Education.
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Abstract
Introduction