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

AbstractThere 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 inflammationrisk factor interactions are prevalent may elicit novel
insights to effector mechanisms in vascular disease generally. (Circulation. 2003;108:2957-2963.)
Key Words: immune system risk factors atherosclerosis

C onsiderable evidence indicates that patients with rheu-

matoid arthritis (RA) are at greater risk of developing
coronary heart disease (CHD).1 Seventeen of 21 relevant
observational studies show an increased standardized moral-
ity 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 Hodgkins disease.1 Cardiovas-
cular 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 respon-
sible candidate pathways are explored in this review.
Inflammation as a Candidate Pathway
for CHD
It is firmly established that systemic markers of inflamma-
tion, 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 inflamma-
tory 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, smok-
ing, 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 inflam-
matory burden in population studies.3,4 Thus, altered circu-
lating 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,

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@clinmed.gla.ac.uk
2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000099844.31524.05

2957
2958 Circulation December 16, 2003
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
The foregoing prompts 2 critical questions, namely, how do
cytokines operate to promote vascular disease at the molec-
ular 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 func-
tional pleiotropy is that the intensity of the metabolic adap-
tations 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 cyto-
kine levels, irrespective of magnitude or cause, is deleterious
and promotes accelerated atherogenesis via aggravation of
several risk factor pathways, including lipoprotein metabo-
lism 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-resis-
tant individuals, are damaging.
From Synovitis to Accelerated Atherogenesis
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-1, and IL-6 are com-
monly present at several-fold higher levels than noted during
the low-grade inflammation discussed above.6 These circu-
lating 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 proathero-
genic changes that includes insulin resistance, a characteristic
dyslipidemia, prothrombotic effects, pro-oxidative stress, and
endothelial dysfunction. These individual pathway pertur-
bances, 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 inflam-
mation in RA is particularly deleterious. Thus, even during
quiescent phases of the disease, systemic levels of cyto-
kines or their regulatory components often remain dysregu-
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 endotheli-
um, to generate a spectrum of proatherogenic changes that
include insulin resistance, characteristic dyslipidemia, pro-
oxidative effects, and endothelial dysfunction and damage. ve
indicates positive; PC, peripheral greater than central; TG, tri-
glyceride; vWF, von Willebrand factor; and tPA, tissue plasmino-
gen activator.
lated relative to non-RA subjects and as such will continue to
promote vascular disease (Figure 2).
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
More than a decade ago, Paolisso and colleagues11 noted
basal hyperinsulinemia and insulin resistance by the eugly-
cemic clamp technique in RA patients, with both abnormal-
ities correlating to the degree of inflammation. More signif-
icantly, 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
 Sattar et al Systemic Inflammation and Vascular Risk 2959

Risk Factor Perturbances in RA, Their Association With the Inflammatory Response in Cross-Sectional
Studies, and Documented Improvements Upon Inflammatory Suppression
Strength of Evidence for Strength of Evidence Linking Evidence for Improvement in Risk
Abnormality of Risk Factor Metabolic Perturbances to Factor in Inflammatory
CHD Risk Factors in RA Inflammatory Response in RA Suppression*
Obesity/insulin resistance
Body fat redistribution ND Steroids and SSZ paradoxically
Hyperinsulinemia enhance insulin sensitivity in
RA11,12
Insulin resistance
Dyslipidemia
FFAs Antiinflammatory treatment
Triglyceride /0 increases HDL cholesterol17 but
data on other lipid mediators
2HDL cholesterol generally lacking
2HDL2
Small, dense LDL
Lipoprotein(a)
Endothelial dysfunction
sICAM-1 sICAM declines with SSZ28
vWF FMD improves with anti-TNF-
therapy31
Microalbuminuria
Impaired vasoreactivity
Arterial stiffness
Oxidative stress
MDA Not examined, but ibuprofen
increased antioxidant levels in
2Vitamin antioxidants cancer subjects
Hemostatic alterations
Fibrinogen Limited data
PAI-1 0
Blood pressure ND ND
Homocysteine pathway
2Vitamin B6 Steroids reduced homocysteine
Homocysteine levels in RA40

0 indicates lack of or conflicting evidence; , moderate supporting evidence; , consistent evidence; ND, no data; SSZ,
sulfasalazine; vWF, von Willebrand factor; FMD, flow-mediated dilation; MDA, malondialdehyde; and PAI-1, plasminogen activator
inhibitor-1.
*The majority of data stem from small, uncontrolled studies.

sensitivity in RA subjects, but relevant studies are currently
lacking.
Dyslipidemia in RA
Numerous modest-sized studies have investigated lipid
concentrations in RA patients. Some of these are prospec-
tive, 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 exam-
ple, RA patients demonstrate low total cholesterol driven
mainly by low HDL cholesterol concentrations. Numerous
studies report an inverse association between inflamma-
tory markers (CRP or erythrocyte sedimentation rate
[ESR]) and HDL cholesterol or its main protein, apoli-
poprotein AI.16,17 Reduction in ESR after 14 days of
treatment with an antiinflammatory agent has been corre-
lated 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 concentra-
tions,18 correlated positively with ESR level in 1 study.17
Fewer studies have shown no difference in lipid parame-
ters 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 inflam-
matory activity, as indicated by plasma phospholipase A2 (PLA2)
concentrations.
Despite lower total cholesterol concentration, an observa-
tion 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 athero-
genic. Low HDL cholesterol is a strong predictor of cardio-
2960 Circulation December 16, 2003
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 rel-
ative to non-RA subjects and thus may continue to promote
vascular risk.
vascular events, whereas small, dense LDL, triglyceride-rich
particles, and elevations in FFAs are proatherogenic (re-
viewed 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 activi-
ty,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
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 stim-
ulating 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 ceru-
loplasmin.23 By contrast, vitamin A and E concentrations are
low in RA in conjunction with negative acute-phase mark-
ers.24 These observations emphasize the potential for feed-
back 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
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 Wille-
brand 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 pa-
tients,27,28 and a fall in sICAM-1 has been correlated to a
decrease in CRP after sulfasalazine introduction.28 Microal-
buminuria, 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 endothe-
lial 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 upregu-
lators of cellular adhesion molecule expression on endothelial
cells, and thus their role in endothelial activation is unambig-
uous. 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 RAinsulin resis-
tance, dyslipidemia, and oxidation can promote endothelial
dysfunction (Figure 1). Therefore, numerous direct and indi-
rect mechanisms link systemic inflammation to endothelial
dysfunction in RA patients.
Hemostatic Changes
There is ample evidence to suggest increased clotting poten-
tial 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 [interquar-
tile 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 cas-
cade, 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
Garnero et al37 reported an increased prevalence of hyperten-
sion in 88 RA patients compared with 72 age- and sex-
 Sattar et al
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 inflam-
matory 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
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 cyto-
kine-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
Other conditions associated with chronic systemic inflamma-
tion, 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 adhe-
sion 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
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 in-
deed 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.
Systemic Inflammation and Vascular Risk 2961
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 acceler-
ation of atherogenesis, and thus risk factors influenced by sys-
temic inflammation will predict risk of future events.
Future Research Questions and Trials
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 retrospec-
tive epidemiological studies, confirmatory data from prospec-
tive 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 stiff-
ness, 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 meta-
bolic 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 mecha-
nisms 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 mea-
surement are likely to be relatively uninformative, as noted
previously.2
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 proper-
ties of statins may offer particular advantages to RA patients.
For example, statins inhibit interferon-inducible macro-
phage 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
2962 Circulation December 16, 2003
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, thiazo-
lidinediones, 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
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 estab-
lished and novel risk factor pathways. From this model, we
predict that long-term suppression of the systemic inflamma-
tory 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 antiinflam-
matory 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.
References
1. Van Doornum S, McColl G, Wicks IP. Accelerated atherosclerosis: an
extraarticular feature of rheumatoid arthritis? Arthritis Rheum. 2002;46:
862 873.
2. del Rincon ID, Williams K, Stern MP, et al. High incidence of cardio-
vascular events in a rheumatoid arthritis cohort not explained by tradi-
tional cardiac risk factors. Arthritis Rheum. 2001;44:27372745.
3. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Cir-
culation. 2002;105:11351143.
4. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation
and cardiovascular disease: application to clinical and public health
practice: a statement for healthcare professionals from the Centers for
Disease Control and Prevention and the American Heart Association.
Circulation. 2003;107:499 511.
5. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid
arthritis. Circulation. 1999;100:2124 2126.
6. McInnes IB. Rheumatoid arthritis: from bench to bedside. Rheum Dis
Clin North Am. 2001;27:373387.
7. Hill AG, Hill GL. Metabolic response to severe injury. Br J Surg.
1998;85:884 890.
8. Banks WA, Phillips-Conroy JE, Jolly CJ, et al. Serum leptin levels in wild
and captive populations of baboons (papio): implications for the ancestral
role of leptin. J Clin Endocrinol Metab. 2001;86:4315 4320.
9. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene
expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:
245270.
10. Pincus T, Callahan LF, Sale WG, et al. Severe functional declines, work
disability, and increased mortality in seventy-five rheumatoid arthritis
patients studied over nine years. Arthritis Rheum. 1984;27:864 872.
11. Paolisso G, Valentini G, Giugliano D, et al. Evidence for peripheral
impaired glucose handling in patients with connective tissue diseases.
Metabolism. 1991;40:902907.
12. Hallgren R, Berne C. Glucose intolerance in patients with chronic inflam-
matory diseases is normalized by glucocorticoids. Acta Med Scand. 1983;
213:351355.
13. Hotamisligil GS, Peraldi P, Budavari A, et al. IRS-1-mediated inhibition
of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-
induced insulin resistance. Science. 1996;271:665 668.
14. Chajek-Shaul T, Friedman G, Stein O, et al. Mechanism of the hypertri-
glyceridemia induced by tumor necrosis factor administration to rats.
Biochim Biophys Acta. 1989;1001:316 324.
15. Khovidhunkit W, Memon RA, Feingold KR, et al. Infection and
inflammation-induced proatherogenic changes of lipoproteins. J Infect
Dis. 2000;181(suppl 3):S462S472.
16. Lee YH, Choi SJ, Ji JD, et al. Lipoprotein(a) and lipids in relation to
inflammation in rheumatoid arthritis. Clin Rheumatol. 2000;19:324 325.
17. Munro R, Morrison E, McDonald AG, et al. Effect of disease modifying
agents on the lipid profiles of patients with rheumatoid arthritis. Ann
Rheum Dis. 1997;56:374 377.
18. Heldenberg D, Caspi D, Levtov O, et al. Serum lipids and lipoprotein
concentrations in women with rheumatoid arthritis. Clin Rheumatol.
1983;2:387391.
19. Hurt-Camejo E, Paredes S, Masana L, et al. Elevated levels of small,
low-density lipoprotein with high affinity for arterial matrix components
in patients with rheumatoid arthritis: possible contribution of phospho-
lipase A2 to this atherogenic profile. Arthritis Rheum. 2001;44:
27612767.
20. Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and
vascular endothelial dysfunction. Atherosclerosis. 1998;138:229 235.
21. Danesh J, Collins R, Peto R. Lipoprotein(a) and coronary heart disease:
meta-analysis of prospective studies. Circulation. 2000;102:10821085.
22. Maziere C, Auclair M, Maziere JC. Tumor necrosis factor enhances low
density lipoprotein oxidative modification by monocytes and endothelial
cells. FEBS Lett. 1994;338:43 46.
23. Gambhir JK, Lali P, Jain AK. Correlation between blood antioxidant
levels and lipid peroxidation in rheumatoid arthritis. Clin Biochem. 1997;
30:351355.
24. Honkanen V, Konttinen YT, Mussalo-Rauhamaa H. Vitamins A and E,
retinol binding protein and zinc in rheumatoid arthritis. Clin Exp
Rheumatol. 1989;7:465 469.
25. Vita JA, Keaney JF Jr. Endothelial function: a barometer for cardiovas-
cular risk? Circulation. 2002;106:640 642.
26. Haskard DO. Cell adhesion molecules in rheumatoid arthritis. Curr Opin
Rheumatol. 1995;7:229 234.
27. Bloom BJ, Miller LC, Tucker LB, et al. Soluble adhesion molecules in
juvenile rheumatoid arthritis. J Rheumatol. 1999;26:2044 2048.
28. Veale DJ, Maple C, Kirk G, et al. Soluble cell adhesion moleculesP-
selectin and ICAM-1, and disease activity in patients receiving sul-
phasalazine for active rheumatoid arthritis. Scand J Rheumatol. 1998;27:
296 299.
29. Pedersen LM, Nordin H, Svensson B, et al. Microalbuminuria in patients
with rheumatoid arthritis. Ann Rheum Dis. 1995;54:189 192.
30. Wong M, Toh L, Wilson A, et al. Reduced arterial elasticity in rheu-
matoid arthritis and the relationship to vascular disease risk factors and
inflammation. Arthritis Rheum. 2003;48:81 89.
31. Hurlimann D, Forster A, Noll G, et al. Anti-tumor necrosis factor-alpha
treatment improves endothelial function in patients with rheumatoid
arthritis. Circulation. 2002;106:2184 2187.
32. Vallance P, Collier J, Bhagat K. Infection, inflammation, and infarction:
does acute endothelial dysfunction provide a link? Lancet. 1997;349:
13911392.
 Sattar et al
33. Ito A, Tsao PS, Adimoolam S, et al. Novel mechanism for endothelial
dysfunction: dysregulation of dimethylarginine dimethylaminohydrolase.
Circulation. 1999;99:30923095.
34. McEntegart A, Capell HA, Creran D, et al. Cardiovascular risk factors,
including thrombotic variables, in a population with rheumatoid arthritis.
Rheumatology. 2001;40:640 644.
35. Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica. 2000;
85:967972.
36. Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and
plaque instability in acute coronary syndromes. Circulation. 2000;101:
28832888.
37. Garnero A, Fasciolo D, Accardo S, et al. Cardiac risk factors in patients
with rheumatoid arthritis? Ann Rheum Dis. 1999;58(suppl):69 70.
38. Chae CU, Lee RT, Rifai N, et al. Blood pressure and inflammation in
apparently healthy men. Hypertension. 2001;38:399 403.
39. Chiang EP, Bagley PJ, Selhub J, et al. Abnormal vitamin B6 status is
associated with severity of symptoms in patients with rheumatoid
arthritis. Am J Med. 2003;114:283287.
40. Lazzerini PE, Capecchi PL, Bisogno S, et al. Reduction in plasma homo-
cysteine level in patients with rheumatoid arthritis given pulsed glucocor-
ticoid treatment. Ann Rheum Dis. 2003;62:694 695.
41. De Vita F, Orditura M, Infusino S, et al. Increased serum levels of tumor
necrosis factor-alpha are correlated to soluble intercellular adhesion
Systemic Inflammation and Vascular Risk 2963
molecule-1 concentrations in non-small cell lung cancer patients. Int J
Mol Med. 1998;1:605 608.
42. Dessi S, Batetta B, Pulisci D, et al. Altered pattern of lipid metabolism in
patients with lung cancer. Oncology. 1992;49:436 441.
43. Gonenc A, Ozkan Y, Torun M, et al. Plasma malondialdehyde (MDA)
levels in breast and lung cancer patients. J Clin Pharm Ther. 2001;26:
141144.
44. Pedersen LM, Milman N. Microalbuminuria in patients with lung cancer.
Eur J Cancer. 1998;34:76 80.
45. Yoshikawa T, Noguchi Y, Doi C, et al. Insulin resistance in patients with cancer:
relationships with tumor site, tumor stage, body-weight loss, acute-phase
response, and energy expenditure. Nutrition. 2001;17:590593.
46. Choi HK, Hernan MA, Seeger JD, et al. Methotrexate and mortality in patients
with rheumatoid arthritis: a prospective study. Lancet. 2002;359:11731177.
47. Palinski W, Napoli C. Unraveling pleiotropic effects of statins on plaque
rupture. Arterioscler Thromb Vasc Biol. 2002;22:17451750.
48. Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for
simvastatin in inflammatory arthritis. J Immunol. 2003;170:1524 1530.
49. Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone
treatment on nontraditional markers of cardiovascular disease in patients
with type 2 diabetes mellitus. Circulation. 2002;106:679 684.
50. Del Puente A, Knowler WC, Pettitt DJ, et al. High incidence and prev-
alence of rheumatoid arthritis in Pima Indians. Am J Epidemiol. 1989;
129:1170 1178.