Rheumatology Advance Access published online on October 16, 2008
Rheumatology, doi:10.1093/rheumatology/ken395
© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Common inflammatory mediators orchestrate pathophysiological processes in rheumatoid arthritis and atherosclerosis
F. Montecucco1 and
F. Mach1
1Division of Cardiology, Department of Medicine, Geneva University Hospital, Foundation for Medical Researches, Geneva, Switzerland.
Correspondence to:
F. Mach, Division of Cardiology, Department of Medicine, Geneva University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland. E-mail: Francois.Mach{at}medecine.unige.ch
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Abstract
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RA is characterized by a systemic inflammatory state, in which
immune cells and soluble mediators play a crucial role. These
inflammatory processes resemble those in other chronic inflammatory
diseases, such as atherosclerosis. The chronic systemic inflammation
in RA can be considered as an independent risk factor for the
development of atherosclerosis, and represents an important
field to investigate the reasons of the increase of acute cardiovascular
events in RA. In the present review, we focused on several mediators
of autoimmunity, inflammation and endothelial dysfunction, which
can be considered the most promising targets to prevent atherogenesis
in RA. Among several mediators, the pro-inflammatory cytokine
TNF-
has been shown as a crucial factor to induce atherosclerosis
in RA patients.
KEY WORDS: Rheumatoid arthritis, Cardiovascular, Cytokine and inflammatory mediators, Inflammation, Chemotactic factors
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Introduction
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RA is a chronic inflammatory disease, which affects
1% of the
population world wide [
1–3]. Its aetiology is still unknown.
However, RA is characterized by a systemic inflammatory state,
involving several organs, including joints, skin, eyes, lung
and blood vessels [
4]. Immune cells and soluble inflammatory
mediators play a crucial role in RA pathogenesis. Various leucocyte
populations, orchestrated by several cytokines, chemokines,
growth factors and hormones, infiltrate rheumatoid tissues and
increase injury [
5]. These inflammatory processes resemble those
in other chronic inflammatory diseases, such as atherosclerosis
[
6]. The activation of monocytes, T and B cells, vascular endothelial
cells and the elevation of circulating inflammatory factors
and markers characterizing both diseases, suggest that different
inflammatory disorders can be induced by common inflammatory
processes. In particular, inflammation in RA is now considered
as an independent risk factor for the development of atherosclerosis
[
7–12]. This is suggested by several independent findings,
indicating a possible strong association between RA and atherosclerosis.
Atherogenesis is accelerated in RA patients [
6] and increases
the mortality of these patients for acute cardiovascular events
[
13–16]. The excess of cardiovascular mortality in RA
patients could be associated with the long-term corticosteroid
treatments against RA [
17] or, intriguingly, with the increase
of circulating inflammatory cardiovascular factors known to
play a crucial role during atherogenesis [
18]. Indeed, several
soluble mediators of autoimmunity, inflammation and endothelial
dysfunction can be considered the most promising targets to
prevent atherosclerosis in RA.
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Role of dyslipidaemia in the pathogenesis of atherosclerosis in RA
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Traditional atherosclerotic risk factors play a crucial role
in the development of atherosclerosis in patients with RA. Among
Framingham risk factors, an unbalance between levels and activation
of lipoproteins contribute to the acceleration of atherosclerosis
in RA. In particular, the suggested mechanisms are subsequent
to endothelial dysfunction. Increased spaces between altered
endothelial cells in RA patients permit the entry of low-density
lipoproteins (LDLs) [
19]. Once retained in the intima, LDLs
are oxidized (OxLDL) and activate endothelial cells to up-regulate
adhesion molecules and the chemokine secretion to recruit circulating
leucocytes within atherosclerotic plaques [
20]. When monocytes/macrophages
infiltrate atherosclerotic plaques, they uptake OxLDL and form
the ‘foam cells’ that are considered key players
by secreting inflammatory mediators. Subjects suffering from
RA have increased levels of native OxLDLs [
21]. Furthermore,
functional abnormalities of the endothelium have been detected
in in various cohorts of RA patients [
22,
23]. Given this evidence,
OxLDL are pivotal molecules in the development of atherosclerosis
in RA. They should be considered a crucial pro-inflammatory
stimulus in the vicious circle, which sustains chronic inflammation
in RA. New therapies targeting the modulation of lipid profile
in RA have been investigated with controversial results [
24,
25]. On the other hand, high-density lipoproteins (HDLs) have
been shown to exert anti-inflammatory activities in both acute
and chronic diseases [
26]. Dimished levels of HDL have been
detected in RA patients [
27]. Therefore, the increase of HDL
concentrations in RA could ameliorate both disease activity
and the associated atherosclerosis. A treatment with an apolipoprotein
A-1 mimetic peptide in combination with pravastatin has inhibited
CIA [
28]. Lipid levels should be monitored in patients with
RA to minimize the cardiovascular disease. Further studies are
needed to determine the impact of specific lipoprotein particles,
small dense LDL and subfractions of HDL on long-term risk of
atherosclerosis in RA [
29].
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Rheumatoid autoimmunity and atherosclerosis: can autoantibodies induce atherosclerosis?
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Autoantibody production is a condition strongly associated with
RA. Little is known about autoantibodies and atherosclerosis
in both humans and animal models [
30]. Although not only specific
for RA [
31], RF increases the risk of developing both RA and
atherosclerosis [
32,
33]. A recent study also showed an association
between autoantibodies against OxLDL and cardiovascular disease
in RA [
34]. Unfortunately, in these studies the authors did
not investigate the autoimmune molecular mechanisms. However,
these studies represent a good starting point for future investigations
targeting autoantibodies (
Fig. 1). The association between aCLs
and atherosclerosis have also been investigated and probably
will be a very promising field of research in the future [
35,
36]. Endothelial cells could be the main target for autoantibodies
[
37–42]. No data are available for antibodies against
citrullinated proteins, which are specific and predictive for
RA [
43].
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FIG. 1. Autoantibody production in RA subjects could increase atherosclerosis. Auto-antigens (autoAg) are captured in the blood stream, and then presented to B lymphocytes by antigen-presenting cells in the lymphnode. Here, B lymphocytes differentiate to plasma cells and produce autoantibodies (autoAb), which might be involved in increasing atherosclerosis in RA.
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Rheumatoid inflammatory mediators and atherosclerosis
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CRP
CRP is a member of the pentraxin family, first described in
1930 by Tillet and Francis [
44] in the sera of patients suffering
from pneumonia. Mainly produced by the liver, CRP was considered
for many decades as a low, specific systemic marker of inflammation.
Recently, it has been shown that several cell types are capable
of secreting CRP in inflammatory microenvironments, such as
rheumatoid synovium and atherosclerotic lesions (
Fig. 2) [
45–47].
In these inflamed tissues, CRP directly activates immune cells
with the secretion of other inflammatory molecules, by initiating
a vicious circle that maintains and increases the inflammatory
state [
48]. This experimental evidence strongly supports CRP
as an active inflammatory mediator with both systemic and local
effects. In addition, this may suggest that inflammatory disorders,
characterized by high levels of CRP, can develop a secondary
immune cell activation, which may result in the increase of
atherogenesis. Therefore, the chronic increased CRP serum levels
in RA patients [
49] can directly induce an acceleration of atherosclerosis
and its complications [
50,
51]. Numerous prospective epidemiological
studies showed that in healthy subjects, serum CRP predicts
myocardial infarction mortality [
51–53], stroke [
54–56]
and arrhythmias, including sudden cardiac death [
57]. A meta-analysis
of 14 prospective long-term studies showed that after correction
for age, smoking and other cardiovascular risk factors, CRP
was strongly related to coronary heart disease [
58]. These studies
show that CRP should be considered a direct pro-inflammatory
factor in the pathogenesis of inflammatory diseases such as
RA and atherosclerosis.
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FIG. 2. CRP increases both atherosclerosis and RA. CRP is mainly secreted by hepatocytes in the blood stream. CRP increases immune and vascular cell functions and tissue inflammation. Inflammatory cells in synovium and atherosclerotic plaque further produce CRP by increasing CRP-mediated local inflammation.
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TNF-
TNF-
is a classical pro-inflammatory mediator and a member of
a cytokine family including Fas ligand and CD40 ligand. TNF-
induces deleterious effects in several inflammatory diseases
through the binding with two different receptors (called types
I and II), which are expressed in all cell types except erythrocytes
[
59]. This suggests that TNF-
, as CRP, can mediate both local
and systemic responses during inflammatory diseases (
Figs 3 and 4
).
RA as well as atherosclerosis represents an inflammatory disorder
in which TNF-
play a crucial role. This is strongly supported
by studies in both humans and animal models. Mouse models of
arthritis have also been developed independent of TNF-
[
60–62].
However, blockade of TNF-
activity has been shown to influence
both disease and inflammatory cells in mice [
63,
64]. In humans,
the direct positive association between serum levels of TNF-
with the activity of RA [
65]. In addition, clinical improvements
obtained in several clinical trials targeting TNF-
indicate
a promising therapeutic strategy [
66]. During atherosclerotic
complications, such as myocardial ischaemia, TNF-
plasma levels
have been shown to be very high [
67–70]. The inflammatory
cascade mediated by TNF-
is quite similar in RA and atherosclerosis,
suggesting a deleterious role of this cytokine in both diseases.
TNF-
may induce atherosclerosis in RA patients by interfering
with various processes. It not only activates inflammatory and
endothelial cells [
71,
72], but also induces pro-thrombotic
states, insulin resistance and dyslipidaemia [
72]. Accordingly,
anti-TNF-
treatment has been shown to increase HDL cholesterol
[
73–75] and improve insulin resistance [
76,
77] and, transiently
also endothelial dysfunction [
78,
79]. Although the benefits
in endothelial function induced by anti-TNF-
treatments are
still controversial [
80,
81], improvement of the other aforementioned
conditions have to be considered a crucial contribution in the
development of secondary atherosclerosis in RA patients [
82].
However, the absence of analysis of acute cardiovascular events
as clinical end-points in clinical trials with anti-TNF-
treatments
is still the strong limitation of the benefits of these therapies
in rheumatoid-associated atherosclerosis (
Fig. 3) [
83–85].
The assessment of cardiovascular global risk, by using serum
markers or other indicators, is clearly not sufficient to propose
new treatment indications in order to to improve the atherosclerotic
burden in RA patients. Therefore, in the future the most important
field of investigation for anti-TNF-
treatments for rheumatoid
patients should be focused not only on improving joint symptoms,
but also on reducing cardiovascular disease burden for these
patients.
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FIG. 3. Rheumatoid joints secrete pro-inflammatory soluble factors, which could accelerate atherosclerosis. Several mediators, released in the blood stream by the inflamed joints, accelerate atherosclerosis in RA patients. Among these, TNF- is the most promising target to reduce athersoclerosis associated with RA.
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FIG. 4. Adipose tissue produces pro- and anti-inflammatory adipocytokines involved in both RA and atherosclerosis pathophysiology. Adiponectin is considered one of the most promising natural anti-inflammatory mediators against RA and atherosclerosis. The other adipocytokines are currently under investigation, with still controversial results in the regulation of inflammatory processes. The majority of publications consider these adipocytokines as ‘pro-inflammatory’, rather than ‘anti-inflammatory’.
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The RANK ligand (RANKL)/RANK/osteoprotegerin (OPG) axis
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The RANKL/RANK/osteoprotegerin (OPG) system is a crucial molecular
mechanism in the bone resorption and joint destruction in RA
[
86]. OPG is a natural decoy for RANKL, which inhibits RANKL
binding with its cognate receptor RANK on the cell surface by
preventing osteoclast differentiation and, thus, reducing bone
resorption. Several cytokines, including IL-1 and TNF-
, have
been shown to regulate this system [
87–89]. Recent evidence
suggests that RANKL and OPG balance is also crucial in atherosclerotic
plaque calcification, a condition which is diffused in long-standing
RA patients [
90] and favours plaque rupture [
91,
92]. The role
of RANKL and OPG in plaque calcification has also been shown
in knockout mouse models [
93–95]. Circulating RANKL induces
plaque instability in humans by inducing monocyte chemoattractant
protein-1 (MCP-1) and MMP production [
96]. On the other hand,
serum levels of OPG are increased in RA patients and independently
associated with coronary artery atherosclerosis [
97]. These
studies indicate that RANKL/OPG could represent a very important
molecular field of investigation to better understand the increase
of cardiovascular risk in RA. The strongest limitation for the
clinical use of these markers is represented by their poor specificity.
However, the RANKL/RANK/OPG axis could be a promising target
for future therapies. In this context, experimental data in
animal models have provided the first evidence for the therapeutic
use of OPG as a possible pharmacological agent to reduce arterial
calcification [
98]. On the contrary, human data have suggested
a direct relationship between increased OPG serum levels and
plaque destabilization. This may imply that elevated OPG levels
could be compensatory rather than causational in atherosclerotic
calcification. Further clinical investigations with large numbers
of patients are required to better clarify the role of serum
sRANKL and OPG in RA-induced atherosclerotic plaque calcification.
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Adipocytokines
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Since the discovery of leptin in 1994 [
99], white adipose tissue
(WAT) has been found to secrete several inflammatory mediators,
which have been called ‘adipokines’ or ‘adipocytokines’
(
Fig. 4). These molecules orchestrate via endocrine, paracrine,
autocrine and juxtacrine mechanisms, and both physiological
and physiopathological processes, including food intake, insulin
sensitivity, immunity and inflammation [
100,
101]. Adipocytokines
induce their activities through the binding to selective transmembrane
receptors on different cell types. At present, the most studied
adipocytokines are adiponectin, leptin, resistin, visfatin and
also TNF-
. Leptin is a non-glycosylated peptide hormone, encoded
by the gene obese (
ob) in mice and by the gene
LEP in humans
[
99]. In animal models, its synthesis is regulated by food intake,
sex hormones and inflammatory mediators, and its levels are
negatively correlated with glucocorticoids and positively with
insulin [
102–105]. The role of sex hormones is also confirmed
by studies performed in humans, showing that leptin levels are
higher in women than in men [
106]. Leptin levels have also been
found increased in humans in several inflammatory diseases,
including obesity, metabolic syndrome, RA and atherosclerosis
[
107–109]. Direct pro-inflammatory activities of leptin
on immune response have been shown in human and murine macrophages
[
110,
111], human neutrophils [
112,
113], NK cells [
114], dendritic
cells [
115], T lymphocytes [
116,
117] and synovial fibroblasts
[
118]. Accordingly, leptin-deficient mice, which suffer from
thymus atrophy, are immunodeficient animals [
119] and are less
prone than non-leptin-deficient mouse to develop inflammatory
disease [
120]. On the basis of these studies, leptin has been
investigated as a marker of disease activity in RA patients.
On this regard, controversial results have been published [
121–124].
Furthermore, anti-TNF-
antibody treatment with adalimumab did
not have any effect on serum levels of leptin in RA patients
[
125]. Therefore, although a crucial role of leptin in inflammatory
processes has been shown in humans and animal models [
126],
further investigations are needed to better understand its active
role in RA and associated atherosclerosis. Probably, leptin
half-life and consumption in rheumatoid joints could be the
most promising field of investigation [
127]. Recently, other
pro-inflammatory adipocytokines have also also discovered. In
humans, resistin is secreted by adipocytes and macrophages,
while in rodents it has been identified in WAT and haematopoietic
tissues [
128]. However, resistin seems to play different roles
in humans and rodents. In humans, resistin has been shown to
induce pro-inflammatory activities on immune cells in chronic
inflammatory diseases, including RA and atherosclerosis [
129–133].
In RA patients, resistin serum levels have been found increased
and associated with higher levels of IL-1Ra [
134,
135]. Accordingly,
anti-TNF-
therapy rapidly reduces resistin serum levels, indicating
that this cytokine is involved in the regulation of resistin
secretion [
136]. On the other hand, although the injection of
resistin into mice joints induces an arthritis-like condition
[
130], other studies indicate that the initial enthusiasm for
animal disease model should be limited [
137]. The main reason
is that resistin levels depend on both nutritional state and
hormonal environment. On the contrary, in murine models of atherosclerosclerosis,
resistin has been detected in sclerotic lesions and its level
has been found correlated with the severity of the lesion [
133].
Therefore, further studies are needed to investigate the role
of restitin in atherosclerosis acceleration in RA. Visfatin,
apelin, vaspin and hepcidin are the most recently discovered
adipocytokines [
137]. Their physiological and pathophysiological
roles in chronic inflammatory diseases are currently unclear
and further investigations are needed. On the contrary, the
adipocytokine adiponectin is considered one of the most promising
targets against chronic inflammatory diseases, including atherosclerosis
and RA. Adiponectin is prevalently produced in WAT and has been
shown to induce anti-inflammatory activities in both humans
and animal models. The ablation of the adiponectin gene induces
a dramatic insulin resistance in mice under high-fat or high-sucrose
diet [
138]. This pro-diabetic condition in combination with
the increased fatty acid levels and increased proliferation
of vascular cells strongly suggests that hypoadiponectinaemia
induces a pro-atherogenic state in mice [
139]. A direct anti-inflammatory
activity of adiponectin has also been shown in humans [
140,
141]. Basic research and clinical studies suggest that adiponectin
could reduce atherosclerosis in both humans and animal models
and should be considered a promising target for anti-atherosclerotic
therapies [
142–144]. The crucial role of adiponectin in
RA also suggests a possible pathophysiological trigger of atherosclerosis
in arthritic patients and animal models [
145,
146]. Anti-TNF-
therapies have already shown to increase adiponectin levels
in RA patients [
147–150]. Further studies in the future
will probably clarify whether therapies increasing adiponectin
levels will be able to reduce the acceleration of atherosclerosis
in RA.
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CD40 ligand
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CD40–CD40 ligand (CD40L) interactions are crucial in both
RA and atherosclerosis pathophysiology [
151,
152]. Therefore,
CD40 could represent another common pro-inflammatory trigger
by which RA accelerates atherosclerosis. CD40 has been shown
on B cell, dendritic cell, monocyte, macrophage, mast cell,
fibroblast and endothelial cell membranes. It regulates several
immune functions, such as the B-cell response, antigen-presenting
cell activity, monocyte migration and survival [
153–155].
Also, platelet activation is induced by CD40–CD40 ligand
interactions [
156]. Although CD40L can also mediate inflammation
independently of its cognate receptor CD40 [
157], their binding
remains a crucial event in triggering immune cell functions
in both humans and animal models [
158,
159]. CD40 binds with
two forms of ligand. The first form (CD154) is expressed on
activated T- and other immune cell membrane, while the second
one is a soluble form, called soluble CD40 ligand (sCD40L) [
155].
The soluble form is of particular interest because it has been
shown as a serological prognostic factor in coronary and cerebral
vascular diseases [
160]. Furthermore, elevated levels of sCD40L
in serum of patients with systemic autoimmune diseases have
been shown [
161]. After the binding with CD40 ligands, CD40
can be internalized. Depending on the cell type, the intracellular
signal is transduced through different pathways, involving TNF
receptor-associated factors (TRAFs) [
162] and several kinases
[
163,
164]. The activity of CD40 ligands is considered pro-inflammatory
in the majority of cell types expressing CD40. Therefore, blocking
CD40–CD40L interactions and the modulation of the downstream
intracellular signal transduction represent a promising target
against inflammatory disorders [
165,
166]. Several pharmacological
agents have been shown to reduce CD40L levels both
in vivo and
in vitro [
167]. Furthermore, anti-CD40L antibody treatment has
been shown to increase atherosclerotic plaque stability [
168]
and limit both atherogenesis [
158] and the evolution of established
atherosclerosis in mice [
159]. The use of mAbs anti-CD154 (the
form of CD40L expressed on cell membranes) could represent a
powerful tool in the treatment of both RA and atherosclerosis
[
169,
170]. Phase I/II trials of anti-CD40L antibody treatments
in humans with lupus nephritis have shown some positive results
[
171]. However, the increase of thrombotic events has temporarily
stopped these studies in humans. Other clinical studies with
the administration of antibodies better tolerated are needed
to evaluate a possible modulation in RA-induced atherosclerosis.
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IL-18
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IL-18 has been originally identified as an IFN-
-inducing factor
in Kupffer cells and macrophages [
172]. More recently, IL-18
has been shown as a crucial inducer of IFN-
secretion in T lymphocytes,
NK cells [
173,
174] and Th1 [
175–177]. Several immune
diseases, such as juvenile idiopathic arthritis and RA, have
been found associated with high levels of IL-18 (
Fig. 3) [
178–181].
At present, the molecular mechanisms by which IL-18 induces
pro-inflammatory activities are under investigation. A recent
paper demonstrated that IL-18 induces not only IFN-
, but also
serum amyloid A (SAA) protein production from rheumatoid synovial
fibroblasts [
182]. Although the molecular pathways remain unknown,
other works showed a clear association between IL-18 levels
and atherosclerosis. IL-18 is highly expressed in mouse atherosclerotic
lesions [
183]. The progression of atherosclerosis is reduced
in IL-18-deficient ApoE knockout mice [
184]. In addition, serum
levels of IL-18 are strong predictors of cardiovascular death
in stable and unstable angina patients and are positively associated
with carotid intima-media thickness [
185–187]. For these
reasons, the increase of IL-18 in RA patients could contribute
to the acceleration of atherosclerosis.
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IL-20
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IL-20 is a cytokine discovered in 2001 [
188] and belonging to
the IL-10 family [
189]. Although 28% of amino acid sequences
of IL-20 are identical to IL-10, crystallographic analysis shows
that IL-20 and IL-10 form different structures (IL-20 is a monomer,
while IL-10 is an intercalating dimer) [
190]. These structural
characteristics could partially explain the different functions
of these two cytokines. Cytokines belonging to the IL-10 family
exhibit substantial sharing of IL-20 receptor complexes (IL-20R1
and IL-20R2), by increasing the well-known cytokine redundancy
[
191]. Despite this reduced selectivity for its two receptors,
several pro-inflammatory activities and clinical implications
of IL-20 have been shown in inflammatory disorders. In a recent
study, detection of IL-20 was increased in both inflamed synovium
and plasma of patients with RA (
Fig. 3) [
192,
193]. Also in
SFs, IL-20 levels were higher than in controls [
192]. This suggests
that IL-20 is secreted by macrophages and synovial fibroblasts
within rheumatoid tissue and also released in the circulation
as a systemic factor. IL-20 also induces local pro-inflammatory
activities in inflamed synovium. In fact, in an autocrine manner
IL-20 promotes the secretion of other inflammatory mediators
by fibroblasts [
192]. The role of IL-20 in atherosclerosis is
still unclear [
194]. Increasing evidence suggests that IL-20
induces atherosclerosis through two different mechanisms shown
in mice and humans. First, as a direct autocrine mechanism,
IL-20, secreted by macrophages localized in atherosclerotic
plaques, induces a local promotion inflammation in mice [
195].
This was observed in Apolipoprotein E-deficient mice. On the
other hand, IL-20 promotes atherosclerosis through an endocrine
systemic pathway. This is an indirect mechanism, secondary to
IL-20 release from local inflammatory sites, such as rheumatoid
synovium or already advanced atherosclerotic plaques. IL-20
in the circulation induces endothelial cell proliferation, with
an increase of neovascolarization in human unstable plaques
[
196–198]. Therefore, IL-20 secreted within atherosclerotic
plaques or released in the circulation, contributes to the development
of atherosclerosis and could be a very promising target for
modulating both RA and atherosclerosis.
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MCP-1
|
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MCP-1, also called CCL2, is a well-known CC chemokine and a
classical chemoattractant for monocytes [
199]. Recent studies
showed that MCP-1 is also capable of attracting CD45RO
+ T lymphocytes
[
200] and NK cells [
201]. Furthermore, MCP-1 is also a potent
histamine-releasing factor [
202], while its activity on dendritic
cells remains controversial [
203,
204]. This evidence support
the relevant role of MCP-1 during inflammatory processes. Both
RA and atherosclerosis, which are characterized by mononuclear
cell infiltrates, are pathological disease models to evaluate
pro-inflammatory activities of MCP-1 [
205–207]. Mice deficient
for either MCP-1 or its cognate receptor (CCR2) develop less
atherosclerosis [
208,
209]. In rats, treatment with blindarit
(an inhibitor of MCP-1) improved the course of adjuvant arthritis
[
210]. In additon, MCP-1 serum levels in humans have been associated
with the incidence of coronary artery disease in the general
population, and with the clinical symptoms of JRA [
211–213].
On the basis of this evidence, MCP-1 should be considered a
potent RA and atherosclerotic factor and a target for selective
therapies (
Fig. 3). Few clinical studies have already been performed.
For instance, pioglytazone has been shown to inhibit stent restenosis
in atherosclerotic rabbits through the reduction of MCP-1 [
214].
A direct demonstration of the benefits of MCP-1 inhibition in
atherosclerosis has been performed by using antibodies anti-MCP1
or anti-MCP-1 gene therapies (
Fig. 3) [
215,
216]. However, much
remains to be studied in RA, since the first clinical trial
using an anti-MCP-1 monoclonal antibody in humans did not result
in clinical or immunohistological improvements [
217].
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Fractalkine
|
|---|
Among the four chemokine families, CXC3C-chemokine family contains
only one member that is called fractalkine or alternatively
CX3CL1 [
218]. Fractalkine has been shown to play a pro-inflammatory
role in the pathogenesis of RA [
219]. This is supported by both
in vitro and
in vivo evidence. Fractalkine and its cognate receptor
CX3CR1 are up-regulated in several inflammatory cell populations
in RA patients (
Fig. 3) [
220–223]. Furthermore, in adjuvant-induced
arthritis rats fractalkine has been found crucial in monocyte
chemotaxis within inflamed joints [
224]. This study was also
confirmed by a more recent work, which showed a significant
improvement in murine CIA when fractalkine was inhibited [
225].
In addition, two clinical studies showed that serum levels of
soluble fractalkine correlate with disease activity of RA and
are not influenced by anti-TNF-
antibody treatment in humans
[
226,
227]. Therefore, strong evidence supports fractalkine
as a pivotal agent in the pathogenesis of RA pathogenesis, independently
on TNF-
. On the other hand, growing evidence also suggests that
fractalkine may also be involved in atherosclerosis. In fact,
high levels of fractalkine mRNA has been detected in atherosclerotic
lesions [
228]. Furthermore, fractalkine increases CD8
+ T lymphocyte
and monocyte recruitment within the plaque [
229,
230]. In addition,
gene polymorphisms of CX3CR1 have been associated with the increase
of coronary artery disease [
231]. In contrast, polymorphisms
of CX3CR1 do not influence peripheral artery disease [
232].
These findings suggest that fractalkine/CX3CR1 interactions
may increase both coronary artery disease and RA. Further studies
are needed to evaluate the role of fractalkine in RA-induced
acceleration of atherosclerosis.
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MMP-9
|
|---|
MMPs are proteolytic enzymes, which regulate the cell–matrix
composition [
233,
234]. The main substrates of MMP-9 are denatured
collagen (gelatins) and type 4 collagen, which are the pivotal
components of the basement membranes. Monocytes and lymphocytes,
activated by cytokines, chemokines, eicosanoids and peptidoglycans
[
235], secrete MMP-9 to cleave basement membranes and enter
into the inflamed tissues. MMP-9 is secreted as an inactive
pro-enzyme (called zymogen), which is activated by the removal
of a domain, which renders the Zn site able for hydrolysis.
MMP-9 activation is a crucial mechanism of tissue injury in
several inflammatory diseases, including RA (
Fig. 3) [
236].
Inhibitors and activators regulate MMP-9 activation [
237]. An
imbalance between MMP and its tissue inhibitors of metalloproteinases
(TIMPs) leads to excess of activated MMP, which results in an
increased cartilage degradation. This local activity is also
supported by the systemic effects of MMPs. In fact, serum levels
of MMP have also been related with the severity of progression
of RA [
237]. Rheumatoid synovium has been proposed as the main
source of MMP-9, which is released in SF and blood circulation
[
238]. Further investigations are needed to evaluate the complex
MMP activity systems, with respectively, inhibitors and activators.
An imbalance between these factors is thought as a crucial step
during atherosclerotic plaque formation and plaque stability.
Expression of MMP-9 mRNA and protein in unstable plaques has
been found much higher than in stable plaques in both humans
and mice [
239–241]. This increase of MMP-9 in unstable
plaques is in accordance with the increased infiltration of
cells responsible for its secretion, such as macrophages and
T lymphocytes [
240]. MMP-9 reduces plaque stability by the degradation
and digestion of the matrix components of the fibrous cap and
by increasing neovascularization [
242,
243]. These studies clearly
indicate that MMP-9 should be considered as an important factor
in atherosclerotic plaque formation in RA patients. Therapies
aimed at reducing or increasing the expression of MMP-9 inhibitors
may serve as promising options in these patients. In this case,
corticosteroids, statins and the intravenous infusion of gamma
globulins have been already shown to decrease the amounts of
MMP-9 [
244–247]. Clinical trials are needed to validate
these therapies.
|
Sex hormones
|
|---|
RA and atherosclerosis are inflammatory diseases influenced
by hormonal profile [
248,
249]. Oestrogens are considered crucial
players in both diseases, by regulating both immune system and
lipid profile [
250,
251]. Oestrogens bind two receptors, called
oestrogen receptor (ER)
or ERβ, and, as a dimer, enhance
gene promoters in several cell types [
252]. Oestrogens modulate
several functions in immune cell, including white blood cell
recruitment at inflammatory sites, endothelial nitric oxide
(NO) production, MMPs and acute-phase protein production [
253].
However, these inflammatory processes regulated by oestrogens
do not give an explanation for the clinical association between
RA and atherosclerosis. In fact, the female hormone profile
should prevent atherosclerosis and increase the risk of RA [
254].
However, atherosclerosis has been found accelerated in pre-menopausal
female patients with RA [
255]. This condition clearly suggests
that accelerated atherosclerosis in RA is a multifactorial process.
Animal models are needed to better clarify the role of oestrogens
in accelerated atherosclerotic processes characterizing RA [
256,
257].
|
Insulin
|
|---|
Other hormones with a possible role during atherogenesis have
been found increased in RA patients [
258–260]. Indeed,
insulin could be considered as a crucial factor in RA-induced
atherosclerosis acceleration. Insulin is an anabolic essential
hormone for the maintenance of glucose homeostasis, tissue growth
and development [
261]. It is secreted by the pancreatic β
cells, mainly through two distinct rhythms, called ‘extrinsic’
(in response to meals) or ‘intrinsic’ (with periods
of 5–10 min and 60–120 min, in the absence of food
intake) [
262]. Rhythm alterations, mainly due to defects on
insulin secretion or insulin properties, characterize the development
of glucose intolerance and the different types of diabetes mellitus
[
262]. Glucose intolerance has been found associated with the
levels of acute-phase reactants in RA [
263]. In these patients,
glucose intolerance is mainly due to the unbalance of two different
mechanisms: (i) the increase of peripheral insulin resistance,
a pro-atherosclerotic condition, which is mediated by pro-inflammatory
cytokines (mainly TNF-
and the other adipocytokines) and free
fatty acids; and (ii) the use of corticosteroid therapy, which
induces iatrogen diabetogenic effects [
264–267]. Surprisingly,
immunosuppressive therapy with corticosteroids has been also
shown to reduce insulin resistance [
263]. This suggests that
insulin resistance in RA is mainly caused by the inflammatory
mediators. Insulin resistance has also been associated with
the increase of cardiovascular disease [
268,
269]. Insulin or
insulin-like growth factor (IGF)-1 increase atherosclerosis
in humans by the direct induction of pro-inflammatory activities
on leucocytes, endothelial cells and vascular smooth muscle
cells [
270–273]. These studies clearly indicate that insulin
could be a promising prognostic marker for therapies targeting
soluble inflammatory mediators in RA. At present, anti-TNF-
therapies have been shown to reduce insulin resistance in RA
patients [
274–277]. Further experimental evidence is needed
to show if the increase of insulin sensitivity could reduce
atherosclerotic processes in RA patients.
|
Rheumatoid-induced endothelial dysfunction and atherosclerosis: adhesion molecules
|
|---|
Endothelial dysfunction is considered as an early step in the
initial phases of the atherosclerotic process [
278]. The endothelium
is a physical barrier between the blood and the intima of vascular
wall, essential for the maintenance of vascular homeostasis.
Endothelial cell activation and dysfunction are the results
of systemic autoimmune processes, in which autoantibodies could
play a crucial role. In RA patients, a marked decrease in arterial
compliance (measured as pulse-wave analysis) has been showed
in the absence of traditional cardiovascular risk factors [
279,
280]. In addition, soluble biomarkers of endothelial dysfunction,
such as vascular cell adhesion molecules (VCAM)-1, intercellular
adhesion molecule (ICAM)-1 and endothelial leucocyte adhesion
molecule (ELAM)-1, are increased in RA patients in comparison
with healthy controls [
281]. The molecular mechanisms, that
generate endothelial dysfunction in RA patients, are still unclear.
Innate immune system and circulating endothelial progenitor
cells have also been investigated, respectively, in mice and
humans, but at present, more evidence is needed to support their
implications in atherosclerotic processes [
282,
283]. The main
contribution appears to involve autoantibody activities, but
much remains to be clarified.
|
Other mediators: microparticles
|
|---|
MPs are small (0.1–1 µm) membrane-bound vesicles
circulating within peripheral blood, which recently have been
shown to be associated with thrombotic and inflammatory diseases
in humans and mice [
284–286]. Because of their small size,
MPs quickly circulate in the blood stream and induce potent
pro-inflammatory activities, through the binding to residual
receptors and ligands expressed on their membrane surface (
Fig. 5).
Platelet MPs are the most dangerous, because they favour monocyte
survival and adhesion to endothelial cells [
287]. Platelet MPs
also induce leucocyte aggregation to other leucocytes [
288]
and secretion of IL-1β [
289]. On the other hand, T-cell-derived
MPs may induce macrophage apoptosis [
290]. On the basis of these
premises, RA and associated atherosclerosis represent an important
disease model, in which mainly platelet MP can induce injury.
Platelet MPs have been found to be elevated in plasma and correlated
with disease activity in RA patients [
291]. Platelet MPs are
also detected in SFs of RA patients, although granulocyte and
monocyte MPs are predominant here [
292]. Within inflamed joints,
MPs promote hypercoaguability and synovial activation, and thus
favour articular destruction [
293]. In the blood stream, increased
levels of MPs have been associated with atherosclerosis. In
this case, mainly endothelial MPs have been found elevated in
acute complications of atherosclerosis, such as acute coronary
syndromes [
294,
295]. Therefore, RA and atherosclerosis appear
to be associated with the increase of different MPs, derived
from different cell types. Further studies are needed to investigate
in more detail a possible clinical role of MPs in these associated
diseases.
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|
FIG. 5. MP involvement in RA and atherosclerosis. MPs from platelets, endothelial cells and leucocytes are currently under investigation for a possible role in atherosclerosis and RA. The role of platelet MP in atherosclerosis acceleration in RA is the most promising field for researches. MP: microparticles.
|
|
|
Conclusions
|
|---|
Clinical studies showed that RA is a condition that accelerates
atherosclerosis. The strong association between these chronic
inflammatory diseases is probably linked to common inflammatory
processes and hormonal profile (
Figs 2–5
). Emerging therapeutic
strategies for reducing the cardiovascular risk in RA are under
investigation [
296–300]. Among several mediators (
Table 1),
cytokines (mainly TNF-
) and chemokines represent the most promising
therapeutic targets to reduce atherosclerosis and its complications
in RA patients [
301]. Anti-TNF-
treatments have shown the crucial
role of this cytokine in the RA. Further studies are also needed
to show benefits in the accelerated atherosclerosis in RA.
|
Acknowledgements
|
|---|
Funding: This work was supported by grants from the Swiss National
Science Foundation to Dr. F. Mach (#320080-105836). The authors
belong to the European Vascular Genomics Network (
http://www.evgn.org)
a Network of Excellence supported by the European Community.
Disclosure statement: The authors have declared no conflicts of interest.
|
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Submitted 20 May 2008;
revised version accepted 10 September 2008.
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Abstract
Introduction