Dyslipidaemia in rheumatological autoimmune diseases.

Abstract

Autoimmunity forms the basis of many rheumatological diseases, and may contribute not only to the classical clinical manifestations but also to the complications. Many of the autoimmune rheumatological diseases, including rheumatoid arthritis and systemic lupus erythematosus are associated with an excess cardiovascular morbidity and mortality. Much of this excess cardiovascular risk can be attributed to atherosclerotic disease. Atherosclerosis is a complex pathological process, with dyslipidaemia and inflammation fundamental to all stages of plaque evolution. The heightened inflammatory state seen in conjunction with many rheumatological diseases may accelerate plaque formation, both through direct effects on the arterial wall and indirectly through inflammation-mediated alterations in the lipid profile. Alongside these factors, antibodies produced as part of the autoimmune nature of these conditions may lead to alterations in the lipid profile and promote atherosclerosis. In this review, we discuss the association between several of the rheumatological autoimmune diseases and dyslipidaemia, and the potential cardiovascular impact this may confer.

Full text

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64 The Open Cardiovascular Medicine Journal, 2011, 5, 64-75


1874-1924/11 2011 Bentham Open
Open Access
Dyslipidaemia in Rheumatological Autoimmune Diseases
Tracey E. Toms1, Vasileios F. Panoulas1 and George D. Kitas1,2,*
1Department of Rheumatology, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital, Dudley, West Midlands, UK
2arc Epidemiology Unit, Manchester University, Manchester, UK
Abstract: Autoimmunity forms the basis of many rheumatological diseases, and may contribute not only to the classical
clinical manifestations but also to the complications. Many of the autoimmune rheumatological diseases, including rheu-
matoid arthritis and systemic lupus erythematosus are associated with an excess cardiovascular morbidity and mortality.
Much of this excess cardiovascular risk can be attributed to atherosclerotic disease. Atherosclerosis is a complex patho-
logical process, with dyslipidaemia and inflammation fundamental to all stages of plaque evolution. The heightened in-
flammatory state seen in conjunction with many rheumatological diseases may accelerate plaque formation, both through
direct effects on the arterial wall and indirectly through inflammation-mediated alterations in the lipid profile. Alongside
these factors, antibodies produced as part of the autoimmune nature of these conditions may lead to alterations in the lipid
profile and promote atherosclerosis. In this review, we discuss the association between several of the rheumatological
autoimmune diseases and dyslipidaemia, and the potential cardiovascular impact this may confer.
Keywords: Autoimmune disease, dyslipidaemia, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, pri-
mary sjogrens syndrome, anti-phospholipid syndrome.
INTRODUCTION

conditions is often attributed to their underlying autoimmune
nature. Autoimmunity contributes to the clinical manifesta-
tions, as well as complications of disease and response to
treatment. Rheumatoid arthritis (RA) and systemic lupus
erythematosus (SLE) have been found to associate with an
increased risk for cardiovascular disease (CVD) [1-3], result-
ing in a significantly shortened lifespan. As a consequence,
much speculation and research has focused on the role of
both traditional and novel, disease specific, risk factors. In
the general population, dyslipidaemia has been shown to be
one of the strongest predictors of CVD, with elevated levels
of low-density lipoproteins (LDL) forming the primary
treatment target according to national guidelines [4]. In this
review we discuss the association between several of the
autoimmune rheumatological conditions (RA, SLE, primary
antiphospholipid sysndrome (primary APS), systemic sclero-
sis (SSc), and primary Sjogrens syndrome (PSS)) and
dyslipidaemia, and the potential impact this has on cardio-
vascular risk, in particular atherosclerotic plaque formation.
The complexity and diversity of many rheumatological
ATHEROSCLEROTIC PLAQUE FORMATION: THE
ROLE OF LIPIDS AND INFLAMMATION

and rupture of atherosclerotic plaques. The term atheroscle-
rosis covers a spectrum of disease ranging from endothelial

Coronary artery disease develops due to the formation

*Address correspondence to this author at the Department of Rheumatol-
ogy, Dudley Group of Hospitals NHS Trust, Russells Hall Hospital,
Pensnett Road, Dudley, West Midlands, DY1 2HQ, United Kingdom;
Tel: +44-1384-244842; Fax: +44-1384-244808;
E-mail: gd.kitas@dgoh.nhs.uk or g.d.kitas@bham.ac.uk
dysfunction and fatty streak development, through to the
formation and rupture of a mature plaque. The development
of atherosclerotic plaques is complex. Inflammation is fun-
damental to all stages of atherosclerotic plaque [5], with an
intense bi-directional interaction occurring between lipids
and inflammation. Rheumatological autoimmune diseases
are associated with a heightened inflammatory state in vary-
ing degrees, thus these processes may be accelerated.

Endothelial dysfunction is the initiating step in plaque
development [6]. Healthy endothelium exerts a number of
vasoprotective effects such as vasodilation, suppression of
smooth muscle cell growth and inhibition of inflammatory
responses, thereby helping to protect against atherosclerosis.
Nitric oxide mediates many of these effects by inhibiting
platelet aggregation and LDL oxidation, as well as opposing
the effects of endothelium-derived vasoconstrictors [7]. En-
dothelial damage occurs when the fine balance between
vasoconstrictive and vasodilatory pathways is disrupted.
Although endothelial dysfunction is likely to be a multi-
factorial process, the major cardiovascular risk factors such
as hypercholesterolaemia, hypertension, diabetes and smok-
ing have been implicated via their ability to increase the pro-
duction of reactive oxygen species [8]. It is postulated that
the increase in reactive oxygen species may in turn reduce
endothelial nitric oxide (NO) availability [9, 10]. Multiple
lipid abnormalities have been associated with endothelial
dysfunction. Hypercholesterolaemia has been shown to
cause focal activation of the endothelium in medium and
large arteries and has been associated with an increased
number of monocytes entering the intima [11]. High levels
of oxidised LDL (oxLDL) may down regulate endothelial
NO synthase (eNOS), thus reducing available NO and re-
stricting coronary vasodilation [12]. High levels of circulat-

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Dyslipidaemia in Rheumatological Autoimmune Diseases The Open Cardiovascular Medicine Journal, 2011, Volume 5 65
ing triglycerides (TGs) may also damage the endothelium via
their oxidative charge and result in disruption of the normal
NO pathway [13, 14]. Studies into the effects of lipoprotein
(a) (Lp(a)) have shown elevated levels to be inversely corre-
lated with small artery compliance and NO production [15,
16]. High levels of systemic inflammation may also disrupt
endothelial homeostasis via the NO pathway, by reducing
the expression of eNOS and increasing the expression of
inducible NO synthase producing a net excess of NO [17].
Too much nitric oxide can also be deleterious to the endothe-
lium, thus a very fine balance of NO needs to be maintained
in order to preserve and protect the endothelium [18].

endothelium, excess LDL infiltrates the artery wall and is
retained in the intima by matrix components. LDL then un-
dergoes modification and oxidation, inducing the endothelial
cells to express leukocyte adhesion molecules [19] and initi-
ating an inflammatory response in the artery wall [20]. The
contribution of oxLDL particles to the development of athe-
rosclerosis is summarised in Fig. (1).
Due to the increased permeability of the dysfunctional

platelets [21]. They adhere via glycoproteins on their sur-
face, triggering further endothelial activation resulting in
leukocyte infiltration [22]. Once in the sub-endothelial
The first cells attracted to the activated endothelium are
space, monocytes are transformed to macrophages and sub-
sequent incorporation of LDL via endocytosis by scavenger
receptors (CD36 and others) differentiates them further into
foam cells. The accumulation of foam cells, smooth muscle
cells and T cells results in the formation of a fatty streak
(Fig. 2a), the earliest recognisable lesion of atherosclerosis
[23].

vanced lesions (Fig. 2b), by amplification of the processes
involved in formation of fatty streaks. The advanced lesions
tend to form a protective fibrous cap that walls off the lesion
from the lumen. Advanced plaques have a lipid-rich necrotic
core containing an abundance of tissue factor, which plays a
vital role in thrombus formation upon plaque rupture [24].
Fatty streaks can progress to form intermediate and ad-

ning or erosion of the fibrous cap. Destabilisation and degra-
dation of the fibrous cap results from the production of in-
flammatory cytokines, proteases, radicals, coagulation fac-
tors and vasoactive molecules, from activated macrophages,
T cells and mast cells [25]. The above events lead to plaque
rupture, exposing the contents of the core of the plaque to the
circulating blood and subsequent activation of the clotting
cascade. As the thrombus forms and enlarges, the arterial
lumen narrows and ischaemic symptoms may present.
Plaque instability and rupture occurs due to uneven thin-








Fig. (1). The role of oxidised LDL.









Fig. (2a). Fatty Streak formation. Fig. (2b). Advanced plaque formation.

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66 The Open Cardiovascular Medicine Journal, 2011, Volume 5 Toms et al.
RHEUMATOID ARTHRITIS

the United Kingdom [26]. RA predominately affects the
synovial joints resulting in joint pain, swelling and stiffness,
but can also produce an array of clinical manifestations as
part of the systemic nature of the disease, ranging from con-
stitutional symptoms to organ involvement. Uncontrolled
inflammation can confer a large personal, socio-economic,
and psychosocial burden as a consequence of significant
joint destruction and deformity.
RA patients have a reduced life expectancy and increased
mortality rates compared to the general population [1, 3],
with CVD accounting for approximately half of all RA
deaths [27]. A recent meta-analysis has shown that the risk
of death from CVD is almost 50% higher in RA patients
compared to healthy controls [28]. Although CVD in RA can
present in many guises (e.g. congestive heart failure, myo-
cardial infarction (MI) and pericarditis), it is those with an
underlying ischaemic pathology that pose the greatest mor-
tality risk, as a consequence of atherosclerotic plaque forma-
tion [29-31]. Despite this, atherosclerotic disease remains
under-diagnosed in RA due to an often atypical or silent
presentation [32]. Although the mechanisms responsible for
this phenomenon still need to be elucidated, differences in
atherosclerotic plaque structure may be responsible. Athero-
sclerotic plaques of RA patients differ morphologically to
those observed in the general population, with less histologi-
cal evidence of atherosclerosis but far greater plaque insta-
bility [33]. Such differences may also offer a potential ex-
planation for the higher fatality rates associated with MI in
RA and the increases seen in post MI complication rates
[34].
RA affects approximately 1% of the adult population in

pathways. Traditional cardiovascular risk factors such as
hypertension [35, 36] and obesity [37-39] may occur more
frequently in RA or be modified through disease specific
mechanisms. In addition, novel risk factors such as systemic
inflammation, hyperhomocysteinaemia [40] and activation of
the coagulation pathway [41] may further escalate athero-
sclerotic plaque formation. In fact, the impact of systemic
inflammation on CVD is so great it has now been recognised
as an independent cardiovascular risk factor in the general
population [42, 43]. Although there is a degree of interplay
between all of the risk factors, systemic inflammation ap-
pears to be fundamental to virtually all. Furthermore, RA
patients may be genetically predisposed to the development
of atherosclerosis and myocardial infarction [44, 45].
Dyslipidaemia is highly prevalent in RA affecting be-
tween 55-65% of patients [46, 47] and can manifest in RA
patients with both early [48] and advanced disease [49]. One
retrospective study on 1078 blood donors has suggested that
the lipid profile may be altered prior to the onset on RA [50].
This study demonstrated that the 79 blood donors who later
developed RA had significantly higher total cholesterol
(TC), triglyceride (TG), apolipoprotein B (apoB) levels, and
lower high density lipoprotein (HDL) levels up to ten years
prior to the onset of RA compared to matched controls. This
suggests that alterations in the lipid profile may render peo-
ple more susceptible to the future development of RA [51] or
that RA patients are genetically predisposed to the develop-
Atherosclerosis in RA may be enhanced through several
ment of RA related dyslipidaemia or that the transcription of
these genes is altered by persistent inflammation.

by a genetic predisposition, it is also influenced by an array
of other factors including disease activity [52], reduced
physical activity secondary to pain and disability [53], and
drug therapy [54, 55]. In untreated RA the lipid profile is
characterised by suppression of HDL and TC levels [51, 56,
57]. At first glance this appears to produce a less atherogenic
profile, however, HDL levels fall disproportionately more
compared to TC levels resulting in an increased atherogenic
index (TC:HDL ratio) [48, 56, 58]. The largest study to
compare the lipid profiles of untreated RA patients to a con-
trol group is the National Health and Nutrition Examination
Survey (NHANES III) [54]. This study included 104 patients
who were naïve to disease modifying anti-rheumatic drugs
(DMARDs) and glucocorticoids (GCs). It confirmed a sig-
nificant fall in HDL and apolipoprotein A-I (apoAI) levels
but failed to demonstrate any significant changes in other
lipid levels. Current data exploring the effects of heightened
disease activity on TG and low density lipoprotein (LDL)
levels is conflicting with some studies reporting a positive
association [56] and others a negative association [59, 60].
These discrepancies may be a consequence of limitations of
study design, including small study size, differences in base-
line characteristics, and incomplete adjustment for con-
founders.
Although dyslipidaemia in RA may be partially governed

potential markers for CVD in the general population [61].
This is rather unsurprising, as apolipoproteins are found in
conjunction with lipid particles (e.g. Apo-AI with HDL and
Apo-B100 with LDL). However, emerging evidence now
indicates a superiority of measuring apolipoproteins as CVD
risk factors, rather than their lipid counterpart (e.g. ApoB
rather than LDL) [62]. In RA, Apo-AI levels decrease [48,
52, 54, 63], mirroring the supression in HDL observed in
active RA. Although, Apo-B levels have also been reported
to be reduced with high levels of inflammation [64] this is to
a lesser degree than Apo-AI levels [48, 52, 64].
For many years, apolipoproteins have been recognised as

basis of CVD risk stratification algorithms [4, 65]. However,
the use of lipid and apolipoprotein ratios is gaining popular-
ity as they have been shown to confer a greater predictive
value of first myocardial infarction than individual lipid lev-
els in the general population [66, 67]. The lipid ratios shown
to be useful in risk stratification, include TC:HDL ratio [68],
LDL:HDL ratio [69] and ApoB: ApoA1 ratio [70]. All three
lipid ratios have been reported to increase in active RA [48,
56]. In addition, lipid ratios have been considered as an at-
tractive alternative method of risk stratification in RA as
they may overcome the inflammatory mediated fluctuations
in individual lipid parameters [71].
Lipoprotein (a) (Lp(a)), is an LDL particle that is bound
to apolipoprotein (a), by a disulphide bond with Apo-B100.
Current evidence suggests Lp(a) is a key factor in the devel-
opment of atherosclerosis [72, 73]. The structure of Lp(a)
may mechanistically contribute to atherosclerotic plaque
formation, through its structural similaririties with plasmino-
gen. Lp(a) competes with plasminogen for its binding site,
and stimulates the production of plasminogen activator in-
For many years individual lipid levels have formed the

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Dyslipidaemia in Rheumatological Autoimmune Diseases The Open Cardiovascular Medicine Journal, 2011, Volume 5 67
hibitor –1 (PAI-1), with the net effect of enhancing plaque
thrombosis [74]. In addition, Lp(a) has been shown to inter-
act with other established cardiovascular risk factors [75],
including lipid parameters (HDL and LDL) [76]. In RA, sev-
eral studies have demonstrated a significant increase in Lp(a)
levels [48, 54, 56, 77, 78], which in the majority of studies
appears to shadow changes in LDL [48, 54, 56]. Although
inflammation may partially control these changes in Lp(a),
genetic factors may also contribute [79]. Apolipoprotein (a)
has several phenotypic variations, due to allelic differences.
A recent study has demonstrated that RA patients have a
higher frequency of the S3 allele compared to healthy con-
trols (70% vs 39.5%) [79]. The presence of the S3 allele
associates with a lower molecular weight of Apo(a) [80].
Furthermore, there is an inverse association between the
molecular weight of Apo(a) and Lp(a) levels [81], thus
potentially accounting for the increased Lp(a) levels
observed in RA.

described in RA. High levels of oxidative stress can occur in
conjunction with the chronic inflammatory burden of RA
[66]. Lipid particles (in particular LDL) exposed to this envi-
ronment both within the synovial fluid and the plasma of RA
patients are susceptible to oxidative modification [82, 83].
Once oxidised, the LDL particles exhibit enhanced pro-
atherogenic properties, through their ability to more readily
infiltrate the arterial wall, form foam cells and initiate a
localised inflammatory response.
Lipid/lipoprotein particles are not uniform and in healthy
individuals are found in a range of sizes and densities. Such
diversity is crucial for maintaining the normal pathways of
lipid metabolism such as reverse cholesterol transport. How-
ever, these structural differences also dictate the atherogenic-
ity of each of the particles. Small dense LDL particles
(LDL3) are more prone to oxidation and more readily able to
infiltrate the arterial wall than their larger counterparts [84],
whereas smaller HDL particles (HDL2) are more successful
Further, intricate changes in lipid metabolism have been
in performing reverse cholesterol transport and thus confer
greater cardio-protection [85]. In RA, the limited available
data appears to suggests that RA patients have a more pro-
atherogenic lipoprotein subfraction profile with higher levels
of small dense LDL particles and lower levels of smaller
HDL particles [86]. Alongside this, the balance of pro-
atherogenic/anti-atherogenic HDL may be further disrupted
through suppression of enzymes including paraoxonase 1
(PON) [87].

the effects of RA on the standard lipid profile (TC, LDL, TG
and HDL levels) (Fig. 3), our understanding of dyslipidae-
mia in RA remains far from complete. Further large-scale
studies are required to investigate the changes in
lipid/lipoprotein structure and function and to establish the
relative contribution of dyslipidaemia in its entirety to CVD
in RA.
In summary, although we have a basic understanding of
SYSTEMIC LUPUS ERYTHEMATOSUS

autoimmune disease that predominately affects premeno-
pausal females, with a peak age of onset between 20-30
years. The condition can manifest with a broad spectrum of
clinical signs and symptoms, ranging from relatively minor
symptoms such as arthralgia to life-threatening organ in-
volvement. SLE has a relapsing remitting course, often re-
sulting in acute ‘flares’ characterised by a dramatic worsen-
ing of clinical symptoms, a heightened inflammatory re-
sponse and elevated auto-antibody levels.
Systemic lupus erythematosus (SLE) is a multisystem

than described in other autoimmune diseases. Patients with a
disease duration greater than 5 years have been reported to
have 52 times greater risk of suffering a myocardial infarc-
tion than matched controls [2]. In fact, the processes under-
lying atherosclerosis are so advanced that subclincal athero-
sclerosis has even been reported in the paediatric age range
SLE confers a massive CVD risk, which is far greater










Fig. (3). The main mechanisms contributing to dyslipidaemia and atherosclerosis in rheumatoid arthritis. IL-6: Interleukin-6, TNF:
Tumour necrosis factor, CRP: C reactive protein, ROS: Reactive oxygen species, OxLDL: oxidised low-density lipoproteins, TC: total cho-
lesterol, HDL: High-density lipoproteins, LDL: low-density lipoproteins, ApoB:ApoA: apolipoproteinB: apolipoproteinA ratio, TC:HDL:
total cholesterol: high-desnity lipoprotein ratio.

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68 The Open Cardiovascular Medicine Journal, 2011, Volume 5 Toms et al.
[88]. Thus, it is unsurprising that SLE has now been identi-
fied as an independent risk factor for the development of
endothelial dysfunction, the earliest vascular change in the
process of atherosclerotic plaque formation [89]. It is now
clear that although traditional risk factors, including dyslipi-
daemia may be more frequent in SLE these alone do not
fully account for the excess cardiovascular morbidity and
mortality [90]. Several disease specific factors have been
implicated including inflammation, oxidative stress and the
presence of anti-phospholipid antibodies [91, 92].
The dyslipidaemia seen in conjunction with SLE is more
typical of that described in the general population in relation
to CVD, with elevations in TG, LDL, TC and ApoB and a
parallel fall in HDL levels [93]. Although the alterations in
the lipid profile appear to be exacerbated by active disease,
significant changes have been observed in patients with inac-
tive disease [94, 95], thus reflecting that factors other than
inflammation may be at play (Fig. 4). Although the lipid
profile seen in conjunction with active SLE (elevations in
TC and LDL levels) appears to differ from that seen in active
RA, there are also similarities (Table 1). Firstly, inflamma-
tory mediators such as CRP and ESR have been shown to
suppress HDL levels and increase TG levels [96]. Secondly,
other markers of disease activity including the systemic lu-
pus erythematosus disease activity index (SLEDAI) [94],
C3d (a specific serological marker of lupus activity) levels
[93], anti-double stranded DNA (dsDNA) levels [97] and
levels of inflammatory cytokines have been found to associ-
ate with lipid levels [98, 99]. One potential inflammation-
mediated mechanism that is thought to control some of the
lipid alterations seen in SLE, is reduced activity of the en-
zyme lipoprotein lipase (LPL) [100], which may be gov-
erned by circulating inflammatory mediators (e.g. tumour
necrosis factor and interleukin-6 (IL-6) [101], and antibodies
directed against LPL (anti-LPL) [102]. LPL is responsible
for the catabolism of chylomicrons and very low density
lipoproteins (VLDL), thus suppression of LPL activity re-
sults in an accumulation of TG-rich particles [100]. The
presence of cytokines including TNF-? and IL-6 also trig-
gers hepatic production of CRP, which may further exacer-
bate HDL suppression. The high levels of circulating IL-6
have been shown to inversely correlate with HDL levels.

tion with SLE result in an increased burden of oxidative
stress [103]. Increased oxidative stress can trigger a broad
range of pro-atherogenic lipid modifications, including the
formation of oxidised LDL (oxLDL), conversion of anti-
inflammatory HDL into pro-inflammatory HDL [104], and
altering the function of key enzymes involved in lipid me-
tabolism and function [93]. The oxidation of LDL is particu-
larly interesting in SLE, as oxidation affects not only the
lipid component of the lipoprotein but also components such
as cardiolipin. Antibodies directed against oxidised cardi-
olipin (anti-phospolipid (aPL) antibodies) are increased in a
proportion of SLE patients, predominately those exhibiting
features of co-existant anti-phospholipid syndrome (APS)
[105]. There are three aPL antibodies found in SLE 1) Lupus
anticoagulant 2) anti-cardiolipin antibodies and 3) antibodies
to ?2 glycoprotein [105]. The presence of aPL antibodies
confers an increased thrombotic risk in SLE [106], thus athe-
rosclerotic plaque rupture often has devastating implications
due to vessel occlusion as a consequence of massive throm-
bus formation. The presence of IgG anti-cardiolipin antibod-
ies have also been associated with low levels of HDL and
apolipoprotein A-1, thus further escalating CVD risk [107].
High levels of systemic inflammation found in conjunc-

oxLDL, which may accelerate the uptake of LDL into the
endothelial wall [108]. In addition, there is expanding evi-
dence that antibodies against oxLDL may cross-react with
IgM and IgG anticardiolipin antibodies [108, 109], thus fur-
ther escalating CVD risk. Of particular interest oxLDL forms
complexes with ?2-glycoprotein I, which have been shown
to amplify arterial thrombosis in patients with APS [110],
and this may also be a pro-atherogenic mechanism in SLE
patients who are positive for APS antibodies.
SLE patients have high levels of antibodies against










Fig. (4). The main mechanisms contributing to dyslipidaemia and atherosclerosis in systemic lupus erythematosus. HDL: High-
density lipoprotein, ApoA1: apolipoprotein A1, APL Abs: anti-phospholipid antibodies, DsDNA: double stranded DNA, TG:triglycerides,
LDL: low-density lipoproteins, TC: total cholesterol.