Vascular Function and Morphology in Rheumatoid

RHEUMATOLOGY
Rheumatology 2011;50:21252139
doi:10.1093/rheumatology/ker275
Advance Access publication 16 September 2011
Original article
Vascular function and morphology in rheumatoid
arthritis: a systematic review
Aamer Sandoo1,2, Jet J. C. S. Veldhuijzen van Zanten1,2, George S. Metsios1,
Douglas Carroll2 and George D. Kitas1,3
Methods. The MEDLINE database was searched to identify publications from 1974 to 1 November 2010
pertaining to vascular function and morphology in RA. The total number of articles included in the present
review was 93. This included 57 cross-sectional studies, 27 longitudinal studies without randomization and
9 longitudinal studies with randomization.
Results. Vascular function and morphology was impaired in RA relative to healthy controls. The majority of
studies reported no associations between systemic inflammation and vascular function. Treatment with
anti-inflammatory medication resulted in both transient and long-term improvements in the vasculature,
but only a few studies reported associations between change in inflammation and change in vascular
function and morphology.
Conclusion. The link between systemic inflammation and vascular function and morphology is not wholly
supported by the available literature. Long-term studies examining specific predictors (including CVD risk
factors) on the vasculature in RA are needed.
Key words: Rheumatoid arthritis, Endothelium, Cardiovascular disease, Systematic review, Endothelial function,
Microvascular, Macrovascular, Atherosclerosis.
Introduction
RA is a chronic systemic inflammatory disease of the
joints with predominant symptoms of pain, swelling and
stiffness [1]. Patients with RA also have a number of extraarticular manifestations, including cardiovascular disease
1
Department of Rheumatology, Dudley Group of Hospitals NHS Trust,
Russells Hall Hospital, Dudley, West Midlands, 2School of Sport and
Exercise Sciences, University of Birmingham, Birmingham and
3
Arthritis Research UK Epidemiology Unit, University of Manchester,
Manchester, UK.
Submitted 17 March 2011; revised version accepted 4 July 2011.

Correspondence to: Aamer Sandoo, Department of Rheumatology,
Dudley Group of Hospitals NHS Trust, Russells Hall Hospital,
Pensnett Road, Dudley, West Midlands DY1 2HQ, UK.
E-mail: aamer.sandoo@dgh.nhs.uk
(CVD), which accounts for 3050% of all deaths [2, 3]. RA

patients have a worse outcome from acute CVD events
than the general population [4, 5]. The exact reasons
for this remain undetermined. They may include a higher
prevalence and severity of classical CVD risk factors such
as hypertension [6, 7], dyslipidaemia [8, 9], obesity [10]
and physical inactivity [11] leading to metabolic abnormalities [12], but also a complex interplay between the systemic inflammation that characterizes RA, CVD risk
factors and vascular function [1315].
The similarities between the chronic inflammatory process in rheumatoid joints and other tissues, and the inflammatory process in the atherosclerotic blood vessels of
CVD are remarkable. In both conditions, concentrations of
CRP, IL-6 and TNF-a are elevated, and there are similar
patterns of cellular recruitment and activation consistent
! The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
CLINICAL
SCIENCE
Objectives. RA associates with significantly increased morbidity and mortality from cardiovascular disease (CVD). This may be due to complex interactions between traditional CVD risk factors, systemic
rheumatoid inflammation and the vasculature. We reviewed the current literature to answer: (i) whether
there is sufficient evidence that patients with RA have altered vascular function and morphology compared
with normal controls; (ii) whether there is sufficient evidence to determine if such changes relate predominantly to systemic inflammation; and (iii) whether any changes of vascular function and morphology in RA
can be modified with therapy.
Downloaded from http://rheumatology.oxfordjournals.org/ at Universitatea Ovidius Constanṭa on October 22, 2014
Abstract
Aamer Sandoo et al.
Non-invasive assessments of the peripheral

vasculature
Assessment of EC function in different vascular beds
The endothelium is the innermost layer of the blood vessels and forms an important part of the vasculature: it
controls vascular function via the release of vasoactive factors, such as NO, prostacyclin (PGI2) and ET-1,
which affect vasomotion, inflammation and thrombosis
[30]. Balanced production of these vasoactive factors is
critical for maintaining an atheroprotective environment within the vessel. Endothelial cell (EC) exposure
to injurious stimuli such as oxidative stress and/or inflammatory mediators, leads to disrupted production of
vasoactive factors; the ensuing imbalance is a major
contributor to ECDan early indicator of atherosclerosis [31]. In recent years, a variety of non-invasive techniques have been used to assess vascular function and
morphology as an easier and safer alternative to direct
assessment of the coronary arteries [32]. These assessments are conducted in the peripheral circulation. Their
use is supported by studies showing that peripheral
vessel function correlates with the coronary circulation
[3335], associates with traditional CVD risk factors [25]
and predicts future cardiovascular events in healthy older
individuals [36], patients with CVD [3740] or peripheral
vascular disease [41].
NO is a vasoactive factor of particular importance. It is
tonically released from EC and regulates the vasodilatory
response to specific stimuli [30]. It also inhibits platelet
aggregation and leucocyte adhesion to the vascular wall
and prevents vascular smooth muscle cell (VSMC) proliferation [42]. Although other factors, such as prostacyclin,
ET-1 and endothelium-derived hyperpolarizing factor, are
involved in vascular homeostasis, their contribution
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appears to be greater when NO levels are reduced [43].

Therefore, techniques assessing peripheral vascular function are designed to primarily reflect endothelial release of
NO and, as such, are considered good markers of EC
function [31].
The principle underlying the assessment of NO bioavailability involves a stimulus that increases NO production
from EC leading to subsequent vessel dilatation, which
can then be quantified. ECs often display different structures and phenotypes depending on the vessel type [44]
and have heterogeneous responses to stimulation in different vascular beds, and even in different sections of the
same vascular bed [4547]. Thus, different types of assessments are commonly used to measure endothelial
function in different vascular beds. For example, the induction of increased blood flow (reactive hyperaemia)
exerts shear stress on EC, activating specific receptors
that cause an increase in NO bioavailability and consequent vasodilatation [48, 49]. Reduced vasodilatation following an increase in shear forces is representative of
impaired NO bioavailability [50]. These phenomena can
be carefully created by the widely used method of flowmediated dilatation (FMD) in the large conduit vessels
(macrovessels) [51]. FMD involves occluding the blood
flow of conduit vessels for 5 min to create reactive hyperaemia. The subsequent dilatation that is expressed as a
percentage increase from the baseline diameter is mainly
dependent on NO activity, with a low percentage indicating poor endothelial function [51]. In contrast, in the small
resistance vessels (microvessels), NO activity is commonly examined via local administration of acetylcholine
(ACh) that binds to muscarinic receptors on EC and stimulates NO release [52].
The release of NO from EC acts on VSMC to cause
vasodilatation [53, 54]. However, impaired vasodilatation
can be the result of either the endothelium not sending the
signals to the VSMC or of the VSMC not being able to
respond to the signal. Therefore, in order to distinguish between ED and smooth muscle dysfunction, endotheliumindependent vasodilatation should also be characterized.
In the macrovessels, this is most often achieved by the
administration of the NO donor glyceryl trinitrate (GTN)
that acts directly on VSMC to cause dilatation [55]. The
assessment is typically carried out for 5 min, which is a
sufficient time to capture the vessels peak dilatory capacity [56, 57]. In the microvessels, administration of
sodium nitroprusside (SNP) is most regularly used as the
NO donor due to its ability to activate smooth muscle cells
to cause vasodilatation [58]. An overview of the most frequently reported assessments of EC and VSMC function
is depicted in Fig. 1.
Assessment of vascular morphology
Assessing vascular morphology is critical for establishing
the extent of atherosclerosis in the vessel. It is thought
that morphological changes follow vascular dysfunction
[59], but there is no evidence that these are two distinct
processes. In contrast, there is evidence of an association between functional and morphological changes in
the vessels of patients with early atherosclerosis [60].
www.rheumatology.oxfordjournals.org
with chronic inflammation [15, 16]. On the basis of this,

and the observation that elevated inflammatory molecules
such as CRP, IL-6 and TNF-a are associated with an
increased risk for CVD events in the general population
[1719], it has been speculated that RA disease-related
inflammation might be contributing to accelerated atherosclerosis [20, 21]. Pro-inflammatory molecules may exert
deleterious effects on the vascular endothelium, which
may subsequently reduce the synthesis of nitric oxide
(NO) and promote endothelial cell dysfunction (ECD)
[22]. Pro-inflammatory molecules may also have metabolic effects on adipose tissue, skeletal muscle and the liver,
which can contribute to the development of traditional
CVD risk factors such as dyslipidaemia, insulin resistance
and obesity [10, 23, 24]; these can also, in turn, contribute
to ECD [25]. Adequate control of disease-related inflammation appears to lead to improvements in the CVD risk
factor profile [26, 27] and reduce cardiac events [28, 29],
both of which may possibly lower CVD mortality in RA.
Non-invasive assessments of vascular function and
morphology in patients with RA provide a means of disentangling these complex pathways and assess interventions that may reduce CVD risk and improve outcome in
these patients.
RA and endothelial dysfunction
FIG. 1 An overview of the vascular assessments performed in different vascular beds.
CIMT
FMD
and GTNmediated dilatation
Laser Doppler
imaging
with Iontophoresis of
ACh and SNP
PWA and PWV
Venous occlusion
plethysmography
Nail-fold
capillaroscopy
Capillary
= functional assessments
Conduit artery
(brachial, radial
or femoral)
= structural assessments
The reduction in NO bioactivity appears to be a key event

leading to a consequent imbalance of other vasoactive
factors, particularly increased ET-1 levels [43]. ET-1 promotes inflammation and VSMC proliferation [42, 61]. ET-1
also has a strong vasoconstrictor effect, and it is highly
likely that poor functional responses of vessels can be
accounted for in part by ET-1 activity [62, 63]. This suggests that rather than functional and morphological
changes occurring at distinct phases of atherosclerosis
[64], they may be interrelated. A number of assessments
can be conducted to measure vascular morphology at
different stages of pre-clinical atherosclerosis.
Overlapping early functional and morphological changes
in the vessel can be assessed by characterizing arterial
wall stiffness using pulse wave velocity (PWV) and pulse
wave analysis (PWA) [65]. During each contraction of the
heart, pressure waveforms leave the aorta during systole
and are reflected back to the heart by peripheral vessels
during diastole. Arterial stiffness can be assessed by measuring the velocity of pressure waveforms (PWV), which
leave the aorta, and/or by analysing the central aortic
pressure waveforms for measures of arterial stiffness
(PWA) [66]. Similar to FMD, arterial elasticity is affected
by advancing age and increased CVD risk factor burden,
both of which increase PWV and PWA [67]. Stiffening of
the vascular wall can occur due to a reduction in NO production from ECs, loss of smooth muscle tone [68], as well
as degeneration of elastin fibres and increased collagen
deposition in the vascular wall [69]. Consequently, arterial
stiffness is dependent on functional and morphological
changes in the vasculature.
Measurement of the carotid intimamedia thickness

(cIMT) is a reliable indicator of more advanced, but still
subclinical atherosclerosis [59, 70]. The assessment detects thickening of the medial layer of the vascular wall,
which is a predictor of cardiac events in patients with early
atherosclerosis [60] and for restenosis following percutaneous coronary intervention [40]. In addition, increased
cIMT has been reported to relate to a number of classical
CVD risk factors such as ageing, hypertension and dyslipidaemia [70]. Increases in cIMT represent a chain
of events also resulting from a disruption in the balance
of NO and ET-1, which, over time, allows increased production/expression of inflammatory cytokines, oxidative
stress, adhesion molecules and thrombotic factors
[7173]. Increased cIMT has also been reported in hypertensive, obese adolescents [74]. A brief overview of the
methods commonly used for assessing vascular morphology are depicted in Fig. 1.
Methods
Following an RA-specific evidence-based tool for searching the literature [75], the MEDLINE database was
searched to identify publications from 1974 to
1 November 2010, in English, pertaining to vascular function
and morphology and RA. The following limits were activated: humans, English language, clinical trial Phases I, II,
III and IV, comparative study, controlled clinical trial, technical report and validation studies. The Medical Subject
Heading (MeSH) term rheumatoid arthritis was employed
in combination with endothelial function (181 articles),
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Conducting artery
(aorta, pulmonary
or carotid artery)
Arteriole
(resistance
vessel)
Aamer Sandoo et al.
2128
was awarded depending on adherence to these criteria,

ranging from 0 points (not mentioned at all) to 2 points
(mentioned in detail). Given the variations in aims between
the studies, there are variations in the highest potential
total score. For example, adjustment for group differences
is not appropriate when only RA patients are included in
the study. Therefore, for easy comparison, the quality
scores were converted into percentages (score
achieved/highest potential score for study 100). Two reviewers (A.S. and J.J.C.S.V.vZ.) assessed the QI score,
and in case of a disagreement, the reviewers discussed
the rationale for awarding the score until a consensus was
reached.
Results
Cross-sectional studies
Microvascular function and morphology
In total, only five cross-sectional studies of highly variable
quality (from 22 to 96%, average 64%) have assessed
microvascular function in RA patients (for details, see
supplementary table 1, available as supplementary data
at Rheumatology Online) [7679, 123]. Four studies included a comparison between RA patients and control
participants (Table 1). These reveal subtle abnormalities
in nail-fold capillary microscopy [78], attenuated response
to endothelium-dependent and endothelium-independent
microvascular stimuli assessed with venous occlusion
plethymsography [76, 123] and increased hyperaemic
vasodilatory response [79] in RA patients compared with
healthy controls.
Microvascular function does not appear to be consistently associated with inflammatory markers (Table 2). For
example, whereas CRP was associated with endotheliumdependent function but not endothelium-independent
function in one study [77], the reverse has also been reported [76]. Endothelial function, expressed as the ratio
between the dilation response to ACh and SNP, was
associated with CRP in a mixed and small sample of RA
patients and healthy control participants [123]. Finally, no
association at all between endothelial function and measures of inflammation has also been reported [79]. Given
the scarcity of available studies and the variety of methods applied, more research is needed to characterize
microvascular function and its associations with inflammation in RA patients.
Macrovascular function
There are 13 cross-sectional studies that have assessed macrovascular function in patients with RA (see
supplementary table 1, available as supplementary data
at Rheumatology Online, for details) [7988, 124126]. The
quality scores range from 32 to 96%, with an average of
64%. Eleven studies conducted a comparison of endothelial function between RA patients and control participants
[7985, 87, 88, 125, 126], eight of which showed attenuated endothelium-dependent macrovascular function in
RA compared with controls (Table 1) [79, 8185, 87, 88].
No differences between RA and control participants were
endothelial dysfunction (56 articles), laser Doppler flowmetry (10 articles), laser Doppler imaging (7 articles),
forearm blood flow (3 articles), venous occlusion plethysmography (1 article), flow mediated dilatation/dilation
(7 articles), augmentation index (8 articles), PWA (9 articles), PWV (8 articles), cIMT (9 articles) and atherosclerosis (58 articles). The initial search identified 357 articles.
The search was checked for duplicate articles that appeared under the different MeSH terms. Full articles
were retrieved for assessment if the information in the
abstract fulfilled both of the following criteria: (i) involving
RA patients and (ii) examining any of the above-mentioned
vascular assessments. Studies incorporating only participants with other types of inflammatory arthritis, degenerative arthritis or other inflammatory or CTDs as well as
studies related to the vasculature of the joint were
excluded. If the title and abstract did not provide sufficient
information, the full-text manuscript was examined in
order to evaluate if the article fitted the inclusion criteria.
From the 337 articles that were initially identified,
68 matched the inclusion criteria and were thus included
in the analysis.
The reference lists of all of the identified articles were
further examined in order to identify publications that were
relevant to microvascular or macrovascular endothelial
function, arterial stiffness or cIMT in RA; 25 additional articles met the inclusion criteria and were included in the
analysis. These additional articles along with those found
from the initial searches brought the total number of articles in the present review to 93. These included 57 crosssectional studies [13, 76131], 27 longitudinal studies
without using randomization [92, 95, 125, 128, 132154]
and 9 randomized controlled trials (RCTs) [131, 142,
155161]. The assessments that were used in these
studies to examine vascular function and morphology include venous occlusion plethysmography, laser Doppler
imaging and flowmetry with iontophoresis, FMD, GTNmediated dilatation, PWA, PWV, cIMT and nail-fold capillaroscopy. For more detail about these assessments see
Fig. 1.
The quality of the RCTs was assessed using a previously described procedure [162]. For the cross-sectional
and longitudinal studies, a quality index (QI) score was
specifically developed. The criteria related to crosssectional study design were choice of patient and control
populations, matching of controls to patients, use of
power calculations to determine sample size, inclusion/
exclusion criteria, reporting medication regimen of patients and controls, adherence to published laboratory
protocol guidelines (e.g. laboratory conditions, participant
preparation/condition, reproducibility, blinding of assessor to test), statistical analysis (e.g. adjustment for group
differences) and performing associations between vascular function and morphology and inflammation if such data
were collected. For longitudinal studies the same criterion
was used, but with the addition of the following categories: follow-up assessments conducted by the same
assessor and statistical adjustment of factors that differ
between populations and/or follow-up. A graded score
TABLE 1 Summary table of cross-sectional studies on microvascular function, macrovascular function, arterial stiffness
and intimamedia thickness in patients with RA compared with control participants
Outcome
RA worse than control
RA not different from control
RA better than control
Microvascular
function
Macrovascular
function
Arterial
stiffness
Intimamedia
thickness
3 (54; 2273)
8 (60; 3273)
3 (76; 3496)
13 (68; 3696)
1 (44)
24 (64; 3290)
4 (62; 3377)
1 (96)
Values are represented as the number of studies (average QI, %; range) for the QI as described in the Methods section.
Study type
Cross-sectional studies
Association
No association
Not reported
Longitudinal studiesa
Association
No association
Not reported
RCTsa
Association
No association
Not reported
Microvascular
function
Macrovascular
function
Arterial
stiffness
Intimamedia
thickness
2 (67; 6173)
2 (82; 6796)
1 (22)
3 (61; 3277)
6 (73; 5496)
4 (52; 3667)
5 (72; 55100)
10 (72; 5496)
1 (36)
8 (66; 3290)
24 (68; 3389)
7 (42; 2955)
1 (65)
5 (53; 2572)
1 (69)
3 (60; 5567)
10 (57; 2388)
2 (64; 3890)
6 (62; 2388)
1 (55)
4 (68; 5877)
4 (2.3; 23)
3 (1.7; 12)
7 (2; 13)
Values are represented as the number of studies (average QI, %; range); for cross-sectional and longitudinal studies, the QI is
as described in the Methods section; for RCTs, published scoring criteria were used [162]. aAssociations between change in
disease activity and change in vascular function.
reported in endothelial-independent function in the three

studies that explored this [80, 81, 85]. The decreased
endothelium-dependent macrovascular function, assessed with FMD, appears to be already evident within
1 year of RA diagnosis [84], but does not appear to be
further influenced by disease duration [80, 83].
Of the studies that assessed the relationship between
measures of disease activity [i.e. CRP, ESR, 28-joint DAS
(DAS-28)] and FMD, six studies (quality score ranging
from 54 to 96%) did not find an association [80, 81, 85,
88, 125, 126]. The three studies that found associations
between disease activity and FMD were mostly of good
quality (32, 75 and 77%) [79, 83, 84], but there were some
inconsistencies that are difficult to reconcile. For example,
FMD was associated with CRP but not ESR in the same
group of patients [79, 83]. A study comparing RA and
diabetes mellitus yielded no difference in FMD, even
though CRP was significantly higher in RA [88]. In separate analyses, the same authors also reported that the
presence of RA and the presence of diabetes were both
independent predictors of poor FMD; however, whereas
in diabetes this was due to classical CVD risk factors,

this did not appear to be the case in RA [88].
Surprisingly, very few studies have examined the effects
of classical CVD risk factors on macrovascular endothelial function in RA [83, 85, 86, 125], despite the fact
that studies in the general population suggest that
these may be major confounders. Associations were
found with lipid levels in some [83, 86], but not all
[85, 125], studies in RA. It is worth noting that endothelium-dependent macrovascular function in RA was lower
than controls even when patients were matched for CVD
risk or the comparison was statistically adjusted for CVD
risk [85, 87, 88].
In summary, there is ample evidence that endotheliumdependent macrovascular function is compromised in
RA compared with normal controls. The potential contribution of disease activity and classical CVD risk factors
to this abnormality remains unclear, and due to the
cross-sectional nature of these studies, no assumptions
can be made as to the directionality of any associations
found.
2129
TABLE 2 Summary table of the number of studies on associations between measures of disease activity (ESR, CRP,
DAS-28) with microvascular function, macrovascular function, arterial stiffness and intimamedia thickness in patients with RA
Aamer Sandoo et al.
Arterial stiffness
cIMT
Most cross-sectional studies on vascular morphology in
RA (39 studies) have assessed cIMT [13, 82, 8488, 91,
97122, 125, 129, 130, 164, 165] (for details see supplementary table 1, available as supplementary data at
Rheumatology Online) (average quality 63%, ranging
from 29 to 90%). Of the 30 studies that reported a comparison between RA and a control population, 24 studies
found cIMT to be increased in RA patients compared with
a control group [82, 84, 85, 87, 88, 97100, 104, 106,
108114, 118120, 130, 164, 165] (Table 1). Unfortunately,
even though most control participants are age and sex
matched to RA patients, the comparison between RA
and control participants has largely been done without
correction for factors that could impact cIMT, such as
global CVD risk or its individual components. This is
surprising, given the fact that they are known to be associated with cIMT in the general population [166] and have
been explored in RA. For example, global cardiovascular
risk, using the Framingham Risk Score, was associated
with higher cIMT [86] in RA. Similarly, the lipid profile
(including total cholesterol, low- and high-density lipoproteins and triglycerides) was also related to cIMT, not only
in univariate [85, 97, 107, 110, 125] but also in multivariate
analyses [107, 111]. However, care should be taken when
interpreting these results, as varying statistical analyses
and multivariate models have been applied to assess
the associations of individual risk factors in RA.
Increased cIMT is apparent even in patients with a
recent diagnosis of RA [120, 131]. However, whether
cIMT further increases with disease duration is not clear
from the available data. Even though several studies provide evidence for greater cIMT with longer disease duration [13, 98, 99, 119, 130], others do not find such an
association [100, 104, 108]. Caution should be exercised
when interpreting these findings, as the impact of age on
this association remains to be determined in the majority
2130
of cases. cIMT is known to increase with age in the general population [167], and is also the most consistent determinant of cIMT in RA, in both univariate and multivariate
analyses [13, 97, 103, 106, 110, 111, 114, 121, 125, 164].
More studies specifically looking at the change over time
are needed to clarify this.
As with the functional vascular assessments described
above, cIMT does not appear to be consistently associated with contemporary markers of disease activity
(Table 2). The majority of the studies do not find an association between IMT and measures of disease activity
[85, 86, 88, 91, 97, 98, 100, 102, 104, 106108, 111,
112, 114116, 119, 121, 122, 125, 129, 164, 165]. It is
possible that classical CVD risk factors moderate the
association between cIMT and inflammation in RA: ESR
was found to associate with cIMT only in the presence of
CVD risk factors in one study [13]. Direct comparison between the associations found in healthy participants and
those found in RA patients might determine whether inflammation affects cIMT (and other vascular parameters)
in RA patients in a different manner. This is likely, given
that the presence of RA has been reported to independently predict cIMT [88, 98, 102, 102, 106].
Summary of cross-sectional studies
Taken together, the cross-sectional studies reveal ample
evidence for an attenuated vascular function in patients
with RA. Even though a large number of studies have been
conducted in this area, the quality of these studies with
regard to study design, adherence to published protocols
and appropriate statistical analyses varies widely (supplementary table 1, available as supplementary data at
Rheumatology Online). Few studies conducted power
analyses for the comparison between groups, and no
data are available on appropriate power to examine factors associated with vascular function in RA. This has profound implications for the interpretation of the available
data, and more research specifically and appropriately
exploring the factors associated with vascular function in
RA is needed.
Given that RA disease-related inflammation is widely
assumed to contribute to the elevated CVD risk through
its impact on the vasculature [20, 21], it is surprising to
find that direct evidence for such an association is still
lacking. In other populations, vascular function has been
shown to be associated with inflammation [168], although
it must be noted that the levels of inflammation that are
generally seen in other populations are significantly lower
than those seen in RA patients. Accordingly, it remains
possible that low- to moderate-grade inflammation characteristic of these other populations, such as diabetic or
cardiovascular patients, is a good predictor of endothelial
function, whereas high-grade inflammation in RA is not
predictive of vascular function or morphology.
It is also possible that it is long-standing, not current,
inflammation that impacts the vasculature in RA patients
[169]. A number of studies have explored disease activity
longitudinally, but with varying methods of quantifying
accumulated disease activity, and also varying results
[83, 92, 9799, 119]. Thus, even though RA has been
Sixteen cross-sectional studies have assessed arterial stiffness in RA and are mostly of good quality
(average 70%, ranging from 36 to 100%; see details in
supplementary table 1, available as supplementary
data at Rheumatology Online) [79, 80, 8796, 126, 127,
130, 163]. Fourteen studies examined the difference in
arterial stiffness between RA patients and a control
group [79, 80, 8794, 126, 127, 130, 163] (Table 1). The
overwhelming majority of these studies have demonstrated increased arterial stiffness in RA compared with
control participants [79, 80, 8793, 96, 126, 127, 130, 163]
(Table 1).
Similar to the functional assessments described above,
no consistent association between arterial stiffness and
markers of disease activity is apparent. The majority of
studies (n = 10) reported no associations between arterial
stiffness and disease activity (average QI = 72%) [79, 80,
8890, 93, 126, 127, 130, 163], while five studies, reported such an association (average QI = 72%) [91, 92,
9496].
Longitudinal studies
Microvascular function
Six studies of low to medium quality (from 25 to 72%)
examined the longitudinal effects of anti-inflammatory
medications on endothelial function [132136, 153]. With
one exception [133], all reported improvements in
endothelial-dependent function after follow-up (ranging
from 2 days to 6 months) (supplementary table 2, available
as supplementary data at Rheumatology Online).
Endothelial-dependent function was even reported to be
no longer significantly different from control participants
following treatment [132, 135], whereas markers of inflammation were still increased relative to the control group
[132]. All but one [153] study reported no changes in
endothelial-independent function following treatment.
Surprisingly, only a single study (of higher quality relative
to most of the others) explored the associations between
(changes in) inflammatory markers and endothelial function and revealed no such association [135]. However,
caution should be exercised when interpreting these
data. This pilot study included a small number of patients
receiving a variety of anti-inflammatory medications and
post-treatment assessments were not carried out at a set
time point. In general, all of these studies are characterized by small sample sizes. Therefore, further research
exploring the effects of anti-inflammatory medications
on microvascular endothelial function is needed.
Macrovascular function
Fourteen studies examined the effects of antiinflammatory medications (in particular anti-TNF-a) on
macrovascular endothelial-dependent function [92, 120,
125, 137147]. The average quality score is 58%, ranging
from 23 to 88%. All [92, 120, 137147] but one [125] study
reported improvements in macrovascular endothelial function after treatment. Despite improvement in endothelialdependent function being observed for as long as
18 months [145], there are also reports of transient improvement in endothelial-dependent function in response
to anti-TNF-a [138, 139, 146]. The only study with no
change in FMD involved patients with <12 months
disease duration. These patients were followed for
18 months and the study did not explore the effects of a

specific medication regime. It is also worth noting that
FMD values at entry to the study were similar to those
of healthy control participants [125]. Macrovascular
endothelial-independent function remained largely unaltered following treatment; however, two studies reported an increase in endothelial-independent function
following 2 weeks of treatment with rituximab [143] and
12 months of treatment with combination DMARD therapy
[148] (supplementary table 2, available as supplementary
data at Rheumatology Online). As can be seen in summary
Table 2, it is striking that only four studies have reported
associations between change in disease activity (either
assessed with DAS-28, CRP or ESR) and endothelial function [120, 141, 145, 147], with equivocal results. Of these
studies, only one found a significant association between
changes in FMD and changes in disease activity [120].
Interestingly, this is the only study that used combination
DMARD therapy as an intervention, with the others employing anti-TNF-a treatment [141, 145, 147]. However,
care should be taken when interpreting the presence or
absence of reported associations given the small sample
sizes in these longitudinal studies. In addition, only two
studies reported a priori power calculations on the basis
of changes in vascular parameters over time [142, 144],
while no power calculations were carried out for the
associations between changes in disease activity and
vascular function.
Arterial stiffness
Eight studies examined the longitudinal effects of antiinflammatory medications on arterial stiffness, with an
average QI of 62%, ranging from 23 to 90% (supplementary table 2, available as supplementary data at
Rheumatology Online) [92, 128, 136, 142, 151154]. The
results of these studies are equivocal. Half of the studies
found that a reduction in disease activity as a result of
anti-rheumatic treatment was not accompanied by an improvement in brachial arterial stiffness [92, 136, 142, 151],
even though an improvement was found in aortic arterial
stiffness [92]. In contrast, anti-TNF-a treatment resulted in
an improvement in arterial stiffness [95, 154], which was
not seen in patients receiving MTX [95]. Atorvastatin was
reported to induce a decrease in arterial stiffness in the
absence of changes in disease activity [152]. Interestingly,
there is also one study reporting an increase in arterial
stiffness after 7 weeks of treatment with anti-TNF-a treatment [128]. Finally, the only two examinations of associations between changes in disease activity and arterial
stiffness reported no significant association [128, 154]
(Table 2).
cIMT
Only five published studies of moderate quality (average
65%, range 5577%) have longitudinally examined cIMT
[125, 145, 147, 149, 150]. Similar to arterial stiffness, the
IMT results in response to successful treatment are
equivocal [145, 147, 150]; successful anti-TNF treatment
induced an attenuation in IMT compared with MTX treatment [150], but no change in response to anti-TNF
2131
reported to be predictive of greater arterial stiffness [88],

as well as IMT [102, 106], this does not seem to be due
solely to disease-related inflammation. A comparison of
RA and diabetes patients, for example, revealed similar
vascular status despite higher levels of inflammation in
the RA patients [88, 118]. As vascular impairments
cannot be fully explained by current levels of inflammation, other factors must be contributing. Unfortunately, to
our knowledge, little attention has been paid to other potential influences. There is, however, preliminary evidence
of an interaction between inflammation and CVD risk factors affecting vascular function in RA [13]. A direct comparison between the association between vascular
function and a range of potential determinants in different
patient groups might help illuminate precisely which
factors are particularly important in RA.
Aamer Sandoo et al.
treatment has also been reported [145]. In addition,

16 weeks of rituximab treatment reduced IMT in three
out of five patients [147]. A comparison with healthy control participants revealed that the change in IMT was
greater in RA patients [125, 149]. The only study to explore
the associations between changes in IMT and disease
activity revealed no such association [147] (Table 2). As
with the functional assessments, these studies all included small sample sizes, and no power calculations
were conducted in order to determine the sample size
for these analyses.
Summary of longitudinal studies
RCTs
In comparison with longitudinal studies, RCTs on vascular
function or morphology are even scarcer (supplementary
table 3, available as supplementary data at Rheumatology
2132
Anti-rheumatic medication
In total, five studies examined the effects of
anti-rheumatic medication on vascular function and
morphology (Jadad score ranged from 1 to 3) [142,
155157, 165] (supplementary table 3, available as supplementary data at Rheumatology Online). IL-1 receptor
antagonist (anakinra) was associated with an acute improvement in FMD [142], whereas 2 weeks of selective
or non-selective cyclooxygenase (COX) inhibitors did
not change FMD or augmentation index (AIx) [156]; 56
weeks of anti-TNF decreased PWV but not AIx or IMT
[157]. Following 5 years of either prednisolone or noprednisolone treatment, there was no difference in IMT
or FMD between the treatment and no-treatment arms
of the trial [155]. However, due to the absence of baseline
vascular assessments, this study does not provide information on changes in cIMT or FMD as a result of treatment with glucocorticoids. Finally, 18 months of treatment
with anti-TNF or MTX did not change cIMT [165]. No
changes were apparent in GTN-mediated dilatation following anti-inflammatory treatment in the two studies
that examined this [142, 156].
Cardiovascular medication
Four studies (all with a Jadad score of 2) examined the
effects of either statins or angiotensin-converting enzyme
inhibitors over a period of 28 weeks [158161] (supplementary table 3, available as supplementary data at
Rheumatology Online). Overall these medications improved FMD and arterial stiffness [158161], which is in
line with studies in other populations [171, 172]. This emphasizes the potential importance of classical CVD risk
factors in vascular function in RA, in particular the influence of lipid profiles. Statin treatment reliably shows an
improvement in endothelium-dependent macrovascular
function [158, 159, 161], which can occur in the absence
of a reduction in disease activity [159]. However, more
detailed and appropriately powered studies are needed
to explore the complex interplay between lipid profiles,
disease activity, and vascular function and morphology
in more detail. There was no change in endothelialindependent function following treatment.
Summary of RCTs
The findings of the RCTs suggest that treatment with cardiovascular medications may have a greater beneficial
effect on endothelial function than treatment with
anti-inflammatory medications. However, given the paucity of RCTs with limited sample size and lack of power
calculations, particularly in those studies testing
anti-rheumatic medication, it is not possible to draw firm
conclusions at this stage.
In sum, the longitudinal studies reveal that the vascular

response to successful treatment is not clearly defined
(supplementary table 2, available as supplementary data
at Rheumatology Online), and there is no consistent evidence for an association between changes in vascular
parameters and changes in disease activity. In addition,
the incongruent findings between studies could be due to
the patients clinical response to treatment. For example,
classification of responders or non-responders according to European League Against Rheumatism (EULAR)
response criteria [170] revealed that patients who responded to medication showed a trend for improved
arterial stiffness compared with non-responders [95].
Indeed, analysis of the British Society of Rheumatology
Biologics Register has revealed that patients who show
a good clinical response after 6 months of anti-TNF-a
treatment have a lower risk of myocardial infarction than
non-responding patients [28]. Collectively, these findings
suggest that the overall reduction in disease-related
inflammation may be more important for improving endothelial function rather than any specific effect of medication. Unfortunately, most of the longitudinal studies
assessing the effects of anti-inflammatory medications
on endothelial function incorporated small sample
sizes, making it difficult to perform such sub-analysis. It
is clear that not all of the inflammatory markers were
significantly reduced after treatment in some studies
[137139, 145]; therefore, further research that characterizes endothelial function according to clinical response
using established guidelines (e.g. EULAR response criteria) in large cohorts will give sufficient power to conduct
responder vs non-responder analysis.
The influence of changes in classical CVD risk factors
on changes in vascular function or structure has not
received much attention in the literature. Even though
changes in lipid profiles have been explored in response
to treatment, the results are equivocal. No reports are
available on associations between changes in CVD risk
factors and changes in vascular function or structure in
RA. However, given the small sample sizes in the available
studies, it remains possible that the studies are underpowered to analyse these associations.
Online) and, unfortunately, none of these studies have

reported the associations between changes in vascular
function and disease activity (Table 2). The following section details the studies according to the treatment group the patients were randomized to and also
provides a quality score based on previously developed
criteria [162].
Conclusion
References
The studies presented in the present review provide clear

evidence that vascular function and morphology are
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cross-sectional or longitudinal studies. This is accentuated by the inconsistent findings in vascular function or
morphology following treatment with anti-rheumatic medication. There are very few studies that have examined the
impact of CVD risk factors on the vasculature, and this
warrants further investigation. In particular, longitudinal
studies assessing the impact of interventions that reduce
CVD risk (such as exercise) on the vasculature are needed.
To our knowledge, there are only two studies that have
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well as multiple potential determining factors. Once it is
known what determines the impaired vascular function,
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Vascular Function and Morphology in Rheumatoid

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Vascular Function and Morphology in Rheumatoid

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RHEUMATOLOGY

Submitted 17 March 2011; revised version accepted 4 July 2011.

(CVD), which accounts for 3050% of all deaths [2, 3]. RA

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Aamer Sandoo et al.

Non-invasive assessments of the peripheral

appears to be greater when NO levels are reduced [43].

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with chronic inflammation [15, 16]. On the basis of this,

RA and endothelial dysfunction

FIG. 1 An overview of the vascular assessments performed in different vascular beds.

PWA and PWV

The reduction in NO bioactivity appears to be a key event

Measurement of the carotid intimamedia thickness

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Aamer Sandoo et al.

was awarded depending on adherence to these criteria,

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RA and endothelial dysfunction

reported in endothelial-independent function in the three

in diabetes this was due to classical CVD risk factors,

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Aamer Sandoo et al.

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RA and endothelial dysfunction

18 months and the study did not explore the effects of a

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reported to be predictive of greater arterial stiffness [88],

Aamer Sandoo et al.

treatment has also been reported [145]. In addition,

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In sum, the longitudinal studies reveal that the vascular

Online) and, unfortunately, none of these studies have

RA and endothelial dysfunction

The studies presented in the present review provide clear

Endothelial dysfunction is evident in patients with

Disclosure statement: The authors have declared no conflicts of interest.

3 DeMaria AN. Relative risk of cardiovascular events in

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Rheumatology key messages

2 Kitas GD, Erb N. Tackling ischaemic heart disease in

Aamer Sandoo et al.

20 Gonzalez-Gay MA, Gonzalez-Juanatey C, Martin J.

33 Anderson TJ, Uehata A, Gerhard MD et al. Close relation

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19 Zhang H, Park Y, Wu J et al. Role of TNF-alpha in vascular

32 Tio RA, Monnink SH, Amoroso G et al. Safety evaluation of

RA and endothelial dysfunction

48 Boo YC, Sorescu G, Boyd N et al. Shear stress stimulates

62 Dagassan PH, Breu V, Clozel M et al. Up-regulation of

52 Cracowski JL, Minson CT, Salvat-Melis M, Halliwill JR.

66 Wilkinson IB, Hall IR, MacCallum H et al. Pulse-wave

53 Ignarro LJ, Harbison RG, Wood KS, Kadowitz PJ.

67 Nichols WW. Clinical measurement of arterial stiffness

54 Jones KA, Wong GY, Jankowski CJ, Akao M, Warner DO.

69 Zieman SJ, Melenovsky V, Kass DA. Mechanisms,

55 Vallance P, Collier J, Moncada S. Effects of

68 Wilkinson IB, Qasem A, McEniery CM, Webb DJ,

70 Oren A, Vos LE, Uiterwaal CSPM, Grobbee DE, Bots ML.

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51 Corretti MC, Anderson TJ, Benjamin EJ et al. Guidelines

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coronary artery atherosclerosis. J Rheumatol 2007;34:

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