Vascular Function and Morphology in Rheumatoid

Original article

Vascular function and morphology in rheumatoidarthritis: a systematic review

Aamer Sandoo1,2, Jet J. C. S. Veldhuijzen van Zanten1,2, George S. Metsios1,Douglas Carroll2 and George D. Kitas1,3

Abstract

Objectives. RA associates with significantly increased morbidity and mortality from cardiovascular dis-

ease (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 predom-

inantly to systemic inflammation; and (iii) whether any changes of vascular function and morphology in RA

can be modified with therapy.

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 extra-

articular manifestations, including cardiovascular disease

(CVD), which accounts for 30�50% 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 abnorm-

alities [12], but also a complex interplay between the sys-

temic inflammation that characterizes RA, CVD risk

factors and vascular function [13�15].

The similarities between the chronic inflammatory pro-

cess in rheumatoid joints and other tissues, and the in-

flammatory 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

1Department of Rheumatology, Dudley Group of Hospitals NHS Trust,Russells Hall Hospital, Dudley, West Midlands, 2School of Sport andExercise Sciences, University of Birmingham, Birmingham and3Arthritis Research UK Epidemiology Unit, University of Manchester,Manchester, UK.

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: [email protected]

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

! The Author 2011. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]

RHEUMATOLOGY

Rheumatology 2011;50:2125�2139

doi:10.1093/rheumatology/ker275

Advance Access publication 16 September 2011

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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

[17�19], it has been speculated that RA disease-related

inflammation might be contributing to accelerated athero-

sclerosis [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 metabol-

ic 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 inflam-

mation 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 dis-

entangling these complex pathways and assess interven-

tions that may reduce CVD risk and improve outcome in

these patients.

Non-invasive assessments of the peripheralvasculature

Assessment of EC function in different vascular beds

The endothelium is the innermost layer of the blood ves-

sels and forms an important part of the vasculature: it

controls vascular function via the release of vaso-

active 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 environ-

ment within the vessel. Endothelial cell (EC) exposure

to injurious stimuli such as oxidative stress and/or inflam-

matory mediators, leads to disrupted production of

vasoactive factors; the ensuing imbalance is a major

contributor to ECD—an early indicator of atheroscler-

osis [31]. In recent years, a variety of non-invasive tech-

niques have been used to assess vascular function and

morphology as an easier and safer alternative to direct

assessment of the coronary arteries [32]. These assess-

ments are conducted in the peripheral circulation. Their

use is supported by studies showing that peripheral

vessel function correlates with the coronary circulation

[33�35], associates with traditional CVD risk factors [25]

and predicts future cardiovascular events in healthy older

individuals [36], patients with CVD [37�40] 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) prolif-

eration [42]. Although other factors, such as prostacyclin,

ET-1 and endothelium-derived hyperpolarizing factor, are

involved in vascular homeostasis, their contribution

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

Therefore, techniques assessing peripheral vascular func-

tion 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 bioavail-

ability involves a stimulus that increases NO production

from EC leading to subsequent vessel dilatation, which

can then be quantified. ECs often display different struc-

tures and phenotypes depending on the vessel type [44]

and have heterogeneous responses to stimulation in dif-

ferent vascular beds, and even in different sections of the

same vascular bed [45�47]. Thus, different types of as-

sessments are commonly used to measure endothelial

function in different vascular beds. For example, the in-

duction of increased blood flow (reactive hyperaemia)

exerts shear stress on EC, activating specific receptors

that cause an increase in NO bioavailability and conse-

quent vasodilatation [48, 49]. Reduced vasodilatation fol-

lowing an increase in shear forces is representative of

impaired NO bioavailability [50]. These phenomena can

be carefully created by the widely used method of flow-

mediated dilatation (FMD) in the large conduit vessels

(macrovessels) [51]. FMD involves occluding the blood

flow of conduit vessels for�5 min to create reactive hyper-

aemia. The subsequent dilatation that is expressed as a

percentage increase from the baseline diameter is mainly

dependent on NO activity, with a low percentage indicat-

ing poor endothelial function [51]. In contrast, in the small

resistance vessels (microvessels), NO activity is com-

monly examined via local administration of acetylcholine

(ACh) that binds to muscarinic receptors on EC and stimu-

lates 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 be-

tween ED and smooth muscle dysfunction, endothelium-

independent 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 vessel’s peak dilatory cap-

acity [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 fre-

quently 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 associ-

ation between functional and morphological changes in

the vessels of patients with early atherosclerosis [60].

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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 pro-

motes 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 sug-

gests 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 mea-

suring 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 pro-

duction 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 intima�media thickness

(cIMT) is a reliable indicator of more advanced, but still

subclinical atherosclerosis [59, 70]. The assessment de-

tects 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 percutan-

eous 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 dysli-

pidaemia [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 pro-

duction/expression of inflammatory cytokines, oxidative

stress, adhesion molecules and thrombotic factors

[71�73]. Increased cIMT has also been reported in hyper-

tensive, obese adolescents [74]. A brief overview of the

methods commonly used for assessing vascular morph-

ology are depicted in Fig. 1.

Methods

Following an RA-specific evidence-based tool for search-

ing 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 acti-

vated: humans, English language, clinical trial Phases I, II,

III and IV, comparative study, controlled clinical trial, tech-

nical report and validation studies. The Medical Subject

Heading (MeSH) term rheumatoid arthritis was employed

in combination with endothelial function (181 articles),

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

= functional assessments = structural assessments

Arteriole(resistance

vessel) Conduit artery

(brachial, radial or femoral)

Conducting artery (aorta, pulmonary or carotid artery)

Capillary

PWA and PWV

Nail-foldcapillaroscopy

Venous occlusion plethysmography

Laser Dopplerimaging

with Iontophoresis of ACh and SNP

FMDand GTN-

mediated dilatation

CIMT

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endothelial dysfunction (56 articles), laser Doppler flow-

metry (10 articles), laser Doppler imaging (7 articles),

forearm blood flow (3 articles), venous occlusion plethy-

smography (1 article), flow mediated dilatation/dilation

(7 articles), augmentation index (8 articles), PWA (9 art-

icles), PWV (8 articles), cIMT (9 articles) and atheroscler-

osis (58 articles). The initial search identified 357 articles.

The search was checked for duplicate articles that ap-

peared 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 partici-

pants with other types of inflammatory arthritis, degenera-

tive 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 art-

icles 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 art-

icles in the present review to 93. These included 57 cross-

sectional studies [13, 76�131], 27 longitudinal studies

without using randomization [92, 95, 125, 128, 132�154]

and 9 randomized controlled trials (RCTs) [131, 142,

155�161]. The assessments that were used in these

studies to examine vascular function and morphology in-

clude venous occlusion plethysmography, laser Doppler

imaging and flowmetry with iontophoresis, FMD, GTN-

mediated dilatation, PWA, PWV, cIMT and nail-fold capil-

laroscopy. For more detail about these assessments see

Fig. 1.

The quality of the RCTs was assessed using a previ-

ously described procedure [162]. For the cross-sectional

and longitudinal studies, a quality index (QI) score was

specifically developed. The criteria related to cross-

sectional 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 pa-

tients and controls, adherence to published laboratory

protocol guidelines (e.g. laboratory conditions, participant

preparation/condition, reproducibility, blinding of asses-

sor to test), statistical analysis (e.g. adjustment for group

differences) and performing associations between vascu-

lar 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 cate-

gories: follow-up assessments conducted by the same

assessor and statistical adjustment of factors that differ

between populations and/or follow-up. A graded score

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 re-

viewers (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) [76�79, 123]. Four studies in-

cluded 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 consist-

ently associated with inflammatory markers (Table 2). For

example, whereas CRP was associated with endothelium-

dependent function but not endothelium-independent

function in one study [77], the reverse has also been re-

ported [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 meas-

ures of inflammation has also been reported [79]. Given

the scarcity of available studies and the variety of meth-

ods applied, more research is needed to characterize

microvascular function and its associations with inflam-

mation in RA patients.

Macrovascular function

There are 13 cross-sectional studies that have as-

sessed macrovascular function in patients with RA (see

supplementary table 1, available as supplementary data

at Rheumatology Online, for details) [79�88, 124�126]. The

quality scores range from 32 to 96%, with an average of

64%. Eleven studies conducted a comparison of endothe-

lial function between RA patients and control participants

[79�85, 87, 88, 125, 126], eight of which showed attenu-

ated endothelium-dependent macrovascular function in

RA compared with controls (Table 1) [79, 81�85, 87, 88].

No differences between RA and control participants were


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reported in endothelial-independent function in the three

studies that explored this [80, 81, 85]. The decreased

endothelium-dependent macrovascular function, as-

sessed 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 sep-

arate 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 endothe-

lial 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 endothe-

lium-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 endothelium-

dependent macrovascular function is compromised in

RA compared with normal controls. The potential contri-

bution 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.

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 intima�media thickness in pa-

tients with RA

Study typeMicrovascular

functionMacrovascular

functionArterial

stiffnessIntima�media

thickness

Cross-sectional studies

Association 2 (67; 61�73) 3 (61; 32�77) 5 (72; 55�100) 8 (66; 32�90)

No association 2 (82; 67�96) 6 (73; 54�96) 10 (72; 54�96) 24 (68; 33�89)Not reported 1 (22) 4 (52; 36�67) 1 (36) 7 (42; 29�55)

Longitudinal studiesa

Association 1 (69)

No association 1 (65) 3 (60; 55�67) 2 (64; 38�90) 1 (55)Not reported 5 (53; 25�72) 10 (57; 23�88) 6 (62; 23�88) 4 (68; 58�77)

RCTsa

Association

No associationNot reported 7 (2; 1�3) 4 (2.3; 2�3) 3 (1.7; 1�2)

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 indisease activity and change in vascular function.

TABLE 1 Summary table of cross-sectional studies on microvascular function, macrovascular function, arterial stiffness

and intima�media thickness in patients with RA compared with control participants

OutcomeMicrovascular

functionMacrovascular

functionArterial

stiffnessIntima�media

thickness

RA worse than control 3 (54; 22�73) 8 (60; 32�73) 13 (68; 36�96) 24 (64; 32�90)RA not different from control 3 (76; 34�96) 1 (44) 4 (62; 33�77)

RA better than control 1 (96)

Values are represented as the number of studies (average QI, %; range) for the QI as described in the Methods section.



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Arterial stiffness

Sixteen cross-sectional studies have assessed ar-

terial 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, 87�96, 126, 127,

130, 163]. Fourteen studies examined the difference in

arterial stiffness between RA patients and a control

group [79, 80, 87�94, 126, 127, 130, 163] (Table 1). The

overwhelming majority of these studies have demon-

strated increased arterial stiffness in RA compared with

control participants [79, 80, 87�93, 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,

88�90, 93, 126, 127, 130, 163], while five studies, re-

ported such an association (average QI = 72%) [91, 92,

94�96].

cIMT

Most cross-sectional studies on vascular morphology in

RA (39 studies) have assessed cIMT [13, 82, 84�88, 91,

97�122, 125, 129, 130, 164, 165] (for details see supple-

mentary table 1, available as supplementary data at

Rheumatology Online) (average quality 63%, ranging

from 29 to 90%). Of the 30 studies that reported a com-

parison 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, 97�100, 104, 106,

108�114, 118�120, 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 asso-

ciated 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 lipopro-

teins 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 pro-

vide evidence for greater cIMT with longer disease dur-

ation [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

of cases. cIMT is known to increase with age in the gen-

eral population [167], and is also the most consistent de-

terminant 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 asso-

ciated with contemporary markers of disease activity

(Table 2). The majority of the studies do not find an asso-

ciation between IMT and measures of disease activity

[85, 86, 88, 91, 97, 98, 100, 102, 104, 106�108, 111,

112, 114�116, 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 be-

tween the associations found in healthy participants and

those found in RA patients might determine whether in-

flammation 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 independ-

ently 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 (supple-


Rheumatology Online). Few studies conducted power

analyses for the comparison between groups, and no

data are available on appropriate power to examine fac-

tors associated with vascular function in RA. This has pro-

found 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 char-

acteristic 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, 97�99, 119]. Thus, even though RA has been


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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 inflamma-

tion, other factors must be contributing. Unfortunately, to

our knowledge, little attention has been paid to other po-

tential influences. There is, however, preliminary evidence

of an interaction between inflammation and CVD risk fac-

tors affecting vascular function in RA [13]. A direct com-

parison 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.

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 [132�136, 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 inflam-

mation 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 func-

tion 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 character-

ized 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 anti-

inflammatory medications (in particular anti-TNF-a) on

macrovascular endothelial-dependent function [92, 120,

125, 137�147]. The average quality score is 58%, ranging

from 23 to 88%. All [92, 120, 137�147] but one [125] study

reported improvements in macrovascular endothelial func-

tion after treatment. Despite improvement in endothelial-

dependent function being observed for as long as

18 months [145], there are also reports of transient im-

provement 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 un-

altered following treatment; however, two studies re-

ported 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 func-

tion [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 em-

ploying 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 anti-

inflammatory medications on arterial stiffness, with an

average QI of 62%, ranging from 23 to 90% (supple-


Rheumatology Online) [92, 128, 136, 142, 151�154]. 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 im-

provement 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 treat-

ment [128]. Finally, the only two examinations of associ-

ations 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 55�77%) 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 treat-

ment [150], but no change in response to anti-TNF



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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 con-

trol 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 in-

cluded small sample sizes, and no power calculations

were conducted in order to determine the sample size

for these analyses.

Summary of longitudinal studies

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 evi-

dence 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 patient’s clinical response to treatment. For example,

classification of ‘responders’ or ‘non-responders’ accord-

ing to European League Against Rheumatism (EULAR)

response criteria [170] revealed that patients who re-

sponded 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-atreatment 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 endo-

thelial function rather than any specific effect of medi-

cation. 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

[137�139, 145]; therefore, further research that character-

izes endothelial function according to clinical response

using established guidelines (e.g. EULAR response cri-

teria) 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 under-

powered to analyse these associations.

RCTs

In comparison with longitudinal studies, RCTs on vascular

function or morphology are even scarcer (supplementary

table 3, available as supplementary data at Rheumatology

Online) and, unfortunately, none of these studies have

reported the associations between changes in vascular

function and disease activity (Table 2). The follow-

ing section details the studies according to the treat-

ment group the patients were randomized to and also

provides a quality score based on previously developed

criteria [162].

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,

155�157, 165] (supplementary table 3, available as sup-

plementary data at Rheumatology Online). IL-1 receptor

antagonist (anakinra) was associated with an acute im-

provement 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 no-

prednisolone 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 infor-

mation on changes in cIMT or FMD as a result of treat-

ment 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 fol-

lowing 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 2�8 weeks [158�161] (supple-


Rheumatology Online). Overall these medications im-

proved FMD and arterial stiffness [158�161], which is in

line with studies in other populations [171, 172]. This em-

phasizes the potential importance of classical CVD risk

factors in vascular function in RA, in particular the influ-

ence 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 endothelial-

independent function following treatment.

Summary of RCTs

The findings of the RCTs suggest that treatment with car-

diovascular medications may have a greater beneficial

effect on endothelial function than treatment with

anti-inflammatory medications. However, given the pau-

city 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.


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Conclusion

The studies presented in the present review provide clear

evidence that vascular function and morphology are

impaired in patients with RA. In addition, the relation-

ship between systemic markers of inflammation and vas-

cular function and morphology is not wholly supported by

cross-sectional or longitudinal studies. This is accentu-

ated by the inconsistent findings in vascular function or

morphology following treatment with anti-rheumatic medi-

cation. 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

assessed accelerated atherosclerosis in RA. In both these

studies, the increase in IMT was greater in RA patients

compared with age- and sex-matched healthy controls

[125, 149]. Unfortunately, with disease activity only as-

sessed at baseline, a direct link between change in inflam-

mation and IMT could not be explored. Longitudinal

studies are necessary to explore the concept of acceler-

ated atherosclerosis further. In order to determine how

fluctuations in disease activity influence vascular changes

over time, measurements must be made over a protracted

period. The vascular assessments described in this review

are generally considered to be associated with an

increased risk for cardiovascular death. There is evidence

for this in the general population [173], but only one study

with a small sample has reported that high levels of IMT

are predictive of hard cardiac end points in RA [174].

Therefore, in order to understand if and how vascular

function is predictive for cardiovascular events, detailed

longitudinal assessments are necessary. These assess-

ments should include multiple vascular parameters as

well as multiple potential determining factors. Once it is

known what determines the impaired vascular function,

interventions, either through medication and/or behaviour-

al change, can be developed to improve vascular function

as well as morphology in RA.

Rheumatology key messages

. Endothelial dysfunction is evident in patients withRA.

. The link between endothelial dysfunction and in-flammation is not wholly supported by the availableliterature.

. Long-term studies examining specific predictors ofendothelial dysfunction in RA are needed.

Disclosure statement: The authors have declared no con-

flicts of interest.

Supplementary data

Supplementary data are available at Rheumatology

Online.

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