Clinical Study Methotrexate, Cyclosporine A, and Biologics...
9
Clinical Study Methotrexate, Cyclosporine A, and Biologics Protect against Atherosclerosis in Rheumatoid Arthritis BartBomiej Kisiel, 1 Robert Kruszewski, 1 Aleksandra Juszkiewicz, 1 Anna Raczkiewicz, 1 Artur Bachta, 1 MaBgorzata TBustochowicz, 1 Jadwiga Staniszewska-Varga, 1 Krzysztof KBos, 2 Krzysztof Duda, 3 Romana BogusBawska-Walecka, 3 RafaB PBoski, 4 and Witold TBustochowicz 1 1 Department of Internal Diseases and Rheumatology, Military Institute of Medicine, Ulica Szaser´ ow 128, 04-141 Warszawa, Poland 2 Department of Infectious Diseases and Allergology, Military Institute of Medicine, Ulica Szaser´ ow 128, 04-141 Warszawa, Poland 3 Department of Radiology, Military Institute of Medicine, Ulica Szaser´ ow 128, 04-141 Warszawa, Poland 4 Department of Medical Genetics, Medical University in Warsaw, Ulica Pawi´ nskiego 3c, 02-106 Warszawa, Poland Correspondence should be addressed to Bartłomiej Kisiel; [email protected] Received 10 September 2014; Revised 16 January 2015; Accepted 20 January 2015 Academic Editor: Clelia M. Riera Copyright © 2015 Bartłomiej Kisiel et al. is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. e risk of cardiovascular disease is increased in rheumatoid arthritis (RA). A meta-analysis showed increased intima media thickness (IMT) in RA. It has been shown that disease modifying antirheumatic drugs (DMARDs) may influence the progression of atherosclerosis. However, it was suggested that biologics may be more efficient than other DMARDs (including methotrexate—MTX) in protecting against atherosclerosis. Objectives. e aim of this study was to assess the influence of different RA characteristics and treatment regimens on IMT and atherosclerotic plaques. Patients and Methods. 317 RA patients and 111 controls were included in the study. IMT was measured in carotid (CIMT) and femoral (FIMT) arteries. Arteries were screened for the presence of plaques. Results. CIMT, FIMT, and prevalence of plaques were lower in patients treated with methotrexate (MTX) ≥ 20 mg/wk, cyclosporine (CsA), or biologics than in patients treated with lower doses of MTX and other disease modifying antirheumatic drugs. No differences in IMT between patients treated with MTX ≥ 20 mg/wk, biologics, or CsA were found. Conclusions. We found a beneficial effect of MTX ≥ 20 mg/wk, biologics, and CsA on atherosclerosis. We do not confirm a stronger influence of biologics on IMT compared with therapeutic doses of MTX. 1. Introduction Cardiovascular disease (CVD) morbidity and mortality rates are increased in RA patients compared to general population [1]. It is estimated that CVD in RA leads to an excess 35–50% of the mortality rate in comparison to general population and reduces life expectancy by 5–10 years [2, 3]. e pathogenesis of accelerated atherosclerosis in RA is postulated to be multi- factorial. It has been shown that traditional CV risk factors like hypertension, diabetes, and hyperlipidemia contribute to the development of atherosclerosis in RA. However, the excess CV risk in RA persists aſter adjustment for established CV risk factors; thus RA is considered as an independent CV risk factor [4–7]. Several noninvasive diagnostic tools such as assessment of endothelial function, measurement of carotid intima media thickness (CIMT), and assessment of coronary artery calcification score may be used to detect subclinical ath- erosclerosis. A meta-analysis showed that CIMT predicts future vascular events in healthy individuals [8]. Some studies suggest that carotid and femoral arteries respond differently to CV risk factors and that inclusion of femoral artery IMT measurements would add information to that provided by the common carotid artery [9]. Studies in RA patients showed a decrease in flow medi- ated dilatation and an increase in augmentation index and pulse wave velocity, which suggests endothelial dysfunction [10–13]. Several studies have also shown increased CIMT and Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 759610, 8 pages http://dx.doi.org/10.1155/2015/759610
Transcript of Clinical Study Methotrexate, Cyclosporine A, and Biologics...
Clinical StudyMethotrexate Cyclosporine A and Biologics Protect againstAtherosclerosis in Rheumatoid Arthritis
BartBomiej Kisiel1 Robert Kruszewski1 Aleksandra Juszkiewicz1
Anna Raczkiewicz1 Artur Bachta1 MaBgorzata TBustochowicz1
Jadwiga Staniszewska-Varga1 Krzysztof KBos2 Krzysztof Duda3
Romana BogusBawska-Walecka3 RafaB PBoski4 and Witold TBustochowicz1
1Department of Internal Diseases and Rheumatology Military Institute of Medicine Ulica Szaserow 128 04-141 Warszawa Poland2Department of Infectious Diseases and Allergology Military Institute of Medicine Ulica Szaserow 128 04-141 Warszawa Poland3Department of Radiology Military Institute of Medicine Ulica Szaserow 128 04-141 Warszawa Poland4Department of Medical Genetics Medical University in Warsaw Ulica Pawinskiego 3c 02-106 Warszawa Poland
Correspondence should be addressed to Bartłomiej Kisiel bartlomiejkisielwppl
Received 10 September 2014 Revised 16 January 2015 Accepted 20 January 2015
Academic Editor Clelia M Riera
Copyright copy 2015 Bartłomiej Kisiel et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
IntroductionThe risk of cardiovascular disease is increased in rheumatoid arthritis (RA) Ameta-analysis showed increased intimamedia thickness (IMT) in RA It has been shown that disease modifying antirheumatic drugs (DMARDs) may influence theprogression of atherosclerosis However it was suggested that biologics may be more efficient than other DMARDs (includingmethotrexatemdashMTX) in protecting against atherosclerosisObjectives The aim of this study was to assess the influence of differentRA characteristics and treatment regimens on IMT and atherosclerotic plaques Patients and Methods 317 RA patients and 111controls were included in the study IMT was measured in carotid (CIMT) and femoral (FIMT) arteries Arteries were screenedfor the presence of plaques Results CIMT FIMT and prevalence of plaques were lower in patients treated with methotrexate(MTX) ge 20mgwk cyclosporine (CsA) or biologics than in patients treated with lower doses ofMTX and other diseasemodifyingantirheumatic drugs No differences in IMT between patients treated with MTX ge 20mgwk biologics or CsA were foundConclusions We found a beneficial effect of MTX ge 20mgwk biologics and CsA on atherosclerosis We do not confirm a strongerinfluence of biologics on IMT compared with therapeutic doses of MTX
1 Introduction
Cardiovascular disease (CVD) morbidity and mortality ratesare increased in RA patients compared to general population[1] It is estimated that CVD in RA leads to an excess 35ndash50of themortality rate in comparison to general population andreduces life expectancy by 5ndash10 years [2 3]The pathogenesisof accelerated atherosclerosis in RA is postulated to be multi-factorial It has been shown that traditional CV risk factorslike hypertension diabetes and hyperlipidemia contributeto the development of atherosclerosis in RA However theexcess CV risk in RA persists after adjustment for establishedCV risk factors thus RA is considered as an independent CVrisk factor [4ndash7]
Several noninvasive diagnostic tools such as assessmentof endothelial function measurement of carotid intimamedia thickness (CIMT) and assessment of coronary arterycalcification score may be used to detect subclinical ath-erosclerosis A meta-analysis showed that CIMT predictsfuture vascular events in healthy individuals [8] Some studiessuggest that carotid and femoral arteries respond differentlyto CV risk factors and that inclusion of femoral artery IMTmeasurements would add information to that provided by thecommon carotid artery [9]
Studies in RA patients showed a decrease in flow medi-ated dilatation and an increase in augmentation index andpulse wave velocity which suggests endothelial dysfunction[10ndash13] Several studies have also shown increased CIMT and
Hindawi Publishing CorporationJournal of Immunology ResearchVolume 2015 Article ID 759610 8 pageshttpdxdoiorg1011552015759610
2 Journal of Immunology Research
formation of plaques within the carotid artery in RA [10 1314] Increased CIMT in RA patients was also confirmed by ameta-analysis [15]
Several studies have focused on the influence of classicalCV risk factors and disease-related factors on atherosclerosisin RA Smoking is one of the most important CV risk factorsbut it is also known as a risk factor for the development ofRA [16] Thus smoking is frequently seen in RA patients andmay provide a potential bias in studies on RA and CVD [17]The relation between body mass index (BMI) RA and CVDis also complex On the one hand obesity is associated withCV morbidity and mortality [18 19] On the other hand CVmortality is also increased in RA patients with a BMI below20 kgm2 [20] A possible explanation for this excess CV riskis that low BMI may indicate the presence of rheumatoidcachexia [17] Hypertension another classical CV risk factoris common in RA and was shown to be associated withatherosclerosis [17 21] The relation between lipid profile andCVD in RA is complex The active inflammatory state ofRA may lower levels of circulating lipids (ie total LDLand HDL cholesterol and triglycerides) [22] However thesechanges in lipid profile are associated with increased CV riskThis phenomenon is called lipid paradox and is probablydue not only to low levels of HDL cholesterol but also tostructural and functional changes of HDL [23 24] Treatmentwith disease modifying antirheumatic drugs (DMARDs) wasshown to increase lipid levels However it is believed thatthese changes may reflect normalization of the lipid profileThus the interpretation of lipid levels for predicting CV riskin RA patients should be cautious [25]
Among RA-related factors influencing atherosclerosisinflammation seems to play a major role Wallberg-Jonssonet al found that high disease activity was associated withincreased risk of CV event and decreased life span [26]A study by Maradit-Kremers et al showed that markers ofsystemic inflammation confer additional risk for CV deathamong patients with RA [2] Innala et al reported thaterythrocyte sedimentation rate (ESR) and cumulative diseaseactivity (defined as area under the curve DAS28) increaseda hazard rate for a new CV event [27] Several studies alsofound the association between markers of inflammation andsubclinical atherosclerosis ESR andC-reactive protein (CRP)were found to be associated with CIMT atheroscleroticplaques arterial stiffness flow-mediated dilatation (FMD)and glyceryl trinitrate-mediated dilatation (GMD) [5 28ndash31] On the other hand some studies failed to find theassociation between cumulative inflammation and markersof atherosclerosis [32ndash34] Other RA-related factors whichmay predict progression of atherosclerosis are rheumatoidfactor (RF) anti-citrullinated peptide antibodies (ACPA)disease duration and radiological damage index [5 34 35]
It is well established that DMARDs therapy decreasesCV morbidity and mortality However most studies focusedon methotrexate (MTX) and biologics while little is knownabout other DMARDs Moreover only few reports comparedinfluence of different DMARDs on subclinical atherosclero-sis A prospective study by Choi et al showed that treatmentwith methotrexate reduces CVmortality in RA patients [36]
A systematic review confirmed that the use ofMTXdecreasesCV morbidity and mortality [37] Few small studies founda beneficial effect of combined DMARDs therapy (MTXhydroxychloroquine and sulfasalazine) on CIMT FMD andGMD [31 38 39] Several studies showed a beneficial effectof anti-TNF-120572 therapy on subclinical atherosclerosis [40ndash42]and systematic review by Westlake et al confirmed that anti-TNF-120572 therapy reduces the likelihood of CVD in RA [43]Interestingly some studies suggest that biologicsmay bemoreefficient than MTX in protecting against atherosclerosis inRA A study by Giles et al showed slower progression ofCIMT in patients treated with anti-TNF-120572 compared to thosenot receiving treatment such association was not observedwith other DMARDs [44] Similarly an analysis of largeRA registry (CORRONA) showed reduction of CV eventsrisk in patients treated with anti-TNF-120572 compared withpatients treatedwithMTXandother nonbiologicalDMARDs[45]
The aim of this study was to assess the influence of dif-ferent RA characteristics and treatment regimens on CIMTFIMT and atherosclerotic plaques
2 Materials and Methods
The study was approved by the local ethical committee Allparticipants signed an informed consent form
21 Patients 317 RA patients fulfilling the 1987 ACR criteriawere recruited Exclusion criteria comprised diabetes melli-tus coronary artery disease and history of stroke A completehistory physical examination and laboratory evaluationwereperformed and recorded in a standard protocol (Table 1)All DMARDs ever used were recorded unless treatmentduration was lt3 months Patients were divided into 2 groupscontinuously (cDMARDs) and discontinuously (dDMARDs)treated with DMARDs (treatment with DMARDS ge 90 andlt90 of RA duration resp) Hands and feet X-rays wereperformed in most patients RA activity was assessed withDAS28 Framingham 10-year risk score (FSS) was used toestimate general CV risk related to classical risk factors[46]
22 Controls 111 age- and sex-matched healthy individualswere included in the control group Clinical and laboratorydata are summarized in Table 1
23 Ultrasonography IMT was measured on the far wallof the common carotid and superficial femoral arteriesAtherosclerotic plaque was defined as a focal structure thatencroaches into the arterial lumen of at least 05mm or50 of the surrounding IMT or demonstrates a thickness ofge15mm as measured from the media-adventitia interface tothe intima-arterial lumen interface CIMT and FIMT weredefined as a mean value of 6 measurements (CIMT 1 2and 3 cm proximal to the bifurcation bilaterally FIMT 12 and 3 cm distal to the bifurcation bilaterally) Commoncarotid and superficial femoral arteries were investigated forthe presence of plaques
Journal of Immunology Research 3
Table 1 Study and control group characteristics
RA (119899 = 317) Controls (119899 = 111) 119875 valueAge years 5761 (1262) 5550 (937) 01Males 58 (1830) 22 (1981) 07Ever-smokers 140 (4416) 62 (5586) 004Pack-years 966 (1604) 1313 (1820) 006BMI kgm2 2554 (437) 2746 (469) 00001Hypertension 137 (4322) 38 (3423) 01Creatinine mgdL 073 (027)Dagger 065 (007)998787 03ESR mmh 3177 (2364) 1063 (919) lt1 times 10
minus6
CRP mgdL 215 (32) 043 (0641) lt1 times 10minus6
Total cholesterol mgdL 2038 (413) 2158 (443) 001LDL cholesterol mgdL 1157 (343)dagger 1274 (405) 0004HDL cholesterol mgdL 632 (197)dagger 665 (19) 01Triglycerides mgdL 1286 (605)dagger 1162 (568) 006Framingham 10-year risk score 717 (54)dagger 786 (632) 03Presence of atherosclerotic plaques in carotid andor femoral arteries 74 (2334) 14 (1261) 0015CIMT mm 0718 (0181) 0682 (0167) 007FIMT mm 0516 (0168) 0457 (0099) 00005Disease duration years 1074 (898)Methotrexate ever 303 (9558)Sulphasalazine ever 148 (4669)Hydroxychloroquine or chloroquine ever 98 (3091)Gold salts ever 46 (1451)Azathioprine ever 18 (568)Cyclophosphamide ever 7 (221)Cyclosporine A ever 77 (2429)Leflunomide ever 123 (388)Biologic agents ever 61 (1924)Infliximab ever 24 (757)Adalimumab ever 12 (378)Etanercept ever 39 (123)Rituximab ever 13 (41)Continuous treatment with DMARDs 141 (4519)para
RF positivity 217 (7068)
ACPA positivity 211 (7729)sect
DAS28 47 (155)Presence of erosions in hand andor feet X-ray 176 (7097)998771
Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables paraData available for 312 patientsData available for 307 patients sectData available for 273 patients DaggerData available for 286 patients daggerData available for 302 patients 998771Data available for 248patients 998787Data available for 102 patients
24 Statistical Analysis All statistical tests were performedwith STATISTICA 100 (StatSoft) Results are reported asmean (SD) for continuous variables and 119899 () for categoricalvariables According to data distribution a parametric (119905-test) or nonparametric (119880 Mann-Whitney) test was usedCategorical variables were compared with chi square exacttest A 119875 value lt 005 was considered significant
3 Results and Discussion
31 Results Patients and controls were age- and sex-matchedThe percentage of ever-smokers LDL and total cholesterol
concentrations and BMI were higher in controls than inRA (Table 1) However total CV risk calculated with FSSwas similar in both groups CIMT and FIMT were higherin RA but only the difference in FIMT was significantAtherosclerotic plaques were more prevalent in RA
The presence of plaques in RA was positively correlatedwith ESR creatinine concentration FSS and presence ofrheumatoid factor (RF) (Table 2) Analysis for associationsbetween plaques and treatment with DMARDs showed asignificant negative correlation between presence of plaquesand treatment with methotrexate (MTX) cyclosporineA (CsA) and biologics Plaques were insignificantly
4 Journal of Immunology Research
Table 2 Associations between presence of atherosclerotic plaques and clinical laboratory and radiological characteristics and use of differentDMARDs
Presence of atherosclerotic plaques incarotid andor femoral arteries
(119899 = 74)
Lack of atherosclerotic plaques incarotid and femoral arteries
(119899 = 242)119875
RA duration years 1054 (941) 1076 (886) 08ESR mmh 3117 (2439) 2249 (214) 00008CRP mgdL 199 (29) 142 (266) 007Creatinine mgdL 081 (03) 07 (021) 00007DAS28 463 (151) 473 (157) 06Framingham 10-year risk score 101 (622) 601 (516) lt1 times 10
minus6
Methotrexate ever 65 (8784) 237 (9793) 00002Sulphasalazine ever 30 (4054) 117 (4835) 02Hydroxychloroquine or chloroquine ever 22 (2972) 76 (314) 08Gold salts ever 8 (1081) 38 (157) 03Azathioprine ever 5 (676) 13 (537) 07Cyclophosphamide ever 2 (27) 5 (207) 07Cyclosporine A ever 10 (1351) 67 (2769) 001Leflunomide ever 28 (3784) 95 (3926) 08Biologic agents ever 5 (676) 56 (2314) 0002Infliximab ever 1 (135) 23 (95) 002Adalimumab ever 0 (0) 12 (496) 00503Etanercept ever 2 (27) 37 (1529) 0004Rituximab ever 0 (0) 13 (537) 004Continuous treatment with DMARDs 27 (3649) 114 (4711) 01RF positivity 59 (7973) 158 (6781)998771 00497ACPA positivity 49 (7656) 162 (7751)dagger 09Presence of erosions in hand andor feet X-ray 42 (6858)Dagger 134 (7166)sect 08Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables Data available for 64 patientsDaggerData available for 61 patients 998771Data available for 233 patients daggerData available for 209 patients sectData available for 187 patients
more prevalent in dDMARDs group than in cDMARDsgroup
We found a positive correlation between CIMT FIMTand FSS (119903 = 0488 119875 lt 0001 and 119903 = 0434 119875 lt 0001resp) ESR (119903 = 0132 119875 = 0018 and 119903 = 0199 119875 lt0001) and creatinine concentration (119903 = 02 119875 lt 0001and 119903 = 0212 119875 lt 0001) However after adjustment forage associations with creatinine became insignificant Nosignificant associations were found between CIMT FIMTand RA duration CRP concentration and DAS28 (data notshown)
CIMT and FIMT were significantly lower in cDMARDsgroup compared with dDMARDs group (Table 3) The asso-ciation remained significant after adjustment for classicalCV risk factors The use of MTX was associated with lowerFIMT Comparison of different doses of MTX revealedsignificantly lower CIMT and FIMT in patients treatedwith doses ge 20mgwk correlation remained significantafter adjustment for classical CV risk factors CIMT wasalso significantly lower in patients treated with CsA andbiologics A similar correlation was observed between CsAbiologics and FIMT but it became insignificant after cor-rection for CV risk factors We did not find significant
differences in CIMT and FIMT in pairwise comparisonsbetween patients treated with MTX ge 20mgwk biolog-ics or CsA (further named MTX20(+)CsA(+)biologics(+)group) a comparison of this group with patients treatedwith different DMARDslower doses ofMTX (further namedMTX20(minus)CsA(minus)biologics(minus) group) revealed a robustdifference in CIMT (0104mm 119875 = 1 times 10minus6) and FIMT(0081mm 119875 = 5 times 10minus5) Interestingly RA activity(measured by DAS28) was similar in both groups 464(154) versus 483 (157) 119875 = 03 No significant differencesin classical CV risk factors were found between patientstreated with MTX ge 20mgwk biologics or CsA CIMT inMTX20(+)CsA(+)biologics(+) was comparable to controlsFIMT was slightly higher in MTX20(+)CsA(+)biologics(+)group than in controls No correlations were found betweenCIMT and FIMT and presence of RF ACPA and boneerosions
32 Discussion RA patients are at higher risk of CVDthan an age-matched general population It is estimatedthat CV risk in RA is increased to a similar magnitude tothat seen in type 2 diabetes [47] Studies assessing IMTin RA showed conflicting results but two meta-analyses
Journal of Immunology Research 5
Table3As
sociations
betweenIM
Tanduseo
fdifferentD
MARD
stre
atmentregim
enpresenceo
fRFAC
PAand
erosions
Sign
ificant
differences
incla
ssicalCV
riskfactors(ieageBM
Ism
okinghypertensio
nlip
idprofi
leandFS
S)betweengrou
psCI
MT
FIMT
CIMTmm
119875119875adj
FIMTmm
119875119875adj
MTX
(+)v
ersusM
TX(minus)
mdash0716(017
8)versus
0784(0235)
02
0511(0159)
versus
0628(0293)
001
003
MTXge20
mgwkversus
MTXlt20
mgwk
MTXge20
mgwkgrou
pwas
youn
ger(5577y
rsversus
5985y
rs)
andhadlower
FSS(657versus
792)
0687(017
1)versus
0758(018
6)000
05000
90492(012
6)versus
0546(0206)
000
4004
Sulphasalazine(+)v
ersussulph
asalazine(minus)
mdash0707(016
8)versus
0731(0192)
02
0505(013
8)versus
0526(019
2)03
Hydroxychloroqu
inechloroqu
ine(+)
versus
hydroxychloroq
uinechloroq
uine(minus)
mdash0703(018
1)versus
0727(018
1)03
0517(016
3)versus
0515(018
1)09
Goldsalts(+)v
ersusg
oldsalts(minus)
mdash0682(013
9)versus
0726(018
7)01
0494(016
6)versus
0520(016
9)03
Azathioprine(+)
versus
azathiop
rine(minus)
mdash0731(0216)
versus
0719(017
9)08
0518(0110)
versus
0516(017
2)096
Cyclo
phosph
amide(+)
versus
cyclo
phosph
amide(minus)
mdash0745(0205)v
ersus0
719
(018
1)07
0669(0427)v
ersus0
512
(015
8)001
02
Cyclo
sporine(+)
versus
cyclo
sporine(minus)
CsA(+)g
roup
was
youn
ger(5303y
rsversus
5846y
rs)a
ndhad
lower
FSS(591v
ersus759)and
hypertensio
nwas
lessprevalent
inthisgrou
p(3247versus
4644
)0665(016
5)versus
0737(018
3)0002
003
0471(0095)
versus
0530(018
4)0007
006
Leflu
nomide(+)
versus
leflu
nomide(minus)
mdash0719(0174)
versus
0720(018
6)096
0514(016
1)versus
0517(0174)
09
Biologicagents(
+)versus
biologicagents(minus)
Biologicagents(
+)grou
pwas
youn
ger(5324y
rsversus
5831
yrs)
0663(016
5)versus
0733(018
2)000
6004
0477(012
4)versus
0525(017
7)004
02
MTX
20(+)Cs
A(+)biologics(+)
versus
MTX
20(minus)Cs
A(minus)biologics(minus)
MTX
20(+)Cs
A(+)biologics(+)
grou
pwas
youn
ger(5547y
rsversus
6159y
rs)a
ndhadlower
FSS(638versus
882)
0684(016
9)versus
0788(018
6)1times10minus6
2times10minus5
0489(012
3)versus
0570(0227)5times10minus5
6times10minus4
MTX
20(+)Cs
A(+)biologics(+)
versus
controls
mdash0684(016
9)versus
0682(016
7)094
0489(012
3)versus
0457(0099)
002
002
MTX
20(+)biologics(minus)v
ersusb
iologics(+)M
TX20(minus)mdash
0703(017
3)versus
0708(017
2)09
0493(012
8)versus
0458(012
3)02
Biologics(+)CsA
(minus)v
ersusC
sA(+)biologics(minus)
mdash0655(018
1)versus
0662(0176)
09
0476(015
5)versus
046
7(010
2)03
CsA(+)MTX
20(minus)v
ersusM
TX20(+)Cs
A(minus)
mdash0661(0144)
versus
0696(016
8)03
0473(0076)v
ersus0
500
(013
4)03
MTXge20biologics(minus)Cs
A(minus)v
ersus
MTXlt20biologics(minus)Cs
A(minus)
MTXge20biologics(minus)Cs
A(minus)g
roup
was
youn
ger(5641yrs
versus
6039
yrs)andhadlower
FSS(671v
ersus8
01)
0708(016
4)versus
0791(0188)
000
090008
0502(013
0)versus
0577(0227)
000
4002
cDMARD
sversusd
DMARD
scD
MARD
sgroup
was
youn
ger(5453
yrsv
ersus5
962y
rs)
0683(017
7)versus
0746(018
2)0002
002
0485(0114)
versus
0544(0200)
0002
001
RF(+)v
ersusR
F(minus)
mdash0733(018
9)versus
0690(016
0)006
0524(016
4)versus
0506(018
2)04
ACPA
(+)v
ersusA
CPA(minus)
mdash0720(018
0)versus
0702(0202)
05
0525(017
1)versus
0480(014
8)006
Bone
erosions(+)v
ersusb
onee
rosio
ns(minus)
mdash0730(019
0)versus
0721(0174)
08
0530(018
4)versus
0501(0121)
02
Dataispresentedas
mean(stand
arddeviation)B
iologics(+)MTX
20(minus)patie
ntstreated
with
biologicsb
utnevertreated
with
MTXge20
mgwkBiologics(+)CsA
(minus)patie
ntstreated
with
biologicsb
utnever
treated
with
CsAC
sA(+)MTX
20(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
MTXge20
mgwkCs
A(+)biologics(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
biologicsMTX
20(+)biologics(minus)
patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsMTX
20(+)Cs
A(minus)patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
CsAM
TX20(+)Cs
A(+)biologics(+)p
atientstreated
with
MTXge20
mgwkandor
CsAandor
biologicagents
MTX
20(minus)Cs
A(minus)biologics(minus)patientsn
ever
treated
with
CsAb
iologicagents
andMTXge20
mgwk
MTXge20biologics(minus)Cs
A(minus)patie
nts
treated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsa
ndCs
AM
TXlt20biologics(minus)Cs
A(minus)patie
ntstreated
with
MTXlt20
mgwkbu
tnever
treated
with
biologicsa
ndCs
A119875
adj119875valuefor
analysis
adjuste
dforc
lassicalCV
Dris
kfactors
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
2 Journal of Immunology Research
formation of plaques within the carotid artery in RA [10 1314] Increased CIMT in RA patients was also confirmed by ameta-analysis [15]
Several studies have focused on the influence of classicalCV risk factors and disease-related factors on atherosclerosisin RA Smoking is one of the most important CV risk factorsbut it is also known as a risk factor for the development ofRA [16] Thus smoking is frequently seen in RA patients andmay provide a potential bias in studies on RA and CVD [17]The relation between body mass index (BMI) RA and CVDis also complex On the one hand obesity is associated withCV morbidity and mortality [18 19] On the other hand CVmortality is also increased in RA patients with a BMI below20 kgm2 [20] A possible explanation for this excess CV riskis that low BMI may indicate the presence of rheumatoidcachexia [17] Hypertension another classical CV risk factoris common in RA and was shown to be associated withatherosclerosis [17 21] The relation between lipid profile andCVD in RA is complex The active inflammatory state ofRA may lower levels of circulating lipids (ie total LDLand HDL cholesterol and triglycerides) [22] However thesechanges in lipid profile are associated with increased CV riskThis phenomenon is called lipid paradox and is probablydue not only to low levels of HDL cholesterol but also tostructural and functional changes of HDL [23 24] Treatmentwith disease modifying antirheumatic drugs (DMARDs) wasshown to increase lipid levels However it is believed thatthese changes may reflect normalization of the lipid profileThus the interpretation of lipid levels for predicting CV riskin RA patients should be cautious [25]
Among RA-related factors influencing atherosclerosisinflammation seems to play a major role Wallberg-Jonssonet al found that high disease activity was associated withincreased risk of CV event and decreased life span [26]A study by Maradit-Kremers et al showed that markers ofsystemic inflammation confer additional risk for CV deathamong patients with RA [2] Innala et al reported thaterythrocyte sedimentation rate (ESR) and cumulative diseaseactivity (defined as area under the curve DAS28) increaseda hazard rate for a new CV event [27] Several studies alsofound the association between markers of inflammation andsubclinical atherosclerosis ESR andC-reactive protein (CRP)were found to be associated with CIMT atheroscleroticplaques arterial stiffness flow-mediated dilatation (FMD)and glyceryl trinitrate-mediated dilatation (GMD) [5 28ndash31] On the other hand some studies failed to find theassociation between cumulative inflammation and markersof atherosclerosis [32ndash34] Other RA-related factors whichmay predict progression of atherosclerosis are rheumatoidfactor (RF) anti-citrullinated peptide antibodies (ACPA)disease duration and radiological damage index [5 34 35]
It is well established that DMARDs therapy decreasesCV morbidity and mortality However most studies focusedon methotrexate (MTX) and biologics while little is knownabout other DMARDs Moreover only few reports comparedinfluence of different DMARDs on subclinical atherosclero-sis A prospective study by Choi et al showed that treatmentwith methotrexate reduces CVmortality in RA patients [36]
A systematic review confirmed that the use ofMTXdecreasesCV morbidity and mortality [37] Few small studies founda beneficial effect of combined DMARDs therapy (MTXhydroxychloroquine and sulfasalazine) on CIMT FMD andGMD [31 38 39] Several studies showed a beneficial effectof anti-TNF-120572 therapy on subclinical atherosclerosis [40ndash42]and systematic review by Westlake et al confirmed that anti-TNF-120572 therapy reduces the likelihood of CVD in RA [43]Interestingly some studies suggest that biologicsmay bemoreefficient than MTX in protecting against atherosclerosis inRA A study by Giles et al showed slower progression ofCIMT in patients treated with anti-TNF-120572 compared to thosenot receiving treatment such association was not observedwith other DMARDs [44] Similarly an analysis of largeRA registry (CORRONA) showed reduction of CV eventsrisk in patients treated with anti-TNF-120572 compared withpatients treatedwithMTXandother nonbiologicalDMARDs[45]
The aim of this study was to assess the influence of dif-ferent RA characteristics and treatment regimens on CIMTFIMT and atherosclerotic plaques
2 Materials and Methods
The study was approved by the local ethical committee Allparticipants signed an informed consent form
21 Patients 317 RA patients fulfilling the 1987 ACR criteriawere recruited Exclusion criteria comprised diabetes melli-tus coronary artery disease and history of stroke A completehistory physical examination and laboratory evaluationwereperformed and recorded in a standard protocol (Table 1)All DMARDs ever used were recorded unless treatmentduration was lt3 months Patients were divided into 2 groupscontinuously (cDMARDs) and discontinuously (dDMARDs)treated with DMARDs (treatment with DMARDS ge 90 andlt90 of RA duration resp) Hands and feet X-rays wereperformed in most patients RA activity was assessed withDAS28 Framingham 10-year risk score (FSS) was used toestimate general CV risk related to classical risk factors[46]
22 Controls 111 age- and sex-matched healthy individualswere included in the control group Clinical and laboratorydata are summarized in Table 1
23 Ultrasonography IMT was measured on the far wallof the common carotid and superficial femoral arteriesAtherosclerotic plaque was defined as a focal structure thatencroaches into the arterial lumen of at least 05mm or50 of the surrounding IMT or demonstrates a thickness ofge15mm as measured from the media-adventitia interface tothe intima-arterial lumen interface CIMT and FIMT weredefined as a mean value of 6 measurements (CIMT 1 2and 3 cm proximal to the bifurcation bilaterally FIMT 12 and 3 cm distal to the bifurcation bilaterally) Commoncarotid and superficial femoral arteries were investigated forthe presence of plaques
Journal of Immunology Research 3
Table 1 Study and control group characteristics
RA (119899 = 317) Controls (119899 = 111) 119875 valueAge years 5761 (1262) 5550 (937) 01Males 58 (1830) 22 (1981) 07Ever-smokers 140 (4416) 62 (5586) 004Pack-years 966 (1604) 1313 (1820) 006BMI kgm2 2554 (437) 2746 (469) 00001Hypertension 137 (4322) 38 (3423) 01Creatinine mgdL 073 (027)Dagger 065 (007)998787 03ESR mmh 3177 (2364) 1063 (919) lt1 times 10
minus6
CRP mgdL 215 (32) 043 (0641) lt1 times 10minus6
Total cholesterol mgdL 2038 (413) 2158 (443) 001LDL cholesterol mgdL 1157 (343)dagger 1274 (405) 0004HDL cholesterol mgdL 632 (197)dagger 665 (19) 01Triglycerides mgdL 1286 (605)dagger 1162 (568) 006Framingham 10-year risk score 717 (54)dagger 786 (632) 03Presence of atherosclerotic plaques in carotid andor femoral arteries 74 (2334) 14 (1261) 0015CIMT mm 0718 (0181) 0682 (0167) 007FIMT mm 0516 (0168) 0457 (0099) 00005Disease duration years 1074 (898)Methotrexate ever 303 (9558)Sulphasalazine ever 148 (4669)Hydroxychloroquine or chloroquine ever 98 (3091)Gold salts ever 46 (1451)Azathioprine ever 18 (568)Cyclophosphamide ever 7 (221)Cyclosporine A ever 77 (2429)Leflunomide ever 123 (388)Biologic agents ever 61 (1924)Infliximab ever 24 (757)Adalimumab ever 12 (378)Etanercept ever 39 (123)Rituximab ever 13 (41)Continuous treatment with DMARDs 141 (4519)para
RF positivity 217 (7068)
ACPA positivity 211 (7729)sect
DAS28 47 (155)Presence of erosions in hand andor feet X-ray 176 (7097)998771
Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables paraData available for 312 patientsData available for 307 patients sectData available for 273 patients DaggerData available for 286 patients daggerData available for 302 patients 998771Data available for 248patients 998787Data available for 102 patients
24 Statistical Analysis All statistical tests were performedwith STATISTICA 100 (StatSoft) Results are reported asmean (SD) for continuous variables and 119899 () for categoricalvariables According to data distribution a parametric (119905-test) or nonparametric (119880 Mann-Whitney) test was usedCategorical variables were compared with chi square exacttest A 119875 value lt 005 was considered significant
3 Results and Discussion
31 Results Patients and controls were age- and sex-matchedThe percentage of ever-smokers LDL and total cholesterol
concentrations and BMI were higher in controls than inRA (Table 1) However total CV risk calculated with FSSwas similar in both groups CIMT and FIMT were higherin RA but only the difference in FIMT was significantAtherosclerotic plaques were more prevalent in RA
The presence of plaques in RA was positively correlatedwith ESR creatinine concentration FSS and presence ofrheumatoid factor (RF) (Table 2) Analysis for associationsbetween plaques and treatment with DMARDs showed asignificant negative correlation between presence of plaquesand treatment with methotrexate (MTX) cyclosporineA (CsA) and biologics Plaques were insignificantly
4 Journal of Immunology Research
Table 2 Associations between presence of atherosclerotic plaques and clinical laboratory and radiological characteristics and use of differentDMARDs
Presence of atherosclerotic plaques incarotid andor femoral arteries
(119899 = 74)
Lack of atherosclerotic plaques incarotid and femoral arteries
(119899 = 242)119875
RA duration years 1054 (941) 1076 (886) 08ESR mmh 3117 (2439) 2249 (214) 00008CRP mgdL 199 (29) 142 (266) 007Creatinine mgdL 081 (03) 07 (021) 00007DAS28 463 (151) 473 (157) 06Framingham 10-year risk score 101 (622) 601 (516) lt1 times 10
minus6
Methotrexate ever 65 (8784) 237 (9793) 00002Sulphasalazine ever 30 (4054) 117 (4835) 02Hydroxychloroquine or chloroquine ever 22 (2972) 76 (314) 08Gold salts ever 8 (1081) 38 (157) 03Azathioprine ever 5 (676) 13 (537) 07Cyclophosphamide ever 2 (27) 5 (207) 07Cyclosporine A ever 10 (1351) 67 (2769) 001Leflunomide ever 28 (3784) 95 (3926) 08Biologic agents ever 5 (676) 56 (2314) 0002Infliximab ever 1 (135) 23 (95) 002Adalimumab ever 0 (0) 12 (496) 00503Etanercept ever 2 (27) 37 (1529) 0004Rituximab ever 0 (0) 13 (537) 004Continuous treatment with DMARDs 27 (3649) 114 (4711) 01RF positivity 59 (7973) 158 (6781)998771 00497ACPA positivity 49 (7656) 162 (7751)dagger 09Presence of erosions in hand andor feet X-ray 42 (6858)Dagger 134 (7166)sect 08Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables Data available for 64 patientsDaggerData available for 61 patients 998771Data available for 233 patients daggerData available for 209 patients sectData available for 187 patients
more prevalent in dDMARDs group than in cDMARDsgroup
We found a positive correlation between CIMT FIMTand FSS (119903 = 0488 119875 lt 0001 and 119903 = 0434 119875 lt 0001resp) ESR (119903 = 0132 119875 = 0018 and 119903 = 0199 119875 lt0001) and creatinine concentration (119903 = 02 119875 lt 0001and 119903 = 0212 119875 lt 0001) However after adjustment forage associations with creatinine became insignificant Nosignificant associations were found between CIMT FIMTand RA duration CRP concentration and DAS28 (data notshown)
CIMT and FIMT were significantly lower in cDMARDsgroup compared with dDMARDs group (Table 3) The asso-ciation remained significant after adjustment for classicalCV risk factors The use of MTX was associated with lowerFIMT Comparison of different doses of MTX revealedsignificantly lower CIMT and FIMT in patients treatedwith doses ge 20mgwk correlation remained significantafter adjustment for classical CV risk factors CIMT wasalso significantly lower in patients treated with CsA andbiologics A similar correlation was observed between CsAbiologics and FIMT but it became insignificant after cor-rection for CV risk factors We did not find significant
differences in CIMT and FIMT in pairwise comparisonsbetween patients treated with MTX ge 20mgwk biolog-ics or CsA (further named MTX20(+)CsA(+)biologics(+)group) a comparison of this group with patients treatedwith different DMARDslower doses ofMTX (further namedMTX20(minus)CsA(minus)biologics(minus) group) revealed a robustdifference in CIMT (0104mm 119875 = 1 times 10minus6) and FIMT(0081mm 119875 = 5 times 10minus5) Interestingly RA activity(measured by DAS28) was similar in both groups 464(154) versus 483 (157) 119875 = 03 No significant differencesin classical CV risk factors were found between patientstreated with MTX ge 20mgwk biologics or CsA CIMT inMTX20(+)CsA(+)biologics(+) was comparable to controlsFIMT was slightly higher in MTX20(+)CsA(+)biologics(+)group than in controls No correlations were found betweenCIMT and FIMT and presence of RF ACPA and boneerosions
32 Discussion RA patients are at higher risk of CVDthan an age-matched general population It is estimatedthat CV risk in RA is increased to a similar magnitude tothat seen in type 2 diabetes [47] Studies assessing IMTin RA showed conflicting results but two meta-analyses
Journal of Immunology Research 5
Table3As
sociations
betweenIM
Tanduseo
fdifferentD
MARD
stre
atmentregim
enpresenceo
fRFAC
PAand
erosions
Sign
ificant
differences
incla
ssicalCV
riskfactors(ieageBM
Ism
okinghypertensio
nlip
idprofi
leandFS
S)betweengrou
psCI
MT
FIMT
CIMTmm
119875119875adj
FIMTmm
119875119875adj
MTX
(+)v
ersusM
TX(minus)
mdash0716(017
8)versus
0784(0235)
02
0511(0159)
versus
0628(0293)
001
003
MTXge20
mgwkversus
MTXlt20
mgwk
MTXge20
mgwkgrou
pwas
youn
ger(5577y
rsversus
5985y
rs)
andhadlower
FSS(657versus
792)
0687(017
1)versus
0758(018
6)000
05000
90492(012
6)versus
0546(0206)
000
4004
Sulphasalazine(+)v
ersussulph
asalazine(minus)
mdash0707(016
8)versus
0731(0192)
02
0505(013
8)versus
0526(019
2)03
Hydroxychloroqu
inechloroqu
ine(+)
versus
hydroxychloroq
uinechloroq
uine(minus)
mdash0703(018
1)versus
0727(018
1)03
0517(016
3)versus
0515(018
1)09
Goldsalts(+)v
ersusg
oldsalts(minus)
mdash0682(013
9)versus
0726(018
7)01
0494(016
6)versus
0520(016
9)03
Azathioprine(+)
versus
azathiop
rine(minus)
mdash0731(0216)
versus
0719(017
9)08
0518(0110)
versus
0516(017
2)096
Cyclo
phosph
amide(+)
versus
cyclo
phosph
amide(minus)
mdash0745(0205)v
ersus0
719
(018
1)07
0669(0427)v
ersus0
512
(015
8)001
02
Cyclo
sporine(+)
versus
cyclo
sporine(minus)
CsA(+)g
roup
was
youn
ger(5303y
rsversus
5846y
rs)a
ndhad
lower
FSS(591v
ersus759)and
hypertensio
nwas
lessprevalent
inthisgrou
p(3247versus
4644
)0665(016
5)versus
0737(018
3)0002
003
0471(0095)
versus
0530(018
4)0007
006
Leflu
nomide(+)
versus
leflu
nomide(minus)
mdash0719(0174)
versus
0720(018
6)096
0514(016
1)versus
0517(0174)
09
Biologicagents(
+)versus
biologicagents(minus)
Biologicagents(
+)grou
pwas
youn
ger(5324y
rsversus
5831
yrs)
0663(016
5)versus
0733(018
2)000
6004
0477(012
4)versus
0525(017
7)004
02
MTX
20(+)Cs
A(+)biologics(+)
versus
MTX
20(minus)Cs
A(minus)biologics(minus)
MTX
20(+)Cs
A(+)biologics(+)
grou
pwas
youn
ger(5547y
rsversus
6159y
rs)a
ndhadlower
FSS(638versus
882)
0684(016
9)versus
0788(018
6)1times10minus6
2times10minus5
0489(012
3)versus
0570(0227)5times10minus5
6times10minus4
MTX
20(+)Cs
A(+)biologics(+)
versus
controls
mdash0684(016
9)versus
0682(016
7)094
0489(012
3)versus
0457(0099)
002
002
MTX
20(+)biologics(minus)v
ersusb
iologics(+)M
TX20(minus)mdash
0703(017
3)versus
0708(017
2)09
0493(012
8)versus
0458(012
3)02
Biologics(+)CsA
(minus)v
ersusC
sA(+)biologics(minus)
mdash0655(018
1)versus
0662(0176)
09
0476(015
5)versus
046
7(010
2)03
CsA(+)MTX
20(minus)v
ersusM
TX20(+)Cs
A(minus)
mdash0661(0144)
versus
0696(016
8)03
0473(0076)v
ersus0
500
(013
4)03
MTXge20biologics(minus)Cs
A(minus)v
ersus
MTXlt20biologics(minus)Cs
A(minus)
MTXge20biologics(minus)Cs
A(minus)g
roup
was
youn
ger(5641yrs
versus
6039
yrs)andhadlower
FSS(671v
ersus8
01)
0708(016
4)versus
0791(0188)
000
090008
0502(013
0)versus
0577(0227)
000
4002
cDMARD
sversusd
DMARD
scD
MARD
sgroup
was
youn
ger(5453
yrsv
ersus5
962y
rs)
0683(017
7)versus
0746(018
2)0002
002
0485(0114)
versus
0544(0200)
0002
001
RF(+)v
ersusR
F(minus)
mdash0733(018
9)versus
0690(016
0)006
0524(016
4)versus
0506(018
2)04
ACPA
(+)v
ersusA
CPA(minus)
mdash0720(018
0)versus
0702(0202)
05
0525(017
1)versus
0480(014
8)006
Bone
erosions(+)v
ersusb
onee
rosio
ns(minus)
mdash0730(019
0)versus
0721(0174)
08
0530(018
4)versus
0501(0121)
02
Dataispresentedas
mean(stand
arddeviation)B
iologics(+)MTX
20(minus)patie
ntstreated
with
biologicsb
utnevertreated
with
MTXge20
mgwkBiologics(+)CsA
(minus)patie
ntstreated
with
biologicsb
utnever
treated
with
CsAC
sA(+)MTX
20(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
MTXge20
mgwkCs
A(+)biologics(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
biologicsMTX
20(+)biologics(minus)
patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsMTX
20(+)Cs
A(minus)patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
CsAM
TX20(+)Cs
A(+)biologics(+)p
atientstreated
with
MTXge20
mgwkandor
CsAandor
biologicagents
MTX
20(minus)Cs
A(minus)biologics(minus)patientsn
ever
treated
with
CsAb
iologicagents
andMTXge20
mgwk
MTXge20biologics(minus)Cs
A(minus)patie
nts
treated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsa
ndCs
AM
TXlt20biologics(minus)Cs
A(minus)patie
ntstreated
with
MTXlt20
mgwkbu
tnever
treated
with
biologicsa
ndCs
A119875
adj119875valuefor
analysis
adjuste
dforc
lassicalCV
Dris
kfactors
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Immunology Research 3
Table 1 Study and control group characteristics
RA (119899 = 317) Controls (119899 = 111) 119875 valueAge years 5761 (1262) 5550 (937) 01Males 58 (1830) 22 (1981) 07Ever-smokers 140 (4416) 62 (5586) 004Pack-years 966 (1604) 1313 (1820) 006BMI kgm2 2554 (437) 2746 (469) 00001Hypertension 137 (4322) 38 (3423) 01Creatinine mgdL 073 (027)Dagger 065 (007)998787 03ESR mmh 3177 (2364) 1063 (919) lt1 times 10
minus6
CRP mgdL 215 (32) 043 (0641) lt1 times 10minus6
Total cholesterol mgdL 2038 (413) 2158 (443) 001LDL cholesterol mgdL 1157 (343)dagger 1274 (405) 0004HDL cholesterol mgdL 632 (197)dagger 665 (19) 01Triglycerides mgdL 1286 (605)dagger 1162 (568) 006Framingham 10-year risk score 717 (54)dagger 786 (632) 03Presence of atherosclerotic plaques in carotid andor femoral arteries 74 (2334) 14 (1261) 0015CIMT mm 0718 (0181) 0682 (0167) 007FIMT mm 0516 (0168) 0457 (0099) 00005Disease duration years 1074 (898)Methotrexate ever 303 (9558)Sulphasalazine ever 148 (4669)Hydroxychloroquine or chloroquine ever 98 (3091)Gold salts ever 46 (1451)Azathioprine ever 18 (568)Cyclophosphamide ever 7 (221)Cyclosporine A ever 77 (2429)Leflunomide ever 123 (388)Biologic agents ever 61 (1924)Infliximab ever 24 (757)Adalimumab ever 12 (378)Etanercept ever 39 (123)Rituximab ever 13 (41)Continuous treatment with DMARDs 141 (4519)para
RF positivity 217 (7068)
ACPA positivity 211 (7729)sect
DAS28 47 (155)Presence of erosions in hand andor feet X-ray 176 (7097)998771
Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables paraData available for 312 patientsData available for 307 patients sectData available for 273 patients DaggerData available for 286 patients daggerData available for 302 patients 998771Data available for 248patients 998787Data available for 102 patients
24 Statistical Analysis All statistical tests were performedwith STATISTICA 100 (StatSoft) Results are reported asmean (SD) for continuous variables and 119899 () for categoricalvariables According to data distribution a parametric (119905-test) or nonparametric (119880 Mann-Whitney) test was usedCategorical variables were compared with chi square exacttest A 119875 value lt 005 was considered significant
3 Results and Discussion
31 Results Patients and controls were age- and sex-matchedThe percentage of ever-smokers LDL and total cholesterol
concentrations and BMI were higher in controls than inRA (Table 1) However total CV risk calculated with FSSwas similar in both groups CIMT and FIMT were higherin RA but only the difference in FIMT was significantAtherosclerotic plaques were more prevalent in RA
The presence of plaques in RA was positively correlatedwith ESR creatinine concentration FSS and presence ofrheumatoid factor (RF) (Table 2) Analysis for associationsbetween plaques and treatment with DMARDs showed asignificant negative correlation between presence of plaquesand treatment with methotrexate (MTX) cyclosporineA (CsA) and biologics Plaques were insignificantly
4 Journal of Immunology Research
Table 2 Associations between presence of atherosclerotic plaques and clinical laboratory and radiological characteristics and use of differentDMARDs
Presence of atherosclerotic plaques incarotid andor femoral arteries
(119899 = 74)
Lack of atherosclerotic plaques incarotid and femoral arteries
(119899 = 242)119875
RA duration years 1054 (941) 1076 (886) 08ESR mmh 3117 (2439) 2249 (214) 00008CRP mgdL 199 (29) 142 (266) 007Creatinine mgdL 081 (03) 07 (021) 00007DAS28 463 (151) 473 (157) 06Framingham 10-year risk score 101 (622) 601 (516) lt1 times 10
minus6
Methotrexate ever 65 (8784) 237 (9793) 00002Sulphasalazine ever 30 (4054) 117 (4835) 02Hydroxychloroquine or chloroquine ever 22 (2972) 76 (314) 08Gold salts ever 8 (1081) 38 (157) 03Azathioprine ever 5 (676) 13 (537) 07Cyclophosphamide ever 2 (27) 5 (207) 07Cyclosporine A ever 10 (1351) 67 (2769) 001Leflunomide ever 28 (3784) 95 (3926) 08Biologic agents ever 5 (676) 56 (2314) 0002Infliximab ever 1 (135) 23 (95) 002Adalimumab ever 0 (0) 12 (496) 00503Etanercept ever 2 (27) 37 (1529) 0004Rituximab ever 0 (0) 13 (537) 004Continuous treatment with DMARDs 27 (3649) 114 (4711) 01RF positivity 59 (7973) 158 (6781)998771 00497ACPA positivity 49 (7656) 162 (7751)dagger 09Presence of erosions in hand andor feet X-ray 42 (6858)Dagger 134 (7166)sect 08Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables Data available for 64 patientsDaggerData available for 61 patients 998771Data available for 233 patients daggerData available for 209 patients sectData available for 187 patients
more prevalent in dDMARDs group than in cDMARDsgroup
We found a positive correlation between CIMT FIMTand FSS (119903 = 0488 119875 lt 0001 and 119903 = 0434 119875 lt 0001resp) ESR (119903 = 0132 119875 = 0018 and 119903 = 0199 119875 lt0001) and creatinine concentration (119903 = 02 119875 lt 0001and 119903 = 0212 119875 lt 0001) However after adjustment forage associations with creatinine became insignificant Nosignificant associations were found between CIMT FIMTand RA duration CRP concentration and DAS28 (data notshown)
CIMT and FIMT were significantly lower in cDMARDsgroup compared with dDMARDs group (Table 3) The asso-ciation remained significant after adjustment for classicalCV risk factors The use of MTX was associated with lowerFIMT Comparison of different doses of MTX revealedsignificantly lower CIMT and FIMT in patients treatedwith doses ge 20mgwk correlation remained significantafter adjustment for classical CV risk factors CIMT wasalso significantly lower in patients treated with CsA andbiologics A similar correlation was observed between CsAbiologics and FIMT but it became insignificant after cor-rection for CV risk factors We did not find significant
differences in CIMT and FIMT in pairwise comparisonsbetween patients treated with MTX ge 20mgwk biolog-ics or CsA (further named MTX20(+)CsA(+)biologics(+)group) a comparison of this group with patients treatedwith different DMARDslower doses ofMTX (further namedMTX20(minus)CsA(minus)biologics(minus) group) revealed a robustdifference in CIMT (0104mm 119875 = 1 times 10minus6) and FIMT(0081mm 119875 = 5 times 10minus5) Interestingly RA activity(measured by DAS28) was similar in both groups 464(154) versus 483 (157) 119875 = 03 No significant differencesin classical CV risk factors were found between patientstreated with MTX ge 20mgwk biologics or CsA CIMT inMTX20(+)CsA(+)biologics(+) was comparable to controlsFIMT was slightly higher in MTX20(+)CsA(+)biologics(+)group than in controls No correlations were found betweenCIMT and FIMT and presence of RF ACPA and boneerosions
32 Discussion RA patients are at higher risk of CVDthan an age-matched general population It is estimatedthat CV risk in RA is increased to a similar magnitude tothat seen in type 2 diabetes [47] Studies assessing IMTin RA showed conflicting results but two meta-analyses
Journal of Immunology Research 5
Table3As
sociations
betweenIM
Tanduseo
fdifferentD
MARD
stre
atmentregim
enpresenceo
fRFAC
PAand
erosions
Sign
ificant
differences
incla
ssicalCV
riskfactors(ieageBM
Ism
okinghypertensio
nlip
idprofi
leandFS
S)betweengrou
psCI
MT
FIMT
CIMTmm
119875119875adj
FIMTmm
119875119875adj
MTX
(+)v
ersusM
TX(minus)
mdash0716(017
8)versus
0784(0235)
02
0511(0159)
versus
0628(0293)
001
003
MTXge20
mgwkversus
MTXlt20
mgwk
MTXge20
mgwkgrou
pwas
youn
ger(5577y
rsversus
5985y
rs)
andhadlower
FSS(657versus
792)
0687(017
1)versus
0758(018
6)000
05000
90492(012
6)versus
0546(0206)
000
4004
Sulphasalazine(+)v
ersussulph
asalazine(minus)
mdash0707(016
8)versus
0731(0192)
02
0505(013
8)versus
0526(019
2)03
Hydroxychloroqu
inechloroqu
ine(+)
versus
hydroxychloroq
uinechloroq
uine(minus)
mdash0703(018
1)versus
0727(018
1)03
0517(016
3)versus
0515(018
1)09
Goldsalts(+)v
ersusg
oldsalts(minus)
mdash0682(013
9)versus
0726(018
7)01
0494(016
6)versus
0520(016
9)03
Azathioprine(+)
versus
azathiop
rine(minus)
mdash0731(0216)
versus
0719(017
9)08
0518(0110)
versus
0516(017
2)096
Cyclo
phosph
amide(+)
versus
cyclo
phosph
amide(minus)
mdash0745(0205)v
ersus0
719
(018
1)07
0669(0427)v
ersus0
512
(015
8)001
02
Cyclo
sporine(+)
versus
cyclo
sporine(minus)
CsA(+)g
roup
was
youn
ger(5303y
rsversus
5846y
rs)a
ndhad
lower
FSS(591v
ersus759)and
hypertensio
nwas
lessprevalent
inthisgrou
p(3247versus
4644
)0665(016
5)versus
0737(018
3)0002
003
0471(0095)
versus
0530(018
4)0007
006
Leflu
nomide(+)
versus
leflu
nomide(minus)
mdash0719(0174)
versus
0720(018
6)096
0514(016
1)versus
0517(0174)
09
Biologicagents(
+)versus
biologicagents(minus)
Biologicagents(
+)grou
pwas
youn
ger(5324y
rsversus
5831
yrs)
0663(016
5)versus
0733(018
2)000
6004
0477(012
4)versus
0525(017
7)004
02
MTX
20(+)Cs
A(+)biologics(+)
versus
MTX
20(minus)Cs
A(minus)biologics(minus)
MTX
20(+)Cs
A(+)biologics(+)
grou
pwas
youn
ger(5547y
rsversus
6159y
rs)a
ndhadlower
FSS(638versus
882)
0684(016
9)versus
0788(018
6)1times10minus6
2times10minus5
0489(012
3)versus
0570(0227)5times10minus5
6times10minus4
MTX
20(+)Cs
A(+)biologics(+)
versus
controls
mdash0684(016
9)versus
0682(016
7)094
0489(012
3)versus
0457(0099)
002
002
MTX
20(+)biologics(minus)v
ersusb
iologics(+)M
TX20(minus)mdash
0703(017
3)versus
0708(017
2)09
0493(012
8)versus
0458(012
3)02
Biologics(+)CsA
(minus)v
ersusC
sA(+)biologics(minus)
mdash0655(018
1)versus
0662(0176)
09
0476(015
5)versus
046
7(010
2)03
CsA(+)MTX
20(minus)v
ersusM
TX20(+)Cs
A(minus)
mdash0661(0144)
versus
0696(016
8)03
0473(0076)v
ersus0
500
(013
4)03
MTXge20biologics(minus)Cs
A(minus)v
ersus
MTXlt20biologics(minus)Cs
A(minus)
MTXge20biologics(minus)Cs
A(minus)g
roup
was
youn
ger(5641yrs
versus
6039
yrs)andhadlower
FSS(671v
ersus8
01)
0708(016
4)versus
0791(0188)
000
090008
0502(013
0)versus
0577(0227)
000
4002
cDMARD
sversusd
DMARD
scD
MARD
sgroup
was
youn
ger(5453
yrsv
ersus5
962y
rs)
0683(017
7)versus
0746(018
2)0002
002
0485(0114)
versus
0544(0200)
0002
001
RF(+)v
ersusR
F(minus)
mdash0733(018
9)versus
0690(016
0)006
0524(016
4)versus
0506(018
2)04
ACPA
(+)v
ersusA
CPA(minus)
mdash0720(018
0)versus
0702(0202)
05
0525(017
1)versus
0480(014
8)006
Bone
erosions(+)v
ersusb
onee
rosio
ns(minus)
mdash0730(019
0)versus
0721(0174)
08
0530(018
4)versus
0501(0121)
02
Dataispresentedas
mean(stand
arddeviation)B
iologics(+)MTX
20(minus)patie
ntstreated
with
biologicsb
utnevertreated
with
MTXge20
mgwkBiologics(+)CsA
(minus)patie
ntstreated
with
biologicsb
utnever
treated
with
CsAC
sA(+)MTX
20(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
MTXge20
mgwkCs
A(+)biologics(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
biologicsMTX
20(+)biologics(minus)
patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsMTX
20(+)Cs
A(minus)patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
CsAM
TX20(+)Cs
A(+)biologics(+)p
atientstreated
with
MTXge20
mgwkandor
CsAandor
biologicagents
MTX
20(minus)Cs
A(minus)biologics(minus)patientsn
ever
treated
with
CsAb
iologicagents
andMTXge20
mgwk
MTXge20biologics(minus)Cs
A(minus)patie
nts
treated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsa
ndCs
AM
TXlt20biologics(minus)Cs
A(minus)patie
ntstreated
with
MTXlt20
mgwkbu
tnever
treated
with
biologicsa
ndCs
A119875
adj119875valuefor
analysis
adjuste
dforc
lassicalCV
Dris
kfactors
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
4 Journal of Immunology Research
Table 2 Associations between presence of atherosclerotic plaques and clinical laboratory and radiological characteristics and use of differentDMARDs
Presence of atherosclerotic plaques incarotid andor femoral arteries
(119899 = 74)
Lack of atherosclerotic plaques incarotid and femoral arteries
(119899 = 242)119875
RA duration years 1054 (941) 1076 (886) 08ESR mmh 3117 (2439) 2249 (214) 00008CRP mgdL 199 (29) 142 (266) 007Creatinine mgdL 081 (03) 07 (021) 00007DAS28 463 (151) 473 (157) 06Framingham 10-year risk score 101 (622) 601 (516) lt1 times 10
minus6
Methotrexate ever 65 (8784) 237 (9793) 00002Sulphasalazine ever 30 (4054) 117 (4835) 02Hydroxychloroquine or chloroquine ever 22 (2972) 76 (314) 08Gold salts ever 8 (1081) 38 (157) 03Azathioprine ever 5 (676) 13 (537) 07Cyclophosphamide ever 2 (27) 5 (207) 07Cyclosporine A ever 10 (1351) 67 (2769) 001Leflunomide ever 28 (3784) 95 (3926) 08Biologic agents ever 5 (676) 56 (2314) 0002Infliximab ever 1 (135) 23 (95) 002Adalimumab ever 0 (0) 12 (496) 00503Etanercept ever 2 (27) 37 (1529) 0004Rituximab ever 0 (0) 13 (537) 004Continuous treatment with DMARDs 27 (3649) 114 (4711) 01RF positivity 59 (7973) 158 (6781)998771 00497ACPA positivity 49 (7656) 162 (7751)dagger 09Presence of erosions in hand andor feet X-ray 42 (6858)Dagger 134 (7166)sect 08Data is presented as mean (standard deviation) for continuous variables and number (percentage) for categorical variables Data available for 64 patientsDaggerData available for 61 patients 998771Data available for 233 patients daggerData available for 209 patients sectData available for 187 patients
more prevalent in dDMARDs group than in cDMARDsgroup
We found a positive correlation between CIMT FIMTand FSS (119903 = 0488 119875 lt 0001 and 119903 = 0434 119875 lt 0001resp) ESR (119903 = 0132 119875 = 0018 and 119903 = 0199 119875 lt0001) and creatinine concentration (119903 = 02 119875 lt 0001and 119903 = 0212 119875 lt 0001) However after adjustment forage associations with creatinine became insignificant Nosignificant associations were found between CIMT FIMTand RA duration CRP concentration and DAS28 (data notshown)
CIMT and FIMT were significantly lower in cDMARDsgroup compared with dDMARDs group (Table 3) The asso-ciation remained significant after adjustment for classicalCV risk factors The use of MTX was associated with lowerFIMT Comparison of different doses of MTX revealedsignificantly lower CIMT and FIMT in patients treatedwith doses ge 20mgwk correlation remained significantafter adjustment for classical CV risk factors CIMT wasalso significantly lower in patients treated with CsA andbiologics A similar correlation was observed between CsAbiologics and FIMT but it became insignificant after cor-rection for CV risk factors We did not find significant
differences in CIMT and FIMT in pairwise comparisonsbetween patients treated with MTX ge 20mgwk biolog-ics or CsA (further named MTX20(+)CsA(+)biologics(+)group) a comparison of this group with patients treatedwith different DMARDslower doses ofMTX (further namedMTX20(minus)CsA(minus)biologics(minus) group) revealed a robustdifference in CIMT (0104mm 119875 = 1 times 10minus6) and FIMT(0081mm 119875 = 5 times 10minus5) Interestingly RA activity(measured by DAS28) was similar in both groups 464(154) versus 483 (157) 119875 = 03 No significant differencesin classical CV risk factors were found between patientstreated with MTX ge 20mgwk biologics or CsA CIMT inMTX20(+)CsA(+)biologics(+) was comparable to controlsFIMT was slightly higher in MTX20(+)CsA(+)biologics(+)group than in controls No correlations were found betweenCIMT and FIMT and presence of RF ACPA and boneerosions
32 Discussion RA patients are at higher risk of CVDthan an age-matched general population It is estimatedthat CV risk in RA is increased to a similar magnitude tothat seen in type 2 diabetes [47] Studies assessing IMTin RA showed conflicting results but two meta-analyses
Journal of Immunology Research 5
Table3As
sociations
betweenIM
Tanduseo
fdifferentD
MARD
stre
atmentregim
enpresenceo
fRFAC
PAand
erosions
Sign
ificant
differences
incla
ssicalCV
riskfactors(ieageBM
Ism
okinghypertensio
nlip
idprofi
leandFS
S)betweengrou
psCI
MT
FIMT
CIMTmm
119875119875adj
FIMTmm
119875119875adj
MTX
(+)v
ersusM
TX(minus)
mdash0716(017
8)versus
0784(0235)
02
0511(0159)
versus
0628(0293)
001
003
MTXge20
mgwkversus
MTXlt20
mgwk
MTXge20
mgwkgrou
pwas
youn
ger(5577y
rsversus
5985y
rs)
andhadlower
FSS(657versus
792)
0687(017
1)versus
0758(018
6)000
05000
90492(012
6)versus
0546(0206)
000
4004
Sulphasalazine(+)v
ersussulph
asalazine(minus)
mdash0707(016
8)versus
0731(0192)
02
0505(013
8)versus
0526(019
2)03
Hydroxychloroqu
inechloroqu
ine(+)
versus
hydroxychloroq
uinechloroq
uine(minus)
mdash0703(018
1)versus
0727(018
1)03
0517(016
3)versus
0515(018
1)09
Goldsalts(+)v
ersusg
oldsalts(minus)
mdash0682(013
9)versus
0726(018
7)01
0494(016
6)versus
0520(016
9)03
Azathioprine(+)
versus
azathiop
rine(minus)
mdash0731(0216)
versus
0719(017
9)08
0518(0110)
versus
0516(017
2)096
Cyclo
phosph
amide(+)
versus
cyclo
phosph
amide(minus)
mdash0745(0205)v
ersus0
719
(018
1)07
0669(0427)v
ersus0
512
(015
8)001
02
Cyclo
sporine(+)
versus
cyclo
sporine(minus)
CsA(+)g
roup
was
youn
ger(5303y
rsversus
5846y
rs)a
ndhad
lower
FSS(591v
ersus759)and
hypertensio
nwas
lessprevalent
inthisgrou
p(3247versus
4644
)0665(016
5)versus
0737(018
3)0002
003
0471(0095)
versus
0530(018
4)0007
006
Leflu
nomide(+)
versus
leflu
nomide(minus)
mdash0719(0174)
versus
0720(018
6)096
0514(016
1)versus
0517(0174)
09
Biologicagents(
+)versus
biologicagents(minus)
Biologicagents(
+)grou
pwas
youn
ger(5324y
rsversus
5831
yrs)
0663(016
5)versus
0733(018
2)000
6004
0477(012
4)versus
0525(017
7)004
02
MTX
20(+)Cs
A(+)biologics(+)
versus
MTX
20(minus)Cs
A(minus)biologics(minus)
MTX
20(+)Cs
A(+)biologics(+)
grou
pwas
youn
ger(5547y
rsversus
6159y
rs)a
ndhadlower
FSS(638versus
882)
0684(016
9)versus
0788(018
6)1times10minus6
2times10minus5
0489(012
3)versus
0570(0227)5times10minus5
6times10minus4
MTX
20(+)Cs
A(+)biologics(+)
versus
controls
mdash0684(016
9)versus
0682(016
7)094
0489(012
3)versus
0457(0099)
002
002
MTX
20(+)biologics(minus)v
ersusb
iologics(+)M
TX20(minus)mdash
0703(017
3)versus
0708(017
2)09
0493(012
8)versus
0458(012
3)02
Biologics(+)CsA
(minus)v
ersusC
sA(+)biologics(minus)
mdash0655(018
1)versus
0662(0176)
09
0476(015
5)versus
046
7(010
2)03
CsA(+)MTX
20(minus)v
ersusM
TX20(+)Cs
A(minus)
mdash0661(0144)
versus
0696(016
8)03
0473(0076)v
ersus0
500
(013
4)03
MTXge20biologics(minus)Cs
A(minus)v
ersus
MTXlt20biologics(minus)Cs
A(minus)
MTXge20biologics(minus)Cs
A(minus)g
roup
was
youn
ger(5641yrs
versus
6039
yrs)andhadlower
FSS(671v
ersus8
01)
0708(016
4)versus
0791(0188)
000
090008
0502(013
0)versus
0577(0227)
000
4002
cDMARD
sversusd
DMARD
scD
MARD
sgroup
was
youn
ger(5453
yrsv
ersus5
962y
rs)
0683(017
7)versus
0746(018
2)0002
002
0485(0114)
versus
0544(0200)
0002
001
RF(+)v
ersusR
F(minus)
mdash0733(018
9)versus
0690(016
0)006
0524(016
4)versus
0506(018
2)04
ACPA
(+)v
ersusA
CPA(minus)
mdash0720(018
0)versus
0702(0202)
05
0525(017
1)versus
0480(014
8)006
Bone
erosions(+)v
ersusb
onee
rosio
ns(minus)
mdash0730(019
0)versus
0721(0174)
08
0530(018
4)versus
0501(0121)
02
Dataispresentedas
mean(stand
arddeviation)B
iologics(+)MTX
20(minus)patie
ntstreated
with
biologicsb
utnevertreated
with
MTXge20
mgwkBiologics(+)CsA
(minus)patie
ntstreated
with
biologicsb
utnever
treated
with
CsAC
sA(+)MTX
20(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
MTXge20
mgwkCs
A(+)biologics(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
biologicsMTX
20(+)biologics(minus)
patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsMTX
20(+)Cs
A(minus)patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
CsAM
TX20(+)Cs
A(+)biologics(+)p
atientstreated
with
MTXge20
mgwkandor
CsAandor
biologicagents
MTX
20(minus)Cs
A(minus)biologics(minus)patientsn
ever
treated
with
CsAb
iologicagents
andMTXge20
mgwk
MTXge20biologics(minus)Cs
A(minus)patie
nts
treated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsa
ndCs
AM
TXlt20biologics(minus)Cs
A(minus)patie
ntstreated
with
MTXlt20
mgwkbu
tnever
treated
with
biologicsa
ndCs
A119875
adj119875valuefor
analysis
adjuste
dforc
lassicalCV
Dris
kfactors
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Immunology Research 5
Table3As
sociations
betweenIM
Tanduseo
fdifferentD
MARD
stre
atmentregim
enpresenceo
fRFAC
PAand
erosions
Sign
ificant
differences
incla
ssicalCV
riskfactors(ieageBM
Ism
okinghypertensio
nlip
idprofi
leandFS
S)betweengrou
psCI
MT
FIMT
CIMTmm
119875119875adj
FIMTmm
119875119875adj
MTX
(+)v
ersusM
TX(minus)
mdash0716(017
8)versus
0784(0235)
02
0511(0159)
versus
0628(0293)
001
003
MTXge20
mgwkversus
MTXlt20
mgwk
MTXge20
mgwkgrou
pwas
youn
ger(5577y
rsversus
5985y
rs)
andhadlower
FSS(657versus
792)
0687(017
1)versus
0758(018
6)000
05000
90492(012
6)versus
0546(0206)
000
4004
Sulphasalazine(+)v
ersussulph
asalazine(minus)
mdash0707(016
8)versus
0731(0192)
02
0505(013
8)versus
0526(019
2)03
Hydroxychloroqu
inechloroqu
ine(+)
versus
hydroxychloroq
uinechloroq
uine(minus)
mdash0703(018
1)versus
0727(018
1)03
0517(016
3)versus
0515(018
1)09
Goldsalts(+)v
ersusg
oldsalts(minus)
mdash0682(013
9)versus
0726(018
7)01
0494(016
6)versus
0520(016
9)03
Azathioprine(+)
versus
azathiop
rine(minus)
mdash0731(0216)
versus
0719(017
9)08
0518(0110)
versus
0516(017
2)096
Cyclo
phosph
amide(+)
versus
cyclo
phosph
amide(minus)
mdash0745(0205)v
ersus0
719
(018
1)07
0669(0427)v
ersus0
512
(015
8)001
02
Cyclo
sporine(+)
versus
cyclo
sporine(minus)
CsA(+)g
roup
was
youn
ger(5303y
rsversus
5846y
rs)a
ndhad
lower
FSS(591v
ersus759)and
hypertensio
nwas
lessprevalent
inthisgrou
p(3247versus
4644
)0665(016
5)versus
0737(018
3)0002
003
0471(0095)
versus
0530(018
4)0007
006
Leflu
nomide(+)
versus
leflu
nomide(minus)
mdash0719(0174)
versus
0720(018
6)096
0514(016
1)versus
0517(0174)
09
Biologicagents(
+)versus
biologicagents(minus)
Biologicagents(
+)grou
pwas
youn
ger(5324y
rsversus
5831
yrs)
0663(016
5)versus
0733(018
2)000
6004
0477(012
4)versus
0525(017
7)004
02
MTX
20(+)Cs
A(+)biologics(+)
versus
MTX
20(minus)Cs
A(minus)biologics(minus)
MTX
20(+)Cs
A(+)biologics(+)
grou
pwas
youn
ger(5547y
rsversus
6159y
rs)a
ndhadlower
FSS(638versus
882)
0684(016
9)versus
0788(018
6)1times10minus6
2times10minus5
0489(012
3)versus
0570(0227)5times10minus5
6times10minus4
MTX
20(+)Cs
A(+)biologics(+)
versus
controls
mdash0684(016
9)versus
0682(016
7)094
0489(012
3)versus
0457(0099)
002
002
MTX
20(+)biologics(minus)v
ersusb
iologics(+)M
TX20(minus)mdash
0703(017
3)versus
0708(017
2)09
0493(012
8)versus
0458(012
3)02
Biologics(+)CsA
(minus)v
ersusC
sA(+)biologics(minus)
mdash0655(018
1)versus
0662(0176)
09
0476(015
5)versus
046
7(010
2)03
CsA(+)MTX
20(minus)v
ersusM
TX20(+)Cs
A(minus)
mdash0661(0144)
versus
0696(016
8)03
0473(0076)v
ersus0
500
(013
4)03
MTXge20biologics(minus)Cs
A(minus)v
ersus
MTXlt20biologics(minus)Cs
A(minus)
MTXge20biologics(minus)Cs
A(minus)g
roup
was
youn
ger(5641yrs
versus
6039
yrs)andhadlower
FSS(671v
ersus8
01)
0708(016
4)versus
0791(0188)
000
090008
0502(013
0)versus
0577(0227)
000
4002
cDMARD
sversusd
DMARD
scD
MARD
sgroup
was
youn
ger(5453
yrsv
ersus5
962y
rs)
0683(017
7)versus
0746(018
2)0002
002
0485(0114)
versus
0544(0200)
0002
001
RF(+)v
ersusR
F(minus)
mdash0733(018
9)versus
0690(016
0)006
0524(016
4)versus
0506(018
2)04
ACPA
(+)v
ersusA
CPA(minus)
mdash0720(018
0)versus
0702(0202)
05
0525(017
1)versus
0480(014
8)006
Bone
erosions(+)v
ersusb
onee
rosio
ns(minus)
mdash0730(019
0)versus
0721(0174)
08
0530(018
4)versus
0501(0121)
02
Dataispresentedas
mean(stand
arddeviation)B
iologics(+)MTX
20(minus)patie
ntstreated
with
biologicsb
utnevertreated
with
MTXge20
mgwkBiologics(+)CsA
(minus)patie
ntstreated
with
biologicsb
utnever
treated
with
CsAC
sA(+)MTX
20(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
MTXge20
mgwkCs
A(+)biologics(minus)patie
ntstreated
with
CsAbu
tnever
treated
with
biologicsMTX
20(+)biologics(minus)
patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsMTX
20(+)Cs
A(minus)patie
ntstreated
with
MTXge20
mgwkbu
tnever
treated
with
CsAM
TX20(+)Cs
A(+)biologics(+)p
atientstreated
with
MTXge20
mgwkandor
CsAandor
biologicagents
MTX
20(minus)Cs
A(minus)biologics(minus)patientsn
ever
treated
with
CsAb
iologicagents
andMTXge20
mgwk
MTXge20biologics(minus)Cs
A(minus)patie
nts
treated
with
MTXge20
mgwkbu
tnever
treated
with
biologicsa
ndCs
AM
TXlt20biologics(minus)Cs
A(minus)patie
ntstreated
with
MTXlt20
mgwkbu
tnever
treated
with
biologicsa
ndCs
A119875
adj119875valuefor
analysis
adjuste
dforc
lassicalCV
Dris
kfactors
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
6 Journal of Immunology Research
confirmed increased IMT in RA [15 48] We also observedincreased IMT in carotid and femoral arteries in RA patientsbut only the difference in femoral arteries was significantAtherosclerotic plaques were more frequently found in RAthan in controls
We found a strong correlation between FSS and IMTand presence of plaques This finding underlines the role ofclassical CV risk factors in pathogenesis of atherosclerosis inRA
CIMT FIMT and presence of plaques were associatedwith ESR However no correlation was found betweenatherosclerosis markers and DAS28 It may be explained bythe fact that DAS28 comprises two parameters which are notcompletely objective VAS and tender joints count Moreoverswollen joints count is related to the local inflammation(synovitis) while progression of atherosclerosis in RA isthought to be due to systemic inflammation Thus ESRas a more objective parameter and a marker of systemicinflammation may be a better predictor of increased risk ofatherosclerosis in RA In this context lack of association withCRP is intriguing CRP was found to be a powerful predictorof cardiovascular disease in general population [49] Theabsence of association in our study may be explained bythe use of conventional CRP assay since the involvementof CRP in atherosclerosis has been demonstrated by highsensitivity CRP assay It must be also emphasized that RAis a disease characterized by periods of exacerbations andremissionsThus a single measure of disease activity may notreflect intensity of disease in a longer period of time Indeedseveral studies suggest that assessment of the cumulativeinflammation for the whole duration of RA may be a betterpredictor of atherosclerosis [34]
Creatinine concentration was significantly higher inpatients with plaques and correlated positively with CIMTand FIMT However after adjustment for age these associ-ations became insignificant (data not presented) It is notsurprising as a concentration of creatinine increases with ageand age is a strong risk factor for atherosclerosis
CIMT FIMT and prevalence of plaques were lower inpatients treated with MTX ge 20mgwk CsA and biologicsThis effect seems to be independent of disease activity asDAS28 was similar in MTX20(+)CsA(+)biologics(+) andMTX20(minus)CsA(minus)biologics(minus) groups Analysis of differentcombinations of DMARDs did not reveal any significantcorrelations (data not shown) There is a lot of evidencesupporting a beneficial effect of biologics on atherosclerosiswhile data concerning MTX are conflicting Several studiesshowed a beneficial influence of anti-TNF-120572 therapy onsubclinical atherosclerosis [40ndash42] A protective effect ofanti-TNF-120572 therapy was also confirmed inmeta-analyses [4350] A study based on data from British Society for Rheuma-tology Biologics Register showed no overall difference inthe risk of myocardial infarction between patients treatedwith anti-TNF-120572 and nonbiologic DMARDs however theauthors reported a reduced risk of myocardial infarction inTNF-120572-responders [51] Giles et al observed slower CIMTprogression in patients treated with anti-TNF-120572 but not inusers of other RA treatments [44] Analysis of CORRONAregistry showed reduction of CV events risk in patients
treated with anti-TNF-120572 compared with patients treated withMTX and other nonbiological DMARDs [45] On the otherhand a systematic review by Westlake et al found that use ofMTX is associated with reduced risk of CV events [37] Ourresults suggest that the observed discrepancy in the literaturemay be due to different doses of MTX For last three decadesdoses of MTX used in RA have increased from 5ndash75mgwkto 30mgwk A study by Giles et al enrolled patients between2004 and 2006 and enrolment to CORRONA registry tookplace between 2001 and 2006 data concerning average dose ofMTX in these studies is missing in the publications howeverwe may speculate that it was below 20mgwk We observed asignificant difference in CIMT and FIMT between patientstreated with MTX ge 20mgwk and lt 20mgwk it shouldbe emphasized that the difference remained significant afterexclusion of patients treated with other drugs influencingIMT (ie CsA and biologics) We did not observe significantdifferences in IMT between patients treated with MTX ge20mgwk (but never using biologics) and patients treatedwith biologics (but never usingMTXge 20mgwk) It suggeststhat the impact of MTX ge20mgwk on IMT was comparableto that of biologics
A beneficial influence of CsA on atherosclerosis inRA is a novel finding Few studies reported a protectiveeffect of CsA on IMT in lupus patients [52] Surprisinglyother synthetic DMARDs recommended in RA (leflunomidesulphasalazine) showed no effect on IMT and presence ofplaques
The differences in CIMT and FIMT between MTX20(+)CsA(+)biologics(+) and MTX20(minus)CsA(minus)biologics(minus)groups were robust (0104mm 119875 = 1 times 10minus6 and 0081mm119875 = 5 times 10
minus5) A large study in general population found thatan absolute carotid IMT difference of 01mm is associatedwith a 10ndash15 higher risk of myocardial infarction and13ndash18 higher risk of stroke [53] Thus the observed effectof MTX biologics and CsA seems to be important
Another factor influencing the atherosclerosis status isregularity of treatment Patients treated continuously withDMARDS had a lower CIMT and FIMT This finding is notsurprising as good RA control is a widely accepted predictorof slower atherosclerosis progression
Lekakis et al suggested that combined assessment ofcarotid and femoral IMT might provide additional informa-tion compared with analysis of carotid IMT only [9] Ourresults suggest that this hypothesis may not be applicable toRA population
4 Conclusions
In conclusion we found a beneficial effect of MTX ge20mgwk biologics and CsA on atherosclerosis We do notconfirm a stronger influence of biologics on IMT comparedwith MTX (in doses ge20mgwk)
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Journal of Immunology Research 7
Acknowledgment
This work was supported by Polish Ministry of Science andHigher Education Grant no N N402 077234 (granted toWitold Tłustochowicz)
References
[1] J A Avina-Zubieta H K Choi M Sadatsafavi M EtminanJ M Esdaile and D Lacaille ldquoRisk of cardiovascular mortalityin patients with rheumatoid arthritis a meta-analysis of obser-vational studiesrdquo Arthritis Care amp Research vol 59 no 12 pp1690ndash1697 2008
[2] H Maradit-Kremers P J Nicola C S Crowson K V Ballmanand S EGabriel ldquoCardiovascular death in rheumatoid arthritisa population-based studyrdquo Arthritis amp Rheumatism vol 52 no3 pp 722ndash732 2005
[3] Y Shoenfeld R Gerli A Doria et al ldquoAccelerated atheroscle-rosis in autoimmune rheumatic diseasesrdquo Circulation vol 112no 21 pp 3337ndash3347 2005
[4] I D del Rincon K Williams M P Stern G L Freemanand A Escalante ldquoHigh incidence of cardiovascular events inrheumatoid arthritis cohort not explained by traditional cardiacrisk factorsrdquoArthritis amp Rheumatology vol 44 no 12 pp 2737ndash2745 2001
[5] I del Rincon G L Freeman R W Haas D H OrsquoLearyand A Escalante ldquoRelative contribution of cardiovascular riskfactors and rheumatoid arthritis clinical manifestations toatherosclerosisrdquo Arthritis and Rheumatism vol 52 no 11 pp3413ndash3423 2005
[6] A Naranjo T Sokka M A Descalzo et al ldquoCardiovasculardisease in patients with rheumatoid arthritis results from theQUEST-RA studyrdquo Arthritis Research amp Therapy vol 10 no 2article R30 2008
[7] M Banks J Flint P A Bacon and G D Kitas ldquoRheumatoidarthritis is an independent risk factor for ischaemic heart dis-easerdquo Arthritis and Rheumatism vol 43 supplement 9 articleS385 2000
[8] M W Lorenz H S Markus M L Bots M Rosvall andM Sitzer ldquoPrediction of clinical cardiovascular events withcarotid intima-media thickness a systematic review and meta-analysisrdquo Circulation vol 115 no 4 pp 459ndash467 2007
[9] J P Lekakis C M Papamichael A T Cimponeriu et alldquoAtherosclerotic changes of extracoronary arteries are associ-ated with the extent of coronary atherosclerosisrdquo AmericanJournal of Cardiology vol 85 no 8 pp 949ndash952 2000
[10] A Sodergren K Karp K Boman et al ldquoAtherosclerosis in earlyrheumatoid arthritis very early endothelial activation and rapidprogression of intima media thicknessrdquo Arthritis Research ampTherapy vol 12 no 4 article R158 2010
[11] M C Adhikari A Guin S Chakraborty P Sinhamahapatraand A Ghosh ldquoSubclinical atherosclerosis and endothelialdysfunction in patients with early rheumatoid arthritis as evi-denced by measurement of carotid intima-media thickness andflow-mediated vasodilatation an observational studyrdquo Seminarsin Arthritis amp Rheumatism vol 41 no 5 pp 669ndash675 2012
[12] G Kocabay H Hasdemir and M Yildiz ldquoEvaluation of pulsewave velocity in systemic lupus erythematosus rheumatoidarthritis and Behcetrsquos diseaserdquo Journal of Cardiology vol 59 no1 pp 72ndash77 2012
[13] M V Veselinovic V I Zivkovic S Toncev et al ldquoCarotid arteryintima-media thickness and brachial artery flow-mediated
vasodilatation in patients with rheumatoid arthritisrdquo Vasa vol41 no 5 pp 343ndash351 2012
[14] S Hannawi B Haluska T H Marwick and R ThomasldquoAtherosclerotic disease is increased in recent-onset rheumatoidarthritis a critical role for inflammationrdquoArthritis Research andTherapy vol 9 no 6 article R116 2007
[15] P N Tyrrell J Beyene B M Feldman B W McCrindleE D Silverman and T J Bradley ldquoRheumatic disease andcarotid intima-media thickness a systematic review and meta-analysisrdquoArteriosclerosisThrombosis and Vascular Biology vol30 no 5 pp 1014ndash1026 2010
[16] M Lahiri C Morgan D P M Symmons and I N BruceldquoModifiable risk factors for RA prevention better than curerdquoRheumatology vol 51 no 3 Article ID ker299 pp 499ndash5122012
[17] D F van Breukelen-van der Stoep B Klop D van ZebenJ M W Hazes and M C Cabezas ldquoCardiovascular risk inrheumatoid arthritis how to lower the riskrdquo Atherosclerosisvol 231 no 1 pp 163ndash172 2013
[18] A Stavropoulos-Kalinoglou G S Metsios V F Panoulas etal ldquoAssociations of obesity with modifiable risk factors forthe development of cardiovascular disease in patients withrheumatoid arthritisrdquoAnnals of the Rheumatic Diseases vol 68no 2 pp 242ndash245 2009
[19] D J Armstrong E M McCausland A D Quinn and G DWright ldquoObesity and cardiovascular risk factors in rheumatoidarthritisrdquo Rheumatology vol 45 no 6 pp 782ndash783 2006
[20] H M Kremers P J Nicola C S Crowson K V Ballman andS E Gabriel ldquoPrognostic importance of low body mass indexin relation to cardiovascular mortality in rheumatoid arthritisrdquoArthritis and Rheumatism vol 50 no 11 pp 3450ndash3457 2004
[21] P H Dessein B I Joffe M G Veller et al ldquoTraditional andnontraditional cardiovascular risk factors are associated withatherosclerosis in rheumatoid arthritisrdquo Journal of Rheumatol-ogy vol 32 no 3 pp 435ndash442 2005
[22] Y B Park S K Lee W K Lee et al ldquoLipid profiles in untreatedpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 26 no 8 pp 1701ndash1704 1999
[23] E Myasoedova C S Crowson H M Kremers et al ldquoLipidparadox in rheumatoid arthritis the impact of serum lipidmea-sures and systemic inflammation on the risk of cardiovasculardiseaserdquo Annals of the Rheumatic Diseases vol 70 no 3 pp482ndash487 2011
[24] B H Hahn J Grossman W Chen and M McMahonldquoThe pathogenesis of atherosclerosis in autoimmune rheumaticdiseases roles of inflammation and dyslipidemiardquo Journal ofAutoimmunity vol 28 no 2-3 pp 69ndash75 2007
[25] E Choy K Ganeshalingam A G Semb Z Szekanecz andM Nurmohamed ldquoCardiovascular risk in rheumatoid arthritisrecent advances in the understanding of the pivotal role ofinflammation risk predictors and the impact of treatmentrdquoRheumatology vol 53 no 12 pp 2143ndash2154 2014
[26] S Wallberg-Jonsson H Johansson M-L Ohman and SRantapaa-Dahlqvist ldquoExtent of inflammation predicts cardio-vascular disease and overall mortality in seropositive rheuma-toid arthritis A retrospective cohort study from disease onsetrdquoJournal of Rheumatology vol 26 no 12 pp 2562ndash2571 1999
[27] L Innala B Moller L Ljung et al ldquoCardiovascular events inearly RA are a result of inflammatory burden and traditionalrisk factors a five year prospective studyrdquoArthritis Research andTherapy vol 13 no 4 article R131 2011
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
8 Journal of Immunology Research
[28] M A Crilly V Kumar H J Clark N W Scott A G Mac-Donald and D J Williams ldquoArterial stiffness and cumulativeinflammatory burden in rheumatoid arthritis a dose-responserelationship independent of established cardiovascular riskfactorsrdquo Rheumatology (Oxford) vol 48 no 12 pp 1606ndash16122009
[29] M A Gonzalez-Gay C Gonzalez-Juanatey A Pineiro CGarcia-Porrua A Testa and J Llorca ldquoHigh-grade C-reactiveprotein elevation correlates with accelerated atherogenesis inpatients with rheumatoid arthritisrdquo Journal of Rheumatologyvol 32 no 7 pp 1219ndash1223 2005
[30] I Del Rincon K Williams M P Stern G L Freeman DH OrsquoLeary and A Escalantel ldquoAssociation between carotidatherosclerosis and markers of inflammation in rheumatoidarthritis patients and healthy subjectsrdquo Arthritis and Rheuma-tism vol 48 no 7 pp 1833ndash1840 2003
[31] S Hannawi T H Marwick and R Thomas ldquoInflammationpredicts accelerated brachial arterial wall changes in patientswith recent-onset rheumatoid arthritisrdquo Arthritis Research ampTherapy vol 11 no 2 article R51 2009
[32] K M Maki-Petaja F C Hall A D Booth et al ldquoRheumatoidarthritis is associated with increased aortic pulse-wave velocitywhich is reduced by anti-tumor necrosis factor-120572 therapyrdquoCirculation vol 114 no 11 pp 1185ndash1192 2006
[33] S W Jonsson C Backman O Johnson et al ldquoIncreasedprevalence of atherosclerosis in patients with medium termrheumatoid arthritisrdquoThe Journal of Rheumatology vol 28 no12 pp 2597ndash2602 2001
[34] A Sandoo N Chanchlani J Hodson J P Smith K MDouglas and G D Kitas ldquoClassical cardiovascular disease riskfactors associate with vascular function and morphology inrheumatoid arthritis a six-year prospective studyrdquo ArthritisResearch andTherapy vol 15 no 6 article R203 2013
[35] A Scarno F M Perrotta F Cardini et al ldquoBeyond thejoint subclinical atherosclerosis in rheumatoid arthritisrdquoWorldJournal of Orthopaedics vol 5 no 3 pp 328ndash335 2014
[36] H K Choi M A Hernan J D Seeger J M Robins and FWolfe ldquoMethotrexate andmortality in patientswith rheumatoidarthritis a prospective studyrdquoThe Lancet vol 359 no 9313 pp1173ndash1177 2002
[37] S L Westlake A N Colebatch J Baird et al ldquoThe effectof methotrexate on cardiovascular disease in patients withrheumatoid arthritis a systematic literature reviewrdquo Rheuma-tology vol 49 no 2 pp 295ndash307 2010
[38] S Chatterjee P Sarkate S Ghosh M Biswas and A GhoshldquoEarly structured disease modifying anti-rheumatic drug(DMARD) therapy reduces cardiovascular risk in rheumatoidarthritis-a single centre study using non-biologic drugsrdquo Jour-nal of Association of Physicians of India vol 61 no 8 pp 531ndash534 2013
[39] A Guin M C Adhikari S Chakraborty P Sinhamahapatraand A Ghosh ldquoEffects of disease modifying anti-rheumaticdrugs on subclinical atherosclerosis and endothelial dysfunc-tion which has been detected in early rheumatoid arthritis 1-year follow-up studyrdquo Seminars in Arthritis and Rheumatismvol 43 no 1 pp 48ndash54 2013
[40] G Kerekes P Soltesz G Szucs et al ldquoEffects of adalimumabtreatment on vascular disease associated with early rheumatoidarthritisrdquo Israel Medical Association Journal vol 13 no 3 pp147ndash152 2011
[41] K Angel S A Provan M K Fagerhol P Mowinckel TK Kvien and D Atar ldquoEffect of 1-year anti-TNF-120572 therapy
on aortic stiffness carotid atherosclerosis and calprotectinin inflammatory arthropathies a controlled studyrdquo AmericanJournal of Hypertension vol 25 no 6 pp 644ndash650 2012
[42] C Gonzalez-Juanatey T R Vazquez-Rodriguez J A Miranda-Filloy et al ldquoAnti-TNF-alpha-adalimumab therapy is associatedwith persistent improvement of endothelial function withoutprogression of carotid intima-media wall thickness in patientswith rheumatoid arthritis refractory to conventional therapyrdquoMediators of Inflammation vol 2012 Article ID 674265 8 pages2012
[43] S L Westlake A N Colebatch J Baird et al ldquoTumour necro-sis factor antagonists and the risk of cardiovascular diseasein patients with rheumatoid arthritis a systematic literaturereviewrdquo Rheumatology vol 50 no 3 pp 518ndash531 2011
[44] J T Giles W S Post R S Blumenthal et al ldquoLongitudinal pre-dictors of progression of carotid atherosclerosis in rheumatoidarthritisrdquo Arthritis and Rheumatism vol 63 no 11 pp 3216ndash3225 2011
[45] J D Greenberg J M Kremer J R Curtis et al ldquoTumournecrosis factor antagonist use and associated risk reduction ofcardiovascular events among patients with rheumatoid arthri-tisrdquoAnnals of the Rheumatic Diseases vol 70 no 4 pp 576ndash5822011
[46] R B DrsquoAgostino Sr R S Vasan M J Pencina et al ldquoGeneralcardiovascular risk profile for use in primary care the Framing-ham heart studyrdquo Circulation vol 117 no 6 pp 743ndash753 2008
[47] V P van HalmM J L Peters A E Voskuyl et al ldquoRheumatoidarthritis versus diabetes as a risk factor for cardiovasculardisease a cross-sectional study the CARRE InvestigationrdquoAnnals of the Rheumatic Diseases vol 68 no 9 pp 1395ndash14002009
[48] A M van Sijl M J Peters D K Knol et al ldquoCarotidintima media thickness in rheumatoid arthritis as comparedto control subjects a meta-analysisrdquo Seminars in Arthritis andRheumatism vol 40 no 5 pp 389ndash397 2011
[49] J Danesh P Whincup M Walker et al ldquoLow grade inflamma-tion and coronary heart disease prospective study and updatedmeta-analysesrdquo British Medical Journal vol 321 no 7255 pp199ndash204 2000
[50] C Barnabe B-J Martin and W A Ghali ldquoSystematic reviewand meta-analysis anti-tumor necrosis factor 120572 therapy andcardiovascular events in rheumatoid arthritisrdquo Arthritis Care ampResearch vol 63 no 4 pp 522ndash529 2011
[51] W G Dixon K D Watson M Lunt et al ldquoReduction in theincidence of myocardial infarction in patients with rheumatoidarthritis who respond to anti-tumor necrosis factor 120572 therapyresults from the British Society for Rheumatology BiologicsRegisterrdquo Arthritis and Rheumatism vol 56 no 9 pp 2905ndash2912 2007
[52] K Oryoji C Kiyohara T Horiuchi et al ldquoReduced carotidintima-media thickness in systemic lupus erythematosuspatients treated with cyclosporine Ardquo Modern Rheumatologyvol 24 no 1 pp 86ndash92 2014
[53] M L Bots A W Hoes P J Koudstaal A Hofman and DE Grobbee ldquoCommon carotid intima-media thickness andrisk of stroke and myocardial infarction the Rotterdam StudyrdquoCirculation vol 96 no 5 pp 1432ndash1437 1997
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
Submit your manuscripts athttpwwwhindawicom
Stem CellsInternational
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Behavioural Neurology
EndocrinologyInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Disease Markers
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
OncologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Oxidative Medicine and Cellular Longevity
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
PPAR Research
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
ObesityJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Computational and Mathematical Methods in Medicine
OphthalmologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Diabetes ResearchJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Research and TreatmentAIDS
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Gastroenterology Research and Practice
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Parkinsonrsquos Disease
Evidence-Based Complementary and Alternative Medicine
Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom
