Re iew doi:10.1093/ heuma ology/keu224
Ca dio ascula isk in heuma oid a h i is: ecen
ad ances in he unde s anding o he pi o al ole o
in lamma ion, isk p edic o s and he impac o
ea men
E nes Choy
1
, Kandeepan Ganeshalingam
2
, Anne G e e Semb
3,
*,
Zol a
´n Szekanecz
4,
* and Michael Nu mohamed
5,
*
Abs ac
Risk o ca dio ascula (CV) disease is inc eased among RA pa ien s. High in lamma o y bu den associa ed
wi h RA appea s o be a key d i e o he inc eased ca dio ascula isk. In lamma ion is linked wi h
accele a ed a he oscle osis and associa ed wi h a pa adoxical in e sion o he ela ionship be ween CV
isk and lipid le els in pa ien s wi h un ea ed RA, ecen ly coined he lipid pa adox. Fu he mo e, he
in lamma o y bu den is also associa ed wi h quali a i e as well as quan i a i e changes in lipop o eins, wi h
he an i-in lamma o y and a he op o ec i e oles associa ed wi h high-densi y lipop o ein choles e ol sig-
ni ican ly al e ed. RA he apies can inc ease lipid le els, which may e lec he no maliza ion o lipids due
o hei in lamma o y-dampening e ec s. Howe e , hese con ounding in luences o in lamma ion and RA
he apies on lipid p o iles pose challenges o assessing CV isk in RA pa ien s and in e p e a ion o
adi ional CV isk sco es. In his e iew we examine he ela ionship be ween he inc eased in lamma o y
bu den in RA and CV isk, explo ing how in lamma ion in luences lipid p o iles, he impac o RA he apies
and s a egies o iden i ying and moni o ing CV isk in RA pa ien s aimed a imp o ing CV ou comes.
Key wo ds: heuma oid a h i is, ca dio ascula disease, in lamma ion, a he oscle osis, dyslipidaemias, an i-
heuma ic agen s.
In oduc ion
I is now well es ablished ha RA is associa ed wi h in-
c eases in bo h mo bidi y and mo ali y compa ed wi h he
gene al popula ion. RA inc eases he isk o ca dio ascu-
la (CV) mo ali y by up o 50% compa ed wi h he gene al
popula ion [13] and CV disease (CVD) is he leading
cause o dea h in RA pa ien s [1,49]. La ge e ospec i e
s udies o RA pa ien s ha e shown he isk o myoca dial
in a c ion (MI), adjus ed o CV isk ac o s, o be
inc eased by up o 2- old compa ed wi h con ol g oups
[4,10]. Two ecen s udies ound ha he inc eased isk o
CVD in RA is compa able o ha obse ed o pa ien s
wi h ype 2 diabe es [11,12]. No ably, he pa e n o
CVD in RA pa ien s appea s o di e om ha in he gen-
e al popula ion; RA pa ien s a e mo e likely no only o
ha e silen ischaemic hea disease and expe ience
sudden dea h, bu also o de elop hea ailu e and die
sho ly he ea e [9].
T adi ional CV isk ac o s, such as hype ension, smok-
ing and ype 2 diabe es, ce ainly con ibu e o he
inc eased isk o mo ali y in RA pa ien s, bu do no
ully explain i [13,14]. Ra he , he high sys emic in lam-
ma o y bu den associa ed wi h RA appea s o be a key
d i e o inc eased CV isk [1,15]. The heigh ened in lam-
ma o y s a e in RA is linked o accele a ed a he oscle -
osis, wi h sys emic in lamma ion exace ba ing ad e se
changes in bo h es ablished and no el CV isk ac o s
[1519]. G owing e idence sugges s his excessi e in-
lamma o y bu den is accoun able o he lipid pa adox
1
Sec ion o Rheuma ology, Ca di Uni e si y School o Medicine,
Ca di , UK,
2
Global Medical A ai s, F. Ho mann-La Roche, Basel,
Swi ze land,
3
Depa men o Rheuma ology, Diakonhjemme Hospi al,
Oslo, No way,
4
Depa men o Rheuma ology, Ins i u e o Medicine,
Uni e si y o Deb ecen, Deb ecen, Hunga y and
5
Depa men s o
In e nal Medicine and Rheuma ology, VU Uni e si y Medical Cen e ,
Ams e dam, The Ne he lands.
Co espondence o: E nes Choy, Sec ion o Rheuma ology, Ca di
Uni e si y School o Medicine, Fi s Floo , Teno us Building, Hea h
Pa k Campus, Ca di CF14 4XN, UK. E-mail: [email p o ec ed]
*Anne G e e Semb, Zol a
´n Szekanecz and Michael Nu mohamed
con ibu ed equally o his s udy.
Submi ed 20 Janua y 2014; e ised e sion accep ed 28 Ma ch 2014.
!The Au ho 2014. Published by Ox o d Uni e si y P ess on behal o he B i ish Socie y o Rheuma ology
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/licenses/by-nc/3.0/), which pe mi s non-comme cial e-use,
dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac [email p o ec ed] 1
RHEUMATOLOGY 53
REVIEW
Rheuma ology Ad ance Access published June 6, 2014
a Uni e si y o Deb ecen, Facul y o Medicine, Cen al Lib a y on July 8, 2014h p:// heuma ology.ox o djou nals.o g/Downloaded om
in RA, in which choles e ol—an impo an CV isk ac o in
he gene al popula ion—is in e sely ela ed o CV isk in
pa ien s wi h un ea ed RA [20,21]. In con as , supp es-
sion o RA-associa ed in lamma ion coincides wi h some
inc eases in lipid alues, bu also a educ ion in CV e en s
[2124].
In ligh o his, he Eu opean League Agains
Rheuma ism (EULAR) ecommenda ions o he manage-
men o CV isk in RA highligh he c i ical impo ance o
adequa e disease con ol in lowe ing CV isk. Annual CV
isk assessmen s a e ecommended o pa ien s wi h RA,
wi h he isk assessmen epea ed when DMARD he apy
is changed [1]. Al hough he EULAR ecommenda ions
ha e u he helped o aise awa eness o inc eased CV
isk in pa ien s wi h in lamma o y a h i is, e idence sug-
ges s ha hese ecommenda ions a e no being p ac-
ised ei he consis en ly o egula ly [25,26]. In addi ion,
he ecommenda ions may also unde es ima e he o e all
CV isk [27,28].
In his e iew we examine he ela ionship be ween he
inc eased in lamma o y bu den in RA and CV isk, explo -
ing how in lamma ion in luences lipid p o iles and he
impac o RA he apies on lipop o eins. Fu he mo e, we
e iew he e idence and discuss s a egies o iden i ying
and moni o ing CV isk in RA pa ien s, wi h he aim o
imp o ing CV ou comes.
In lamma o y bu den and CV isk in RA
In lamma ion has consis en ly been shown o be a majo
CV isk ac o and he e is now subs an ial e idence o
sugges ha educing in lamma ion lowe s CV isk in RA
[2933]. Thus, compa ed wi h he gene al popula ion, he
inc ease in CV e en s in RA appea s o be a ea u e o he
sys emic in lamma ion associa ed wi h RA disease ac i -
i y. In his ega d, he applica ion o adi ional CV isk
ac o assessmen equa ions, such as F amingham and
he Sys ema ic Co ona y Risk E alua ion (SCORE)
models, o pa ien s wi h RA a e epo ed o unde es ima e
hei isk, as hey do no ully inco po a e he impac o
sys emic in lamma ion and he con ounding in luence o
in lamma ion on lipid p o iles [13,25,26,28]. E en wi h
he applica ion o a mul iplie o 1.5 ( ecommended by he
EULAR) o pa ien s wi h RA who mee wo o h ee c i e ia
consis ing o (i) a disease du a ion >10 yea s, (ii) RF o
an i-CCP posi i i y and (iii) he p esence o se e e ex a-
a icula mani es a ions, his modi ied SCORE (mSCORE)
may s ill esul in a subs an ial p opo ion o RA pa ien s a
high isk o CVD emaining uniden i ied [2628,34].
Pi o al ole o in lamma ion in he pa hophysiology o
CVD in RA
A b oad body o e idence indica es ha in lamma ion
con ibu es o he onse and pa hogenesis o a he oscle -
osis and CVD in he gene al popula ion [3537].
Epidemiological s udies sugges ha a numbe o p o-in-
lamma o y molecules, such as CRP, ib inogen and cy o-
kines, a e in ol ed in media ing his p ocess [3840].
Le els o hese p o-in lamma o y molecules and cy okines
a e inc eased in RA pa ien s; hey no only p omo e
endo helial dys unc ion and s uc u al essel abno mal-
i ies, bu also induce o he CV isk ac o s, such as
changes in lipid le els, insulin esis ance and oxida i e
s ess [4143]. Indeed, in RA, many s udies ha e demon-
s a ed a signi ican associa ion be ween in lamma o y
measu es, pa icula ly ESR, and he isk o CVD [21,
4451].
In lamma ion unde lies he accele a ed
a he oscle osis in RA
In lamma ion con ibu es o all s ages o a he oscle osis,
om plaque o ma ion o ins abili y and e en ual plaque
up u e [5,43,52]. A he oscle osis and RA sha e many
common in lamma o y pa hways, and he mechanisms
leading o syno ial in lamma ion a e simila o hose
ound in uns able a he oscle o ic plaque [39,43,52]. Fo
example, he high le els o TNF, IL-6 and IL-1 associa ed
wi h RA a e also cen al o he de elopmen o a he o-
scle osis [53,54]. Indeed, IL-6 has been shown o be sig-
ni ican ly associa ed wi h a he oscle osis in RA pa ien s,
independen o known CVD isk ac o s [55].
Fu he mo e, acu e phase eac an s (APRs), ypically
ele a ed in RA, ha e been shown o be associa ed wi h
subclinical a he oscle osis, indica ed by inc eased ca o id
a e y in imamedia hickness (cIMT) [56] and CV mo bid-
i y and mo ali y in pa ien s wi h RA [57]. In he gene al
popula ion, CRP le el is an independen p edic o o CV
isk, pa icula ly MI [58], while in bo h RA pa ien s and
heal hy subjec s, CRP is associa ed wi h he numbe o
a he oscle o ic plaques and cIMT [49,59]. No ably, highe
IL-6 le els a e also associa ed wi h inc eased mo ali y in
pa ien s wi h acu e co ona y synd omes [60] and wi h
inc eased isk o u u e MI in heal hy men [61]. Two
ecen la ge-scale gene ic and bioma ke s udies ha e
iden i ied IL-6 ecep o (IL-6R) signalling as ha ing a
causal ole in he de elopmen o co ona y hea disease
(CHD), sugges ing ha IL-6R blockade could be con-
side ed a po en ial he apeu ic app oach o he p e en-
ion o CHD [62,63].
The impac o in lamma ion on dyslipidaemia in RA
In RA, in lamma ion is associa ed wi h a pa adoxical in-
e sion o he usual ela ionship be ween CV isk and lipid
le els [21,29,64]. A simila in e se ela ionship has also
been obse ed wi h o he ch onic in lamma o y diseases,
in sepsis, in cance and in he immedia e pos -MI se ing,
whe e inc eased CRP is associa ed wi h lowe le els o
ci cula ing lipids (Fig. 1)[6569]. This ela ionship has also
been no ed in he pe iod immedia ely a e su ge y, whe e
an in e se associa ion has been obse ed be ween IL-6
ele a ion and choles e ol le el [70]. Impo an ly, se e al
s udies ha e epo ed inc eases in lipid le els wi h a suc-
cess ul educ ion in RA disease ac i i y ollowing an i-
in lamma o y ea men [71]. These obse a ions imply
ha he adi ional in e p e a ion o lipid p o iles o p e-
dic ing CV isk in he gene al popula ion may be con-
ounded by disease ac i i y in RA pa ien s [21,29].
The mechanisms by which he in lamma o y p ocess
can lead o hese lipid changes a e no ully unde s ood,
2www. heuma ology.ox o djou nals.o g
E nes Choy e al.
a Uni e si y o Deb ecen, Facul y o Medicine, Cen al Lib a y on July 8, 2014h p:// heuma ology.ox o djou nals.o g/Downloaded om
bu may include supp ession o he e iculoendo helial
sys em and educed low-densi y lipop o ein (LDL) pa icle
syn hesis [29]. I is possible ha unde high in lamma o y
bu den, excessi e APR p oduc ion may impai a icking
o choles e ol in he li e o impede no mal choles e ol
p oduc ion. Addi ionally, CRP media es he up ake o
LDL and oxidized LDL by mac ophages, induces LDL
deposi ion and inc eases LDL up ake by hepa ocy es
[72,73].
The in lamma o y bu den in RA is associa ed wi h quali-
a i e as well as quan i a i e changes in lipop o eins
[74]. High-densi y lipop o ein (HDL) has nume ous an i-
in lamma o y and a he op o ec i e oles, p omo ing e-
e se choles e ol anspo om ci cula ion o he li e
and p e en ing LDL oxida ion [75]. This p o ec i e unc ion
may be impai ed du ing pa hological p ocesses ha ac-
cele a e CV e en s [7681]. P o eomic s udies ha e ound
ha he sub ac ion composi ion o HDL isola ed om RA
pa ien s was signi ican ly al e ed, wi h he esul an loss o
an i-in lamma o y and e e se choles e ol anspo unc-
ion (summa ized in Fig. 2)[74,82,83]. O he wo k has
sugges ed ha he an i-in lamma o y na u e o HDL may
be a mo e sensi i e ma ke o CVD han absolu e HDL
le els. A good example o his comes om s udies o
he choles e ol es e ans e p o ein inhibi o s, dalce a-
pib and o ce apib, in which ci cula ing HDL le els we e
inc eased by as much as 3070%, ye no addi ional
ca diop o ec i e e ec was obse ed [84,85]. Taken o-
ge he , hese indings indica e ha bo h quan i a i e and
quali a i e changes need o be conside ed when assess-
ing lipid p o iles in RA [8688].
Impac o an i- heuma ic he apies on lipid p o iles
and CV isk in RA
T adi ional DMARDs
T adi ional DMARDs, such as MTX, SSZ and HCQ, ha e a
p o ec i e ole agains CV isk [30]. The mechanisms by
which DMARD use in luences CV isk a e poo ly unde -
s ood, bu lend suppo o he hypo hesis ha educing
in lamma ion is impo an in educing CV isk. O he ad-
i ional DMARDs, MTX is he mos widely used and is
known as he ancho d ug in RA [89], ye he mechanisms
unde lying i s an i-in lamma o y p ope ies a e no ully
unde s ood [90]. MTX inc eases o al choles e ol (TCh),
LDL, HDL and iglyce ide le els in RA [91,92].
Howe e , i is belie ed ha hese changes a e likely o
be due o he in lamma o y-dampening e ec o he
d ug and may essen ially e lec no maliza ion o he
lipid le els o hose seen in he gene al popula ion [93].
These lipid inc eases a e he e o e no gene ally belie ed
o inc ease CV isk. On he con a y, he e is e idence
om sys ema ic e iews and la ge obse a ional s udies
ha MTX he apy may dec ease CV mo bidi y and mo -
ali y in RA pa ien s, al hough indings should be in e -
p e ed wi h cau ion gi en po en ial con ounding by
issues o missing da a, channelling and bias [9496].
Po en ial mechanisms o CV isk educ ion wi h MTX a e
also no well unde s ood [57,94], al hough supp ession o
in lamma ion is likely o pa ially explain he pe cei ed
ca diop o ec i e e ec s o MTX. Cu en ly, in he CV
In lamma ion Reduc ion T ial, low-dose MTX (1520 mg/
week) is being es ed o de e mine whe he inhibi ion o
FIG.1Rep esen a ion o he in e se ela ionship be ween
changes in in lamma o y and lipid pa ame e s
The pa adigm by which an inc ease in he in lamma o y
bu den in RA is associa ed wi h he lowe ing o lipid le els
has also been no ed in o he ch onic in lamma o y con-
di ions, a e MI, a e su ge y and in cance ea men [21,
29,6470]. In RA, a educ ion o in lamma ion h ough
ea men wi h adi ional and/o biologic DMARDs is
e lec ed in ele a ions in lipid le els [71]. Da a, al hough
limi ed, sugges he ex en o which lipid le els change
may be di e en be ween RA he apies; howe e , u he
s udies a e equi ed o ully asce ain he ela ionship
be ween supp ession o in lamma ion, lipid ele a ions
and u u e ca dio ascula isk [71,102]. MI, myoca dial
in a c ion.
FIG.2In lamma ion induces quali a i e changes o HDL
subpa icle composi ion
Sys emic in lamma ion associa ed wi h RA may con e
bo h quan i a i e and quali a i e changes o HDL choles-
e ol unde lying he loss o some an i-in lamma o y and
a he op o ec i e p ope ies. Known changes o subpa i-
cle composi ion induced by in lamma ion a e summa ized
in his igu e [74,7683,8688]. apoA1: apolipop o ein A1;
apoJ: apolipop o ein J; CETP: choles e yl es e ans e
p o ein; HDL: high-densi y lipop o ein; LCAT: leci hin
choles e ol acyl ans e ae; LDL: low-densi y lipop o ein;
PAF-AH: pla ele -ac i a ing ac o ace ylhyd olase;
PON-1: pa aoxonase 1; SAA: se um amyloid A; sPLA
2
:
sec e o y non-panc ea ic phospholipase A
2
.
www. heuma ology.ox o djou nals.o g 3
In lamma ion and CV isk in RA
a Uni e si y o Deb ecen, Facul y o Medicine, Cen al Lib a y on July 8, 2014h p:// heuma ology.ox o djou nals.o g/Downloaded om
in lamma ion pe se imp o es CVD ou comes (clinical-
ials.go , iden i ie NCT01594333). The ou come o his
s udy will be pi o al, as a posi i e inding would s ongly
suppo he in lamma o y hypo hesis o a he o h ombosis
and u he es ablish in lamma ion as a key d i e o CV
e en s [97].
Biologic agen s: TNF inhibi ion
TNF, a pi o al cy okine in ch onic in lamma ion, also a -
ec s lipid me abolism, insulin esis ance and endo helial
unc ion [98,99]. An i-TNF he apy educes in lamma ion,
including le els o CRP and ESR [100,101], modi ies he
lipop o ein spec um and, in combina ion wi h MTX o
DMARDs, has been associa ed wi h a educ ion o CV
isk in RA pa ien s [3133]. Me a-analyses indica e ha
an i-TNFs a e gene ally associa ed wi h signi ican in-
c eases in HDL, TCh and iglyce ides in RA [71,102],
bu a ecen s udy also sugges s ha an i-TNF he apy
may signi ican ly inc ease LDL [103]. No ably, mos s u-
dies demons a e ha he lipid a io, TCh:HDL, is no ap-
p eciably al e ed by an i-TNF he apy, o ha inc eases
a e modes (425%) [29]. Al hough hese s udies we e
gene ally small and/o pos hoc, a clea o e all end
was obse ed o inc eased ci cula ing lipid le els wi h
an i-TNF he apy. Again, his may e lec a no maliza ion
o lipid le els o he le el p io o RA disease, and al hough
inc eases in iglyce ides appea o be g ea e han hose
obse ed wi h MTX, his may be due o mo e p o ound
supp ession o in lamma ion wi h an i-TNFs [91].
Despi e inc eases in lipid le els, sys ema ic e iews
ha e consis en ly ound an associa ion be ween an i-
TNF he apy and a dec eased isk o CV mo bidi y in RA
[104,105], wi h an o e all 54% educ ion in isk o all CV
e en s [105]. A less de ini e associa ion has been seen o
isk o he indi idual e en s o MI, s oke and hea ailu e,
bu hese analyses may ha e been con ounded by com-
pa isons wi h pa ien s ecei ing o he DMARDs, including
MTX, known o be associa ed wi h a dec eased isk o
CVD [94,104].
In e es ingly, se e al s udies ha e ound ha he le el o
esponse o an i-TNFs may be impo an , wi h esponde s
ha ing a signi ican ly lowe isk o CV- ela ed e en s ela-
i e o non- esponde s [31,104]. Al hough s udies ha e
gene ally been small and bese wi h some me hodo-
logical issues, an i-TNF he apy has been shown o
modi y o he ac o s associa ed wi h a he oscle o ic
CVD isk in RA, including educ ions in endo helial dys-
unc ion [106109], enhancemen o HDL an i-oxida i e
capaci y [110] and imp o emen s in insulin sensi i i y
[99]. La ge s udies a e equi ed o con i m hese indings.
Addi ionally, i is no ye known whe he he impac o
an i-TNFs on lipid p o ile and CV isk is a class e ec o
all an i-TNFs.
Biologic agen s: IL-6R inhibi ion
Tocilizumab inhibi s IL-6 signalling ia he blockade o
IL-6R, esul ing in a s ong and sus ained impac on in-
lamma ion, wi h apid no maliza ion o CRP and ESR
[111114]. S udies ha e consis en ly shown ha ocilizu-
mab is associa ed wi h inc easing lipid le els in he
con ex o dec easing le els o in lamma o y ma ke s
[111,113,115119]. Howe e , hese ele a ions ha e
been shown o espond o lipid-lowe ing he apies [120].
The mechanisms by which ocilizumab inc eases lipids
a e no ye ully unde s ood, pa icula ly since polymo ph-
isms o he IL-6R-yielding unc ional a ian s appea o
ha e no e ec on lipid concen a ions bu do inc ease
le els o ci cula ing IL-6 while educing le els o APRs
[62,63].
Impo an ly, simila o an i-TNF he apy, all main
lipop o eins—HDL, TCh, LDL and iglyce ides— a e
inc eased wi h ocilizumab ea men and a e ela ed o
ela i ely s able LDL:HDL and TCh:HDL a ios. These
a ios a e known o be mo e closely associa ed wi h CV
isk han indi idual lipid measu es, which can be con-
ounded by he e ec o in lamma ion [35,121,122]. The
a io o apolipop o ein (apo) B:apoA1, which has been
shown o p edic CV isk mo e accu a ely han any o he
choles e ol index, emained s able o e 6 mon hs o oci-
lizumab ea men [113,123,124].
In he double-blind phase IV Adalimumab Ac em a
(ADACTA) s udy, which e alua ed ocilizumab mono he -
apy s adalimumab (an i-TNF) mono he apy in RA pa ien s
in ole an o MTX o o whom con inued MTX was
deemed inapp op ia e, mo e pa ien s in he ocilizumab
g oup han in he adalimumab g oup had inc eased LDL
along wi h signi ican ly g ea e educ ions in CRP, ESR,
28-join DAS (DAS28) and o he composi e measu es o
disease ac i i y a 24 weeks [125]. Quali a i e changes in
lipid sub ac ions wi h ocilizumab he apy ha e been
examined in he placebo-con olled MEASURE s udy (a
andomized, pa allel-g oup, open-label, mul icen e
s udy o e alua e he e ec s o ocilizumab on accina ion
in subjec s wi h ac i e RA ecei ing backg ound MTX),
which ound ha ocilizumab + MTX did no inc ease he
concen a ion o small, dense LDL pa icles, which a e
gene ally belie ed o be p o-a he ogenic [35,126128],
compa ed wi h MTX alone a 12 o 24 weeks [129]. In
con as , small and medium HDL pa icles, conside ed
o be an i-a he ogenic, we e signi ican ly inc eased wi h
ocilizumab. In e es ingly, he s udy also demons a ed
signi ican changes in pa aoxonase 1 le els, HDL-asso-
cia ed se um amyloid A (SAA) and sec e ed g oup IIA
phospholipase A
2
(sPLA
2
-IIa) wi h ocilizumab, sugges ing
ha ea men al e s HDL composi ion om a p o-in lam-
ma o y s a e o a less in lamma o y s a e.
Da a om he ocilizumab clinical de elopmen p o-
g amme and long- e m ex ension s udies p o ide some
eassu ance o he lack o a nega i e e ec o lipid p o ile
changes seen wi h ocilizumab on CV isk. In he double-
blind phase o he i e co e phase III s udies o ocilizu-
mab, a es o MI we e nume ically lowe wi h bo h doses
o ocilizumab s con ols [120], while analysis o he long-
e m sa e y o ocilizumab (n= 4171; median ea men
du a ion 3.9 yea s) demons a ed a s able a e o CV
e en s o e ime wi h ocilizumab exposu e [120,130].
These clinical da a a e suppo ed by imaging s udies
ha show ha ocilizumab does no appea o inc ease
cIMT [131,132].
4www. heuma ology.ox o djou nals.o g
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In e p e a ion o he e ec s o ocilizumab on in lam-
ma o y bu den using only CRP o composi e disease
ac i i y measu es ha inco po a e an APR componen
can be misleading due o he powe ul e ec o IL-6
inhibi ion on hepa ic APR p oduc ion [133,134].
Howe e , in he ADACTA s udy, ocilizumab induced
no only a g ea e educ ion in ESR and CRP a all
ime poin s compa ed wi h adalimumab, bu also a
g ea e educ ion in he Clinical Disease Ac i i y Index
(CDAI), which does no include an APR componen
[125]. In e es ingly, inc eased CRP le els ha e also
been es ablished as a p ecu so o insulin esis ance
de elopmen , an impo an CV isk ac o , and a
ecen subanalysis o he TOWARD (Tocilizumab in
Combina ion Wi h T adi ional DMARD The apy) s udy
ound ha ocilizumab signi ican ly imp o ed insulin e-
sis ance in RA pa ien s [135,136]. ENTRACTE, an on-
going andomized, open-label s udy e alua ing he a e
o CV e en s wi h ocilizumab s e ane cep in pa ien s
wi h RA, will p o ide u he insigh on he e ec s o
ocilizumab compa ed wi h an i-TNFs (clinical ials.go
iden i ie NCT01331837).
O he RA he apeu ic agen s
Rela i ely li le is known ega ding he impac o o he bio-
logics ( i uximab, aba acep o anakin a) on lipid p o iles
o CV isk in RA. Analyses o i uximab sa e y ha e
demons a ed no no able di e ences s placebo in CV
e en a es a 6 mon hs and no e idence o an inc eased
associa ion be ween MI and i uximab in longe - e m
ollow-up [137]. A ecen analysis sugges s i uximab
has bene icial e ec s on he choles e ol p o ile and al e -
a ion o HDL o a less p o-a he ogenic composi ion
du ing 6 mon hs o ea men [82]. Rapid i uximab-
induced imp o emen s in low-media ed dila a ion and
dec eases in cIMT, coinciding wi h dec eases in TCh
and inc eases in HDL, ha e also been demons a ed in a
small s udy [138].
To aci inib, an o al Janus kinase inhibi o , has ecen ly
been app o ed by he US Food and D ug Adminis a ion
(FDA) as an RA medica ion. Lipid p o ile changes wi h
o aci inib appea o be simila o hose obse ed wi h
ocilizumab, wi h inc eases in bo h LDL and HDL, how-
e e , CRP does no appea o be educed o he same
ex en [139142]. In a phase III s udy, LDL and HDL le els
inc eased o a g ea e ex en wi h o aci inib han wi h he
an i-TNF adalimumab a 3 mon hs, despi e a nume ically
simila impac on measu es o disease ac i i y—indica ing
ha he e may be mechanisms in ol ed o he han
dampening o in lamma ion wi h o aci inib [139]. A o a-
ci inib phase II s udy including co-adminis a ion o he
lipid-lowe ing agen a o as a in indica ed ha he in-
c ease in LDL and TCh could be educed o below base-
line le els [143]. Analysis o majo ad e se CV e en s in
he o aci inib clinical de elopmen p og amme demon-
s a ed a simila incidence ac oss g oups in he phase III
p og amme, wi h lowe a es in long- e m ex ension s u-
dies, sugges ing no inc eased CV isk o e 3 yea s o
ollow-up [144].
Managemen o lipid p o iles and CV isk in RA
Gi en he high le el o sys emic in lamma o y bu den ha
cha ac e izes RA, which is ega ded as a key CV isk
ac o , alongside an inc eased p e alence o adi ional
isk ac o s, EULAR ecommenda ions highligh he im-
po ance o adequa e disease con ol in o de o lowe
CV isk (Table 1)[1]. The ulne abili y o he ca o id
plaque has been shown o be in luenced by RA disease
ac i i y, and emission may alle ia e his h ea [145].
The e o e e ec i e CV isk managemen will likely com-
p ise no only adequa e ea men o con en ional isk ac-
o s, bu also igh and sus ained disease ac i i y con ol
[27]. The complex impac o in lamma ion on lipid pa icle
composi ion as well as he phenomenon o he lipid pa a-
dox in RA makes in e p e a ion o ci cula ing lipid le els
di icul , po en ially limi ing hei use ulness as a ma ke o
CV isk [21,29]. Mo eo e , in a pos hoc analysis om he
Apolipop o ein- ela ed Mo ali y Risk (AMORIS) s udy, he
associa ion be ween TCh and acu e MI was ound o be
weake among pa ien s wi h RA han he gene al popula-
ion [10]. This may sugges ha he adi ional in e p e -
a ion o hype choles e olaemia as a isk o CVD may no
apply and ha lipid le els om RA pa ien s may be a con-
ounding ac o in CV isk algo i hms.
The po en supp ession o in lamma ion wi h biologic
he apies in RA is accompanied by inc eases in lipid pa -
ame e s ha a e no mally associa ed wi h inc eased CV
isk in he gene al popula ion. Thus, in o de o app op i-
a ely manage lipid le els in RA pa ien s, i is ad isable o
eassess he lipid p o iles o pa ien s a e dampening in-
lamma ion. S a egies such as ea - o- a ge , wi h dis-
ease emission o low disease ac i i y as he clinical
goal, as soon as RA is diagnosed can be highly e ec i e
o apidly educe in lamma ion and achie e igh con ol o
disease ac i i y (an o e iew o he bene i s o dampening
in lamma ion on CV isk in RA is shown in Fig. 3)[146].
Lipid p o iles can hen be moni o ed and, i app op ia e,
ea ed wi h lipid-lowe ing d ugs acco ding o na ional
guidelines [147149].
The EULAR ecommenda ions o CV managemen ,
based on a sys ema ic li e a u e e iew and he opinion
o an in e disciplina y ask o ce, a e a highly welcome
s a ing poin o iden i ying and imp o ing he manage-
men o CV isk in pa ien s wi h RA. Al hough i was
acknowledged by he EULAR ask o ce ha hei ap-
p oach was conse a i e, e idence sugges s ha , e en
a e applying he mul iplica ion ac o , he mSCORE isk
ac o equa ion may s ill no accu a ely es ima e CV isk
o indi idual RA pa ien s [26,27,150]. One aspec po en-
ially con ibu ing o his unde es ima ion o isk is he use
o a disease du a ion >10 yea s as a c i e ia o inc eased
CV isk, as mos e idence now suppo s inc eased isk o
CVD ea ly in disease [151153]. Thus mo e disc imina ing
ools o iden i ying RA pa ien s wi h highe isk o CVD
a e needed.
Se e al alida ed non-in asi e imaging echniques a e
now a ailable o de e mining subclinical a he oscle osis
in RA [34,154,155]. O hese, ul asonog aphic assess-
men o cIMT and he p esence o plaques has been
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iden i ied as use ul o s a i ying RA pa ien s wi h high CV
isk [34,56,149]. In a ecen s udy 60% o pa ien s
iden i ied as ha ing mode a e CV isk acco ding o he
mSCORE had e idence o ca o id plaques and/o cIMT
>0.90 mm (bo h conside ed ac o s indica i e o CV p og-
nosis in he gene al popula ion) [34]. Fu he mo e, he p o-
po ion o pa ien s iden i ied as ha ing high o e y high
CV isk inc eased om 9.2% wi h he mSCORE o 47.7%
wi h addi ional ca o id US esul s [27,34]. Non-in asi e
imaging echniques such as ca o id ul asonog aphy
may hus be use ul alongside CV isk assessmen
models o enhance he iden i ica ion o RA pa ien s wi h
inc eased CV isk. Howe e , he easibili y o pe o ming
hese assessmen s wi hin a heuma ology clinic o in pa -
ne ship wi h a specialis ca diology clinic needs o be es-
ablished [27].
Conclusion
The CV isk in RA is inc eased o a simila magni ude o
ha seen in ype 2 diabe es and is ela ed o he sys emic
in lamma o y bu den associa ed wi h RA as well as an
inc eased p e alence o adi ional isk ac o s. An i-
heuma ic he apies ha a e highly e ec i e a educing
in lamma ion appea o inc ease TCh and LDL le els, al-
hough in ligh o he lipid pa adox in RA, he bene i s o
supp ession o in lamma ion a e likely o ou weigh lipid
changes ha migh o he wise be conside ed o be ad-
e se. In his ega d, he supp ession o in lamma ion
h ough igh and sus ained disease con ol is impo an
o lowe ing CV isk, bu also o pe mi accu a e sc eening
o pa ien s a high CV isk.
The op imal app oach o iden i ica ion o pa ien s wi h
inc eased CV isk has ye o be ully es ablished, bu i
is key ha (i) all RA pa ien s be sc eened and (ii) he
app op ia e managemen o hose who a e a high
isk be unde aken. Cu en assessmen ools and
TABLE 1Ten ecommenda ions om EULAR o CV isk managemen in RA
1 RA should be ega ded as a condi ion associa ed wi h highe isk o CV disease. The inc eased isk appea s o be due
o bo h an inc eased p e alence o adi ional isk ac o s and he in lamma o y bu den.
2 Adequa e con ol o disease ac i i y is necessa y o lowe he CV isk.
3 CV isk assessmen using na ional guidelines is ecommended o all pa ien s wi h RA. Risk assessmen s should be
epea ed when an i- heuma ic ea men has been changed.
4 Risk sco e models should be adap ed o pa ien s wi h RA by in oducing a 1.5 mul iplica ion ac o . This mul iplica ion
ac o should be used when he pa ien wi h RA mee s wo o he ollowing h ee c i e ia:
(i) disease du a ion >10 yea s, (ii) RF o an i-CCP posi i i y and (iii) he p esence o ce ain ex a-a icula
mani es a ions.
5 TCh/HDL choles e ol a io should be used when he SCORE model is used.
6 In e en ion should be ca ied ou acco ding o na ional guidelines.
7 S a ins, ACE inhibi o s and/o AT-II blocke s a e p e e ed ea men op ions.
8 The ole o coxibs and mos NSAIDs in CV isk is no well es ablished and needs u he in es iga ion. Hence we should
be e y cau ious abou p esc ibing hem, especially o pa ien s wi h a documen ed CV disease o in he p esence o
CV isk ac o s.
9 Co icos e oids: use he lowes dose possible.
10 Recommend smoking cessa ion.
CV: ca dio ascula ; coxibs: cyclooxygenase (COX) inhibi o s; TCh: o al choles e ol; HDL: high-densi y lipop o ein choles e ol;
ACE: angio ensin-con e ing enzyme. Adap ed om Pe e s e al. [1].
FIG.3Impac o igh con ol o in lamma ion and disease
ac i i y in ela ion o he educ ion o ca dio ascula isk
in RA
The heigh ened in lamma o y s a e in RA is linked wi h
accele a ed a he oscle osis, wi h sys emic in lamma ion
exace ba ing ad e se changes in bo h es ablished
and no el ca dio ascula (CV) isk ac o s [1619].
Addi ionally, he use o some an i-in lamma o y medica-
ion is also associa ed wi h inc easing CV isk [6].
T ea - o- a ge s a egies wi h adi ional and/o biologic
DMARDs can be highly e ec i e o apidly educe in-
lamma ion and achie e igh con ol o disease ac i i y
[146]. Lipid p o iles can hen be moni o ed and, i app o-
p ia e, ea ed wi h lipid-lowe ing d ugs acco ding o
na ional guidelines [147149].
6www. heuma ology.ox o djou nals.o g
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ecommenda ions may unde es ima e CV isk in some pa-
ien s. The use o non-in asi e imaging ools may help o
imp o e he sensi i i y o CV assessmen s, bu u he e-
sea ch is needed o assess he easibili y o inco po a ing
hese echniques in o ou ine p ac ice.
Rheuma ology key messages
.In lamma ion in RA is associa ed wi h a pa adoxical
in e sion o he ela ionship be ween ca dio ascula
isk and lipid le els.
.Inc eases in lipid le els by RA he apies e lec no -
maliza ion o lipids due o hei in lamma o y-
dampening e ec s.
.Mo e disc imina ing ools o iden i ying RA pa ien s
wi h a highe isk o ca dio ascula disease a e
needed.
Acknowledgemen s
Suppo o hi d-pa y w i ing assis ance o his manu-
sc ip was p o ided by F. Ho mann-La Roche L d. All
iews in his a icle a e hose o he au ho s.
Disclosu e s a emen : E.C. epo s g an s and pe sonal
ees om F. Ho man-La Roche Chugai Pha ma and
UCB and pe sonal ees om P ize , MSD, AbbVie and
BMS du ing he p epa a ion o he manusc ip , as well
as pe sonal ees om Abbo Labo a o ies, Boeh inge
Ingelheim, Daiichi Sankyo, Eli Lilly, ISIS, MedImmune
and Syno a e and g an s om Fe ing Pha macue ical,
GSK and Jazz Pha maceu icals ou side he submi ed
wo k. A.G.S. epo s pe sonal ees om Me ck/
Sche ing-Plough, Abbo , P ize /Wye h, F. Ho man-La
Roche and BMS and g an s om Raaghol s i elsen,
No wegian Ex a Founda ion o Heal h and
Rehabili a ion, Sou h Eas e n Regional Heal h Au ho i y
o No way and G e e Ha bi z lega ou side he submi ed
wo k. K.G. is employed by F. Ho mann-La Roche L d. All
o he au ho s ha e decla ed no con lic s o in e es .
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