Aterosklerosis Sle Medscape

7/25/2019 Aterosklerosis Sle Medscape

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Systemic Lupus Erythematosus and Cardiovascular

Disease

Prediction and Potential for Therapeutic Intervention

Maureen McMahon; Bevra H Hahn; Brian J Skaggs

Expert Rev Clin Immunol. 2!!;"#2$%22"&2'!.

Abstract and Introduction

Abstract

(atients )ith s*stemic lupus er*thematosus have a signi+icantl* increase, risk o+ car,iovascular events ,ue to

atherosclerosis. -ra,itional car,iac risk +actors cannot +ull* explain this increase, risk. Recent evi,ence strongl*

suggests that atherosclerotic plaue is largel* ,riven /* in+lammation an, an active immunological response0 incontrast to the long&hel, /elie+ that plaue is a passive accumulation o+ lipi,s in the arterial )all. Current

approaches to the prevention o+ atherosclerosis in s*stemic lupus er*thematosus involve targeting mo,i+ia/le

car,iac risk +actors. 1uture preventive strategies ma* inclu,e therapies that counteract the immunologic

responses that lea, to plaue +ormation.

Introduction

(remature atherosclerosis is a maor comor/i, con,ition in s*stemic lupus er*thematosus #S3E$. 4hile t*pical

+eatures o+ S3E0 such as nephritis an, vasculitis0 have /een the tra,itional +ocus o+ treatment0 the i,enti+ication

o+ comor/i, con,itions such as atherosclerosis has /ecome more important as the treatments +or S3E improve

an, patients live longer.

-he increase, risk o+ car,iovascular ,isease in S3E )as +irst recogni5e, in !6"7 /* 8ro)it5 et al.)ho

,escri/e, a /imo,al pattern o+ mortalit* in their -oronto S3E cohort.9!:+ the !! ,eaths in their cohort0 six

occurre, )ithin ! *ear o+ ,iagnosis0 an, )ere attri/ute, to active S3E ,isease. 1ive patients ,ie, at a mean o+

':-his risk is increase, compare, )ith the general population; +or example0 in a S)e,ish lupus

population ,escri/e, in !6''&*ear age group )ere over ?&times more likel* to have a MI than )omen o+

a similar age in the 1ramingham ++spring Stu,*.92:

-he inci,ence o+ su/clinical atherosclerosis is also increase, in S3E. In a cross&sectional stu,*0 Roman et al.

compare, !6" lupus patients an, !6" matche, controls using caroti, ultrasoun,0 an, +oun, that plaue )as

present in @"= o+ S3E patients compare, )ith !?= o+ controls #p A .!$.97:In a short&term longitu,inal

+ollo)&up stu,* o+ the S3E patients in this cohort0 atherosclerosis ,evelope, or progresse, at an average rate o+!= per *ear. 1urther stu,ies have re+lecte, similar prevalences o+ su/clinical atherosclerosis in S3E. 9":Man5i

an, colleagues +oun, su/clinical caroti, atherosclerosis in '= o+ their cohort. 9


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controls.96:4hen en,othelial ,*s+unction0 another marker o+ su/clinical atherosclerosis0 )as use, as a marker o+

atherosclerosis0 ??= o+ S3E patients ha, impaire, +lo)&me,iate, ,ilation0 compare, )ith 27.@= o+ control

su/ects.9!:

4hat accounts +or the increase, risk o+ atherosclerosis seen in patients )ith S3E -ra,itional car,iac risk

+actors ,e+ine, /* the 1ramingham stu,ies0 such as ol,er age0 high /loo, pressure an, high cholesterol levels0 9!!:

,o appear to pla* a role; ho)ever0 these +actors alone ,o not a,euatel* explain the increase, inci,ence o+

car,iovascular ,isease seen in patients )ith S3E0 inclu,ing increase, risk +or MI #increase, relative risk% !.!$

an, stroke #increase, relative risk% ".6$.9!2:-hus0 the etiolog* o+ the increase, risk o+ atherosclerosis in S3E is

likel* multi+actorial0 resulting +rom a complex interpla* /et)een tra,itional car,iac risk +actors an, S3E&,riven

in+lammation. -o ,evelop a +uller un,erstan,ing o+ atherosclerosis in S3E0 an, to ,evelop strategies +or the

prevention an, treatment o+ car,iovascular complications0 it is important to +irst have a complete un,erstan,ing

o+ the role that /oth tra,itional an, nontra,itional risk +actors pla* in the pathogenesis o+ atherosclerosis in S3E.

Traditional Risk actors ! the Patho"enesis of Atherosclerosis in SLE

lthough the* ,o not +ull* explain the increase in atherosclerosis seen in S3E patients0 /oth tra,itional

car,iovascular risk +actors ,e+ine, /* the 1ramingham Heart Stu,ies 9!@:an, S3E&speci+ic risk +actors have /een

i,enti+ie, in patients. ssessment o+ car,iovascular risk +actors in the Hopkins 3upus Cohort reporte, in !6620,emonstrate, that ?@= o+ patients )ith S3E ha, at least three tra,itional risk +actors; 9':ho)ever0 in a risk

assessment +or coronar* heart ,isease&relate, events using the 1ramingham risk assessment mo,el0 the mean !&

*ear risk o+ a car,iac event ,i, not ,i++er /et)een 2? patients )ith S3E an, 2? controls. 9!':Ho)ever0 this

stu,* ,i, reveal a higher prevalence o+ nontra,itional car,iac risk +actors in patients )ith S3E0 inclu,ing

premature menopause0 se,entar* li+est*le an, increase, )aist&to&hip ratio.9!':1urther evi,ence o+ the

contri/ution o+ nontra,itional0 or S3E&speci+ic0 car,iac risk +actors )as ,emonstrate, in a Cana,ian cohort0

)hich reveale, that the relative risk o+ overall coronar* arter* ,isease in patients )ith S3E )as at least

seven+ol, greater compare, )ith pre,ictions /ase, on tra,itional 1ramingham risk +actors. 9!2:Devertheless0

although the* cannot +ull* account +or the increase, risk0 tra,itional car,iac risk +actors ,o contri/ute to

increase, atherosclerosis an, car,iovascular events in S3E. In a 3on,on cohort0 tra,itional car,iac risk +actors

,i, pre,ict a higher risk o+ coronar* ,isease in S3E patients un,er the age o+ ' *ears. 9!?:In a,,ition0 most S3Ecohort stu,ies have i,enti+ie, at least one tra,itional car,iac risk +actor as a signi+icant pre,ictor o+ car,iac

events or su/clinical atherosclerosis using multivariate mo,eling. summari5es the various risk +actors

contri/uting to the ,evelopment o+ accelerate, atherosclerosis in patients )ith S3E.

Table #$ Traditional and nontraditional cardiac risk factors in patients %ith systemic lupus

erythematosus$

Risk factor References sho%in" positive associationReferences sho%in"

no association

Traditional risk factors

*slipi,emia 9


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Renal ,isease 9!702'027: 92":

S3E ,isease activit*

an, ,uration97>.'

mgFkgF,a*$ ,oses )ith ,ecrease, IM- in chil,ren 927: an,

a,ults 92":

IM-% Intima&me,ia thickness; S3E% S*stemic lupus er*thematosus.

SLE&specific Risk actors

Disease Activity ! Duration

-he association /et)een S3E ,isease activit* an, atherosclerosis has /een poorl* un,erstoo, to ,ate. Man5i et

al.+oun, an inverse relationship /et)een S3E activit* an, plaue si5e0 an, note, that longer ,isease ,uration

)as in,epen,entl* associate, )ith caroti, plaue.

9


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the pathogenesis o+ S3E itsel+0 the interpla* o+ multiple in+lammator* me,iators0 inclu,ing leukoc*tes0

c*tokines0 chemokines0 a,hesion molecules0 complement an, anti/o,ies0 results in the +ormation o+

atherosclerotic plaues.9@2:-o un,erstan, the role o+ in+lammation in the ,evelopment o+ atherosclerosis in S3E0

it is important to +irst un,erstan, the ,evelopment o+ the atherosclerotic plaue.

Recruitment of Inflammatory Cells to the Arterial ,all

therosclerotic lesions /egin )ith the recruitment o+ in+lammator* cells such as monoc*tes an, - cells to the

en,othelial )all. 1irst0 the vascular en,othelial cells are stimulate, to express leukoc*te a,hesion molecules0

inclu,ing E&selectin0 vascular cell a,hesion molecule&! #GCM&!$ an, inter&cellular a,hesion molecule&!

#ICM&!$.9@2:-hese cell&sur+ace proteins are upregulate, ,uring perio,s o+ in+lammation0 an, can /e in,uce, /*

proin+lammator* c*tokines such as -D1& an, I3&!.9@2:GCM&! is also in,uce, )hen en,othelial cells are

expose, to other in+lammator* signals0 such as the lipopol*sacchari,es o+ ram&negative /acteria0

l*sophosphati,*lcholine0 an, oxi,i5e, phospholipi,s such as oxi,i5e, lo)&,ensit* lipoprotein #x33$.9@@0@':

High&,ensit* lipoproteins #H3$ inhi/it the expression o+ a,hesion molecules #1igure !$.9@?0@7:


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i"ure #$


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Effects of hi"h&density lipoprotein and proinflammatory hi"h&density lipoprotein on atherosclerosis

initiation and pro"ression$ -A.Illustration o+ the interaction /et)een 330 the entrance o+ monoc*tes into the

arter* )all0 +ormation o+ oxi,i5e, 33 #x33$0 an, the engul+ment o+ x33 /* macrophages to +orm +oam

cells. H3 interrupts this atherosclerotic process /* reverse cholesterol transport o+ oxi,i5e, lipi,s +rom +oam

cells0 /* /locking en,othelial cell activation0 an, /* prevention o+ oxi,ation o+ 33 via antioxi,ative en5*mes

in the normal H3 particle such as paraoxonase. -).(roin+lammator*0 pro&oxi,ant H3 cannot carr* out man*

o+ the protective +unctions o+ normal +unctioning H30 lea,ing to the +ormation o+ x330 the release o+

chemokines an, c*tokines0 the engul+ment o+ x33 /* C@7 receptors on macrophages to +orm +oam cells

an, ultimatel* atherosclerotic plaue.

H3% High&,ensit* lipoprotein; 33% 3o)&,ensit* lipoprotein; MC(&!% Monoc*te chemotactic protein&!;

piH3% (roin+lammator* high&,ensit* lipoprotein; RS% Reactive ox*gen species.

-he importance o+ these a,hesion molecules in the ,evelopment o+ atherosclerosis is highlighte, /* the +act that

atherosclerosis&prone apoE&,e+icient mice )ho are also ,e+icient in E&selectin ,evelop +e)er plaue lesions.9@":

lso0 solu/le levels o+ GCM&! can /e ,etecte, in the s*stemic circulation0 an, elevate, levels o+ this a,hesion

molecule have /een +oun, in humans )ith coronar* arter* ,isease.9@


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Role of Cytokines in Atherosclerosis

- cells0 primaril* o+ the -h! su/t*pe0 are also a/un,ant in atherosclerotic lesions0 an, ma* pla* a role in the

+ormation o+ plaue through the casca,e o+ c*tokines that is initiate, /* their activation. 97':Gascular en,othelial

an, smooth muscle cells are important targets +or in+lammator* c*tokines an, these cells can pro,uce a,,itional

c*tokines )hen stimulate,.9@:t least t)o stimuli +or -h! ,i++erentiation are present in the atherosclerotic

plaue. I3&!2 is expresse, /* macrophages0 smooth muscle cells an, en,othelial cells0 an, is an important

stimulus +or -h! ,i++erentiation.97?:Elevate, levels o+ I3&!2 have /een +oun, in atherosclerotic plaues0 97?:an,

the inhi/ition o+ I3&!2 using a vaccination techniue that +ull* /locks the action o+ I3&!2 has /een sho)n to

,ecrease atherosclerosis in mice.977:I3&!2 pro,uction is upregulate, in monoc*tes expose, to x33.97?:

I1D&L has also /een ,etecte, in human plaues.9@2:It is a po)er+ul gro)th inhi/itor +or smooth muscle cells0

en,othelial cells an, collagen pro,uction0 an, thus promotes plaue insta/ilit*.97":In a,,ition0 I1D&L in,uces the

expression o+ secretor* phospholipase 20 lea,ing to the pro,uction o+ in+lammator* lipi, me,iators such as

l*sophosphati,*lcholine0 platelet&activating +actor an, eicosanoi,s.97

,o)nregulates paraoxonase mRD levels.9


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in the pathogenesis o+ atherosclerosis.96@06':(atients )ith primar* antiphospholipi, s*n,rome have /een sho)n to

have thicker caroti, arter* intima&me,ia at the caroti, /i+urcation an, internal caroti, arter* compare, )ith

controls0 especiall* those over ' *ears o+ age.96?:In health* men0 elevate, antiphospholipi, anti/o,ies have

/een correlate, )ith an increase, risk o+ +uture MI096706":an, in renal transplant patients0 the presence o+

antiphospholipi, anti/o,ies has /een associate, )ith a relative risk +or an atherosclerotic event o+ 2.


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s note,0 apo&I is the maor apolipoprotein component o+ H3. Re,uce, levels o+ apo&I have /een +oun, in

rheumatoi, arthritis patients09!


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levels o+ oxi,ation.9!':In this stu,*0 +our out o+ +our S3E patients )ith a histor* o+ ,ocumente, atherosclerosis

ha, piH30 +urther suggesting that H3 pla*s an important role in the pathogenesis o+ atherosclerosis.

Su/seuent stu,ies have in,icate, that


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)ith S3E0 statin therap* shoul, /e limite, to pu/lishe, gui,elines such as the Dational Cholesterol E,ucation

(anel.9!":

1ypertension

Similar to the recommen,ations +or management o+ ,*slipi,emia0 patients )ith S3E shoul, /e treate, to the

target /loo, pressure levels recommen,e, +or those )ith other high&risk comor/i, con,itions such as ,ia/etes

#i.e.0 s*stolic /loo, pressure A!@ mmHg; ,iastolic /loo, pressure A

)ith S3E treate, )ith antimalarial agents.9!


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3imetic Peptides in Rheumatic Diseases

xi,i5e, lipi,s represent another potential ne) target +or therap*0 not onl* in the prevention o+ atherosclerosis

in S3E0 /ut also in the treatment o+ in+lammator* ,isease mani+estations. -here is great interest in the

therapeutic potential o+ speci+ic pepti,es ,erive, +rom H3&relate, proteins in the prevention o+ atherosclerosis.

Several pepti,e +ragments +rom apo&I0 such as the '&1 pepti,e0 have /een selecte, +or their a/ilit* to prevent

the in+lammation in,uce, /* oxi,i5e, lipi,s.9!6!:

nimal mo,els suggest that a s*nergistic com/ination o+ therapies0 such as statins an, apo&I mimetic pepti,es0

ma* /e a success+ul strateg* to reverse oxi,i5e, lipi,s an, possi/l* atherosclerosis.9!620!6@:ral a,ministration o+

&'1 plus pravastatin regresses esta/lishe, lesions in apoE&null mice an, ren,ers H3 anti&in+lammator* in

monke*s0 suggesting a com/ination treatment strateg* ma* /e particularl* e++ective in treating human

atherosclerosis.9!6':&'1 is currentl* in clinical trials in humans0 an, a (hase I trial recentl* ,emonstrate, sa+et*

an, tolera/ilit*0 as )ell as an a/ilit* to improve the H3 in+lammator* in,ex.9!6?:It is possi/le that previousl*

unexpecte, negative trial results0 such as the 3upus therosclerosis (revention Stu,* #3(S$ trial o+ statins in

S3E0 ma* /e partiall* explaine, /* the ina/ilit* o+ a single agent to reverse oxi,i5e, lipi,s. 9!7":-he +uture o+

therap* in rheumatic ,iseases ma* )ell entail com/ination therap*0 )ith agents to inhi/it generali5e,

in+lammation an, ,isease activit*0 an, other agents to target oxi,i5e, lipi,s.

)ing to the anti&in+lammator* nature o+ these pepti,es0 it ma* not /e surprising that there have also /een

implications that apo&! mimetics ma* /e o+ use in treating other in+lammator* mani+estations o+ ,isease.

recent stu,* )ith the 3&'1 pepti,e plus pravastatin in a murine S3E mo,el #apoEKFK1asKFKC?"B3F7$ resulte, in

signi+icant re,uctions in proteinuria0 glomerulonephritis an, osteopenia. ortic lesion si5e )as increase, in

treate, mice; ho)ever0 there )as evi,ence o+ anti&in+lammator* plaue remo,eling0 )ith ,ecreases in

macrophage in+iltration an, proatherogenic chemokines0 an, increase, smooth muscle content.9!67:1uture )ork

)ill ,etermine i+ these mimetic pepti,es are use+ul +or preventing atherosclerosis an,For other complications in

patients )ith S3E.

Discovery of (ovel Tar"ets for Atherosclerosis Prevention in SLE

1uture stu,ies into the mechanisms /ehin, increase, atherosclerosis in S3E ma* i,enti+* ne) path)a*s that can

/e targete, +or therap*. 1or example0 recent )ork /* enn* et al.,escri/e, an a/normal phenot*pe an,

+unctionalit* in en,othelial progenitor cells an, m*elomonoc*tic circulating angiogenic cells in S3E su/ects0

in,icative o+ en,othelial ,*s+unction.9!7:-hese a/normalities )ere triggere, /* I1D&0 an, neutrali5ation o+

inter+eron path)a*s restore, a normal en,othelial progenitor cellsFcirculating angiogenic cells phenot*pe. 9!7:t

least t)o monoclonal anti/o,ies against I1D& are currentl* entering clinical trials in S3E patients; i+

e++icacious0 +uture stu,ies shoul, examine their e++ectiveness in preventing atherosclerosis.

ur group recentl* reporte, that (1 receptor& #(1R$ is upregulate, in monoc*tes +rom S3E patients

)ith piH3 an, caroti, arter* plaue.9!6":Both monoc*te chemotaxis an, -D1& secretion )ere signi+icantl*

increase, )hen cells )ere treate, )ith piH3 in vitrocompare, )ith normal H3. Dota/l*0 piH3&,rivenchemotaxis an, -D1& levels )ere re,uce, to levels o/serve, in cells treate, )ith normal H3 )ith

concomitant treatment using the small&molecule (1R kinase inhi/itor imatini/ #leevecP0 Dovartis0 Basel0

S)it5erlan,$. Cells treate, )ith normal H3 an, imatini/ ,i, not /ehave ,i++erentl* to normal H3&treate,

cells alone0 suggesting that piH3 ,*sregulates the (1R signaling axis in monoc*tes an, a therapeutic

intervention in this signaling path)a* coul, neutrali5e atherogenic cells. lthough chronic imatini/ treatment

+or su/ects )ith atherosclerosis )oul, not /e recommen,e, ,ue to multiple si,e e++ects0 inclu,ing the

controversial possi/ilit* o+ car,iotoxicit*09!622:mechanistic stu,ies into atherosclerosis&speci+ic ,*sregulate,

signaling path)a*s ,riving monoc*te an, - cells coul, lea, to novel0 sa+e molecular targets +or the treatment o+

accelerate, preclinical atherosclerosis in autoimmune ,iseases.

E0pert Commentary ! ive&year 4ie%

It is no) )ell recogni5e, that patients )ith S3E are at an increase, risk o+ car,iovascular ,isease.

Car,iovascular risk in patients )ith S3E is multi+actorial0 comprising /oth an increase, inci,ence o+ man*

tra,itional car,iovascular risk +actors an, the occurrence o+ S3E&speci+ic +actors0 inclu,ing ,isease activit* an,


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,uration0 an, ,rug therap*. Management o+ /oth tra,itional an, S3E&speci+ic risk +actors is important to

e++ectivel* prevent an, treat car,iovascular ,isease in patients )ith S3E. lthough tra,itional car,iac risk

+actors cannot +ull* account +or the increase, risk o+ atherosclerosis in S3E0 the* ,o contri/ute0 an, at this time0

the* provi,e our /est strateg* +or mo,i+*ing car,iovascular risk in our patients. ata +rom several cohorts

suggest that control o+ tra,itional risk +actors has not /een optimi5e, in the S3E patient population; +or example0

the ne) ualit* in,icators +or S3E recommen, that S3E su/ects /e screene, annuall* +or car,iac risk +actors;92@:ho)ever0 in a Boston cohort0 onl* 27= o+ the patients ha, +our car,iac risk +actors assesse, annuall*.92':

Similarl*0 in the S*stemic 3upus International Colla/orative Clinics cohort0 h*percholesterolemia )as not

treate, in up to t)o&thir,s o+ patients.92?:In the +uture0 long&term0 )ell&controlle, trials )ill provi,e evi,ence to

support the use o+ tra,itional preventive strategies0 as )ell as increase, un,erstan,ing o+ the role o+ current

immunosuppressive an, +uture therapies +or com/ating atherosclerosis in S3E.

In+lammation is associate, )ith the increase, ,evelopment o+ atherosclerosis in patients )ith S3E. It is unclear0

ho)ever0 i+ targeting ,isease activit* )ith anti&in+lammator* therapies )ill /e a,euate to ,ecrease the

inci,ence o+ car,iovascular ,isease in patients )ith S3E. 8nans)ere, uestions inclu,e ho) existing an,

,eveloping therapies +or S3E )ill a++ect +uture car,iovascular risk0 an, )hether tra,itional an, novel

/iomarkers o+ car,iovascular risk in S3E patients can /e use, to monitor response to these therapies. ,vances

in the next ?>! *ears ma* make clear the /est strategies +or preventing atherosclerosis in our S3E patient

population.

Sidebar

5ey Issues

In,ivi,uals )ith s*stemic lupus er*thematosus #S3E$ have a signi+icantl* increase, risk +or ,eveloping

car,iovascular ,isease #CG$ at a *ounger age.

Increase, inci,ence o+ CG in S3E is ,ue to a com/ination o+ tra,itional #1ramingham$ an, S3E&

speci+ic risk +actors.

-he longer a patient has ha, S3E0 the higher the risk o+ ,eveloping CG; it is unclear at this time

)hether long&term an,For high glucocorticoi, use #as S3E therap*$ promotes or protects against +ull

CG.

Dovel /iomarkers +or accelerate, CG in S3E i,enti+ie, in recent *ears inclu,e elevate, homoc*steine

an, leptin levels0 in a,,ition to ,*s+unctional high&,ensit* lipoprotein.

Current therapeutic approaches to prevent CG in S3E inclu,e +ollo)ing recommen,e, national

gui,elines to target mo,i+ia/le tra,itional car,iac risk +actors such as h*pertension0 ,*slipi,emia0 BMI0

,ia/etes an, to/acco use.

1uture novel therapeutic approaches to counteract accelerate, CG speci+icall* in S3E ma* inclu,e

po&I mimetic pepti,es an, B&cell ,epletion therap*0 as )ell as ,elineating ,*sregulate, path)a*s in

immune cells that ,irectl* contri/ute to atherosclerosis initiation an, progression then targeting

molecules in these path)a*s )ith small molecule inhi/itors.

References

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in )omen )ith s*stemic lupus er*thematosus% comparison )ith the 1ramingham Stu,*.Am. J.

Epidemiol.!'?#?$0 ''!? #!66"$.


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2@@" #2!$.

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!7. Gon 1el,t JM0 Scal5i 3G0 Cucchiara J et al.Homoc*steine levels an, ,isease ,uration in,epen,entl*

correlate )ith coronar* arter* calci+ication in patients )ith s*stemic lupus er*thematosus.Arthritis

Rheum.?'#"$0 222>222" #27$.


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!". rueke -B0 Mass* T. therosclerosis in CQ% ,i++erences +rom the general population.Nat. Rev.

Nephrol.7#!2$0 "2@>"@? #2!$.

!!27" #!66'$.

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mem/ranous nephropath*. $emin. Nephrol.2@#'$0 '7>'!! #2@$.

2!. r,one5 J0 Hiatt R0 Qille/re) EJ0 1ireman BH. -he increase, risk o+ coronar* heart ,isease

associate, )ith nephrotic s*n,rome.%idney &nt.''#@$0 7@7'2 #!66@$.

22. -heo,ori,ou 0 Bento 30 NCru5 (0 Qhamashta M0 Hughes R. (revalence an, associations o+ an

a/normal ankle&/rachial in,ex in s*stemic lupus er*thematosus% a pilot stu,*.Ann. Rheum. Dis.72#!2$0

!!66>!2@ #2@$.

2@. Manger Q0 Qusus M0 1orster C et al.1actors associate, )ith coronar* arter* calci+ication in *oung

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