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ww w . r e u m a t o l o g i a . c o m . b r

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Brief

communication

Is

there

an

association

between

systemic

lupus

erythematosus

and

periodontal

disease?

Débora

Cerqueira

Calderaro

a,∗

,

Gilda

Aparecida

Ferreira

b

,

Santuza

Maria

Souza

de

Mendonc¸a

c

,

Jôice

Dias

Corrêa

d

,

Fabrícia

Xavier

Santos

e

,

João

Guilherme

Capinam

Sanc¸ão

e

,

Tarcília

Aparecida

da

Silva

f

,

Antônio

Lúcio

Teixeira

g

aPost-GraduatePrograminInfectiousandParasiticDiseases,MedicineSchool,UniversidadeFederaldeMinasGerais(UFMG),Belo

Horizonte,MG,Brazil

bDepartmentofLocomotorSystem,SchoolofMedicine,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

cDentalSchool,CentroUniversitárioNewtondePaiva,BeloHorizonte,MG,Brazil

dPost-GraduatePrograminCellBiology,BiologicalSciencesInstitute,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,

Brazil

eUniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

fDepartmentofClinics,PathologyandSurgery,DentalSchool,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

gMedicineSchool,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received31July2014

Accepted1March2015

Availableonline8September2015

Keywords:

Systemiclupuserythematosus

Periodontitis

Chronicperiodontitis

a

b

s

t

r

a

c

t

Periodontaldiseaseresultsfromtheinteractionbetweenpathogenicbacteriathatcolonize

supragingivalandsubgingivalbiofilmsandthehost,triggeringaninflammatoryresponse,

withsystemiceffectsleadingtoimmune-mediateddestructionoftheattachment

appara-tusandlossofsupportingalveolarbone.Immunologicalpathwaysandpredisposinggenetic

factorscommontoperiodontaldiseaseandrheumaticdiseases,includingsystemiclupus

erythematosus,havebeendescribed.Casereportshavesuggestedgreaterseverityof

peri-odontaldiseaseinpatientswithsystemiclupuserythematosus.However,studiesevaluating

theinfluenceofthetreatmentofonediseaseontheclinicalandlaboratorymanifestations

oftheotherhaveyieldedconflictingresults.

©2015ElsevierEditoraLtda.Allrightsreserved.

associac¸ão

entre

o

lúpus

eritematoso

sistêmico

e

a

doenc¸a

periodontal?

Palavras-chave:

Lúpuseritematososistêmico

Periodontite

Periodontitecrônica

r

e

s

u

m

o

Adoenc¸aperiodontalresultadainterac¸ãoentrebactériaspatogênicasquecolonizamos

filmessupraesubgengivaleohospedeiroedeflagramumarespostainflamatórialocal,com

efeitossistêmicos,quelevaàdestruic¸ãoimunomediadadostecidosdesustentac¸ãodos

dentesedoossoalveolar.Viasimunológicasefatoresgenéticospredisponentescomuns

StudylinkedtotheMedicineSchoolandDentalSchool,UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil.

Correspondingauthor.

E-mails:dccalderaro@gmail.com,dccalderaro@hotmail.com(D.C.Calderaro).

http://dx.doi.org/10.1016/j.rbre.2015.08.003

(2)

àdoenc¸aperiodontaleàsdoenc¸asreumáticas,entreelasolúpuseritematososistêmico,

vêmsendodescritos.Relatosdecasosugerirammaiorgravidadedadoenc¸aperiodontal

em pacientescomlúpuseritematoso sistêmico. Noentanto,estudosqueavaliaramas

influênciasdotratamentodeumasobreasmanifestac¸õesdaoutraapresentaramresultados

conflitantes.

©2015ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Currently,therelationshipbetweenconnectivetissuediseases

andperiodontaldisease (PD)hasbeen thesubjectofmuch

discussion.1

PDisagroupofinfectiousandinflammatorydiseasesthat

resultfrom the interaction betweenperiodontal pathogens

present in supragingival and subgingival biofilms and the

host,generatinganinflammatoryresponseofvariable

inten-sity,whichcanleadtoimmune-mediateddestructionofthe

attachmentapparatusandlossofsupportingalveolarbone.

Gingivitis,themostcommonformofperiodontaldisease,is

aninflammatoryprocesscharacterizedbyerythema,edema

andgingivalbleeding.Periodontitisischaracterizedby

gingi-valinflammationaccompaniedbyaninflammatoryresponse

bythehost,whichresultsindestructionoftheattachment

apparatusandlossofsupportingalveolarboneandthathave

systemiceffects.Thechangesfoundindentalevaluationof

periodontitisareanincreaseinprobingdepth(probingpocket

depth –PPD), whichreflects the distancefrom the bottom

ofthe pockettothe gingivalmargin, thepresenceof

clini-calattachmentloss(CAL),whichmeasuresthepositionofthe

softtissueinrelationtothecemento-enameljunction,and

theoccurrenceofgingivalbleedingonprobing(BOP),mobility

andtoothandalveolarboneloss.2

Theexistenceofimmunepathwaysandofagenetic

predis-positioncommontoPDandconnectivetissuediseases,among

thesesystemiclupuserythematosus(SLE),isrecognizedand

hasbeendescribed.1

In this brief communication, we reviewed studies

pub-lishedinEnglishorPortuguese,whichinvestigatedpossible

associationsbetweenPDandSLE,foundthrougha

system-aticsearchinPubMed/MedlineandLILACSdatabases,using

theterms“LupusErythematosus,Systemic”and

“Periodon-titis”,“Periodontitis,Chronic”or“Periodontitis,Adult”.There

wasnorestrictionaboutthesearchperiod.Twenty-two

arti-clesfromPubMed/MedlineandfivearticlesfromLILACSwere

found.Thirteenoriginalarticlesthatdealtwiththetopicwere

includedinthisreview.3–15Amanualsearchofthereferences

ofincluded articleswas carried out, and fivearticles were

selected.16–20

Studies

of

association

between

SLE

and

periodontal

disease

Casereportssuggestingthatclinicalandtherapeutic

associ-ations betweenSLEand PDhave been publishedsincethe

1980s,3–5 reportingagreaterseverityofPDinpatientswith

SLE,probablyassociatedwithimmunosuppressioncausedby

thedisease,oritstreatment.

ThefrequencyofperiodontitisinSLEpatientsvariedin

dif-ferentstudies,between60and93.8%(Table1).6–11AJapanese

study reportedthatSLEpatientshadahigher frequencyof

PD versus the generalpopulation of that country,9 but no

studyhascomparedthefrequencyofPDwithacontrolgroup

(healthyvolunteers).Thevariabilityofthefrequencyof

peri-odontitisfoundindifferentstudiesisprobablyassociatedwith

theuseofdifferentcriteriaforitsdiagnosis,ortodifferences

inpatientgroupswithSLEwithregardtodiseaseseverityor

activity.Thus,thequestion offrequencyofperiodontitisin

patientswithSLEremainsanopenone,andcontrolled

stud-iesareneededforsettingupwhetherperiodontitisisactually

morecommoninSLEpatients.

Several authors evaluated the severity of PD in SLE

patientscomparedtohealthyvolunteers,ortopatientswith

PD without SLE, and their results were conflicting.

Peri-odontal parameters were found to be: similar,9,10,12,13 less

severe,9,10,13–15ormoresevere16–18(Table2).

These controversial data prompted some questions as:

immunosuppressioninducedbySLEoritstreatmentwould

increase, would not affect,or would reducethe infectious

andinflammatoryperiodontaldestruction?Thestudiesthat

foundlowerseverityofperiodontalparametersinSLEsuggest

a smaller immune-mediated periodontal destruction

asso-ciatedwithimmunosuppressivedrugs.9,10,13–15 However,the

composition biasofthecontrol group,consistingprimarily

ofpatientsreferredforspecializedtreatmentandpotentially

withmoreseriousperiodontitis,wasnotcontrolled.Studies

werealsopublishedthatsuggestagreaterseverityofPDin

patientswithSLE,especiallywhenthediseaseisactive.16–18

Then, immunosuppression would increase the periodontal

decayassociatedwithchronicinfection?Thispointalsoisnot

definedandrequiresfurtherstudiesthatincludepatientswith

activeandinactiveSLE,evaluatingtheinfluenceofSLE

activ-ityandoftheimmunosuppressivetreatmentonperiodontal

parameters,withtheinclusionofacontrolgroup

representa-tiveofthegeneralpopulation,withpeoplewithandwithout

PD.

Biological

basis

of

the

association

between

SLE

and

PD

InPD,theguminfectiontriggersaseriesofimmuneresponses

thatinvolvetheparticipationofimmunecellsandcytokines,

that results in the destruction of the attachment

appara-tus and alveolar bone loss. A study reported an increase

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Table1–PeriodontitisfrequencyinpatientswithSLE.

Study Numberofpatients

withSLE

Frequencyofperiodontitis observed

Frequencyofperiodontitis ingeneralpopulation

RhodusandJohnson6 16 93.8% Notreported

Novoetal.7,8 30 60% Notreported

Kobayashietal.9 60 70% 30–40%

Kobayashietal.10 71 64.8% Notreported

Fabbrietal.11 55 89% Notreported

and serum levelsof variouscytokines, including: IL-1␣,

IL-1␤,IL-6, IL-8,TNF-␣,TNF-␤,IFN-␥(inflammatory)and IL-10

(anti-inflammatory).19

ThereceptorsfortheconstantregionofimmunoglobulinG

(Fc␥R)participateintheimmuneresponse,facilitating

phago-cytosis by opsonization and acting in antibody-dependent

cellularcytotoxicityandintheactivationofthe toxic

gran-ule release by inflammatorycells. There isevidence of an

associationbetweencertaingeneticpolymorphismsofgenes

encoding these receptors and infectious and autoimmune

diseases. Kobayashi et al. 9,10 found higher expression of

Fc␥RIIa-R131 allele in patients with SLE and periodontitis

versuspatientswithSLEbutwithoutperiodontitis,andalso

healthy volunteers.9 These authors have also shown that

patientswithSLEandperiodontitisexhibitedthe

combina-tion ofpolymorphismsFc␥RIIa-R131andFc␥RIIB-232Tmore

oftenthanSLEpatientswithoutperiodontitis,patientswith

periodontitisbutwithoutsystemicdisease,andhealthy

vol-unteers.Combinedallelesalsowereassociatedwithgreater

severityofperiodontalparametersinpatientswithSLE.10

Ontheotherhand,sofar,studieshavenotidentifiedan

association betweenperiodontitisorperiodontalevaluation

parametersandevidenceofinflammatoryactivity(ESRand/or

CRP)inSLEorSLEDAI.13,16

Table2–PDseverityclassificationinSLEpatientsandtheinfluenceoftreatmentofadiseaseovertheother.

Study Studydesign Patientsincluded Assessedoutcomes Results

Mutluetal.14 Case–control 27SLE

25controls

PPD LowerinSLE. Meyeretal.12 Case–control 46SLE

50controls

VPI,GBI,BOP% Similar. Kobayashietal.9 Case–control 42SLE+PD

42PD

PPD,CAL,SP%,BOP% SmallerPPD,CALandBOP%in SLE.SimilarSP%andBOP%. Souza13 Case–control 16JSLE

14controls

VPI,GBI,CAL,PPD Lowerpercentageofsiteswith PPD≥3mminJSLE.SimilarVPI, GSIandpercentageofsiteswith CAL≥2mm.ActiveJSLE presentedhigherVPIandGSI versusinactiveJSLE. Micelietal.15 Case–control 17JSLE

14controls

PPD Lowerpercentageofsiteswith PPD≥4mminSLE.

Kobayashietal.10 Case–control 46SLE+PD

48PD

PPD,CAL,BOP%,SP% LowerPPD,CAL,BOP%,andSP% inSLE.SimilarSP%.

Fernandesetal.16 Case–control 48JSLE

48controls

VPI,GBI HigherinJSLE.Cumulative prednisonedosagecorrelatedto VPIandGBI.

UmbelinoJr.etal.17 Caseseries 155SLE Dentalcalculus,gingival

bleeding,periodontal pockets.

Gingivalbleedingand

periodontalpocketsweregreater inSLEpatients,whencompared toepidemiologicaldatafrom generalpopulation. Meyeretal.18 Caseseries 46SLE Oralmucosalesions,teeth

loss,gingivalinflammation.

Greaterinpatientswithsevere SLE.

Salesetal.20 Seriesofcasessubmittedto

clinicaltreatmentofPD.

6SLE+PD Bacterialplaque,BOP%and PPD,SLEDAI,CRP.

Improvementofperiodontal parameterswithnochangesof SLEDAI.

Fabbrietal.11 Randomized,controlled

trialonPDtreatment.

49SLE+PD: 32treated 17untreated

PPD,CAL,GBI,SLEDAI,CRP, ESR.

Improvementofperiodontal parametersandSLEDAIon treatmentgroup

SLE,systemiclupuserythematosus;PD,periodontaldisease(periodontitis);PPD,probingpocketdepth;VPI,visibleplaqueindex;GBI,gingival bleedingindex;ABL,alveolarboneloss;SP%,percentageofsiteswithplaque;BOP%:percentageofsiteswithbleedingonprobing;JSLE,juvenile systemiclupuserythematosus;SLEDAI,SystemicLupusErythematosusDiseaseActivityIndex;CRP,C-reactiveprotein;CAL,clinicalattachment level;ESR,erythrocytesedimentationrate.

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Twostudiesexaminedinflammatorycytokinesingingival

crevicularfluid(whichcanbefoundinperiodontalpockets)

andinserum.Souza13foundhighercrevicularfluidlevelsof

totalandfreeelastaseandlowercrevicularfluidlevelsof

IL-18,buthigherserumlevelsofIL-18inpatientswithjuvenile

SLEversuscontrolgroup.CALshowedanegativecorrelation

withcrevicularfluidIL-18levels(r=−0.5;p<0.05),suggesting

thatthiscytokinecouldhaveaprotectiveeffectonthetissue

destructionassociatedwithPD.InthestudybyMicelietal.,15

healthyadolescentshadhigherlevelsofIL-1-␤increvicular

fluidversuspatientswithjuvenileSLEwhowereevaluatedfor

presenceofperiodontaldisease.

Twostudiesevaluatedtheassociationbetweenthe

pres-ence of antineutrophil cytoplasmic antibodies (ANCA) and

periodontitisinsubjects withoutrheumatic disease and in

patientswithSLEorrheumatoidarthritis(RA).7,8 Halfofthe

subjectswithperiodontitiswerepositiveforANCA.Amongthe

18patientswithSLEandperiodontitis,83.3%werepositivefor

ANCA.HalfofthepatientswithRAhadperiodontitis,butthis

diseasewasnotassociatedwithahigheroccurrenceofANCA.

ThesignificanceoftheassociationbetweenANCAand

peri-odontitisinhealthysubjectsorinpatientswithSLEremains

unclear.7,8

Insummary,thereisevidenceofacommongenetic

predis-position(sharedpolymorphisms)ofSLEandPD,whichcould

explaintheassociationbetweenthesetwoconditions.Still,at

leastfromatheoreticalpointofview,thereare

pathophysio-logicalmechanismscommontoPDandLESthatneedtobe

betterdescribedandunderstood,becausetheymayrepresent

prospectsforfuturetherapeuticapproaches.

Specific

treatment

and

influence

on

SLE

and

periodontal

disease

Fernandesetal.16 foundapositivecorrelationbetweenthe

cumulativedose ofcorticosteroidsand increasesinplaque

and gingival bleeding rates in patients with juvenile SLE

(respectively, r=0.385, p=0.01; r=0.471; p=0.001), but did

notidentifyanassociationwiththeuse ofantimalarialsor

immunosuppressiveagents(Table2).16

TwostudiesevaluatedtheinfluenceofthetreatmentofPD

onSLEactivity(Table2).Salesetal.20selectedsixpatientswith

SLE(meanofSLEDAI=3.5)and PD.Thepatientsunderwent

non-surgicaltreatmentofperiodontitisandwerereassessed

45daysafteritscompletion.Therewassignificant

improve-mentintheirperiodontalindices.SLEDAIandCRPlevelsdid

notchangesignificantlyafterperiodontaltreatment.20

Fabbri et al.11 selected 49 patients withactive SLE and

PD,dividedintotwogroups:onegroupwithtreatmentofPD

performedduringthestudy(n=32)andagroupwhose

treat-mentofPDwasdelayedforatimeaftercompletionofthe

study.TherewasnosignificantdifferenceinbaselineSLEDAI

in treated and control groups. Patients were reassessed 3

monthsafterthetreatmentofPD,whenasignificant

reduc-tioninSLEDAIwasobservedinthetreatmentgroup(5.9±4.2

vs.3.4±3.3,p=0.04),butdidnotoccurintheuntreatedgroup.

NosignificantdifferenceswerenotedinESRorCRPinboth

groups(Table2).11

Thehighestcumulativedoseofcorticosteroids,givenlocal

and systemic immunosuppressiveand metabolic effectsof

theseagents(withaninterferenceinbonemetabolism),could

beassociatedwiththeworstoutcomeoftheinfectious

pro-cessand,consequently,withgreaterperiodontaldestruction

inpatientswithSLEandPD.Studiesareneededtoestablish

whethertheconcomitantuseofimmunosuppressantswould

haveaprotectiveeffector,onthecontrary,wouldcontribute

togreaterperiodontaldestructioninSLEandPDpatients.

StudiesevaluatingtheinfluenceofPDtreatmentonSLEDAI

inSLEpatientsshowedconflictingresults.Onestudy,which

showed no change inSLEDAI, included asmall number of

patientswithouthighactivityofthedisease.20Anotherstudy

evaluated agreater numberofpatientswithactiveSLE, all

onmonthlyintravenousinfusionsofcyclophosphamideand

corticosteroids, and showed significant decline in SLEDAI,

compared tobaseline,in patientstreated forperiodontitis,

whichdidnotoccurinthegroupuntreatedforthisdisease;

thissuggestsapossibleroleofthetreatmentofperiodontitis

inthecontrolofactiveSLE.11Thisresultisquiteinteresting,

becauseitopensuppromisingprospectsinSLEapproaches,

howeveritmustbeconfirmedbyprospectivecontrolled

stud-ies.Theoretically,thecontrolofchronicinfectionrelatedto

PDcouldreducethedegreeofactivationoftheimmune

sys-tem,favoringtheresponseofSLEtotheimmunosuppressive

treatment.

Conclusion

The data about possible associations between SLE and PD

arecontroversial.Thegoodclinicalpractice,however,

recom-mendsattentiontotheoralhealthofpatientswithSLE,ideally

withperiodicdentalevaluation.IntheeventofPD

identifica-tion,itstreatmentshouldbeperformed,asitcanpositively

influencethehoweverofSLE.Furtherstudieswillbeneededto

establishtheassociationbetweenSLEandPD,aswellastheir

biologicalbasis,andtoclearlydefinetheeffectoftreatment

ofaconditionovertheother.

Conflict

of

interests

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.GonzalesTS,ColemanGC.Periodontalmanifestationsof collagenvasculardisorders.Periodontology2000. 1999;21:94–105.

2.WilderRS,MorettiAJ.Gingivitisandperiodontitisinadults:

classificationanddentaltreatment.In:UptoDate.Available

from http://www.uptodate.com/contents/gingivitis-and- periodontitis-in-adults-classification-and-dental-treatment?source=searchresult&selectedTitle=1%7E97

[accessed27.02.14].

3.VogelRI.Periodontaldiseaseassociatedwith

amegakaryocyticthrombocytopeniainsystemiclupus erythematosus.JPeriodontol.1981;52:20–3.

(5)

4. JaworkskiCP,KoudelkaBM,RothNA,MarshallKJ.Acute necrotizingulcerativegingivitisinacaseofsystemiclupus erythematosus.JOralMaxillofacSurg.1985;43:43–6.

5. NaglerRM,LorberM,Ben-AriehY,LauferD,PollackS. Generalizedperiodontalinvolvementinayoungpatientwith systemiclupuserythematosus.Lupus.1999;8:770–2.

6. RhodusNL,JohnsonDK.Theprevalenceoforal manifestationsofsystemiclupuserythematosus. QuintessenceInt.1990;21:461–5.

7. NovoE,MacGregorEG,NavaS,PeriniL.Apossibledefective estimationofantineutrophilcytoplasmicantibodiesin systemiclupuserythematosusduetothecoexistenceof periodontitis:preliminarobservations.PRJSJ.1997;16:369–73.

8. NovoE,Garcia-MacGregorE,VieiraN,ChaparroN,CrozzoliY. Periodontitisandanti-neutrophilcytoplasmicantibodiesin systemiclupuserythematosusandrheumatoidarthritis:a comparativestudy.JPeriodontol.1999;70:185–8.

9. KobayashiT,ItoS,YamamotoK,HasegawaH,SugitaN, KurodaT,etal.Riskofperiodontitisinsystemiclupus erythematosusisassociatedwithFc␥receptor polymorphisms.JPeriodontol.2003;74:378–84.

10.KobayashiT,ItoS,YasudaK,KurodaT,YamamotoK,Sugita N,etal.Thecombinedgenotypesofstimulatoryand inhibitoryFc␥receptorsassociatedwithsystemiclupus erythematosusandperiodontitisinJapaneseadults.J Periodontol.2007;78:467–74.

11.FabbriC,FullerR,BonfáE,GuedesLK,D’AllevaPS,BorbaEF. Periodontitistreatmentimprovessystemiclupus

erythematosusresponsetoimmunosuppressivetherapy.Clin Rheumatol.2014;33:505–9.

12.MeyerU,KleinheinzJ,HandschelJ,Kruse-LöslerB,Weingart D,JoosU.Oralfindingsinthreedifferentgroupsof

immunocompromisedpatients.JOralPatholMed. 2000;29:153–8.

13.SouzaAA.Condic¸õesperiodontaisempacientescomlúpus eritematososistêmicojuvenil.TeseapresentadaàFaculdade deOdontologiadaUERJ,comorequisitoparaobtenc¸ãodo títulodeDoutoraemPeriodontia,RiodeJaneiro;2006.p.70.

14.MutluS,RichardsA,MaddisonP,ScullyC.Gingivaland periodontalhealthinsystemiclupuserythematosus. CommunityDentOralEpidemiol.1993;21:158–61.

15.MiceliVC,BragaF,ÁreasA,FigueredoCMS,SztajnbokF, FischerRG.Condic¸õesclínicaseníveisdeIL1-␤empacientes adolescentescomlúpuseritematososistêmico.RPeriodontia. 2006;16:21–7.

16.FernandesEGC,SaviolliC,SiqueiraSTT,SilvaCAA.Oral healthandthemasticatorysysteminjuvenilesystemiclupus erythematosus.Lupus.2007;16:713–9.

17.UmbelinoAAJr,CantisanoMH,KlumbEM,DiasEP,SilvaAA. Achadosbucaiselaboratoriaisempacientecomlúpus eritematososistêmico.JBrasPatolMedLab.2010;46: 479–86.

18.MeyerU,KleinheinzJ,GaubitzM,SchulzM,WeingartD,Joos U.Oralmanifestationsinpatientswithsystemiclupus erythematosus.MundKieferGesichtschir.1997;1:90–4 [abstract].

19.AgarwalS,SuzukiJB,RiccelliAE.Roleofcytokinesinthe modulationofneutrophilchemotaxisinlocalizedjuvenile periodontitis.JPeriodontRes.1994;29:127–37.

20.SalesLAR,ChavesMGAM,VassaloS.Efeitodotratamento periodontalnacondic¸ãodoperiodontoenaatividade inflamatóriasistêmicaemportadoresdelúpuseritematoso sistêmico.RevIntEstExp.2010;2:94–9.

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