w w w . r e u m a t o l o g i a . c o m . b r
REVISTA
BRASILEIRA
DE
REUMATOLOGIA
Review
article
Periodontitis
and
systemic
lupus
erythematosus
夽
Manuela
Rubim
Camara
Sete
a,∗,
Carlos
Marcelo
da
Silva
Figueredo
a,
Flavio
Sztajnbok
b,c,daUniversidadedoEstadodoRiodeJaneiro(UERJ),RiodeJaneiro,RJ,Brazil
bUniversidadeFederaldoRiodeJaneiro(UFRJ),RiodeJaneiro,RJ,Brazil
cDivisionofPediatricRheumatology,InstitutodePuericulturaePediatriaMartagãoGesteira(IPPMG),UniversidadeFederaldoRiode
Janeiro(UFRJ),RiodeJaneiro,RJ,Brazil
dSectorofRheumatology,NúcleodeEstudosdaSaúdedoAdolescente(NESA),UniversidadedoEstadodoRiodeJaneiro(UERJ),Riode
Janeiro,RJ,Brazil
a
r
t
i
c
l
e
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n
f
o
Articlehistory:
Received5January2015 Accepted3July2015
Availableonline21November2015
Keywords:
Periodontitis
Systemiclupuserythematosus Immunology
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Alargenumberofstudieshaveshownapotentialassociationbetweenperiodontaland autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythemato-sus (SLE).Similarmechanismsoftissuedestructionconcerning periodontitisandother autoimmunediseaseshavestimulatedthestudyofapossiblerelationshipbetweenthese conditions.Thisstudyaimstoreviewtheliteratureaboutthispotentialassociationand theirdifferentpathogenicmechanisms.Consideringthatperiodontaldiseaseisadisease characterizedbyinflammationinfluencedbyinfectiousfactors,suchasSLE,itisplausibleto suggestthatSLEwouldinfluenceperiodontaldiseaseandviceversa.However,thisissueis notyetfullyelucidatedandseveralmechanismshavebeenproposedtoexplainthis associ-ation,asderegulationmainlyininnateimmunesystem,withactionofphagocyticcellsand proinflammatorycytokinessuchasIL-1andIL-18inbothconditions’pathogenesis,leading totissuedestruction.However,studiesassessingtherelationshipbetweenthesediseases arescarce,andmorestudiesfocusedoncommonimmunologicalmechanismsshouldbe conductedtofurtherunderstanding.
©2015ElsevierEditoraLtda.Allrightsreserved.
Doenc¸a
periodontal
e
lúpus
eritematoso
sistêmico
Palavras-chave:
Periodontite
Lúpuseritematososistêmico Imunologia
r
e
s
u
m
o
Umgrandenúmerodeestudostemmostradoumapotencialassociac¸ãoentredoenc¸as peri-odontaisedoenc¸asautoimunes,comoartritereumatoideelúpuseritematososistêmico (LES).Osmecanismosdedestruic¸ãotecidualsemelhantesentreaperiodontiteeasdemais doenc¸asautoimunestêmestimuladooestudodepossíveisrelac¸õesentreessascondic¸ões.
夽
ThisworkisapartnershipbetweentheDepartmentofDentistry,UniversidadedoEstadodoRiodeJaneiro(UERJ),andtheSectorof Rheumatology,NúcleodeEstudosdaSaúdedoAdolescente(NESA),UniversidadedoEstadodoRiodeJaneiro(UERJ),RiodeJaneiro,RJ, Brazil.
∗ Correspondingauthor.
E-mail:manuelarubim@hotmail.com(M.R.C.Sete).
http://dx.doi.org/10.1016/j.rbre.2015.09.001
Opresenteestudotemcomoobjetivorevisaraliteraturaacercadessapotencialassociac¸ãoe dosseusdiferentesmecanismospatogênicos.Considerando-seadoenc¸aperiodontaluma doenc¸adecaráterinflamatórioquesofreinfluênciadefatoresinfecciosos,assimcomoo LES,éplausívelsugerirqueoLESinfluenciariasuaprogressão,assimcomoaperiodontite influenciariaaprogressãodoLES.Entretanto,essaquestãoaindanãoétotalmenteelucidada eváriosmecanismostêmsidopropostosparaexplicartalassociac¸ão,comodesregulac¸ões, principalmentenosistemaimuneinato,comac¸õesdecélulasfagocíticasedecitocinas pró-inflamatórias,comoIL-1eIL-18,napatogênesedeambasascondic¸ões,oquecontribuipara adestruic¸ãotecidual.Existem,contudo,poucosestudosnaliteraturaqueavaliamarelac¸ão entreessasdoenc¸asemaistrabalhosfocadosnosmecanismosimunológicoscomunsa ambasascondic¸õesdevemserfeitosparaummaiorentendimento.
©2015ElsevierEditoraLtda.Todososdireitosreservados.
Introduction
Periodontitisisachronicdestructiveinflammationthatleads tothelossofsupportingtissuesofteethandeventuallyeven totoothloss.Theperiodontalligamentandbonetissueare destroyedbyanimmuneandinflammatoryresponsetothe presenceofbacteria,particularlygram-negativeones,inthe gingivalsulcus.Theseverityofinflammationvariesbetween individuals,irrespective ofthedegreeofbacterialinfection, suggesting that a dysregulation of the host inflammatory responsemaycontributetoitsexistence.1
Ontheotherhand,systemiclupuserythematosus(SLE)is anautoimmunediseaseofunknownorigin,whichaffectsthe connectivetissueand thusvariousorgansinthebody.The clinicalmanifestationsofSLEvarywiththeseverityofthe dis-ease,anditscoursemayexhibitperiodsofexacerbationand remission.2SLEischaracterizedbyimmuneresponsesagainst
alargenumberofautoantigens,affectingmoreoftenwomen inthesecondandthirddecadesoflife.3
Alargenumberofstudieshaveshownapotential associa-tionbetweenchronicperiodontitisandautoimmunedisease, especially rheumatoid arthritis,4 as well as inflammatory
bowel disease and glomerulonephritis.5 A high prevalence
of periodontitis has also been detected in patients with SLE.6,7
The similar mechanisms of tissue destruction for peri-odontitis and other autoimmune diseases have stimulated thestudyofpotentialassociationsbetweentheseconditions. In spiteof presentingdifferent etiologies, the existenceof similar destructive mechanisms could explainan eventual associationbetweenperiodontitisandSLE.8Thesepotential
mechanismsincommonmayinvolvederegulation,especially intheinnateimmunesystem,withactionofphagocytecells andofproinflammatorycytokines, suchasIL-1 andIL-18, inthepathogenesisofbothconditions,contributingtotissue destruction.6,9
Theliteraturedescribingoralconditionsofpatientswith lupus is scarce, and pertinent information is conflicting. ConsideringthepossibilityofSLEasamodifyingconditionof theperiodontalhealth-diseaseprocessandthelackof infor-mationtoclarifythisinterrelationship,ouraimistoreview theliteratureonSLEandapotentialrelationshipwith peri-odontaldisease.Despite itshigh prevalenceinrheumatoid arthritis, onlya limited number ofstudies have examined
oral conditions, in particular periodontal disease in SLE patients.10,11
Literature
review
and
discussion
Definition
Periodontaldiseaseisdefinedasanyhereditaryoracquired disorder of tooth surrounding and supporting tissues (periodontium).Periodontaldiseasehasneoplastic, develop-mental,inflammatory,traumatic,metabolicorgeneticorigin. However, the term periodontal disease generally refers to thosecommoninflammatorydisordersofgingivitisand peri-odontitis,whicharecausedbypathogenicmicroorganismsin abiofilmorplaquethatformsadjacenttotheteeth.Gingivitis, themildest formofperiodontaldisease,ishighlyprevalent andreadilyreversiblewithaneffectiveoralhygiene.Onthe otherhand,theinflammationthatextendsdeepintotissues andcauseslossofsupportingconnectivetissueandalveolar boneisknownasperiodontitis.Itresultsintheformationofa softtissuepocketbetweenthegumandrootoftheteethand canresultintoothloss.12
On theother hand,systemiclupuserythematosusisan autoimmune diseasethataffects theconnectivetissueand mayextendtovariousorgansofthebody.Theclinical man-ifestationsvarygreatlybetweenorgansandsystemsandthe courseofthediseasegoesthroughperiodsofexacerbationand remission.2,10
Etiology
Periodontitishasitsonsetandisperpetuatedbyagroupof bacteria, predominantly gram-negativeandanaerobes, that colonizethesubgingivalarea.Today,itisalreadyclearthat thesebacteriacauseindirecttissuedestruction,activating var-iousmechanismsofhostimmunity.13
Immunechanges
In periodontal disease, host response has been tradition-ally mediated by T and B lymphocytes, neutrophils and monocytes/macrophages.Thesecellsaretriggeredtoproduce inflammatory mediators, including cytokines, chemokines, arachidonicacidmetabolitesandproteolyticenzymes,which collectivelycontributetothedegradationoftissueandbone resorptionbyactivationofmultipledegradationpathways.15
Immunological changes in SLE include B lympho-cyte hyperactivity and result in increased synthesis of immunoglobulinsandantibodies,alsoresultingindeposition ofimmunecomplexes and subsequentdamageto connec-tivetissue and tomultiple organs. Theinteraction among hypereactiveBcells,abnormallyactivatedTcellsandantigen presentingcells leads tothe productionofvarious inflam-matory cytokines, apoptosis, autoantibodies and immune complexes which, in turn, activate effector cells and the complementsystem,leadingtotissueinjuryandtodamage thatarethehallmarkofclinicalmanifestationsofSLE.
Periodontitis,althoughaninfectiousdisease,exhibitsvery similarcharacteristicstoSLEpathophysiology.Alargenumber ofBlymphocytesandplasmacellshavealsobeendetected inperiodontallesions.16Previousstudieshavedemonstrated
specificIgGresponsesagainstperiodontopathogenicbacteria ininflamedgingivaltissueandcrevicularfluid.17,18
Inperiodontitis,tissuedamagealsoderivesfroman exces-sive and unregulated production of various inflammatory mediatorsanddestructiveenzymes,inresponsetothe pres-enceofthebacterialbiofilm.
Geneticandfamilialfactors
In periodontal disease, hosts responddifferently to bacte-rial invasion, and the quantity and quality of the biofilm cannot explainthe different responses.19 Only 20% of the
variabilityin theexpression ofperiodontaldiseases seems to be explained by the presence of pathogenic bacteria.20
Recently,studieshavesuggestedthatasignificantpartofthis responsevariationistheresultofgeneticpredisposition.21,22
Otherriskfactors,suchassmokinganddiabetes,arealready wellestablished.23Polymorphismsofinterleukin-1genewere
described as the first genetic markers related to chronic periodontitis.24 Since then, a number of other
polymor-phisms have been studied. Trevillato et al.,25 forinstance,
havedemonstratedthatIL-6polymorphismisassociatedwith susceptibilitytochronicperiodontitisinBrazilianCaucasian patients.
GeneticandgeneexpressionstudiesinpatientswithSLE have also revealed new genetic mutations and alterations in cytokines that can explain several features of the dis-ease,aswellasitsgeneticsusceptibility.TheFc␥receptor(an immunoglobulinGreceptor)genefamilyisoneofthemost studied,andhasanimportantroleintheregulationofhost immune response to bacterial challenge.26 Polymorphisms
inthis receptorare relatedto someautoimmune diseases, includingSLEandjuvenileidiopathicarthritis(JIA).Thereare somestudieslinkingpolymorphismsinthisreceptoralsowith periodontitis.Kobayashietal.7foundanincreasedfrequency
of Fc␥RIIa-R131 alleles in SLE and periodontitis patients,
comparedtohealthy patientswithoutperiodontitis.In this study,theauthorsconcludedthatpatientswithSLEpresenting polymorphisminFc␥RIIagenehaveahigherriskofdeveloping periodontitis.Thispolymorphismisassociatedwithaligand deficiencywithIgG2,whichiscommoninperiodontitisand SLE.
Cytokinesasbiomarkers
Several studies point to cytokines as important medi-ators associated with the pathogenesis of periodontitis. Bacterial products induce synthesis of proinflammatory cytokinessuchasinterleukin-1beta(IL-1),interleukin-6 (IL-6),Interleukin-8(IL-8)andtumornecrosisfactor(TNF),mainly bymacrophages.27
Amongvarious cytokines, TNF and IL-1, mediatorsthat canpotentiallyparticipateinthisprocess,standout.These cytokinesstimulateboneresorptionbydirectlyinducingthe proliferationofosteoclastprogenitors,andindirectlyby stim-ulating the resorptive activity of mature osteoclasts28 and
increasingcollagenasesynthesis.29
InSLE,IL-6,aswellasIL-10,TNF,IL-17andIL-18,levelshave been correlated with disease activity;and a predominance of Th2 response has been reported.30 The balance among
cytokinesandtheirreceptorsmightalsobeimportant,notjust consideringtheirabsolutelevel.HigherserumlevelsofIL-12 andIL-18wereidentifiedinthestudybyRobaketal.31inSLE
patientsversushealthypatients,andthisfindingcould indi-cateapathogeneticrole.However,theirlevelsdidnotcorrelate withdiseaseactivityandwerenotresponsiveto immunosup-pressivetreatment.
IL-18,anIL-1familymember,isexpressedinvariouscell types,includingmacrophages,Tlymphocytes,Blymphocytes, and dendriticcells. Studies have shown that IL-18 playsa majorroleinthepathogenesisofvarious autoimmune dis-eases,beingstronglyexpressedbothlocallyandsystemically inadultpatientswithSLE.32Areasetal.33showedthatserum
levels ofIL-18were increasedinadolescents withSLE and thattheselevelscorrelatedpositivelywithSLEDAIindex.On theother hand,thereisscarceinformationaboutthe pres-ence androleofIL-18intheperiodontium.Whatisknown isthatgingivalepithelialcells expressthiscytokine consti-tutively,producingitunderinvitrostimulation.34Thestudy
by Miranda et al.35 showed increased serum levels of
IL-18 inpatients with juvenile idiopathic arthritis and found asignificantcorrelationbetweenperiodontalmeasurements (periodontalpocketdepthandclinicalattachmentlevel)and IL-18,indicatingapossibleroleofthiscytokinealsoin peri-odontitis.
OralmanifestationsofSLEandperiodontaldisease
OralinvolvementisoneofthediagnosticcriteriaforSLE (pres-enceoforalulcers).InthestudybyRhodusandJohnson,10the
prevalenceoforalmanifestations(drymouth,dentalcaries, mucositis,angularcheilitis,ulceration,amongothers)ranged from81.3to87.5%.Allstudypatientsexhibitedxerostomia, and93.8%hadperiodontitis.Ontheotherhand,inthestudy by Khatibi et al.36 54.3% ofpatients had oral lesions, and
withalonger disease duration, thenumber oforallesions decreases.Thisoccursbecausemostlesionsarefoundinthe activeperiod,and thatwiththecourseofthedisease after diagnosis,thecontrolandtreatmentleadtoagreater stabil-ityofthedisease,progressingtoaninactivephaseandthus tendingtoasmallernumberoforallesions.
Severalstudiesimplyingapotentialassociationbetween periodontitisandrheumatoidarthritis(RA)werepublished,4,5
andsuggestedahigherrelativeriskofperiodontitisinthese patients.5 On the other hand,studies evaluating
periodon-talinvolvementinSLEpatientsare scarce.Thereare some casereports, as acase ofacute necrotizing ulcerative gin-givitis (ANUG) in a patient with SLE,37 periodontitis38 and
gingivitis.39InthestudybyMutluetal.,11theauthorsdidnot
findevidenceforagreaterpredispositiontoperiodontal dis-easeinSLEpatientsversushealthycontrols.Theyidentified shallowerpocketsinpatientswithSLE,afindingparalleled byFigueredoetal.,40andthisresultcouldberelatedtothe
use ofanti-inflammatory agents.Onthe other hand,other authors found greater presence of periodontal disease in SLEpatientsthan inhealthycontrols.6,41,42 In thestudy by
Fabbrietal.,1theseauthorsobservedforthefirsttime
reduc-tionofSLEactivitywiththeuseofSLEDAIindex,inparallel witha dropofperiodontal indexesafterperiodontal treat-ment. Importantly, in this study the control group, which alsoreceivedtreatmentwithimmunosuppressivedrugsfor SLE,showednosignificantdropinSLEDAI,demonstratinga directassociationbetweenperiodontaltreatmentandindex improvement.Improvement inperiodontal status and sys-temicdiseaseactivitywasalsoevidentinsimilarstudieson patientswithrheumatoidarthritis.43,44
Biologicalplausibility
Periodontitiscanbeacriticalfactorinmaintainingthe inflam-matoryresponsethatoccursinSLE.Infact,infectionhasbeen regardedasatriggeringfactorforautoimmunediseases45and
inSLE,andthisconditionhasbeenresponsibleforthe main-tenanceofdisease activity.Severalmechanisms havebeen proposedtoexplainthisconnection,forexample,anadjuvant effectofproductsofmicroorganisms.45InthestudybyRose,46
theinjectionofthyroglobulinand mycobacteriumproducts inducedtheproductionofspecificautoantibodies,aswellas inflammatorythyroid lesions.Inaddition, infectiousagents can interactwiththe immune system inseveral ways, for instance,molecularmimicry,achangeinapoptosisofhost cellsandexposureofcamouflagedantigenstotheimmune systembycertainmicroorganisms.Allofthesemechanisms maygiverisetodysfunctionsoftheimmunesystem.47
Anotherpotentialmechanismisthepresenceofchangesin endothelialcells.C-reactiveproteincontributesto hypercoag-ulationandincreasestheexpressionofadhesionmoleculesin thesecells.Itslevelsareelevatedinpatientswithperiodontal disease,andautoantibodiesdirectedagainstthisproteinare alsoincreasedinSLEpatients,suggestingapossiblebinding routebetweenthesetwoconditions,inadditiontobeingarisk factorfordevelopingcardiovasculardiseases.48Moreover,as
alreadymentioned,polymorphisminFc␥receptorhavebeen associatedwithperiodontitisandautoimmunediseases,such asrheumatoidarthritisandSLE.7,26
Inflammatorycytokinesalsoappeartoplayanimportant roleinthisinterrelationship.Theyareofteninvolvedinthe vascular process (vascular occlusionand perivascular infil-trates)inpatientswithSLE.49Furthermore,changesinlocal
levelsofseveralpro-inflammatorycytokinessuchasIL-1, IL-6andTNF-␣havebeenassociatedwithapossibleroleinthe processofperiodontaldisease.50Elastase,anenzymeofthe
protease class,also appearsto beinvolved inthe associa-tionbetweenperiodontaldiseaseandSLE.Figueredoetal.40
foundgreateractivityofthisenzymeinthegingivalcrevicular fluidofinflamedsitesofSLEpatients,eveninthepresenceof lowerlevelsofIL-18andIL-1.Thisgreateractivitysuggests neutrophilhyperactivityinSLE,possiblygeneratedbya pri-maryeffectcausedbyincreasedIL-18plasmalevelsinthese patients.
TheexactpathogenesisofSLE,aswellasperiodontitis,is stillunknown.AccordingtoMarksandTullus,51SLEin
chil-drenandadultsoccursingeneticallysusceptibleindividuals, inwhomtheinflammatorysystemistriggeredduetoa sec-ondary stimulus (such asanenvironmentalstimulus,p.ex. infection), resultingin an abnormalcytokine environment. This change incytokines isalso foundin periodontitis,as reportedbyFigueredoetal.52andRescalaetal.53
Cytokines playanimportantroleinthe pathogenesisof periodontitis.Today,manyarticlesinthisareawerepublished, beingofparticularinteresttheiruseasbiomarkersofdisease activity.Measurementsofthesecytokinescouldserveasan alternativetohelpinidentifyingoutbreakperiodsandfor ther-apyresponsemonitoring.Inperiodontics,measuressuchas pocketdepthandclinicalattachmentlevelareused;butthese variablesdonotmeasuretheactivityofperiodontaldisease, onlyitssequels.Thecurrentgoalsaretoidentifyacytokineor acombinationofcytokinestoprovidesuchinformation.
Influenceofmedications
RegardingtheassociationbetweenSLEandperiodontal dis-eases, the divergence observed between studies may be explainedinpart bytheinfluenceofmedication.The con-tinued useofdrugsmightmaskormitigatetheseverityof periodontaldisease.Theuseofdifferentdrugsandin differ-entdosagecomplicatestheanalysisofthesepatients,since theyexhibitdifferentclinicalmanifestationsand,therefore, differenttreatments.Thecontroversyiswhethertheobserved improvementinpatientsisaresultofperiodontaltreatment itself,oroftheuseofimmunosuppressivemedication.Itis knownthattheuseofcorticosteroidsmayexhibitantagonistic functions,sincethisdrugpredisposestoinfectionand,atthe sametime,maymaskclinicalcharacteristicsoftheinfection asaresultofitsimmunosuppressiveandanti-inflammatory effects.2
Also, it is important to evaluate other factors, such as socio-demographic data, disease duration, clinical activity, laboratory tests,amongothers,tohomogenize asmuchas possible the study groups, thus allowing an evaluation of the influence of periodontal treatment on disease course, without the influence of other factors. These precautions were notobservedinsomestudies suchasMutluet al.’s11
and Kobayashietal.’s.7 Ontheother hand,inthe studyby
ofmedications used,durationofdiseaseand inflammatory markersamongpatients.
Childrenandadolescentsundertreatmentwith immuno-suppressive drugs are at a higher risk of developing systemiccomplicationsfromoralinfections.54Thedamping
ofperiodontal infection progression, thankstoperiodontal treatment,woulddecreasethelevelsofinflammatorymarkers suchasIL-6,TNF-␣andC-reactiveprotein,whicharecommon toSLEandperiodontitis,andthiswouldcontributetodecrease thesystemicinflammationinthesepatients.48
Conclusion
Consideringperiodontaldiseaseasaconditioncharacterized byinflammationand influencedbyinfectious factors,such asSLE,itisreasonabletosuggestthatSLEwouldinfluence theprogressionofperiodontaldisease,andviceversa. Stud-iesevaluatingtherelationshipbetweenSLEandperiodontitis arescarce.Morestudiesfocusedontheimmunological mech-anismscommontobothconditions mustbeconducted, to obtainabetterunderstanding.Thehypothesisofapossible linkbetweenSLEand periodontitisandbetweenSLE activ-ity and periodontal destruction needto beinvestigated by longitudinalstudies,forabetterunderstanding ofpossible commonpathogenicprocesses.
Conflicts
of
interest
Theauthorsdeclarenoconflictofinterests.
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