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Recurrentaphthousstomatitis

JOralMaxillofacPathol.2011SepDec15(3):252256.
doi:10.4103/0973029X.86669
PMCID:PMC3227248

Recurrentaphthousstomatitis
LPreeti,KTMagesh,1KRajkumar,andRaghavendharKarthik
Addressforcorrespondence:Dr.PreetiL,15/9VenkatramanStreet,R.A.
Puram,Chennai600028,India.Email:preetianand29@gmail.com
Copyright:JournalofOralandMaxillofacialPathology
ThisisanopenaccessarticledistributedunderthetermsoftheCreative
CommonsAttributionNoncommercialShareAlike3.0Unported,whichpermits
unrestricteduse,distribution,andreproductioninanymedium,providedthe
originalworkisproperlycited.

INTRODUCTION
ThetermaphthousisderivedfromaGreekwordaphtha
whichmeansulceration.Recurrentaphthousstomatitis
(RAS)isoneofthemostcommonpainfuloralmucosal
conditionsseenamongpatients.Thesepresentasrecurrent,
multiple,small,round,orovoidulcers,withcircumscribed
margins,havingyelloworgrayfloorsandaresurroundedby
erythematoushaloes,presentfirstinchildhoodor
adolescence.[1]
CLINICALPRESENTATION
RASischaracterizedbyrecurrentboutsofsolitaryor
multipleshallowpainfululcers,atintervalsoffewmonthsto
fewdaysinpatientswhoareotherwisewell.[2]RAShas
beendescribedunderthreedifferentclinicalvariantsas
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classifiedbyStanleyin1972.[3]
1.MinorRASisalsoknownasMiculiz'saphthaeormild
aphthousulcers.Itisthemostcommonvariant,
constituting80%ofRAS.Ulcersvaryfrom8to10mm
insize.Itismostcommonlyseeninthenonkeratinized
mucosalsurfaceslikelabialmucosa,buccalmucosa,and
floorofthemouth.Ulcershealwithin1014days
withoutscarring.
2.MajorRASisalsoknownasperiadenitismucosa
necroticarecurrensorSutton'sdisease.Itaffectsabout
1015%ofpatients.Ulcersexceed1cmindiameter.
Mostcommonsitesofinvolvementarelips,softpalate,
andfauces.Masticatorymucosalikedorsumoftongueor
gingivamaybeoccasionallyinvolved.[4]Theulcers
persistforupto6weeksandhealwithscarring.
3.Herpetiformulcerationischaracterizedbyrecurrent
cropsofmultipleulcersmaybeupto100innumber.
Thesearesmallinsize,measure23mmindiameter.
Lesionsmaycoalescetoformlargeirregularulcers.
Theseulcerslastforabout1014days.Unlikeherpetic
ulcers,thesearenotprecededbyvesiclesanddonot
containviralinfectedcells.Thesearemorecommonin
womenandhavealaterageofonsetthanotherclinical
variantsofRAS.[5]
Predisposingfactors

Ageneticpredispositionforthedevelopmentof
apthousulcerisstronglysuggestedasabout40%ofpatients
haveafamilyhistoryandtheseindividualsdevelopulcers
earlierandareofmoreseverenature.[2]Variousassociations
withHLAantigensandRAShavebeenreported.These
associationsvarywithspecificracialandethnicorigins.
Genetics

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Traumatotheoralmucosaduetolocalanesthetic
injections,sharptooth,dentaltreatments,andtoothbrush
injurymaypredisposetothedevelopmentofrecurrent
aphthousulceration(RAU).[1]Wrayetal.[6]in1981
proposedthatmechanicalinjurymayaidinidentifyingand
studyingpatientspronetoaphthousstomatitis.
Trauma

Severalstudiesrevealnegativeassociationbetween
cigarettesmoking,smokelesstobaccoandRAS.Possible
explanationsgivenincludeincreasedmucosalkeratinization
whichservesasamechanicalandprotectivebarrieragainst
traumaandmicrobes.[79]Nicotineisconsideredtobethe
protectivefactorasitstimulatestheproductionofadrenal
steroidsbyitsactiononthehypothalamicadrenalaxisand
reducesproductionoftumornecrosisfactoralpha(TNF)
andinterleukins1and6(IL1andIL6).[10]Nicotine
replacementtherapyhasbeensuggestedastreatmentfor
patientswhodevelopRAUoncessationofsmoking.[11]
Tobacco

Certaindrugshavebeenassociatedwithdevelopment
ofRAUtheseincludeangiotensinconvertingenzyme
inhibitorcaptopril,goldsalts,nicorandil,phenindione,
phenobarbital,andsodiumhypochloride.NSAIDSsuchas
propionicacid,diclofenac,andpiroxicammayalsocause
oralulcerationsimilartoRAS.[12]
Drugs

Deficienciesofiron,vitaminB12,and
folicacidpredisposedevelopmentofRAS.Deficienciesof
thesehematinicsaretwicemorecommonintheseindividuals
thancontrols.Contraryfindingsinvariousstudiesrelating
theassociationofhematinicdeficiencyandRAShavebeen
explainedasduetovaryinggeneticbackgroundsanddietary
habitsofthestudypopulation.[2,12]
Hematinicdeficiency

Glutensensitiveenteropathy/celiacdisease,inflammatory
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boweldisease

Glutensensitiveenteropathy(GSE)isanautoimmune
inflammatorydiseaseofsmallintestinethatisprecipitatedby
theingestionofgluten,awheatproteininsusceptible
individuals.Itischaracterizedbyseveremalnutrition,
anemia,abdominalpain,diarrhea,aphthousoralulcers,
glossitis,andstomatitis.RASmaybethesolemanifestation
ofthedisease.Theuseofglutenfreedietintheimprovement
ofRASisconsidereduncertain.Ithasbeensuggestedthat
evaluationforceliacdiseasemaybeappropriateforRAS
patients.[13]InflammatoryboweldiseasessuchasCrohn's
diseaseandulcerativecolitismaypresentwithapthouslike
ulceration.[1]
Sodiumlaurylsulfatecontainingtoothpaste Anincreased

frequencyintheoccurrenceofRAShasbeenreportedon
usingsodiumlaurylsulfate(SLS)containingtoothpaste
withsomereductioninulcerationonuseofSLSfreetooth
paste.However,becauseofthewidespreaduseofSLS
containingdentifrice,ithasbeenproposedthatthismaynot
trulypredisposetoRAS.[1]
Conflictingreportsexistregarding
associationofhormonalchangesinwomenandRAU.
Studiesstateassociationoforalulcerationwithonsetof
menstruationorinthelutealphaseofthemenstrualcycle.
McCartanetal.[14]in1992establishednoassociation
betweenapthousstomatitisandpremenstrualperiod,
pregnancy,ormenopause.
Hormonalchanges

Stresshasbeenemphasizedasacausativefactorin
RAU.Ithasbeenproposedthatstressmayinducetraumato
oralsofttissuesbyparafunctionalhabitssuchasliporcheek
bitingandthistraumamaypredisposetoulceration.Amore
recentstudyshowslackofdirectcorrelationbetweenlevels
Stress

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ofstressandseverityofRASepisodesandsuggeststhat
psychologicalstressmayactasatriggeringormodifying
factorratherthanetiologicalfactorinsusceptibleRAS
patients.[15]
Microorganismsimplicatedinapthousulcers

Severalmicroorganismshavebeenimplicatedinthe
pathogenesisofRAS.Severalcontraryfindingshavebeen
reportedinthevariousstudiespublished.
RASandoralstreptococci Oralstreptococcihavebeen

consideredasmicrobialagentsinthepathogenesisofRAS.
Theyhavebeenimplicatedasmicroorganismsdirectly
involvedinthepathogenesisoftheselesionsorasagents
whichserveasantigenicstimuli,whichinturnprovoke
antibodyproductionthatcrossreactwithoralmucosa.Ithas
beensuggestedthatLformofhemolytic
streptococci,Streptococcussanguislateridentified
asStreptococcusmitiswasthecausativeagentofthis
disease.Hooveretal.[16]in1986demonstratedlowlevelsof
crossreactivityoforalStreptococciandoralmucosal
antigensandconsideredthereactivitytobenonspecificand
clinicallyinsignificant.
H.pylorihasbeenimplicatedas
oneoftheorganismsintheetiopathogenesisofRAS.H.
pyloriisagramnegative,Sshapedbacteriumthathasbeen
associatedwithgastritisandinchronicallyinfectedduodenal
ulcers.H.pylorihasbeenreportedtobepresentinhigh
densityindentalplaque.[17]Porteretal.[18]in1997
measuredthelevelsofIgGantibodiesagainstH.pyloriin
patientswithRASandshowedthatnothefrequencyofanti
H.pyloriseropositivitywasnotsignificantlyelevatedin
patientswithRASandotherulcerativeandnonulcerative
RASandHelicobacterpylori

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oralmucosaldisorders.
Variousviruseshavebeen
implicatedintheetiopathogenesisofrecurrentapthous
stomatitis.Therehavebeenseveralsuggestive,butasyet
thereexistsinconclusiveevidencetowardaviraletiology.
Characteristicsofaphthousulcerswhichareindicativeof
infectiousetiologyincluderecurrentulceration,lymphocytic
infiltration,perivascularcuffing,presenceofautoantibodies,
inclusionbodiesincaseofherpetiformulcersandsimilarity
ofRAUtoviralulcerativediseasesinanimals.[19]
Virtanenetal.[17]in1995demonstratedthepresenceof
humancytomegalovirusDNA(HCMV)inbiopsiesoforal
mucosalulcers,buttheywereunabletoruleoutthepresence
ofthisviruswhichmayhaveexistedasasuperinfectionor
coinfectionfromexistingHCMVinsaliva.Sunetal.[20]in
1996demonstratedthepresenceofHCMVgenomesby
polymerasechainreactioninpreulcerativeoralapthous
tissues.Theypostulatedthatwhenviralinfectionoccursin
oralepithelialcellsexpressingmajorhistocompatibility
complexclassIImolecules(MHCII),anintenseTcell
responseiselicitedagainstviruscontainingoralepithelial
cells.TheyconcludedthatHCMVmayplayrolein
perpetuatinglocalimmuneresponseingenetically
predisposedindividuals.
VirusesasetiologicagentsinRAS

Sunetal.[21]in1998demonstratedthepresenceofEpstein
barrvirus(EBV)genomesbypolymerasechainreactionin
preulcerativeoralapthoustissuesinRAUpatients.They
postulatedapossibleroleofassociationofEBVinpre
ulcerativeorallesionsinpatientsofRAU.
RoleoftumornecrosisfactoralphainRAS

Tumornecrosisfactoralpha(TNF)isaproinflammatory
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cytokineandisoneofthemostimportantcytokineimpliedin
thedevelopmentofnewapthousulcersinpatients.The
associationofTNFinthedevelopmentofRASgains
credenceduetothefactthatimmunomodulatorydrugssuch
asthalidomideandpentoxifyllinehavebeenfoundeffective
inthetreatmentofRAS.Thalidomidereducesactivityof
TNFbydegradingitsmessengerRNAandpentoxifylline
inhibitsTNFproduction.[22,23]Antigenicstimulationof
oralmucosalkeratinocytesresultsintheproductionofpro
inflammatorycytokinessuchasIL2andTNF.TNFalso
causesexpressionofclassImajorhistocompatability
complex,subsequentlythesecellsaretargetedforattackby
cytotoxicTcells.[1]
INDEXFORDETERMININGIMPACTOFORAL
ULCERACTIVITYINPATIENTSOFRAS
Mumucuetal.[24]in2009proposedacompositeindexto
monitortheclinicalmanifestationsassociatedwithoral
ulcersinpatientsofRASandBehcet'sdisease.They
proposedthatsuchindicesservetoprovideimportant
informationregardingprognosisofdiseaseandtherapeutic
effectofmedication.
Theindexevaluatedtheoralulceractivity,ulcerrelatedpain,
andfunctionaldisability.Oralulceractivitywasrecordedas
numberofulcersinthepast1month.Thiswasscoredzeroif
therewerenoulcersandasone,ifthenumberofulcerwas
greaterorequaltothanone.Thepainstatuswasevaluatedon
avisualanaloguescale(VAS).Thisisa100mmlinewith
extremevaluesateitherend.Thepatientshavetomarkthe
intensityofpainontheline.
Functionalstatusevaluation

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Thisinvolvedtheevaluationofeffectsoforalulcerson
tasting,speaking,andeating/chewing/swallowing.Thiswas
evaluatedbybothLikerttypescaleandVASscale.Scoring
isdoneas0,whennoneofthetime1,littleofthetime2,
someofthetime3,mostofthetime4,allofthetimeand
VAS(0100mm).
Useofvisualanalogscaletoevaluatethepaincausedby
ulcersishighlysubjectiveandisriddenwithinterpersonal
variation.Thisisacontinuousscalewithnodiscretelevelsas
wouldbesuggestedbygradessuchasnone,mild,moderate,
orsevere.Furtherstudiesindifferentpopulationandethnic
groupsneedtobecarriedoutusingthiscriteriatovalidate
thisindex.
HISTOPATHOLOGYOFRAS
Themicroscopicpictureofaphthousulcerisnonspecific,
anddiagnosismustbebasedonhistoryandcarefulclinical
examination.Themucousmembraneofaphthousulcer
showssuperficialtissuenecrosiswithafibrinopurulent
membranecoveringtheulceratedarea.Thenecrosisis
coveredbytissuedebrisandneutrophils.Epitheliumis
infiltratedbylymphocytesandfewneutrophils.Intense
inflammatorycellinfiltration,predominantlyneutrophils
presentimmediatelybelowtheulcer,mononuclear
lymphocytesareseeninadjacentareas.Minorsalivary
glandscommonlypresentinareasofaphthaeexhibitfocal
periductalandperialveolarfibrosisandchronic
inflammation.[12,25]
DIAGNOSIS
DiagnosisofRASisbasedonhistory,clinical
manifestations,andhistopathology.Othercausesofrecurrent
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oralulcerationmustberuledout.Systemicdiseaseswhich
presentwithrecurrentoralulcerationsaresummarizedin
Table1.DiagnosticcriteriaforminorRAUwereproposed
byNatahetal.[12]in2004.Theyproposedthatadiagnosis
ofidiopathicRAUandsecondaryRAU(associatedwith
systemicdisease)isestablishedwhenfourmajorandone
minorcriteriaarefulfilled.Themajorandminorcriteriafor
diagnosisofminorRAUareillustratedinTables2and3.
Management

ThereisnodefinitivecurativetreatmentforRAS.Possible
systemicassociationwithRASmustberuledout,especially
incaseswherethereissuddendevelopmentofulcerationin
adulthood.[2]Laboratoryinvestigationssuchascomplete
bloodcounts,redcellfolate,serumferritinlevels,and
vitaminB12recommended.ScreeningforGSEmustbedone
incaseswhereassociatedsystemicmanifestationsofGSE
arepresent.Varioustopicalandsystemicagentsusedin
treatmentofRASaresummarizedinTable4.
CONCLUSION
Recurrentapthousstomatitisisaverycommon,recurrent
painfululcerationoccurringintheoralcavity.The
etiopathogenesisofthisdiseaseisyetunclear.Treatment
strategiesmustbedirectedtowardprovidingsymptomatic
reliefbyreducingpain,increasingthedurationofulcerfree
periods,andacceleratingulcerhealing.
FOOTNOTES
SourceofSupport:Nil.
ConflictofInterest:Nonedeclared.

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FIGURESANDTABLES
Table1

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Systemicdiseaseswithrecurrentoralulceration(modified
fromreference1)
Table2

MajorcriteriafordiagnosisofRAUminor(Natahetal.[12]
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2004)
Table3

MinorcriteriafordiagnosisofRAUminor
Table4

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TopicalandsystemicagentsusedintreatmentofRAS
ArticlesfromJournalofOralandMaxillofacialPathology:
JOMFPareprovidedherecourtesyofMedknowPublications

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