AnnalsoftheRhewnaticDiseases1990;49:1017-1020HYPOTHESISNodalgeneralise - PDF document

AnnalsoftheRhewnaticDiseases1990;49:1017-1020HYPOTHESISNodalgeneralisedosteoarthritisisanautoimmunediseaseMichaelDoherty,MartinPattrick,RichardPowellNatureofosteoarthritisOsteoarthritis(OA),thecommonestabnormalitytoaffectsynovialjoints,hasaccompaniedmanthroughouthisevolutionaryhistory,andasimilarprocessoccursinotheranimalsthatfuseepiphysesintheadult."13SuchprevalenceandphylogeneticpreservationsuggestthatOAisaprocessratherthanadisease,reflectingtheresponseofarticulartissuestoextrinsicorintrinsicinsult,orboth.45Therecognisedsyntheticactivityofosteoarthritictissues,"theradiographicremodellingandfavourableout-cdoneseeninmanypatientswithOA,7-9andtheprevalenceofasymptomatic'disease'31011sup-porttheconceptofOAasarepairprocess.4'5Likeanyrepairprocess,OAmaysucceedorfailwhenrespondingtoavarietyoftriggeringorperpetuatinginsults(fig1).ThepathogenesisandvariabilityofOAarepoorlyunderstood,butmultiplefactors,includinggenetic,consti-tutional,andenvironmental,arelikelytoplayapart.31213Markedvariabilityinthenatureandchronicityoftheinsult(s),andhostdifferencesineffectiverepairresponse,resultintheconfus-ingheterogeneityofradiographicandclinicalmaniestations.The'subset'ofnodalgeneralisedOA(NGOA)InanattempttounderstandOAbetterandtoidentifyfactorsinitiatingandinfluencingcompensation(nosymptoms,goodoutcome)ordecompensation(symptoms,functionalimpair-FigureIRepresentationofosteoarthritisasarepairprocessthatmaycompensateorfailinresponsetoavarietyofinsults.ment,'jointfailure'),OAhasbeenincreasinglydividedintoclinicallydeterminedsubsets.3Suchcategorisationhasbeenbydistributionofjointdisease(generalised,pauciarticular,mono-articular'4);predominanceofcertainradio-graphicfeatures('atrophic','hypertrophic'l5);associatedcrystaldeposition(pyrophosphatearthropathy,16apatiteassociateddestructivearthritis'7);andpresumedaetiologicalfactors-forexample,epiphysialdysplasia,Kashin-Beckdisease.Suchsubsetting,especiallyforcommonformsofOA,hasprovedproblematicbecauseofoverlap,'618temporaltransitionfromonesub-settoanother,'619anddifficultiesinradio-graphicinterpretationandcrystalidentifi-cation."'21Nevertheless,severalgroupsaregenerallyaccepted.3NodalgeneralisedOA,thebestrecognisedsubset,ischaracterisedbypolyarticularhandOA(principallyinterphalangealandfirstcarpometacarpaljoints),femalepreponderance,earlysymptomaticinflammatorycomponent,andHeberden(withorwithoutBouchard)nodeformation,orboth31422:ofallOAsubsets,familialtendencyisparticularlyrecognised.'3ErosiveOAisalesscommongeneralisedsubsetsharingmanyfeaturesofNGOAbutdifferinginhavingmarkedsubchondralerosivechange,amorefloridandprolongedinflammatorycom-ponent,andatendencytointra-articularosseousfusion.32324MinorsubchondralerosionsinNGOA,however,arenotun-commonandwhethererosiveOAisadiscretesubsetormerelythemoresevereendoftheNGOAspectrumhasbeenquestioned.25Manyelderlysubjectshavepatchyhandinterphalan-gealOAornodes:thismayrelatetoobviouspriortrauma,butisoftenasymptomaticandapparentlysporadic.AlthoughthereisnosharpdivisionbetweensuchhandOAandNGOA,thelatterisclassicallysymptomaticinmiddleage,presentingasastuttering-onset'mono-arthritismultiplex',isunrelatedtoobvioustrauma,andaffectsmostifnotallrays.Atsitesotherthanthehand,suchasthehip,thetendencytobilateraldiseaseandtodiffuse(concentric/central)ratherthanfocal(supero-lateral)cartilageloss2627furthersupportstheseparationofNGOAasaninflammatorysubsetofOA.GeneticassociationsSurprisingly,despitemarkedfamilialpredis-RheumatologyUnit,CityHospital,NotthamNG51PBMDohertyMPattrickDepartmentofImmulology,Queen'sMedicalCentre,NotnhamRPowellCorrespondenceto:DrDoherty.Acceptedforpublication16March1990InsultsRepair1017 Doherty,Paunch,Powellposition,fewstudieshavesearchedforgeneticmarkersinNGOA.'3UntilrecentlyonlyfourstudieshadexaminedthefrequenciesofHLAantigens,withconflictingresults:LawrenceetalreportingincreasedfrequencyofHLA-A1B8,8BrodskyetalanincreaseinHLA-B8,29andtwostudiesfindingnoassociations.3031ArecentlargestudybyPattricketal,however,confirmedincreasedfrequencyofHLA-AlB8in90unrelatedpatientswithNGOA(relativeriskcomparedwithreferencepopulation2-79;p)anindependentlyincreasedfrequencyoftheMZa,antitrypsinphenotypewasalsoshown(relativerisk3-7;p)2AlthoughintheoryrelativealantitrypsindeficiencymightenhanceenzymerelatedjointtissuedamageandthuspromotedevelopmentofOA,occurrenceofnormala,antitrypsinconcentra-tionsinallpatientsfavouredgeneticlinkageratherthanproteaseinhibitordeficiency.BoththeHLAanda,antitrypsinassociationsrelatedtodevelopmentratherthanseverityasjudgedbyradiographichandOAscores.Interestingly,asubgroupwitherosiveOAhadbothhigherradiographicscores(correctedforthepresenceoferosions)andincreasedfrequencyoftheMSa1antitrypsinphenotype(p)perhapssupportingtheconceptoferosiveOAassevereNGOAwithadditionalgeneticfactorsinfluenc-ingseverity.ThesefindingsareofparticularinterestasHLA-AlB8isinlinkagedisequilibriumwithDR3andcommonlyassociateswithconditionsinwhichanautoimmunecomponentiswellrecognised-forexample,systemiclupusery-thematosus,33autoimmunethyroiddisease,3mSjogren'ssyndrome.33Anassociationwithaparticulara1antitrypsinphenotypemayalsoberelevanttoanautoimmunepathogenesisbecausea1antitrypsinisencodedonchromosome14neartheGmlocusforIgG,`anditisconceiv-ablethatgeneticallydeterminedvariabilityinimmunoglobulinheavychainmorphologycouldpredisposetoautoimmunephenomenaandresultantdisease.338InvestigationofGmallo-types,orothermoredirectlyinvolvedgeneproductsinlinkagewitha1antitrypsinonchromosome14,mightthereforebeofrelevanceinNGOA.Otherstudieshaveconcentratedongenesrelatingtocollagenformationontheassump-tionthatinherentdefectsofparticularformsoftypeIIcollagenmaypredisposetobiomechani-calfaultsincartilageand'decompensation'undernormalmechanicalloading.PalotieetalrecentlydescribedtwoFinnishfaeswithpremature'generalisedOA'.39UsingrestrictionfragmentlengthpolymorphismswithinandaroundthetypeIIcollagengeneonchromo-some12,theynotedlinkagebetweenthecartilagespecificgene(COL2A1)andthedevelopmentofarthritis,supportingtheprimacyofcrdlagestructure(specificallythecollagennetwork)indevelopmentof'jointfailure'.Althoughclinicaldetailsweresparse,theageofonset,distribution,andautosomaldominantinheritancefavoureddysplasiaratherthanNGOA.HullandPopereportedincreasedfrequencyofacloselysituatedrestrictionfrag-mentlengthpolymorphism(BamHI)inagroupObsemationswhichsupportautoimnemechanisminnodalgeneralisedosearthrisGeneicassociatons:HLA-AlB8MZa,antitrypnFemalepreponderancePeimnomusalonaet(Hormalinluenceondiseaseexpression)AssociationwithotherautoimmunediseaseSj6gren'ssyndrome(?erosiveosteoarthritisonly)ThyroiddiseaseImmunologicalfindingsinsynoviumandcartisgeIncreasedfrequencyofrheumatoidfactorofwomenwithOAaffectingmorethanonejointbeforeage60,'thoughastudyofCOL2genesinalargenumberofEnglishpatientswithwelldefinedNGOAfailedtoshowanyassocia-tions(PriestleyL,FergussonC,OgilvieD,etal,unpublisheddata),thusquestioningtherelevanceofcollagengenestotheNGOAsubset.Insummarytherefore,thegeneticinformationavailableforNGOAconcursonlytosuggestthatimmunemechanismsmightbeinvolvedinitspathogenesis.HormonalinfluenceondiseaseexpressionWhatfurthersupportisthereforthepossibilitythatNGOAisanautoimmunedisease?Inadditiontosharedgenetic(HLA)associations,twocommoncharacteristicsofautoimmunediseasearefemalepreponderanceandhormonalinfluenceondiseaseexpression(table).Symp-tomaticNGOAisprincipallyafemaleconditionwithonsetcommonlyaroundthemenopause:indeedthisassociationissostrikingitwaspreviouslylabelled'menopausalarthritis'.4Nosuchassociationwithnon-nodalOAhasbeenmade,againsupportingseparationofNGOAasadistinctsubset.Theinfluenceofsexhormonesondevelop-mentofOA,includingasuggestedrelationwithprevioushysterectomy,42hasrecentlybeenreviewed.43Thepositiveassociationswithobesity,perimenopausalonset(changingsexhormoneprofiles),fibroids,anddysfunctionaluterinebleeding,andthenegativecorrelationwithosteoporosismayallbeexplainedbyanabsoluteorrelativeoestrogenexcess.43SupportforthiscomesfromcertainanimalmodelsofOAwhichshowdeteriorationwithoestrogensandimprovementwithtamoxifen.4Suggestedmechanismsusuallyemphasisethedirecthormonaleffectsoncartilagematrixhomeo-stasis344:thisisnotaltogethersurprisingascartilage,rightlyorwrongly,remainsthemainfocusforresearchinterestinOA.45Anequallyvalidinterpretation,however,isthathormonalfluctuation/imbalancemaypredisposetoNGOAthroughmodulationoftheimmunesystemratherthanbyconnectivetissueactivity,therebeingabundantevidenceforhypoandro-genic/hyperoestrogenicstatesbeingcontributorytodevelopmentorexacerbationof'autoimmunedisease'throughsucheffects.46Auto'nmunediseaseassociationsAnassociationwithotherautoimmunepheno-menawouldobviouslystrengthenthecase.Althoughthequestionofautoimmunityin1018 NodalgeneralisedostoarthisisanaumnmmedtseaseNGOAhasnotbeenspecificallyconsidered,severalobservationsoffertantalisingclues.Anincreasedprevalenceofautoimmunethyroiddiseasewasreportedinacontrolledstudyofpatientswithpyrophosphatearthropathy,mostofwhomwerewomen,manywithNGOA94:thelackofanassociationbetweenhypothyroid-ismandchondrocalcinosis48suggeststhatthismighthavearisenthroughassociationwithNGOA.ThereportedassociationbetweenSjogren'ssyndromeanderosiveOA49isalsoofinterest,particularlyiferosiveOAisasevereratherthanseparateformofgeneralisedOA.'Similarly,theincreasedfrequencyofrheuma-toidfactorsinNGOA'450mayreflectanautoimmunediathesis.Controlledstudiesdeter-miningfrequenciesoforganspecificantibodies,rheumatoidfactors,andautoimmunediseaseinNGOAwouldthusseemwarranted.ImmunohistochemicalevidenceTheincreasinglyrecognisedinflammatorycomponentinOA,5'52andimmunohistologicalstudiesofOAsynoviumandcartilage5256lendfurthersupporttotheinvolvementofimmunemechanismsinpathogenesis.Itispossibleofcoursethatthefindingofimmunoglobulin(particularlyIgA),complement,and'immunecomplexes'inOAcartilage,225256andtheidentificationoflymphoidandmononuclearpopulationsinOAsynovium(identicalwith,thoughlesswidespreadthanthosefoundinrheumatoidarthritis525355)reflectmerelynon-specificreactiontotissuedamageratherthaninflammationdrivenprimarilybyimmunologicalevents.Nevertheless,itisofinterestthatsuchcartilageandsynovialabnor-malities(atthehip)aremorecommonandpronouncedin'primary'polyarticularNGOAthanin'secondary'pauciarticularOA,2252againsupportingthepossibilityofasystemic(?primary)ratherthanjustlocal(secondary)inflammatoryreaction.Althoughcartilagemightenjoythestatusofimmunologicalprivilegebyvirtueofitsanatomicstructure,autoimmunitytocartilagemighttheoreticallydevelopifsequesteredantigenswereexposedorbecameautoantigenicbyinter-actionwithexogenousorintrinsicfactors.AnticollagenantibodiesandcellmediatedimmmuneresponsestocollagenhaveindeedbeenshowninpatientswithOA,butalsoinpatientswithacutejointtraumaandinflammatoryjointdisease.5758Whetherornotsuchimmuneresponsesplayapartinperpetuationofjointdisease,theirlackofspecificityfavoursasecondaryratherthanprimaryroleincausation.IfautoimmunityplaysapartinNGOAitismostlikelytoexertitsinitialinflammatoryeffectsonnon-cartilaginousarticulartissues.Fromaclinicalstandpointthesynovium/capsule(orevenbone)wouldseemalikelytarget.SingleshotinsultAsinallarthropathiesthedistributionofjointdiseaseinNGOAremainsunexplained.Hypo-thesestoexplainpreferentialdistributionincludedifferingmechanicalforcesatdifferentsites5960agegeneticpredisposition\oestrogenstatus1//senvironmentalagenttriggeringofimmunesystemsymptomaticmonoarthritismultiplexIrepairprocesscompensatedjointdamageinpatternofNGOAFigre2Outlineofnodalgeneralisedosteoarthritis(NGOA)asanautoimmdisease.andeffectsonjointdesignresultingfromvaryingratesofevolutionarychange.6'Thebilateral,'symmetrical'distributionofNGOAisalsounexplained.Althoughtheroleofneuro-genicfactorsinthesymmetryofinflammatoryjointdiseaseshasbeendiscussed,"Lanalternativehypothesisforautoimmunebaseddiseaserelatestotheselectivityofpathwaysundertakenbycirculatinglymphocytes,whichlimitsthedistributionofimmunemediateddisease.63Thesymmetryanddistributionofdiseasemightthusprimarilyreflectpredetermined'homing'oflymphocytesratherthantargetingdeter-minedbylocalevents-forexample,mechanicalinsultandusage.59AgenerallygoodprognosishasrecentlybeenconfirmedbyacontrolledstudyofpatientswithestablishedNGOAwhichshowedthatcompen-satedOAhaslittlesymptomaticorfunctionalimpactontheaginghand.'IfsymptomaticNGOAisanautoimmuneconditionitwouldthusseemtobeaselective'singleshot'diseaseaffectingtargetjointsofgeneticallypredisposedsubjectsatatimeconditionedbyage,hormonalandotherconstitutionalfactors.Thereisincreasingevidencethatmanyautoimmunediseasesaretriggeredbyexternal(predominantlyinfective)agents,6566andanunidentifiedexternaltriggerforNGOAmayexist.Whateveritsnature,thisimmunemediatedjointinsulttriggersahypertrophicrepairprocesswhich,despitemarkedcartilageloss,thenusuallycompensatesintermsofsymptomsandfunc-tion.Oncetheinflammatoryphasehassettledthepatientisleftwitharchitecturallyabnormaljoints,whichwerecogniseas'OA'(fig2).InclusionofNGOAwithintheautoimmuneumbrellamayfurtherstimulateinterestinwhathaspreviouslybeenregardedbysomeasanunexciting'degenerative'condition.Fromcur-rentlyavailableinformationitwouldseemthatfurtherstudiesofgenetic,constitutional,andimmunologicalfactorsarewarrantedifwearetoimproveourunderstandingofNGOA,andhencetheinherentrepairprocessofsynovialjoints.WeareindebtedtotheArthritisandRheumatismCouncilforfinancialsupport.1019 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