Rev. Bras. Reumatol. vol.55 número3

r e v b r a s r e u m a t o l . 2015;55(3):310–312

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

REVISTA

BRASILEIRA

DE

REUMATOLOGIA

Case

report

Infliximab

is

effective

in

difficult-to-control

peripheral

ulcerative

keratitis.

A

report

of

three

cases

夽

Flávia

Maria

Zandavalli,

Glaucio

Ricardo

Werner

de

Castro,

Maiara

Mazzucco,

Maria

Eduarda

Carvalho

Wagnes

Stöfler,

Ivânio

Alves

Pereira

UniversidadedoSuldeSantaCatarina,Florianópolis,SC,Brazil

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Articlehistory: Received10May2013 Accepted9May2014

Availableonline14January2015

Keywords: Keratitis Cornealulcer Monoclonalantibody

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Peripheralulcerativekeratitisiscausedbyaninflammatoryanddestructiveprocessofthe perilimbalperipheralcornea.Thisinflammationisduetoimmunecomplexdepositionin thisregionofthecorneaandinadjacentvessels.Itcanbeidiopathic,oramanifestationof systemicdiseasesuchasrheumatoidarthritis,vasculitisofsmallvesselsassociatedwith ANCA,relapsingpolychondritis,systemiclupuserythematosusandCrohn’sdisease.Its treatmentincludestheuseofhigh-dosecorticosteroidsand,insomecases,theconcomitant useofimmunosuppressantssuchasmethotrexate,azathioprine,mycophenolatemofetil, cyclophosphamideorcyclosporine.Theuseofimmunobiologicalagentscanbeastrategy incasesofdifficultcontrol.Theauthorsdescribethetreatmentofthreepatientswho,after failurewiththeuseofcorticosteroidsorimmunosuppressants,showedgoodresponseafter theuseofinfliximab.

©2014ElsevierEditoraLtda.Allrightsreserved.

Infliximabe

é

eficaz

em

ceratite

ulcerada

periférica

de

difícil

controle.

Um

relato

de

três

casos

Palavras-chave: Ceratite Úlceradecórnea Anticorpomonoclonal

r

e

s

u

m

o

Ceratiteulceradaperiféricaécausadaporumprocessoinflamatórioedestrutivodacórnea periféricaperilimbar.Essainflamac¸ãosedeveàdeposic¸ãodeimunocomplexosnessaregião dacórneaenosvasosadjacentesaela.Podeseridiopáticaouumamanifestac¸ãodedoenc¸a sistêmicacomoartritereumatoide,vasculitesdepequenosvasosassociadasaoANCA,à policondriterecidivante, aolúpuseritematososistêmicoeà doenc¸adeCrohn. O trata-mentoincluiousodecorticoideemdosealtaeemalgunscasosousoconcomitantede imunossupressores,comometotrexate,azatioprina,micofenolatomofetil,ciclofosfamida ouciclosporina.Ousodeagentesimunobiológicospodeserumaestratégianoscasosde

夽

StudyoriginatedatUniversidadedoSuldeSantaCatarina. ∗ _{Correspondingauthor.}

E-mail:ivanioreumato@gmail.com(I.A.Pereira).

http://dx.doi.org/10.1016/j.rbre.2014.05.006

rev bras reumatol.2015;55(3):310–312

311

difícilcontrole.Osautoresdescrevemotratamentodetrêspacientesqueapósfalhaaouso decorticoideouimunossupressoresapresentaramboarespostaapósousodeinfliximabe. ©2014ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Theperipheralcorneaissituatedveryclosetothe conjunc-tiva,whichhasthecriticalelementsforgeneratinganimmune response.Ascomparedwiththecentralcornea,thiscorneal regionhasagreaternumberofinflammatorycells,allowing theformationofimmunecomplexes.1

Peripheralulcerativekeratitisisadestructiveprocessthat involvesinflammationoftheperilimbalcornea1_andoverlying

epithelialdefects.2 _{Thediseasescommonlyinvolvedinthis}

regionare Moorenulcers,autoimmunityagainstthecornea itself,1 _{or manifestations of systemic disease,}3 _especially

rheumatoidarthritisandvasculitides.4_{Whentheperipheral}

cornealulcerisaccompaniedbynecrotizingscleritis, perfora-tionandconsequentlylossofvisioncanoccur,whichconfirms theseverityofthiseyedisease.

Thetreatmentofthisdisease includescorticosteroidsin theacutephaseandimmunosuppressantsinsevere periph-eral ulcerative keratitis, especially when associated with systemicdisorders.Recently,theuseofbiologicalagentssuch asrituximab,anantibodyagainstCD20,andmonoclonal anti-bodiesagainstpro-inflammatorycytokineTNFalpha(tumor necrosisfactor)hasbeenshowntobeanalternative.5–8

Case

reports

Case1

Male patient, 20 years old, five years with recurrent red eyeandeyepain. Anophthalmologicalinvestigation found the presence of peripheral ulcerative keratitis; the patient was introduced in topical steroids, prednisone 20mg/day and NSAIDs, without improvement. The picture evolved withincreasedperipheralulceration,significantconjunctival inflammatorycomponent,andincreasedpain.Twoyearsago thepatientreceivedpulsetherapywithmethylprednisolone 1g/dayforthreedays,andinfliximabwasstartedatadose of3mg/kgatweekszero,twoandsix,andtheneveryeight weeks, with significant improvement of ulceration, hyper-emia,andeyepain.Currently,thepatientremainsintheuse ofonlyinfliximab,withoutrecurrenceofocularinflammation.

Case2

Femalepatient,59yearsold,diagnosedwithperipheral ulcer-ative keratitis for 10 years,but withsymptoms of red eye andeyepainfor17years.Treatedwithprednisone40mg/day andcyclosporin3mg/kg/day,withnoresponse.During evo-lution, methotrexate was associated with the medication, andduetonon-improvement,methotrexatewasreplacedby azathioprine.Afterafurtherfailureofthisnewtherapeutic combination(azathioprineandcyclosporine),threeyearsago

infliximabwasstartedatadoseof3mg/kgatintervalsofeight weeks,withexcellentresponse.Currently,thepatientexhibits cornealinjuryhealing,withnoevidenceofrecurrenceof per-ilesionalinflammation.

Case3

Malepatient,36yearsold.Startedsevenyearsagowith recur-rent episodesofsevereeyepain,red eyeand photophobia. Anulcerwasdiagnosedinperilimbarcornea,withfrequent recurrence. Thepatient wastreatedwithprednisone60mg andcyclosporine;withoutresponse.Duetoclinical worsen-ingofhiseyediseaseandthedifficultyinreducingthedose ofcorticosteroids,infliximabwasstartedatadoseof3mg/kg atweekszero,twoandsixandtheneveryeightweeks,with almostcompleteresolutionofthecorneallesion.

Discussion

Peripheralulcerativekeratitisisaconditioncharacterizedby inflammation ofthe peripheralcornea that causes ulcera-tion ofdifficultresolution,2 _{whichcanoccurinisolationor}

as part of a systemic inflammation.9,10 _{Multipleinfections}

candeterminecornealulcer;thus,thedifferentialdiagnosis iscritical.10

Approximately 50% of cases of non-infectious periph-eralulcerativekeratitisareassociatedwithsomeconnective tissuedisease,5,11 _{especiallyrheumatoidarthritis.Other}

eti-ologiesincludepolyarteritisnodosa,relapsingpolychondritis, vasculitisassociatedwithANCA,forexample, granulomato-sis with polyangiitis (Wegener’s) and granulomatosis with eosinophilic polyangiitis (Churg-Strauss syndrome).5,9,12 _A

studypublishedin2012showedthat211of701patientswith granulomatosis with polyangiitis had someocular involve-mentinthediagnosisand147othersdevelopedthecondition in the course of the disease. Among the changes found, peripheralulcerativekeratitiswasobserved.13

Thecornealsignalsaresimilarinthosevariousdiseases causingtheproblem:redeye,pain,photophobiaandcorneal opacity.5,9_{Thisconditionmayoccurafterseveralyearsof}

sys-temicdisease,ormaybeitsfirstmanifestation.9,12

Peripheralulcerativekeratitisisassociatedwithhighvisual andsystemicmorbidity.Itscomplicationsareperforationof thecorneaanddecreasedvisualacuity.Inflammationofthe eyemaybeaninitialpresentationofasystemic inflamma-torydiseasewithsubclinicalinvolvementofotherorgansand systemsofthehumanbody.9

Thetreatmentforthisconditionisdifficultandisbasedon theseverityofcornealsymptomsandontheextentof extraoc-ulardisease.9_{Initially,thetreatmentconsistsoftopicaland}

systemiccorticosteroids,suchasprednisoneat1mg/kg/day; thistreatmentmightnotbeabletopromoteremission.3,4,7_The

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severityofthediseaseandtheriskofvisionloss.14

Cyclophos-phamidePO(2mg/kg/day)orinmonthlyintravenouspulses maybeusedinconjunctionwithglucocorticoidsincaseswith riskofperforationorinthecontextofsystemicvasculitides. Somepatientsmayrespondtotheuse ofmethotrexate,as demonstratedinacasereportofa25year-oldwomanwho hadasignificantimprovementofidiopathicperipheral ulcer-ativekeratitiswith10mgofmethotrexateperweekand,after fourweeks,thedosewasincreasedto25mg,withexcellent response.15_{Cyclosporineisanoptiontobeattempted,with}

reportsofresponseincasesofMooren’sulcer.16_Furthermore,

the use of immunobiological products such as rituximab, amonoclonalantibodyagainstCD20expressedby lympho-cytesBingranulomatosiswithpolyangiitis,5_{and especially}

infliximab,ananti-TNF,canproduceaquickresponseinthe suppressionofcornealinflammationandofpain,thus deter-miningtheclinicalimprovementincasesofdifficultcontrol, suchasinthepatientsherereported.5,7,8,13,15,17_Thecytokine

TNFisimportantinthepathogenesisofperipheralulcerative keratitis,bothinidiopathiccases,asinthoseassociatedwith rheumatoidarthritisorvasculitis.TNFstimulatestheactivity ofmetalloproteinases,inparticularMMP-9,whichhasbeen confirmedinadose-dependent mannerinculturedhuman cornealepithelialcells.Theincreasedexpressionand activ-ityofMMP-9weredemonstratedinsamplesofhumancornea withulcerativekeratitis.Thus,theinhibitionofthecytokine TNFwiththeuse ofmonoclonalantibodiescanreducethe inflammation and destruction of extracellular matrix and cornealcollagendegradationduetoanunregulatedactivity ofmatrixmetalloproteinases.18–20

Odorcicetal.intheirstudyreportedthatthereisnota rec-ommendeddoseofinfliximabincasesofperipheralulcerative keratitis,andthatreducingtheintervalbetweeninfusionsto onceeveryfourweeksmaybenecessary.4_{Galoretal.showed,}

in a study, stability in visual acuity in 68% of 12 patients withrheumatoidarthritisassociatedwithperipheral ulcerat-ivekeratitis,followingtreatmentwithcyclophosphamideor methotrexate.9

In the three cases here presented, we had favorable responsestoinfliximabinthetreatmentofulcerativekeratitis, prescribedafterfailureofcorticosteroidsand/or immunosup-pressants, like other publications. Moreover, there was no recurrenceofperipheralulcerativekeratitisinanyofthethree patientsreportedbyus.Allthreecasesshowednoassociation withconnectivetissuediseases.Randomized,controlledtrials withalargernumberofcaseswillgivemoresupportforthe useofbiologictherapy,inparticularanti-TNF,inpatientswith thiscondition.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1.MondinoBJ.Inflammatorydiseasesoftheperipheralcornea. Ophthalmology.1988;95:463–72.

2.LeungAK,MireskandariK,AliA.Peripheralulcerative keratitisinachild.JAAPOS.2011;15:486–8.

3.AtchiaII,KiddCE,BellRW.Rheumatoidarthritis-associated necrotizingscleritisandperipheralulcerativekeratitistreated successfullywithinfliximab.JClinRheumatol.2006;12:291–3.

4.OdorcicS,KeystoneEC,MaJJ.Infliximabforthetreatmentof refractoryprogressivesterileperipheralulcerativekeratitis associatedwithlatecornealperforation.Cornea.

2009;28:89–92.

5.YagciA.Updateonperipheralulcerativekeratitis.Clin Ophthalmol.2012:747–54.

6.ThomasJW,PflugfelderSC.Therapyofprogressive rheumatoidarthritis-associatedcornealulcerationwith infliximab.Cornea.2005;24(6):742–4.

7.AlbertM,BeltránE,Martínez-CostaL.Rituximabin rheumatoidarthritis-associatedperipheralulcerative keratitis.ArchSocEspOftalmol.2011;86:118–20.

8.OhJY,KimMK,WeeWR.Infliximabforprogressiveperipheral ulcerativekeratitisinapatientwithjuvenilerheumatoid arthritis.JpnJOphthalmol.2001;5:70–1.

9.GalorA,ThorneJE.Scleritisandperipheralulcerative keratitis.RheumDisClinNorthAm.2007;33:835–54.

10.SantosNC,SousaLB,TrevisaniVF,FreitasD,VieiraLA. Manifestac¸õesdestrutivasdacórneaeescleraassociadasa doenc¸asdotecidoconectivo–Relatodenovecasos.ArqBras Oftalmol.2004:67.

11.TauberJ,SainzdelaMazaM,Hoang-XuanT,FosterCS.An analysisoftherapeuticdecisionmakingregarding

immunosuppressivechemotherapyforperipheralulcerative keratitis.Cornea.1990;9:66–73.

12.LadasJG,MondinoBJ.Systemicdisordersassociatedwith peripheralcornealulceration.CurrOpinOphthalmol. 2000;11:468–71.

13.GarrityJA.Ocularmanifestationsofsmall-vesselvasculitis. CleveClinJMed.2012:73.

14.BachmannB,JacobiC,CursiefenC.Inflammationoftheeye insystemicinflammatorydisorders:keratitis.KlinMonbl Augenheilkd.2011;228:413–8.

15.FaillaceC,AraújoFA,DeCarvalhoJF.Idiopathicperipheral ulcerativekeratitiswithgoodresponsetomethotrexate.Acta ReumatolPort.2012;37:102–3.

16.HillJC,PotterP.TreatmentofMooren’sulcerwithcyclosporin A:reportofthreecases.BritJOphthalmol.1987;71:11–5.

17.PhamM,ChowCC,BadawiD,TuEY.Useofinfliximabinthe treatmentofperipheralulcerativekeratitisinCrohndisease. AmJOphthalmol.2011;152:183–8.

18.FontanaL,ParenteG,NeriP,RetaM,TassinariG.Favourable responsetoinfliximabinacaseofbilateralrefractory Mooren’sulcer.ClinExpOphthalmol.2007;35(9):871–3.

19.LiDQ,LokeshwarBL,SolomonA,MonroyD,JiZ,Pflugfelder SC.RegulationofMMP-9productionbyhumancorneal epithelialcells.ExpEyeRes.2001;73(4):449–59.