canine and feline pemphigus foliceus

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Home>Canineandfelinepemphigusfoliaceus:Improvingyourchancesofasuccessfuloutcome

Canineandfelinepemphigusfoliaceus:ImprovingyourchancesofasuccessfuloutcomeAthoughtfuldiagnosticandtherapeuticprocessiscriticaltomanagingdogsandcatssufferingfromthispotentiallyfataldermatologicdisease.

Jan01,2010ByKathyC.Tater,DVM,DACVD,ThierryOlivry,DrVet,PhD,DACVD,DECVDVETERINARYMEDICINE

Pemphigusfoliaceus,themostcommonautoimmuneskinconditionindogsandcats,ischaracterizedbypustules,erosions,andcrusts.Inthisarticle,wefocusonthediagnosisandtreatmentofpemphigusfoliaceusindogsandcats.

PATHOGENESIS

Pemphigusfoliaceusaffectstheepidermis,theoutermostsuperficialskinlayer.Tohelptheepidermisactasabarriertotheoutsideworld,theepidermisiscomposedprimarilyoftightlyadherentkeratinocytes.Twotypesofadhesionstructuresholdkeratinocytestogether.Desmosomesareresponsibleforcelltocelladhesion.Hemidesmosomesareresponsibleforcelltomatrixadhesion.Intheskin,hemidesmosomesbindthedeeporbasilarepidermalkeratinocytestothebasementmembrane.

Thepemphigusvariantsoccurwhenautoantibodiestargetthedesmosomesbetweenkeratinocytes.Desmosomedisruptionresultsinseparationofthekeratinocytes,whichisreferredtoasacantholysis.Keratinocytesthathavelosttheircelltocelladhesionarecalledacantholytickeratinocytes,notacanthocytes(i.e.crenatedredbloodcells).

Inpemphigusfoliaceusinpeople,themostcommontargetofautoantibodiesisthedesmoglein1(DSG1)glycoproteininthedesmosome.1,2TheautoantibodyresponseprimarilyinvolvesIgG(IgG4subclass).3InitialstudiesindogswithpemphigusfoliaceusonlyrarelydetectedanIgGautoantibodyresponse,4,5butmorerecentworkusingdifferentsubstratesinindirectimmunofluorescencetestingconfirmsthatIgGautoantibodiesareimportantincaninepemphigusfoliaceus.6

However,DSG1isnotcommonlytargetedinpemphigusfoliaceusindogs7itisnotyetknownwhichpartofthedesmosomeistargetedinmostcaninepemphigusfoliaceuscases.Earlyimmunoblottingstudiesrevealedthatthetargetwasa148kDaor160kDaprotein.8,9Immunoelectronmicroscopyshowsthatthesiteofautoantibodybindingisintheextracellularregionofthedesmosome.10

Thewordpemphigusisusedfortheentiregroupofautoimmuneblisteringdiseasesinwhichintraepidermalseparationoccursviaacantholysis.Pemphigusfoliaceusisaspecifictypeofsuperficialpemphigusandisclinicallydistinctfromdeeppemphigusdiseases.Anotherexampleofsuperficialpemphigusdiseaseispemphiguserythematosus.Examplesofdeeppemphigusdiseasesincludeparaneoplasticpemphigus,pemphigusvulgaris,andbullouspemphigoid.

Thesignsofanattackonkeratinocyteadhesionstructuresareclinicallyevident.Whenthetightbondsbetweensuperficialkeratinocytesareaffected,itmanifestsasvesiclesandpustules.Whenthetightbondsbetweenbasilarkeratinocytesandtheskin'sbasementmembraneareaffected,itmanifestsasbullae(largeblisters)andulcers.

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Morerecently,pemphigusfoliaceushasbeenproposedasthegeneraltermforallsuperficialpemphigusdiseases,sincethereisanoverlapinclinical,histologic,andimmunologiccharacteristicsamongallthesuperficialpemphigusconditions.11Deeppemphigusconditions,though,stillremainclinicallyandimmunologicallydistinctfromthesuperficialpemphigusconditions.Thus,thetermpemphigusshouldnotbeusedasadiagnosisbyitselfforanypatientbecauseitreferstoaheterogeneousgroupofbothsuperficialanddeeppemphigusconditions.

SIGNALMENTANDCAUSES

Geneticfactorscaninfluencethedevelopmentofpemphigusfoliaceus.Indogs,itismorefrequentlydiagnosedintwobreedswithcloselyrelatedgenotypes,12Akitasandchows.4Pemphigusfoliaceushasalsobeenreportedinlittermates.13Nobreeddispositionhasbeennotedinfelinepemphigusfoliaceus.

Sexandageappeartobeunrelatedtothedevelopmentofpemphigusfoliaceusindogsandcats.Theageofonsetisvariableandrangesfrom1to16yearsindogs4,5,14andlessthan1yearofage4toupto17yearsofage15incats.

Ultravioletlight

Ultravioletexposurefromthesunisapotentialenvironmentaltriggerforpemphigusfoliaceus.Theskinlesionsindogswithpemphigusfoliaceuscanworseninthesummerandimproveinthewinter.16,17ExposingdogswithfacialpemphigusfoliaceustoultravioletB(UVB)resultsinincreasedepidermalacantholysis.18WethinkthereisalowerprevalenceofcaninepemphigusfoliaceusincoolerU.S.regionscomparedwithwarmerU.S.regionswithmoresunexposure.

Drugs

Drugscaninfluencethedevelopmentofpemphigusfoliaceus.19Somedrugsdirectlyinduceacantholysis(druginducedpemphigusfoliaceus).Drugscanactivateproteolyticenzymesintheskinthatthendisruptdesmosomesandresultinbiochemicalacantholysis.Drugscanalsostimulatethedevelopmentofautoantibodiesagainstdesmosomes,resultinginimmunologicacantholysis.20Drugtriggeredpemphigusfoliaceusoccursinpatientspredisposedtopemphigusfoliaceus.Thecombinationofthedrugandotherpatientfactorsthentriggersaflareupofpemphigusfoliaceus.19

Humandruginducedpemphigusfoliaceusisusuallyassociatedwithexposuretomedicationswithchemicalstructuresthatcancontributetotheactivationofproteolyticenzymesintheskin.ThesedrugsincludethiolcompoundscontainingSH,orsulfhydryl,groups(e.g.penicillamine),medicationsthatcanundergometabolicchangesandformactiveSHgroups(e.g.penicillins,cephalosporins),ormedicationsthatcontainactiveamidegroups(e.g.enalapril).20Indogsandcats,pemphigusfoliaceushasbeensuspectedtobeassociatedwithavarietyofmedicationssuchascimetidine,21cephalexin,22amoxicillinandclavulanicacid,23

ampicillin,24andtrimethoprimsulfonamidecombinations.25

Manypatientswithnewlydiagnosedpemphigusfoliaceushaveahistoryofexposuretomultiplemedications.Ifapatienthaseitherdruginducedordrugtriggeredpemphigusfoliaceus,discontinuingthemedicationcouldhelpmanagethepemphigusfoliaceusorcausethepemphigusfoliaceustogointoremission.Itisdifficult,though,toproveanassociationbetweenanydrugandthepemphigusfoliaceus.Drugrechallengewoulddefinitivelyconfirmdruginducedpemphigusfoliaceus,butsincethiscouldharmthepatient,wedonotrecommenddrugrechallengeincutaneousdrugreactions.Observingapoptotickeratinocyteshistologicallycannotbeusedasamarkerforadrugreactionsinceapoptotickeratinocytesmaybeseenindogswithpemphigusfoliaceus.26

Ifdrugrelatedpemphigusfoliaceusissuspected,reviewthepatient'sdrughistorycarefully.Cutaneousdrugreactionstypicallydevelopmorethansevendaysafterthefirstadministrationofadrug.Ifthepatienthasbeenpreviouslyexposedtothedrug,reactionsarequickandoccurwithin24hoursofdrugreexposure.27

Morerecently,weareawareofreportsthatadministrationofatopicalspotonproductcontainingmetaflumizoneandamitraz(ProMerisFortDodgeAnimalHealth)hasbeenassociatedwithpemphigusfoliaceusindogs.Themechanismfor

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1.Apustulejustcaudaltotheplanumnasaleofadogalopeciaanderythemaarealsopresentinthedorsalnasalregion.

2.Crustsfromrupturedpustulesonadog'snasalplanumanddorsalnasalregion.

3.Ulcerationfromadeeppyodermainapatientwithpemphigusfoliaceus.Ulcersshouldnotbeseeninpemphigusfoliaceuspatientsunlessanotherconditionsuchasapyodermaispresent.Notethesymmetricalappearanceofthefaciallesions.

thisreactioniscurrentlyunknownbutisanareaofactiveresearchatoneofourlaboratories(T.O.).

Othercauses

Avarietyofotherfactorsarepossibletriggersforhumanpemphigusfoliaceus.Fogoselvagem,aformofhumanpemphigusfoliaceusendemictosomeruralareasofBrazil,islikelyduetoacombinationofenvironmentalfactorsandpossiblythepatient'sgeneticsusceptibility.28,29Nutrition(thiolcontainingfoodssuchasgarlicandonions30,31)andinfection32havealsobeenassociatedwithsomecasesofhumanpemphigusfoliaceus.Itisunknownifanyofthesefactors,especiallydiet,aretriggersincanineandfelinepemphigusfoliaceus.

Caninepemphigusfoliaceuscanbeassociatedwithahistoryofchronicskindiseasesuchasallergies,33althoughnostudieshavedefinitivelyprovedthislink.Caninepemphigusfoliaceushasalsobeenreportedinpatientswithotherconditionssuchashypothyroidism,34

leishmaniasis,35thymoma,36andsystemiclupuserythematosus.37Pemphigusfoliaceusmaybepresentinthesepatientsthroughcoincidence,orpemphigusfoliaceusmaybeoccurringinthesepatientsthroughtheinductionofdesmosomeautoantibodiestriggeredbythesesystemicconditions.

CLINICALSIGNS

Theearliestlesionsofpemphigusfoliaceusconsistoferythematousmaculesthatthenprogressrapidlytoapustularstage.Pustulestendtobelarge,irregular,andcoalescing(Figure1).Multiplehairshaftsprotrudingfrompustulesaremoreconsistentwithpemphigusfoliaceusandhelpdifferentiatepemphigusfoliaceusfromthemorecommoncauseofpustules,bacterialfolliculitis.38Becausepustulesarefragileandeasilyruptured,onlycrustsorthedriedexudatefromrupturedpustulesmaybenoted(Figure2).Forthisreason,crustsratherthanpustulesarethemostcommonlyseenlesionincasesofpemphigusfoliaceus.4,5,14

Erosionscanbenoted,especiallyifacrustisremoved.Ulcersarerarebecausepemphigusfoliaceusisasuperficialepidermalskindisease.Ulcerscanbeseenincasesofpemphigusfoliaceusthathaveaconcurrentconditionthataffectsthedeepersectionsofskinsuchasadeeppyoderma(Figure3).Rarely,erosions,crusts,andpustulescanbegroupedintoanannularorpolycyclicpattern.Pemphigusfoliaceuslesionstypicallyhaveawaxingandwaningcourse.Lesionsareusuallybilateralandsymmetrical.

Lesionsontheconcavepinnaeshouldincreaseyourclinicalsuspicionofpemphigusfoliaceussincefewotherpustularconditionsaffecttheconcavepinnae(Figure4).Mucosallesionsarerareinpemphigusfoliaceus.

Inmostdogs,lesionsinitiallyappearontheface(thedorsalmuzzle,

planumnasale,periocularskin,andears)and

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4.Crustsanddriedexudateontheconcavepinnaofadogwithpemphigusfoliaceus.(PhotocourtesyofLaurenPinchbeck,DVM,DACVD.)

5.Crustsonthefootpadsofadogwithpemphigusfoliaceus.

6.Erosionsandcrustsonthefaceandearsofacatwithpemphigusfoliaceus.

7.Pedalpemphigusfoliaceusinacat.

thenregionalizeorgeneralizeoverthecourseofmonths.Rarely,somedogswilleitherstartwithageneralizeddistributionorhaveonlyalocalizedformofthedisease.

Indogandcatswithgeneralizedpemphigusfoliaceuslesions,widespreaderythemaandexfoliationcanbenoted.Massiveexfoliation,especiallyifextendingbeyondthebordersoftheoriginallesions,ismoresuggestiveofbacterialinfectionsthanpemphigusfoliaceus.Systemicsignssuchasfever,lethargy,anorexia,andlymphadenopathycanoccurwithpemphigusfoliaceus.15,33Systemicsignsseemmorecommoninpatientswithgeneralizedlesions.Pruritus,especiallyinpatientswithgeneralizeddisease,isvariableindogsandcatswithpemphigusfoliaceus.5,14,15Carefulquestioningofapetownercanrevealwhethertheskinlesionsdevelopedbeforethepruritus.Thistimingoflesiondevelopmentisincontrasttoallergies,whichusuallystartwithpruritus.

Caninepemphigusfoliaceuscaninvolvethefootpadsalongwithothersitesonthebody.Rarely,caninepemphigusfoliaceusislocalizedonlytothefootpads.Pustulesareonlyrarelyseenonthefootpads,probablybecausethepustulesrupturewhilethepatientwalks.Clinically,pemphigusfoliaceusonthefootpadsresultsinlamenessandhyperkeratosis(Figure5).39,40Caninepemphigusfoliaceuscanalsorarelyoccurjustaroundtheclaws.41

Inmostcats,pemphigusfoliaceusisamildandlocalized

diseaseconsistingoferosionsandyellowishcrusts.Pemphigusfoliaceuscanalsospreadandbecomegeneralizedincats.15Felinepemphigusfoliaceusmostcommonlybeginsonthehead(Figure6).Lesionscanalsoaffectthepinnae.Catscanhavemarkedsuppurationandcrustsonoraroundthefootpadsorungualfoldsoftheclaws(caseousparonychiaFigure7).42,43Anonychodystrophycanalsooccurwiththesenailfoldlesions.

DIFFERENTIALDIAGNOSES

Infectiouscausesofpustulardermatitiscanmimicorcomplicatepemphigusfoliaceus.

SuperficialpustulardermatophytosisisafungalinfectioninvolvingTrichophytonspecies.Thelesionscanlookclinicallyandhistopathologicallysimilartothoseofpemphigusfoliaceus.44Whilepustulardermatophytosisisuncommon,45werecommendevaluatingeachcaseofsuspectedpemphigusfoliaceusfordermatophytosisbecauseofthenegativeconsequencesofimmunosuppressive

treatmentinpatientswithadermatophyteinfection.

Adermatophyteculturecandiagnosesuperficialpustulardermatophytosis,andcytologicexaminationofthemacroconidiafromthegrowthcanidentifythefungalspecies.TheTrichophytonspeciesthatcausesthisformofdermatophytosiscanbepresentbothintheepidermisandinthehairfollicle.Scaleorcrustalongwithhairshouldbesampledforthedermatophyteculture.AperiodicacidSchiff(PAS)stainis

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Table1:DiagnosticCriteriaforCanineandFelinePemphigusFoliaceus*

8.Cytologicexaminationofanintactpustulefromadogwithpemphigusfoliaceusshowingraftsofacantholytickeratinocytes(arrows)andmanynondegenerateneutrophils(DiffQuikDadeBehring1000X).

requiredtodifferentiatesuperficialpustulardermatophytosisfrompemphigusfoliaceushistologically.

Bacterialskininfectionsareanotherdifferentialdiagnosisforpemphigusfoliaceus.Somestaphylococciproduceanexfoliativetoxinthattargetsdesmosomes,resultinginclinicalsignssimilartothoseofpemphigusfoliaceus.46Inthesecases,largeepidermalcollarettes,oftenextendingcentrifugally,arepresent.Exfoliationtendstobemoresevereinbacterialskininfectionsthaninpemphigusfoliaceus.Patientswithbacterialskininfectionswillalsodemonstratebacteriacytologically.Cytologicexaminationoftenshowsdegenerativeneutrophilswiththebacteria.Cultureoftheexudatefromwithinapustulecanidentifythebacterialspecies.

DIAGNOSIS

Pemphigusfoliaceusisdiagnosedbyevaluatingtheclinicalhistory,physicalexaminationfindings,andresultsofdiagnostictestssuchascytologicandhistologicexaminations(Table1).Becauseofthepotentialforseveresideeffects,pemphigusfoliaceusshouldbedefinitivelydiagnosedbeforesystemicimmunosuppressivetherapyisstarted.

Cytology

Cytologicexaminationofanintactpustule(Tzanckpreparation)canbeausefulinclinicdiagnostictestfortentativelydiagnosingpemphigusfoliaceuspendingbiopsyandhistologicexaminationresults.Cytologicexaminationofanintactpustuleinpemphigusfoliaceusshowsnondegenerateneutrophilswithacantholytickeratinocytes(Figure8).Thecytologicabsenceofbacteriamakesbacterialskininfectionalesslikelycauseoftheclinicalsigns.Sincesomecasesofsuperficialpustulardrugreactionsanddermatophytosiscanhavesimilarcytologicfindingstothoseofpemphigusfoliaceus,biopsyandhistologicexaminationarestillrecommendedbeforetreatmentofpemphigus

foliaceus.

Bloodtests

Nohematologicchangesarespecifictopemphigusfoliaceus.Dogscanhaveamildtomoderateleukocytosiswithneutrophiliaandamildtomoderatenonregenerative,normocytic,andnormochromicanemia(anemiaofchronicdisease).5Catscanhavesimilarchangesinadditiontobasophilia,eosinophilia,lymphopenia,andmonocytosis.15Incats,noassociationexistsbetweenfelineleukemiavirusorfelineimmunodeficiencyvirusandpemphigusfoliaceus.Whileacompletebloodcountandserumchemistryprofilecannotdiagnosepemphigusfoliaceus,theycanhelpdiagnoseanyconcurrentsystemicdiseasesthatcouldbeexacerbatedbyimmunosuppressivetherapyforpemphigusfoliaceus.Bloodworkisalsorecommendedtoestablishbaselinevaluesbeforestartingimmunosuppressivetreatment.Anantinuclearantibodytestisnotnecessaryincasesofsuspectedpemphigusfoliaceus.

Histology

Biopsiesshouldideallybeperformedonpustules.Micropustulescanbepresentundercrustsand,thus,visibleonhistologicexamination.Forthisreason,ifanintactpustulecannotbefound,biopsyofacrustisanotheroption.Toavoiddisruptingpustulesorcrusts,donotscrubthebiopsysite.Instead,gentlyclipthebiopsysitewhileavoidingtheremovalofsurfacecrusts.Thebiopsysitecanthenbegentlyblottedwithalcohol.

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9.Histologicexaminationofpustuleobtainedbyskinbiopsyfromacatwithpemphigusfoliaceusrevealssubcornealacantholytickeratinocytesandneutrophils(hematoxylineosin20X).

Biopsyresultsaremorelikelytobediagnosticifglucocorticoids,bothtopicalandsystemic,arediscontinuedbeforebiopsy.15Werecommenddiscontinuingglucocorticoidsforatleastoneweekbeforebiopsy.Submitsamplestoadermatopathologistalongwithacompletehistoryanddescriptionoftheclinicallesions.Thedistributionofthelesionsisalsoimportant.AlistingofdermatopathologistscanbefoundonlineontheVeterinaryInformationNetwork(http://www.vin.com|~http://www.vin.com)searchfor"dermatopathologistregistry")orbycontactingyourlocaldermatologist.AllowthedermatopathologisttoperformPASstainssothatthebiopsycanbeevaluatedforpustulardermatophytosis.

Histologicexaminationdemonstratespredominantlysuperficial,eosinophilic,orneutrophilicpustuleswithacantholytickeratinocytes(Figure9).Rarely,earlycasesofpemphigusfoliaceuscanshoweosinophilicpustuleswithspongiosis(intercellularedema)intheepidermisoraroundhairfolliclesbutnoacantholysis.47

Whenbacterialskininfections(impetigoandexfoliativepyoderma)arepresentwithpemphigusfoliaceus,itcanbedifficulttodeterminewhichhistologicchangesareduetothepemphigusfoliaceusandwhichchangesareduetobacteria.Ingeneral,pemphigusfoliaceusismorecommonlyassociatedwithagreaterdensityofacantholyticcellsandlargepustulesthatspanacrossmultiplehairfolliclescomparedwithbacterialskininfections.38Treatanyconcurrentbacterialinfectionswithantimicrobialsbeforebiopsytoincreasethechancesofacleardiagnosisfromhistologicexamination.Ifyoureceiveaskinbiopsyreportthatlistsbothbacterialskininfectionandpemphigusfoliaceusaspossiblediagnoses,apracticalnextstepistotreatthepossiblebacterialskininfectionwithantimicrobialtherapy.Bacterialcultureoftheskinmaybenecessarytoselectanappropriateantibiotic.Fullresolutionoflesionswithonlyantimicrobialtherapyisconsistentwithabacterialskininfectionratherthanpemphigusfoliaceus.

Systemicimmunosuppressionisnotrecommendedwithoutafirmdiagnosisofpemphigusfoliaceus.Ifapatientissuspectedofhavingpemphigusfoliaceusbutdiagnostictestresultsareinconclusive,additionalbiopsyofotherlesionsor,preferably,referraltoadermatologistisrecommended.

Immunopathology

Immunofluorescencetestingisusedprimarilyforresearchpurposestocharacterizetheimmunologicresponseinpemphigusfoliaceus.TheidentificationofintercellularepidermalIgGviadirectimmunofluorescenceisnotspecifictopemphigusfoliaceusindogs.4,14Indirectimmunofluorescenceidentifiescirculatingautoantibodiesbutishighlydependentonthesubstrate.Immunofluorescenceisnotnecessarytoclinicallydiagnoseandmanagepatientswithpemphigusfoliaceus.

INITIALTREATMENTCONSIDERATIONS

Pemphigusfoliaceusisoftenachronicskinconditionwithawaxingandwaningcourse.Clientsshouldbeawareofthepossibilityofdiseaserecurrenceafterremission.Becauseofthepotentialsideeffectsofmedications,dosesshouldbetaperedinresponsetoclinicalsigns.

Itisimportanttoeducateclientsaboutmedicationsideeffectssothattheyunderstandwhymedicationdosesneedtobetapered.Remindclientsthatpemphigusfoliaceusflaresmayoccurafterdecreasingthemedicationdose.Withoutclienteducation,itiseasyforownerstobecomefrustratedandperceivethatthemedicationsarenothelping.Thelongtermcostsofrecheckexaminationsandteststomonitorpemphigusfoliaceuspatientsreceivingtherapycanalsobehigh.Aclienthandoutcanhelpeducateownersaboutpemphigusfoliaceus(todownloadahandout,gotohttp://www.dvm360.com/pemphigus|~http://www.dvm360.com/pemphigus).

Onceclientshavebeenfullyinformedoftheprognosisandmedicationsideeffectsoftreatment,initiatepemphigusfoliaceustreatment.Nosetprotocolexistsfortreating

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canineandfelinepemphigusfoliaceus.Instead,medicationsandtheirdosesneedtobeselectedforeachindividualpatientbasedontheseverityofclinicalsignsandthemedications'efficacyandsideeffects.

Caninecasesofpemphigusfoliaceuswithlocalizedskinlesionsmaybemanagedwithtopicalglucocorticoids.Inmildcases,topicalglucocorticoidscanbeusedalone.Inmoreseverecases,topicalglucocorticoidscanbeusedtominimizethedoseofsystemicimmunosuppressivetherapy.Topicalglucocorticoidsarelesscommonlyusedincatsbecauseitcanbemoredifficulttoapplytopicalmedicationstocats.Inmostdogsandcats,systemicimmunosuppressionremainstheinitialtreatmentofchoiceforpemphigusfoliaceus.Concurrentsystemicantibiotictherapyshouldbeconsideredifthereisabacterialskininfection.

MEDICATIONSUSEDFORPEMPHIGUSFOLIACEUS

Glucocorticoids

Topicalglucocorticoidscanbeusedasmonotherapyformildcasesofpemphigusfoliaceus,especiallyindogswithlocalizedfaciallesions.Theycanalsobeusedincombinationwithothersystemicmedicationsinmorerefractorycases.Avarietyofglucocorticoidsmorepotentthanhydrocortisonehavebeenusedtopicallyforpemphigusfoliaceussuchasbetamethasoneortriamcinolone,bothofwhichareavailableinavarietyofconcentrations.Sinceglucocorticoidscancauseskinatrophy,protecttheareaofglucocorticoidapplicationfromtrauma.Mildskinatrophycanbemanagedbyswitchingtoalowerpotencytopicalglucocorticoid.Moresevereskinatrophyshouldbemanagedbystoppingalltopicalglucocorticoids.

Systemicimmunosuppressionwithglucocorticoidsprovidesthemostrapidclinicalresponseindogsandcatswithpemphigusfoliaceus.Prednisoneisinitiallystartedat2mg/kg/dayorallyindogs,andprednisoloneisinitiallystartedat2to4mg/kg/dayorallyincats.Thedoseofprednisoneorprednisolonemaythenbeincreasedifnoimprovementinclinicalsignsisevidentwithinoneortwoweeks.Catsmayrespondbettertoglucocorticoidsotherthanprednisonebecauseofthelowerbioavailabilityofprednisonecomparedwithotherglucocorticoidsincats.48Ifglucocorticoidsofdifferentpotenciesareused,equivalentdosesshouldbecalculated.Incats,triamcinolonecanbeinitiallydosedat2to4mg/kg/dayorally,anddexamethasonecanbeinitiallydosedat0.3to0.6mg/kg/dayorally.Theglucocorticoiddoseshouldbeselectedbasedontheclinicalsigns.Dogsandcatswithmildpemphigusfoliaceuslesionsmayrespondtolowerdosesofglucocorticoids.

Longactinginjectableglucocorticoidssuchasmethylprednisoloneacetate(DepoMedrolPfizerAnimalHealth)arenotrecommendedfortreatingpemphigusfoliaceusthedoseofanyimmunosuppressivemedicationshouldideallybeadjustedinresponsetothepatient'sclinicalsigns.

Dermatologistsoccasionallyusehighdosepulseoralandintravenousglucocorticoidadministrationtotreatpemphigusfoliaceusindogs.Thesehighdosages(oralprednisoneat10mg/kg/day49orintravenousmethylprednisolonesuccinateat11mg/kg/day50)aretypicallygivenforthreedaysfollowedbyamuchlowerdoseoforalprednisone(0.5to2mg/kg/day).Highdoseglucocorticoidadministrationisusedprimarilyinseverepemphigusfoliaceuscasesinwhichquickremissionofsignsisrequired.Relapseisstillpossibleoncetheglucocorticoiddoseisdecreased.Atthistime,highdosepulseglucocorticoidtherapyshouldbeconsideredexperimentalfurtherstudiesareneededtodemonstrateitsbenefit.

Initialsideeffectsofglucocorticoidsincludepolyuria,polydipsia,andpolyphagia.Withlongertermuse,amyriadofothersideeffectscandevelopsuchasgastriculceration,hepatopathy(dogs),diabetesmellitus,calcinosiscutis,skinatrophy,andsecondaryinfections.Inaretrospectivestudy,theuseofgastroprotectantssuchassucralfateorhistaminereceptorblockers(famotidine)hadnoeffectonsurvivaltimeindogswithpemphigusfoliaceusreceivingglucocorticoids.51

Inmanydogs,glucocorticoidsaloneareinsufficienttomanagepemphigusfoliaceussigns.Inpaststudies,glucocorticoidmonotherapyresultedinacceptablemanagementofpemphigusfoliaceussignsinonly35%to39%ofdogs.5,52Glucocorticoidmonotherapyismoreeffectiveincats.Completeremissionwithonlyglucocorticoidsoccursin62%to100%ofcatswithpemphigusfoliaceusreceivingprednisoneandtriamcinolone,respectively.15

Anyoralglucocorticoidshouldbetaperedgraduallyonce

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Table2:SystemicMedicationsUsedwithGlucocorticoidsinDogswithPemphigusFoliaceus

Table3:SystemicMedicationsUsedwithGlucocorticoidsinCatswithPemphigusFoliaceus

clinicalremissionofthepemphigusfoliaceusisachieved(nonewpustulesorerosions).Theexactglucocorticoidtaperingprotocolwillvaryineachpatient,but,ingeneral,glucocorticoidscanbetaperedbyabout25%eachtimethedoseisadjusted.Recheckthepatientaftereachchangeintheoralglucocorticoiddose.Ifthepemphigusfoliaceusrecurswhentheglucocorticoidistapered,anotherimmunosuppressivemedicationshouldbeadded.Likewise,whenglucocorticoidsalonecannotinduceremissionofpemphigusfoliaceus,otherimmunosuppressivemedicationsarethenusedasadjunctivetherapysothattheglucocorticoiddosemayinitiallybedecreasedandglucocorticoidadministrationcaneventuallybediscontinued(Tables2&3).

Azathioprine

Azathioprineisapurineanaloguethatinterfereswithcellularnucleicacidsynthesis.

Thus,itsgreatestcytotoxiceffectisonproliferatingcellssuchaslymphocytes.Azathioprineismoreeffectiveatsuppressinghumoralimmunitythancellmediatedimmunity.

Azathioprineisthemedicationmostcommonlyusedtomanagecaninepemphigusfoliaceuswhenlesionsdonotrespondtoglucocorticoidmonotherapy.Inthesecases,lesionsworsenorstaythesamewithglucocorticoidsorsignsrelapsewithlowerdosagesofglucocorticoids.Addingazathioprineinadogwithpemphigusfoliaceuscanthenreducetheneedforsystemicglucocorticoidsandpotentiallyenablediscontinuationoftheglucocorticoid.

Azathioprineiscommonlystartedat2to2.5mg/kg/dayorallyindogswithpemphigusfoliaceus.Ifazathioprineisbeingusedwithglucocorticoidstomanagepemphigusfoliaceussigns,donotreducethedoseorfrequencyofglucocorticoidsimmediatelyafterstartingazathioprinesinceazathioprinecantakeweekstohaveaneffect.

Sideeffectsofazathioprineincludebonemarrowsuppressionresultinginleukopenia,anemia,andthrombocytopenia.Vomiting,diarrhea,hepatotoxicosis,andacutepancreatitiscanalsooccur.Inourexperience,hepatotoxicosisisthemostcommonsideeffect.Completebloodcountsandserumchemistryprofilesmustbeperformedregularlywhileapatientisreceivingazathioprine,usuallyeverytwotothreeweeksduringinitialtherapy.Whenazathioprineandglucocorticoidsareusedtogether,itcanbedifficulttomonitorforazathioprineinducedhepatotoxicosisbecauseoftheusualelevationofserumliverenzymeactivitiescausedbyglucocorticoidadministration.

Azathioprineismetabolizedbyanenzymecalledthiopurinemethyltransferase(TPMT).LowTPMTconcentrationsincreasetheriskofmyelosuppression.VariationsinTPMTconcentrationshavebeennotedindogs.53CatshavelowerTPMTconcentrationsthandogsdo,54andazathioprineisusuallyavoidedincatsbecauseofthehighlikelihoodofseveremyelosuppression.

Chlorambucil

ChlorambucilisanalkylatingagentthatcausescrosslinkingofcellularDNA.Dosesrangefrom0.1to0.2mg/kgorallyevery24to48hours.Sideeffectsincludevomiting,diarrhea,anorexia,andmyelosuppression.52Chlorambucilisespeciallyusedincatswithpemphigusfoliaceusthatfailtorespondtoglucocorticoidssinceazathioprineisnotatreatmentoptionforcats.Completebloodcountsandserumchemistryprofilesmustbeperformedregularlywhileapatientisreceivingchlorambucil,usuallyeverytwotothreeweeksduringinitialtherapy.

Cyclosporine

CyclosporineisacalcineurininhibitorthatblocksthetranscriptionofcytokinegenesinactivatedTcells.55Cyclosporineisanapprovedtreatmentforcanineatopicdermatitis(AtopicaNovartisAnimalHealth)andisusedextralabelforavarietyof

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otherimmunemediatedconditionsindogsandcats.56Cyclosporine'ssideeffectsindogsandcatsincludeinappetence,vomiting,diarrhea,gingivalhyperplasia,hirsutism,papillomas,psoriasiformlichenoidlikedermatosis,anddisseminatedtoxoplasmosis.57,58Themicroemulsionformofcyclosporine(AtopicaNeoralNovartis)ismorereadilyabsorbedindogsandcatsandshouldbeusedinsteadofotherformsofcyclosporinesuchasSandimmune(Novartis).Completebloodcountsandserumchemistryprofilesmustbeperformedregularlywhileapatientisreceivingcyclosporinetherapy.Incatsreceivingcyclosporine,elevatedliverenzymeactivitiescanbeasignoftoxoplasmosis.59

Inasmallpilotstudy,cyclosporinemonotherapyat5to10mg/kg/daywasineffectiveinmanagingpemphigusfoliaceussignsinfouroutoffivedogs.60Sincethepublicationofthatinitialstudy,therehavebeenanecdotalreportsofusingcyclosporineat10mg/kg/dayorgreatertomanagepemphigusfoliaceusindogs,especiallythosewithmilderpresentations.

Cyclosporineismoreeffectiveforpemphigusfoliaceuswhenusedincombinationwithothertherapies.Inthreedogswithpemphigusfoliaceusalreadyreceivingazathioprineandglucocorticoids,oralcyclosporineat7.5to10mg/kg/daywasusedwithoralketoconazoleat2.5to5mg/kg/daytosuccessfullyinduceremission.61Theketoconazolewasusedtoincreasecyclosporineconcentrations.Alldogswerethenabletohaveglucocorticoidsdiscontinuedwithinthreeto12weeksofaddingthecyclosporineandketoconazole.Signsdidnotworsenwhentheglucocorticoidswerediscontinued.Cyclosporinewasusedsuccessfullywithprednisonetoinduceremissionofpemphigusfoliaceussignsinanotherstudyinvolvingfivedogs.62Initialdosesrangedfrom1to2.6mg/kg/dayand5to18mg/kg/dayfortheprednisoneandcyclosporine,respectively.Whiletheinitialcyclosporinedosewasmaintainedineachpatient,theprednisonedosewasthentaperedto0.5mg/kgeveryotherdaywithnorelapseofsigns.Thecyclosporinewascontinuedandeventuallytaperedto3to4mg/kgeveryotherday.Nostudiesexistonusingcyclosporinetomanagefelinepemphigusfoliaceus,butwehaveusedcyclosporinetomanagesomepatients.

Inourexperience,cyclosporinecantakeweekstohaveaclinicaleffectonpemphigusfoliaceuslesions.Thisdelayedeffectmaybebecauseofcyclosporine'sactiononTlymphocytes,thecellsthatdrivetheautoimmunereaction,withoutdirecteffectonautoantibodiesthatcausetheskinlesions.Thus,ifcyclosporineisusedwithglucocorticoidstomanagepemphigusfoliaceussigns,donotreducethedoseorfrequencyofglucocorticoidsimmediatelyafterstartingcyclosporine.

Tacrolimus

Tacrolimus,anothercalcineurininhibitor,hasbeenusedtopicallyforconditionssuchaslocalizedatopyindogs63andpeople.Indogswithaformofsuperficialpemphigus(pemphiguserythematosus),applyingtacrolimus0.1%asathinfilmonfaciallesionstwiceadayhelpedmanageclinicalsigns.64Inthatstudy,tacrolimuswasusedasthesoletherapyinonedogwithsuperficialpemphigus,whiletheotherdogwasalsomanagedwithsystemicimmunosuppressivemedications.Ofnoteisthatpemphiguserythematosusissuspectedtobeacrossoverbetweendiscoidlupusandpemphigusfoliaceus.Itispossiblethatthenasallesionsofpemphiguserythematosusthatrespondedtotacrolimuswerethelupuslikelesions.Inouropinion,ingeneral,pemphigusfoliaceusdoesnotappeartorespondtotacrolimusointment.

Tacrolimuscancauseapruriticorburningsensationduringtheinitialfewdaysofapplicationinpeople,andsignsofpruritusandirritationhavebeenobservedindogswithinitialuse.63Thesesignstypicallyresolvedespitecontinuationoftherapy.In2005,thetacrolimuslabelwaschangedtoincludeawarningthatsomepeoplehavedevelopedcancerwhilereceivingthismedication.Clientsshouldweargloveswhenapplyingthismedication.

Niacinamidewithtetracyclineordoxycycline

Tetracyclineisanantibioticthatalsomodulatestheimmunesystembysuppressingneutrophilchemotaxisandlymphocyteactivation.65Tetracyclineisusedincombinationwithniacinamideforavarietyofimmunemediateddermatologicconditions.

Fordogs10kg,thedoseis500mgofeacheveryeighthours.

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Table4:PrinciplesofTreatingPemphigus

Tetracyclineandniacinamidearetypicallynotusedincatsbecauseitisdifficulttoadministertheselargersizedoralmedicationstomostcats.Doxycyclinehastheadvantageofneedinglessfrequentdosingthantetracycline.Ithasbeensubstitutedfortetracyclineandusedatadoseof5to10mg/kgorallyindogsevery12to24hours.However,thereisnodocumentationofthebenefitofdoxycyclinewhenitissubstitutedfortetracyclinetotreatcaninepemphigusfoliaceus.

Tetracyclineandniacinamideappeartobemorehelpfulasasoletherapyinmildcasesofpemphigusfoliaceus,especiallythosecaseswithlesionslocalizedtotheface.Itcanalsobeusedincombinationwithglucocorticoidsorazathioprine.66Itcantakeseveralweeksfortetracyclineandniacinamidetohaveaclinicaleffect.Onceremissionoccurswithtetracyclineandniacinamide,thefrequencyofadministrationcanbedecreasedtoonceortwiceaday.

Sideeffectsincludelethargy,anorexia,diarrhea,andincreasedriskofseizures.Lethargyandanorexiaareespeciallyassociatedwithniacinamide.Iftheniacinamideneedstobediscontinued,thetetracycline(ordoxycycline)alonecancontinuetohaveimmunomodulatoryactivity.

Othermedications

Avarietyofothertherapieshavebeenusedforpemphigusfoliaceus,includingcyclophosphamide,injectablegoldsalts,intravenousimmunoglobulins,mycophenolatemofetil,anddapsone.Referraltoaveterinarydermatologistisrecommendedbeforeusingthesetherapies.Referralisalsorecommendediftreatmentfailureoccurswithanyofthemedicationsdiscussedinthisarticle.

MONITORING

Nomatterwhichmedicationsarechosentomanagepemphigusfoliaceus,frequentrecheckexaminationsareimportanttoassessclinicalresponseandtodeterminewhentotapermedications.Werecommendrecheckingallpemphigusfoliaceuspatientswithinoneortwoweeksofstartingmedicalmanagement.Asubstantialimprovementinclinicalsignswithin10daysofstartingglucocorticoidtherapyindogsisapositiveprognosticfactorinthesuccessfulmanagementofpemphigusfoliaceus.5

Glucocorticoidsareoftenusedforpemphigusfoliaceustreatmentinductionbecauseoftheirrapidonset.Ifmarkedclinicalimprovementisnoted,theglucocorticoiddoseorfrequencyofadministrationshouldbetaperedbyabout25%.Ifclinicalsignshavestayedthesameorworseneddespiteglucocorticoidtherapy,theglucocorticoiddoseshouldbeincreasedorcombinationtherapyshouldbestarted.Combinationtherapyshouldalsobestartedifremissionofthepemphigusfoliaceuscannotbemaintainedwhentheglucocorticoiddoseistapered.Werecommendrecheckingpatientsbeforeandaftereachchangeinmedicationtypeordosetohelpmonitorclinicalsigns.

Cutaneoussideeffectsofimmunosuppressionsuchasabacterialskininfection,demodicosis,ordermatophytosiscanlookclinicallysimilartoapemphigusfoliaceusflare.Itisimportanttoruleouttheseconditionsinsteadofassumingthatanynewdermatologiclesionsareduetopemphigusfoliaceus,otherwiselesionsmayworsenfromimmunosuppression,andrefractorypemphigusfoliaceusmaybeerroneouslydiagnosed.Skinscrapesandhairplucksshouldbeperformedonnewareasofalopecia,andcytologicexaminationshouldbeusedtoevaluatelesionsforsecondaryskininfections.

Dependingonthemedicationbeingusedtomanagethepemphigusfoliaceus,bloodworkmaybenecessarytomonitorformedicationsideeffects.Regularurinebacterialculturesarerecommendedfordogsandcatsreceivingsystemicimmunosuppressivetherapytomonitorforocculturinarytractinfections.5Urinalysistoidentifyanactivesediment(whitebloodcellsintheurine)isnotaneffectivewaytoscreenforurinarytractinfectionsinmostpatientswithpemphigusfoliaceusbecausesystemicimmunosuppressionmaysuppressthenumberofwhitebloodcellsintheurineevenwhenaurinarytractinfectionispresent.TheprinciplesoftreatingcanineandfelinepemphigusfoliaceusaresummarizedinTable4.

Theoutcomeoftreatingpemphigusfoliaceusindogsandcatsisvariable40%51to88%4ofdogswithpemphigusfoliaceushave

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FoliaceusinDogsandCats

theirconditionmanagedsuccessfully.Neitherayoungerageofonsetnoralocalizeddiseasepatterncorrelatewithimprovedsurvivaltimes.51Theonlyfactorthathasinfluencedlongterm

survivaltimeindogswithpemphigusfoliaceusistheconcurrentuseofantimicrobialswithimmunosuppressivemedications,likelybecausetheantimicrobialsminimizethedevelopmentofsecondarybacterialskininfectionsandurinarytractinfections.Prolongedremissionafterimmunosuppressivetherapycanoccurindogsandcatswithpemphigusfoliaceus.15,67

Mortalityfrompemphigusfoliaceuscanoccurbecauseofdiseaseprogression,medicationsideeffects,orclientrequestedeuthanasia.Severecasesofpemphigusfoliaceuscanresultinmarkedcachexiaorsepsissecondarytoinfections.Adverseeffectsarecommonwithmostofthemedicationsusedforpemphigusfoliaceus.Euthanasiaaccountedforalmost70%ofdeathsinpemphigusfoliaceusdogsinoneretrospectivestudy.51Reasonsforclientrequestedeuthanasiaincludednotbeingabletocontrolthepemphigusfoliaceus,aperceivedpoorqualityoflife,andthedevelopmentofadverseeffectsfrommedications.Forallthesereasons,pemphigusfoliaceusshouldbeconsideredapotentiallyfataldermatologiccondition.Consultationwithaspecialistorreferralcanbehelpfulwhenmanagingpemphigusfoliaceuscases.

SUMMARY

Pemphigusfoliaceusisapustularandcrustingautoimmunedermatologiccondition.Theprognosisforpemphigusfoliaceusindogsandcatsisvariable,andsignscanwaxandwane.Adiagnosisisbasedonthepatient'sclinicalhistory,ahistologicexaminationofskinsamples,andadiagnosticworkupthatrulesoutotherneutrophilicandpustularskinconditions.Avarietyofimmunomodulatorymedicationscanbeusedtomanagepemphigusfoliaceus.Frequentrecheckexaminationsandclientcommunicationareimportantformanagingpemphigusfoliaceus.Becauseofthepotentialforseveremedicationsideeffects,medicationsshouldbeselectedandtaperedbasedontheseverityofclinicalsigns.

KathyC.Tater,DVM,DACVDAngellAnimalMedicalCenter350S.HuntingtonAve.Boston,MA02130

ThierryOlivry,DrVet,PhD,DECVD,DACVDDepartmentofClinicalSciencesCollegeofVeterinaryMedicineNorthCarolinaStateUniversityRaleigh,NC27606

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