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Canineandfelinepemphigusfoliaceus:Improvingyourchancesofasuccessfuloutcome

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Home>Canineandfelinepemphigusfoliaceus:Improvingyourchancesofasuccessfuloutcome

Canineandfelinepemphigusfoliaceus:Improving
yourchancesofasuccessfuloutcome
Athoughtfuldiagnosticandtherapeuticprocessiscriticaltomanagingdogsandcats
sufferingfromthispotentiallyfataldermatologicdisease.

Jan01,2010
ByKathyC.Tater,DVM,DACVD,ThierryOlivry,DrVet,PhD,DACVD,DECVD
VETERINARYMEDICINE
Pemphigusfoliaceus,themostcommonautoimmuneskinconditionindogsandcats,
ischaracterizedbypustules,erosions,andcrusts.Inthisarticle,wefocusonthe
diagnosisandtreatmentofpemphigusfoliaceusindogsandcats.
PATHOGENESIS
Pemphigusfoliaceusaffectstheepidermis,theoutermostsuperficialskinlayer.To
helptheepidermisactasabarriertotheoutsideworld,theepidermisiscomposed
primarilyoftightlyadherentkeratinocytes.Twotypesofadhesionstructureshold
keratinocytestogether.Desmosomesareresponsibleforcelltocelladhesion.
Hemidesmosomesareresponsibleforcelltomatrixadhesion.Intheskin,
hemidesmosomesbindthedeeporbasilarepidermalkeratinocytestothebasement
membrane.
Thepemphigusvariantsoccurwhenautoantibodiestargetthedesmosomes
betweenkeratinocytes.Desmosomedisruptionresultsinseparationofthe
keratinocytes,whichisreferredtoasacantholysis.Keratinocytesthathavelosttheir
celltocelladhesionarecalledacantholytickeratinocytes,notacanthocytes(i.e.
crenatedredbloodcells).
Inpemphigusfoliaceusinpeople,themostcommontargetofautoantibodiesisthe
desmoglein1(DSG1)glycoproteininthedesmosome.1,2 Theautoantibody
responseprimarilyinvolvesIgG(IgG4subclass).3 Initialstudiesindogswith
pemphigusfoliaceusonlyrarelydetectedanIgGautoantibodyresponse,4,5 butmore
recentworkusingdifferentsubstratesinindirectimmunofluorescencetesting
confirmsthatIgGautoantibodiesareimportantincaninepemphigusfoliaceus.6
However,DSG1isnotcommonlytargetedinpemphigusfoliaceusindogs7 itisnot
yetknownwhichpartofthedesmosomeistargetedinmostcaninepemphigus
foliaceuscases.Earlyimmunoblottingstudiesrevealedthatthetargetwasa148kDa
or160kDaprotein.8,9 Immunoelectronmicroscopyshowsthatthesiteof
autoantibodybindingisintheextracellularregionofthedesmosome.10
Thewordpemphigusisusedfortheentiregroupofautoimmuneblisteringdiseases
inwhichintraepidermalseparationoccursviaacantholysis.Pemphigusfoliaceusisa
specifictypeofsuperficialpemphigusandisclinicallydistinctfromdeeppemphigus
diseases.Anotherexampleofsuperficialpemphigusdiseaseispemphigus
erythematosus.Examplesofdeeppemphigusdiseasesincludeparaneoplastic
pemphigus,pemphigusvulgaris,andbullouspemphigoid.
Thesignsofanattackonkeratinocyteadhesionstructuresareclinicallyevident.
Whenthetightbondsbetweensuperficialkeratinocytesareaffected,itmanifestsas
vesiclesandpustules.Whenthetightbondsbetweenbasilarkeratinocytesandthe
skin'sbasementmembraneareaffected,itmanifestsasbullae(largeblisters)and
ulcers.
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Morerecently,pemphigusfoliaceushasbeenproposedasthegeneraltermforall
superficialpemphigusdiseases,sincethereisanoverlapinclinical,histologic,and
immunologiccharacteristicsamongallthesuperficialpemphigusconditions.11 Deep
pemphigusconditions,though,stillremainclinicallyandimmunologicallydistinct
fromthesuperficialpemphigusconditions.Thus,thetermpemphigusshouldnotbe
usedasadiagnosisbyitselfforanypatientbecauseitreferstoaheterogeneous
groupofbothsuperficialanddeeppemphigusconditions.
SIGNALMENTANDCAUSES
Geneticfactorscaninfluencethedevelopmentofpemphigusfoliaceus.Indogs,itis
morefrequentlydiagnosedintwobreedswithcloselyrelatedgenotypes,12 Akitas
andchows.4 Pemphigusfoliaceushasalsobeenreportedinlittermates.13 Nobreed
dispositionhasbeennotedinfelinepemphigusfoliaceus.
Sexandageappeartobeunrelatedtothedevelopmentofpemphigusfoliaceusin
dogsandcats.Theageofonsetisvariableandrangesfrom1to16yearsin
dogs4,5,14 andlessthan1yearofage4 toupto17yearsofage15 incats.
Ultravioletlight
Ultravioletexposurefromthesunisapotentialenvironmentaltriggerforpemphigus
foliaceus.Theskinlesionsindogswithpemphigusfoliaceuscanworseninthe
summerandimproveinthewinter.16,17 Exposingdogswithfacialpemphigus
foliaceustoultravioletB(UVB)resultsinincreasedepidermalacantholysis.18 We
thinkthereisalowerprevalenceofcaninepemphigusfoliaceusincoolerU.S.
regionscomparedwithwarmerU.S.regionswithmoresunexposure.
Drugs
Drugscaninfluencethedevelopmentofpemphigusfoliaceus.19 Somedrugsdirectly
induceacantholysis(druginducedpemphigusfoliaceus).Drugscanactivate
proteolyticenzymesintheskinthatthendisruptdesmosomesandresultin
biochemicalacantholysis.Drugscanalsostimulatethedevelopmentof
autoantibodiesagainstdesmosomes,resultinginimmunologicacantholysis.20 Drug
triggeredpemphigusfoliaceusoccursinpatientspredisposedtopemphigus
foliaceus.Thecombinationofthedrugandotherpatientfactorsthentriggersaflare
upofpemphigusfoliaceus.19
Humandruginducedpemphigusfoliaceusisusuallyassociatedwithexposureto
medicationswithchemicalstructuresthatcancontributetotheactivationof
proteolyticenzymesintheskin.Thesedrugsincludethiolcompoundscontaining
SH,orsulfhydryl,groups(e.g.penicillamine),medicationsthatcanundergo
metabolicchangesandformactiveSHgroups(e.g.penicillins,cephalosporins),or
medicationsthatcontainactiveamidegroups(e.g.enalapril).20 Indogsandcats,
pemphigusfoliaceushasbeensuspectedtobeassociatedwithavarietyof
medicationssuchascimetidine,21 cephalexin,22 amoxicillinandclavulanicacid,23
ampicillin,24 andtrimethoprimsulfonamidecombinations.25
Manypatientswithnewlydiagnosedpemphigusfoliaceushaveahistoryofexposure
tomultiplemedications.Ifapatienthaseitherdruginducedordrugtriggered
pemphigusfoliaceus,discontinuingthemedicationcouldhelpmanagethe
pemphigusfoliaceusorcausethepemphigusfoliaceustogointoremission.Itis
difficult,though,toproveanassociationbetweenanydrugandthepemphigus
foliaceus.Drugrechallengewoulddefinitivelyconfirmdruginducedpemphigus
foliaceus,butsincethiscouldharmthepatient,wedonotrecommenddrug
rechallengeincutaneousdrugreactions.Observingapoptotickeratinocytes
histologicallycannotbeusedasamarkerforadrugreactionsinceapoptotic
keratinocytesmaybeseenindogswithpemphigusfoliaceus.26
Ifdrugrelatedpemphigusfoliaceusissuspected,reviewthepatient'sdrughistory
carefully.Cutaneousdrugreactionstypicallydevelopmorethansevendaysafterthe
firstadministrationofadrug.Ifthepatienthasbeenpreviouslyexposedtothedrug,
reactionsarequickandoccurwithin24hoursofdrugreexposure.27
Morerecently,weareawareofreportsthatadministrationofatopicalspoton
productcontainingmetaflumizoneandamitraz(ProMerisFortDodgeAnimal
Health)hasbeenassociatedwithpemphigusfoliaceusindogs.Themechanismfor
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thisreactioniscurrentlyunknownbutisanareaofactiveresearchatoneofour
laboratories(T.O.).
Othercauses
Avarietyofotherfactorsarepossibletriggersforhumanpemphigusfoliaceus.Fogo
selvagem,aformofhumanpemphigusfoliaceusendemictosomeruralareasof
Brazil,islikelyduetoacombinationofenvironmentalfactorsandpossiblythe
patient'sgeneticsusceptibility.28,29 Nutrition(thiolcontainingfoodssuchasgarlic
andonions30,31 )andinfection32 havealsobeenassociatedwithsomecasesof
humanpemphigusfoliaceus.Itisunknownifanyofthesefactors,especiallydiet,are
triggersincanineandfelinepemphigusfoliaceus.
Caninepemphigusfoliaceuscanbeassociated
withahistoryofchronicskindiseasesuchas
allergies,33 althoughnostudieshavedefinitively
provedthislink.Caninepemphigusfoliaceushas
alsobeenreportedinpatientswithother
conditionssuchashypothyroidism,34
leishmaniasis,35 thymoma,36 andsystemiclupus
erythematosus.37 Pemphigusfoliaceusmaybe
presentinthesepatientsthroughcoincidence,or
pemphigusfoliaceusmaybeoccurringinthese
patientsthroughtheinductionofdesmosome
autoantibodiestriggeredbythesesystemic
conditions.

1.Apustulejustcaudaltothe
planumnasaleofadog
alopeciaanderythemaarealso
CLINICALSIGNS
presentinthedorsalnasal
region.
Theearliest
lesionsofpemphigusfoliaceusconsistof
erythematousmaculesthatthenprogress
rapidlytoapustularstage.Pustulestendtobe
large,irregular,andcoalescing(Figure1).
Multiplehairshaftsprotrudingfrompustules
aremoreconsistentwithpemphigusfoliaceus
andhelpdifferentiatepemphigusfoliaceus
fromthemorecommoncauseofpustules,
bacterialfolliculitis.38 Becausepustulesare
fragileandeasilyruptured,onlycrustsorthe
driedexudatefromrupturedpustulesmaybe 2.Crustsfromrupturedpustulesona
noted(Figure2).Forthisreason,crustsrather dog'snasalplanumanddorsalnasal
region.
thanpustulesarethemostcommonlyseen
4,5,14
lesionincasesofpemphigusfoliaceus.
Erosionscanbenoted,especiallyifacrustis
removed.Ulcersarerarebecausepemphigus
foliaceusisasuperficialepidermalskindisease.
Ulcerscanbeseenincasesofpemphigusfoliaceus
thathaveaconcurrentconditionthataffectsthe
deepersectionsofskinsuchasadeeppyoderma
(Figure3).Rarely,erosions,crusts,andpustulescan
begroupedintoanannularorpolycyclicpattern.
Pemphigusfoliaceuslesionstypicallyhaveawaxing
andwaningcourse.Lesionsareusuallybilateraland
symmetrical.
3.Ulcerationfromadeep
pyodermainapatientwith
pemphigusfoliaceus.Ulcers
shouldnotbeseenin
pemphigusfoliaceus
patientsunlessanother
conditionsuchasa
pyodermaispresent.Note
thesymmetricalappearance
ofthefaciallesions.

Lesionsontheconcavepinnaeshouldincreaseyour
clinicalsuspicionofpemphigusfoliaceussincefew
otherpustularconditionsaffecttheconcavepinnae
(Figure4).Mucosallesionsarerareinpemphigus
foliaceus.

Inmostdogs,
lesionsinitially
appearonthe
face(thedorsal
muzzle,
planumnasale,periocularskin,andears)and
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thenregionalizeorgeneralizeoverthecourse
ofmonths.Rarely,somedogswilleitherstart
withageneralizeddistributionorhaveonlya
localizedformofthedisease.
Indogandcatswithgeneralizedpemphigus
foliaceuslesions,widespreaderythemaand
exfoliationcanbenoted.Massiveexfoliation,
especiallyifextendingbeyondthebordersof
theoriginallesions,ismoresuggestiveof
bacterialinfectionsthanpemphigusfoliaceus.
4.Crustsanddriedexudateonthe
Systemicsignssuchasfever,lethargy,
concavepinnaofadogwith
anorexia,andlymphadenopathycanoccur
15,33
pemphigusfoliaceus.(Photo
withpemphigusfoliaceus.
Systemic
courtesyofLaurenPinchbeck,DVM,
signsseemmorecommoninpatientswith
DACVD.)
generalizedlesions.Pruritus,especiallyin
patientswithgeneralizeddisease,isvariable
indogsandcatswithpemphigusfoliaceus.5,14,15 Carefulquestioningofapetowner
canrevealwhethertheskinlesionsdevelopedbeforethepruritus.Thistimingof
lesiondevelopmentisincontrasttoallergies,whichusuallystartwithpruritus.
Caninepemphigusfoliaceuscaninvolvethe
footpadsalongwithothersitesonthebody.Rarely,
caninepemphigusfoliaceusislocalizedonlytothe
footpads.Pustulesareonlyrarelyseenonthe
footpads,probablybecausethepustulesrupture
whilethepatientwalks.Clinically,pemphigus
foliaceusonthefootpadsresultsinlamenessand
hyperkeratosis(Figure5).39,40 Caninepemphigus
foliaceuscanalsorarelyoccurjustaroundthe
claws.41
Inmostcats,
5.Crustsonthefootpadsofa
pemphigus
dogwithpemphigus
foliaceusisamild
foliaceus.
andlocalized
diseaseconsistingoferosionsandyellowish
crusts.Pemphigusfoliaceuscanalsospreadand
becomegeneralizedincats.15 Felinepemphigus
foliaceusmostcommonlybeginsonthehead
(Figure6).Lesionscanalsoaffectthepinnae.
Catscanhavemarkedsuppurationandcrustson
oraroundthefootpadsorungualfoldsofthe
claws(caseousparonychiaFigure7).42,43 An
6.Erosionsandcrustsonthe
onychodystrophycanalsooccurwiththese
faceandearsofacatwith
nailfoldlesions.
pemphigusfoliaceus.
DIFFERENTIALDIAGNOSES
Infectiouscausesofpustulardermatitiscan
mimicorcomplicatepemphigusfoliaceus.
Superficialpustulardermatophytosisisa
fungalinfectioninvolvingTrichophyton
species.Thelesionscanlookclinicallyand
histopathologicallysimilartothoseof
pemphigusfoliaceus.44 Whilepustular
dermatophytosisisuncommon,45 we
recommendevaluatingeachcaseof
suspectedpemphigusfoliaceusfor
7.Pedalpemphigusfoliaceusina
dermatophytosisbecauseofthenegative
cat.
consequencesofimmunosuppressive
treatmentinpatientswithadermatophyteinfection.
Adermatophyteculturecandiagnosesuperficialpustulardermatophytosis,and
cytologicexaminationofthemacroconidiafromthegrowthcanidentifythefungal
species.TheTrichophytonspeciesthatcausesthisformofdermatophytosiscanbe
presentbothintheepidermisandinthehairfollicle.Scaleorcrustalongwithhair
shouldbesampledforthedermatophyteculture.AperiodicacidSchiff(PAS)stainis
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requiredtodifferentiatesuperficialpustulardermatophytosisfrompemphigus
foliaceushistologically.
Bacterialskininfectionsareanotherdifferentialdiagnosisforpemphigusfoliaceus.
Somestaphylococciproduceanexfoliativetoxinthattargetsdesmosomes,resulting
inclinicalsignssimilartothoseofpemphigusfoliaceus.46 Inthesecases,large
epidermalcollarettes,oftenextendingcentrifugally,arepresent.Exfoliationtendsto
bemoresevereinbacterialskininfectionsthaninpemphigusfoliaceus.Patientswith
bacterialskininfectionswillalsodemonstratebacteriacytologically.Cytologic
examinationoftenshowsdegenerativeneutrophilswiththebacteria.Cultureofthe
exudatefromwithinapustulecanidentifythebacterialspecies.
DIAGNOSIS
Pemphigusfoliaceusisdiagnosedbyevaluatingthe
clinicalhistory,physicalexaminationfindings,and
resultsofdiagnostictestssuchascytologicand
histologicexaminations(Table1).Becauseofthe
potentialforseveresideeffects,pemphigusfoliaceus
shouldbedefinitivelydiagnosedbeforesystemic
immunosuppressivetherapyisstarted.
Cytology
Cytologic
examinationof
anintact
Table1:DiagnosticCriteria
pustule(Tzanck forCanineandFeline
preparation)
PemphigusFoliaceus*
canbeauseful
inclinicdiagnostictestfortentatively
diagnosingpemphigusfoliaceuspending
biopsyandhistologicexaminationresults.
Cytologicexaminationofanintactpustulein
pemphigusfoliaceusshowsnondegenerate
neutrophilswithacantholytickeratinocytes
8.Cytologicexaminationofanintact (Figure8).Thecytologicabsenceofbacteria
pustulefromadogwithpemphigus makesbacterialskininfectionalesslikely
foliaceusshowingraftsof
causeoftheclinicalsigns.Sincesomecases
acantholytickeratinocytes(arrows) ofsuperficialpustulardrugreactionsand
andmanynondegenerate
dermatophytosiscanhavesimilarcytologic
neutrophils(DiffQuikDade
findingstothoseofpemphigusfoliaceus,
Behring1000X).
biopsyandhistologicexaminationarestill
recommendedbeforetreatmentofpemphigus
foliaceus.
Bloodtests
Nohematologicchangesarespecifictopemphigusfoliaceus.Dogscanhaveamild
tomoderateleukocytosiswithneutrophiliaandamildtomoderatenonregenerative,
normocytic,andnormochromicanemia(anemiaofchronicdisease).5 Catscanhave
similarchangesinadditiontobasophilia,eosinophilia,lymphopenia,and
monocytosis.15 Incats,noassociationexistsbetweenfelineleukemiavirusorfeline
immunodeficiencyvirusandpemphigusfoliaceus.Whileacompletebloodcountand
serumchemistryprofilecannotdiagnosepemphigusfoliaceus,theycanhelp
diagnoseanyconcurrentsystemicdiseasesthatcouldbeexacerbatedby
immunosuppressivetherapyforpemphigusfoliaceus.Bloodworkisalso
recommendedtoestablishbaselinevaluesbeforestartingimmunosuppressive
treatment.Anantinuclearantibodytestisnotnecessaryincasesofsuspected
pemphigusfoliaceus.
Histology
Biopsiesshouldideallybeperformedonpustules.Micropustulescanbepresent
undercrustsand,thus,visibleonhistologicexamination.Forthisreason,ifanintact
pustulecannotbefound,biopsyofacrustisanotheroption.Toavoiddisrupting
pustulesorcrusts,donotscrubthebiopsysite.Instead,gentlyclipthebiopsysite
whileavoidingtheremovalofsurfacecrusts.Thebiopsysitecanthenbegently
blottedwithalcohol.
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Biopsyresultsaremorelikelytobediagnostic
ifglucocorticoids,bothtopicalandsystemic,
arediscontinuedbeforebiopsy.15 We
recommenddiscontinuingglucocorticoidsfor
atleastoneweekbeforebiopsy.Submit
samplestoadermatopathologistalongwitha
completehistoryanddescriptionoftheclinical
lesions.Thedistributionofthelesionsisalso
important.Alistingofdermatopathologistscan
befoundonlineontheVeterinaryInformation
Network
(http://www.vin.com|~http://www.vin.com)
searchfor"dermatopathologistregistry")orby
contactingyourlocaldermatologist.Allowthe
dermatopathologisttoperformPASstainsso
thatthebiopsycanbeevaluatedforpustular
dermatophytosis.

9.Histologicexaminationofpustule
obtainedbyskinbiopsyfromacat
withpemphigusfoliaceusreveals
subcornealacantholytic
keratinocytesandneutrophils
(hematoxylineosin20X).

Histologicexaminationdemonstratespredominantlysuperficial,eosinophilic,or
neutrophilicpustuleswithacantholytickeratinocytes(Figure9).Rarely,earlycasesof
pemphigusfoliaceuscanshoweosinophilicpustuleswithspongiosis(intercellular
edema)intheepidermisoraroundhairfolliclesbutnoacantholysis.47
Whenbacterialskininfections(impetigoandexfoliativepyoderma)arepresentwith
pemphigusfoliaceus,itcanbedifficulttodeterminewhichhistologicchangesare
duetothepemphigusfoliaceusandwhichchangesareduetobacteria.Ingeneral,
pemphigusfoliaceusismorecommonlyassociatedwithagreaterdensityof
acantholyticcellsandlargepustulesthatspanacrossmultiplehairfollicles
comparedwithbacterialskininfections.38 Treatanyconcurrentbacterialinfections
withantimicrobialsbeforebiopsytoincreasethechancesofacleardiagnosisfrom
histologicexamination.Ifyoureceiveaskinbiopsyreportthatlistsbothbacterialskin
infectionandpemphigusfoliaceusaspossiblediagnoses,apracticalnextstepisto
treatthepossiblebacterialskininfectionwithantimicrobialtherapy.Bacterialculture
oftheskinmaybenecessarytoselectanappropriateantibiotic.Fullresolutionof
lesionswithonlyantimicrobialtherapyisconsistentwithabacterialskininfection
ratherthanpemphigusfoliaceus.
Systemicimmunosuppressionisnotrecommendedwithoutafirmdiagnosisof
pemphigusfoliaceus.Ifapatientissuspectedofhavingpemphigusfoliaceusbut
diagnostictestresultsareinconclusive,additionalbiopsyofotherlesionsor,
preferably,referraltoadermatologistisrecommended.
Immunopathology
Immunofluorescencetestingisusedprimarilyforresearchpurposestocharacterize
theimmunologicresponseinpemphigusfoliaceus.Theidentificationofintercellular
epidermalIgGviadirectimmunofluorescenceisnotspecifictopemphigusfoliaceus
indogs.4,14 Indirectimmunofluorescenceidentifiescirculatingautoantibodiesbutis
highlydependentonthesubstrate.Immunofluorescenceisnotnecessarytoclinically
diagnoseandmanagepatientswithpemphigusfoliaceus.
INITIALTREATMENTCONSIDERATIONS
Pemphigusfoliaceusisoftenachronicskinconditionwithawaxingandwaning
course.Clientsshouldbeawareofthepossibilityofdiseaserecurrenceafter
remission.Becauseofthepotentialsideeffectsofmedications,dosesshouldbe
taperedinresponsetoclinicalsigns.
Itisimportanttoeducateclientsaboutmedicationsideeffectssothatthey
understandwhymedicationdosesneedtobetapered.Remindclientsthat
pemphigusfoliaceusflaresmayoccurafterdecreasingthemedicationdose.Without
clienteducation,itiseasyforownerstobecomefrustratedandperceivethatthe
medicationsarenothelping.Thelongtermcostsofrecheckexaminationsandtests
tomonitorpemphigusfoliaceuspatientsreceivingtherapycanalsobehigh.Aclient
handoutcanhelpeducateownersaboutpemphigusfoliaceus(todownloada
handout,goto
http://www.dvm360.com/pemphigus|~http://www.dvm360.com/pemphigus).
Onceclientshavebeenfullyinformedoftheprognosisandmedicationsideeffectsof
treatment,initiatepemphigusfoliaceustreatment.Nosetprotocolexistsfortreating
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canineandfelinepemphigusfoliaceus.Instead,medicationsandtheirdosesneedto
beselectedforeachindividualpatientbasedontheseverityofclinicalsignsandthe
medications'efficacyandsideeffects.
Caninecasesofpemphigusfoliaceuswithlocalizedskinlesionsmaybemanaged
withtopicalglucocorticoids.Inmildcases,topicalglucocorticoidscanbeusedalone.
Inmoreseverecases,topicalglucocorticoidscanbeusedtominimizethedoseof
systemicimmunosuppressivetherapy.Topicalglucocorticoidsarelesscommonly
usedincatsbecauseitcanbemoredifficulttoapplytopicalmedicationstocats.In
mostdogsandcats,systemicimmunosuppressionremainstheinitialtreatmentof
choiceforpemphigusfoliaceus.Concurrentsystemicantibiotictherapyshouldbe
consideredifthereisabacterialskininfection.
MEDICATIONSUSEDFORPEMPHIGUSFOLIACEUS
Glucocorticoids
Topicalglucocorticoidscanbeusedasmonotherapyformildcasesofpemphigus
foliaceus,especiallyindogswithlocalizedfaciallesions.Theycanalsobeusedin
combinationwithothersystemicmedicationsinmorerefractorycases.Avarietyof
glucocorticoidsmorepotentthanhydrocortisonehavebeenusedtopicallyfor
pemphigusfoliaceussuchasbetamethasoneortriamcinolone,bothofwhichare
availableinavarietyofconcentrations.Sinceglucocorticoidscancauseskin
atrophy,protecttheareaofglucocorticoidapplicationfromtrauma.Mildskinatrophy
canbemanagedbyswitchingtoalowerpotencytopicalglucocorticoid.Moresevere
skinatrophyshouldbemanagedbystoppingalltopicalglucocorticoids.
Systemicimmunosuppressionwithglucocorticoidsprovidesthemostrapidclinical
responseindogsandcatswithpemphigusfoliaceus.Prednisoneisinitiallystartedat
2mg/kg/dayorallyindogs,andprednisoloneisinitiallystartedat2to4mg/kg/day
orallyincats.Thedoseofprednisoneorprednisolonemaythenbeincreasedifno
improvementinclinicalsignsisevidentwithinoneortwoweeks.Catsmayrespond
bettertoglucocorticoidsotherthanprednisonebecauseofthelowerbioavailabilityof
prednisonecomparedwithotherglucocorticoidsincats.48 Ifglucocorticoidsof
differentpotenciesareused,equivalentdosesshouldbecalculated.Incats,
triamcinolonecanbeinitiallydosedat2to4mg/kg/dayorally,anddexamethasone
canbeinitiallydosedat0.3to0.6mg/kg/dayorally.Theglucocorticoiddoseshould
beselectedbasedontheclinicalsigns.Dogsandcatswithmildpemphigus
foliaceuslesionsmayrespondtolowerdosesofglucocorticoids.
Longactinginjectableglucocorticoidssuchasmethylprednisoloneacetate(Depo
MedrolPfizerAnimalHealth)arenotrecommendedfortreatingpemphigus
foliaceusthedoseofanyimmunosuppressivemedicationshouldideallybeadjusted
inresponsetothepatient'sclinicalsigns.
Dermatologistsoccasionallyusehighdosepulseoralandintravenous
glucocorticoidadministrationtotreatpemphigusfoliaceusindogs.Thesehigh
dosages(oralprednisoneat10mg/kg/day49 orintravenousmethylprednisolone
succinateat11mg/kg/day50 )aretypicallygivenforthreedaysfollowedbyamuch
lowerdoseoforalprednisone(0.5to2mg/kg/day).Highdoseglucocorticoid
administrationisusedprimarilyinseverepemphigusfoliaceuscasesinwhichquick
remissionofsignsisrequired.Relapseisstillpossibleoncetheglucocorticoiddose
isdecreased.Atthistime,highdosepulseglucocorticoidtherapyshouldbe
consideredexperimentalfurtherstudiesareneededtodemonstrateitsbenefit.
Initialsideeffectsofglucocorticoidsincludepolyuria,polydipsia,andpolyphagia.
Withlongertermuse,amyriadofothersideeffectscandevelopsuchasgastric
ulceration,hepatopathy(dogs),diabetesmellitus,calcinosiscutis,skinatrophy,and
secondaryinfections.Inaretrospectivestudy,theuseofgastroprotectantssuchas
sucralfateorhistaminereceptorblockers(famotidine)hadnoeffectonsurvivaltime
indogswithpemphigusfoliaceusreceivingglucocorticoids.51
Inmanydogs,glucocorticoidsaloneareinsufficienttomanagepemphigusfoliaceus
signs.Inpaststudies,glucocorticoidmonotherapyresultedinacceptable
managementofpemphigusfoliaceussignsinonly35%to39%ofdogs.5,52
Glucocorticoidmonotherapyismoreeffectiveincats.Completeremissionwithonly
glucocorticoidsoccursin62%to100%ofcatswithpemphigusfoliaceusreceiving
prednisoneandtriamcinolone,respectively.15
Anyoralglucocorticoidshouldbetaperedgraduallyonce
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clinicalremissionofthepemphigusfoliaceusisachieved(no
newpustulesorerosions).Theexactglucocorticoidtapering
protocolwillvaryineachpatient,but,ingeneral,glucocorticoids
canbetaperedbyabout25%eachtimethedoseisadjusted.
Recheckthepatientaftereachchangeintheoralglucocorticoid
dose.Ifthepemphigusfoliaceusrecurswhentheglucocorticoid
istapered,anotherimmunosuppressivemedicationshouldbe
added.Likewise,whenglucocorticoidsalonecannotinduce
remissionofpemphigusfoliaceus,otherimmunosuppressive
medicationsarethenusedasadjunctivetherapysothatthe
glucocorticoiddosemayinitiallybedecreasedand
Table2:Systemic glucocorticoidadministrationcaneventuallybediscontinued
MedicationsUsed (Tables2&3).
with
Azathioprine
Glucocorticoidsin
Dogswith
Azathioprineisapurine
Pemphigus
analoguethatinterfereswith
Foliaceus
cellularnucleicacidsynthesis.
Thus,itsgreatestcytotoxiceffectisonproliferating
cellssuchaslymphocytes.Azathioprineismore
effectiveatsuppressinghumoralimmunitythan
cellmediatedimmunity.
Azathioprineisthemedicationmostcommonly
usedtomanagecaninepemphigusfoliaceuswhen
lesionsdonotrespondtoglucocorticoid
monotherapy.Inthesecases,lesionsworsenor
staythesamewithglucocorticoidsorsignsrelapse Table3:SystemicMedications
UsedwithGlucocorticoidsin
withlowerdosagesofglucocorticoids.Adding
CatswithPemphigusFoliaceus
azathioprineinadogwithpemphigusfoliaceus
canthenreducetheneedforsystemic
glucocorticoidsandpotentiallyenablediscontinuationoftheglucocorticoid.
Azathioprineiscommonlystartedat2to2.5mg/kg/dayorallyindogswithpemphigus
foliaceus.Ifazathioprineisbeingusedwithglucocorticoidstomanagepemphigus
foliaceussigns,donotreducethedoseorfrequencyofglucocorticoidsimmediately
afterstartingazathioprinesinceazathioprinecantakeweekstohaveaneffect.
Sideeffectsofazathioprineincludebonemarrowsuppressionresultingin
leukopenia,anemia,andthrombocytopenia.Vomiting,diarrhea,hepatotoxicosis,and
acutepancreatitiscanalsooccur.Inourexperience,hepatotoxicosisisthemost
commonsideeffect.Completebloodcountsandserumchemistryprofilesmustbe
performedregularlywhileapatientisreceivingazathioprine,usuallyeverytwoto
threeweeksduringinitialtherapy.Whenazathioprineandglucocorticoidsareused
together,itcanbedifficulttomonitorforazathioprineinducedhepatotoxicosis
becauseoftheusualelevationofserumliverenzymeactivitiescausedby
glucocorticoidadministration.
Azathioprineismetabolizedbyanenzymecalledthiopurinemethyltransferase
(TPMT).LowTPMTconcentrationsincreasetheriskofmyelosuppression.Variations
inTPMTconcentrationshavebeennotedindogs.53 CatshavelowerTPMT
concentrationsthandogsdo,54 andazathioprineisusuallyavoidedincatsbecause
ofthehighlikelihoodofseveremyelosuppression.
Chlorambucil
ChlorambucilisanalkylatingagentthatcausescrosslinkingofcellularDNA.Doses
rangefrom0.1to0.2mg/kgorallyevery24to48hours.Sideeffectsincludevomiting,
diarrhea,anorexia,andmyelosuppression.52 Chlorambucilisespeciallyusedincats
withpemphigusfoliaceusthatfailtorespondtoglucocorticoidssinceazathioprineis
notatreatmentoptionforcats.Completebloodcountsandserumchemistryprofiles
mustbeperformedregularlywhileapatientisreceivingchlorambucil,usuallyevery
twotothreeweeksduringinitialtherapy.
Cyclosporine
Cyclosporineisacalcineurininhibitorthatblocksthetranscriptionofcytokinegenes
inactivatedTcells.55 Cyclosporineisanapprovedtreatmentforcanineatopic
dermatitis(AtopicaNovartisAnimalHealth)andisusedextralabelforavarietyof
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otherimmunemediatedconditionsindogsandcats.56 Cyclosporine'ssideeffectsin
dogsandcatsincludeinappetence,vomiting,diarrhea,gingivalhyperplasia,
hirsutism,papillomas,psoriasiformlichenoidlikedermatosis,anddisseminated
toxoplasmosis.57,58 Themicroemulsionformofcyclosporine(AtopicaNeoral
Novartis)ismorereadilyabsorbedindogsandcatsandshouldbeusedinsteadof
otherformsofcyclosporinesuchasSandimmune(Novartis).Completebloodcounts
andserumchemistryprofilesmustbeperformedregularlywhileapatientisreceiving
cyclosporinetherapy.Incatsreceivingcyclosporine,elevatedliverenzymeactivities
canbeasignoftoxoplasmosis.59
Inasmallpilotstudy,cyclosporinemonotherapyat5to10mg/kg/daywasineffective
inmanagingpemphigusfoliaceussignsinfouroutoffivedogs.60 Sincethe
publicationofthatinitialstudy,therehavebeenanecdotalreportsofusing
cyclosporineat10mg/kg/dayorgreatertomanagepemphigusfoliaceusindogs,
especiallythosewithmilderpresentations.
Cyclosporineismoreeffectiveforpemphigusfoliaceuswhenusedincombination
withothertherapies.Inthreedogswithpemphigusfoliaceusalreadyreceiving
azathioprineandglucocorticoids,oralcyclosporineat7.5to10mg/kg/daywasused
withoralketoconazoleat2.5to5mg/kg/daytosuccessfullyinduceremission.61 The
ketoconazolewasusedtoincreasecyclosporineconcentrations.Alldogswerethen
abletohaveglucocorticoidsdiscontinuedwithinthreeto12weeksofaddingthe
cyclosporineandketoconazole.Signsdidnotworsenwhentheglucocorticoidswere
discontinued.Cyclosporinewasusedsuccessfullywithprednisonetoinduce
remissionofpemphigusfoliaceussignsinanotherstudyinvolvingfivedogs.62 Initial
dosesrangedfrom1to2.6mg/kg/dayand5to18mg/kg/dayfortheprednisoneand
cyclosporine,respectively.Whiletheinitialcyclosporinedosewasmaintainedin
eachpatient,theprednisonedosewasthentaperedto0.5mg/kgeveryotherday
withnorelapseofsigns.Thecyclosporinewascontinuedandeventuallytaperedto3
to4mg/kgeveryotherday.Nostudiesexistonusingcyclosporinetomanagefeline
pemphigusfoliaceus,butwehaveusedcyclosporinetomanagesomepatients.
Inourexperience,cyclosporinecantakeweekstohaveaclinicaleffecton
pemphigusfoliaceuslesions.Thisdelayedeffectmaybebecauseofcyclosporine's
actiononTlymphocytes,thecellsthatdrivetheautoimmunereaction,withoutdirect
effectonautoantibodiesthatcausetheskinlesions.Thus,ifcyclosporineisusedwith
glucocorticoidstomanagepemphigusfoliaceussigns,donotreducethedoseor
frequencyofglucocorticoidsimmediatelyafterstartingcyclosporine.
Tacrolimus
Tacrolimus,anothercalcineurininhibitor,hasbeenusedtopicallyforconditionssuch
aslocalizedatopyindogs63 andpeople.Indogswithaformofsuperficial
pemphigus(pemphiguserythematosus),applyingtacrolimus0.1%asathinfilmon
faciallesionstwiceadayhelpedmanageclinicalsigns.64 Inthatstudy,tacrolimus
wasusedasthesoletherapyinonedogwithsuperficialpemphigus,whiletheother
dogwasalsomanagedwithsystemicimmunosuppressivemedications.Ofnoteis
thatpemphiguserythematosusissuspectedtobeacrossoverbetweendiscoidlupus
andpemphigusfoliaceus.Itispossiblethatthenasallesionsofpemphigus
erythematosusthatrespondedtotacrolimuswerethelupuslikelesions.Inour
opinion,ingeneral,pemphigusfoliaceusdoesnotappeartorespondtotacrolimus
ointment.
Tacrolimuscancauseapruriticorburningsensationduringtheinitialfewdaysof
applicationinpeople,andsignsofpruritusandirritationhavebeenobservedindogs
withinitialuse.63 Thesesignstypicallyresolvedespitecontinuationoftherapy.In
2005,thetacrolimuslabelwaschangedtoincludeawarningthatsomepeoplehave
developedcancerwhilereceivingthismedication.Clientsshouldweargloveswhen
applyingthismedication.
Niacinamidewithtetracyclineordoxycycline
Tetracyclineisanantibioticthatalsomodulatestheimmunesystembysuppressing
neutrophilchemotaxisandlymphocyteactivation.65 Tetracyclineisusedin
combinationwithniacinamideforavarietyofimmunemediateddermatologic
conditions.
Fordogs<10kg,250mgeachoftetracyclineandniacinamidearegivenorallyevery
eighthours.Fordogs>10kg,thedoseis500mgofeacheveryeighthours.
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Tetracyclineandniacinamidearetypicallynotusedincatsbecauseitisdifficultto
administertheselargersizedoralmedicationstomostcats.Doxycyclinehasthe
advantageofneedinglessfrequentdosingthantetracycline.Ithasbeensubstituted
fortetracyclineandusedatadoseof5to10mg/kgorallyindogsevery12to24
hours.However,thereisnodocumentationofthebenefitofdoxycyclinewhenitis
substitutedfortetracyclinetotreatcaninepemphigusfoliaceus.
Tetracyclineandniacinamideappeartobemorehelpfulasasoletherapyinmild
casesofpemphigusfoliaceus,especiallythosecaseswithlesionslocalizedtothe
face.Itcanalsobeusedincombinationwithglucocorticoidsorazathioprine.66 Itcan
takeseveralweeksfortetracyclineandniacinamidetohaveaclinicaleffect.Once
remissionoccurswithtetracyclineandniacinamide,thefrequencyofadministration
canbedecreasedtoonceortwiceaday.
Sideeffectsincludelethargy,anorexia,diarrhea,andincreasedriskofseizures.
Lethargyandanorexiaareespeciallyassociatedwithniacinamide.Ifthe
niacinamideneedstobediscontinued,thetetracycline(ordoxycycline)alonecan
continuetohaveimmunomodulatoryactivity.
Othermedications
Avarietyofothertherapieshavebeenusedforpemphigusfoliaceus,including
cyclophosphamide,injectablegoldsalts,intravenousimmunoglobulins,
mycophenolatemofetil,anddapsone.Referraltoaveterinarydermatologistis
recommendedbeforeusingthesetherapies.Referralisalsorecommendedif
treatmentfailureoccurswithanyofthemedicationsdiscussedinthisarticle.
MONITORING
Nomatterwhichmedicationsarechosentomanagepemphigusfoliaceus,frequent
recheckexaminationsareimportanttoassessclinicalresponseandtodetermine
whentotapermedications.Werecommendrecheckingallpemphigusfoliaceus
patientswithinoneortwoweeksofstartingmedicalmanagement.Asubstantial
improvementinclinicalsignswithin10daysofstartingglucocorticoidtherapyindogs
isapositiveprognosticfactorinthesuccessfulmanagementofpemphigus
foliaceus.5
Glucocorticoidsareoftenusedforpemphigusfoliaceustreatmentinductionbecause
oftheirrapidonset.Ifmarkedclinicalimprovementisnoted,theglucocorticoiddose
orfrequencyofadministrationshouldbetaperedbyabout25%.Ifclinicalsignshave
stayedthesameorworseneddespiteglucocorticoidtherapy,theglucocorticoiddose
shouldbeincreasedorcombinationtherapyshouldbestarted.Combinationtherapy
shouldalsobestartedifremissionofthepemphigusfoliaceuscannotbemaintained
whentheglucocorticoiddoseistapered.Werecommendrecheckingpatientsbefore
andaftereachchangeinmedicationtypeordosetohelpmonitorclinicalsigns.
Cutaneoussideeffectsofimmunosuppressionsuchasabacterialskininfection,
demodicosis,ordermatophytosiscanlookclinicallysimilartoapemphigusfoliaceus
flare.Itisimportanttoruleouttheseconditionsinsteadofassumingthatanynew
dermatologiclesionsareduetopemphigusfoliaceus,otherwiselesionsmayworsen
fromimmunosuppression,andrefractorypemphigusfoliaceusmaybeerroneously
diagnosed.Skinscrapesandhairplucksshouldbeperformedonnewareasof
alopecia,andcytologicexaminationshouldbeusedtoevaluatelesionsfor
secondaryskininfections.

Table4:
Principlesof
Treating
Pemphigus

Dependingonthemedicationbeingusedtomanagethe
pemphigusfoliaceus,bloodworkmaybenecessarytomonitorfor
medicationsideeffects.Regularurinebacterialculturesare
recommendedfordogsandcatsreceivingsystemic
immunosuppressivetherapytomonitorforocculturinarytract
infections.5 Urinalysistoidentifyanactivesediment(whiteblood
cellsintheurine)isnotaneffectivewaytoscreenforurinarytract
infectionsinmostpatientswithpemphigusfoliaceusbecause
systemicimmunosuppressionmaysuppressthenumberofwhite
bloodcellsintheurineevenwhenaurinarytractinfectionis
present.Theprinciplesoftreatingcanineandfelinepemphigus
foliaceusaresummarizedinTable4.
Theoutcomeoftreatingpemphigusfoliaceusindogsandcatsis
variable40%51 to88%4 ofdogswithpemphigusfoliaceushave

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Foliaceusin
theirconditionmanagedsuccessfully.Neitherayoungerageof
DogsandCats onsetnoralocalizeddiseasepatterncorrelatewithimproved
survivaltimes.51 Theonlyfactorthathasinfluencedlongterm
survivaltimeindogswithpemphigusfoliaceusistheconcurrentuseofantimicrobials
withimmunosuppressivemedications,likelybecausetheantimicrobialsminimizethe
developmentofsecondarybacterialskininfectionsandurinarytractinfections.
Prolongedremissionafterimmunosuppressivetherapycanoccurindogsandcats
withpemphigusfoliaceus.15,67
Mortalityfrompemphigusfoliaceuscanoccurbecauseofdiseaseprogression,
medicationsideeffects,orclientrequestedeuthanasia.Severecasesofpemphigus
foliaceuscanresultinmarkedcachexiaorsepsissecondarytoinfections.Adverse
effectsarecommonwithmostofthemedicationsusedforpemphigusfoliaceus.
Euthanasiaaccountedforalmost70%ofdeathsinpemphigusfoliaceusdogsinone
retrospectivestudy.51 Reasonsforclientrequestedeuthanasiaincludednotbeing
abletocontrolthepemphigusfoliaceus,aperceivedpoorqualityoflife,andthe
developmentofadverseeffectsfrommedications.Forallthesereasons,pemphigus
foliaceusshouldbeconsideredapotentiallyfataldermatologiccondition.
Consultationwithaspecialistorreferralcanbehelpfulwhenmanagingpemphigus
foliaceuscases.
SUMMARY
Pemphigusfoliaceusisapustularandcrustingautoimmunedermatologiccondition.
Theprognosisforpemphigusfoliaceusindogsandcatsisvariable,andsignscan
waxandwane.Adiagnosisisbasedonthepatient'sclinicalhistory,ahistologic
examinationofskinsamples,andadiagnosticworkupthatrulesoutother
neutrophilicandpustularskinconditions.Avarietyofimmunomodulatory
medicationscanbeusedtomanagepemphigusfoliaceus.Frequentrecheck
examinationsandclientcommunicationareimportantformanagingpemphigus
foliaceus.Becauseofthepotentialforseveremedicationsideeffects,medications
shouldbeselectedandtaperedbasedontheseverityofclinicalsigns.
KathyC.Tater,DVM,DACVD
AngellAnimalMedicalCenter
350S.HuntingtonAve.
Boston,MA02130
ThierryOlivry,DrVet,PhD,DECVD,DACVD
DepartmentofClinicalSciences
CollegeofVeterinaryMedicine
NorthCarolinaStateUniversity
Raleigh,NC27606
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