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AutoimmuneBlisteringDiseasesDermatologyMKSAP17

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Chapter12:AutoimmuneBlisteringDiseases
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AutoimmuneBlisteringDiseases
Theautoimmuneblisteringdiseasesresultfromautoantibodiestodifferentantigensintheskinand
havesimilarbutdistinctpresentations.Clinically,theyarecharacterizedbypersistentpruriticto
painfulblisterswitherosionsandvariablemucosalandocularinvolvementandscarring(Table19).
Thesediseasesoftenariseinolderpersons.
Table19.OpeninNewWindowCharacteristicsofAutoimmuneBlisteringDiseases
Disease

Pemphigus
vulgaris

ClinicalCharacteristics

Tender,fragileblistersand
erosionsseeninoralmucosa
andskinmucousmembrane
lesionsmuchmorecommon
thaninbullouspemphigoid
Nikolskysign(rubbingofthe
skinresultsinblister
formation)ispositive

Pathology
Suprabasilarclefting
comparedwith
subepidermalclefting
seeninbullous
pemphigoid
DIF/IIF:intercellular
patternwithinthe
epidermis

Comments

Incidencevariesby
countryandethnicity
andisestimatedtobe
0.5to3.2casesper
100,000personsper
year

Incidencevariesby
countrywithestimated
occurrenceof0.5to6.6
casespermillion
personsperyear.

Pemphigus
foliaceus

Highgranularor
subcornealclefting
Endemicpemphigus
Scalingandcrustedlesionson comparedwith
faceanduppertrunk,and
suprabasalcleftingseen foliaceus(fogo
selvagem)occursin
erythrodermawithnomucosal inPV
centralandsouthwestern
involvementNikolskysignis
DIF/IIF:intercellular BrazilandColumbia
positive
patternwithinthe
andhasahigher
epidermis
incidencewithupto50
casespermillion
personsperyearandup
to3.4%ofthe
populationaffected.

Painfuloral,conjunctival,
esophageal,andlaryngeal
erosionsoccurmore

Mixedpatternofboth
suprabasalacantholysis
andinterfacedermatitis
DIF/IIF:IgGbindsin

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Highmortalityrate(up
to90%)andassociation
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Paraneoplastic
pemphigus

commonlythaninpemphigus
vulgarisitisapolymorphous
skineruptionmarkedby
confluenterythema,bullae,
erosions,andintractable
stomatitispatientsalsohave
respiratoryproblemsthatmay
befatal

IgApemphigus

Avesicopustulareruptionwith
clearblistersthatrapidly
transformintopustulestrunk
andproximalextremitiesare
mostcommonlyinvolvedwith
relativesparingofthemucous
membranes

Bullous
pemphigoid

Tenseblistersprecededby
intensepruritusorurticarial
lesionsmostcommonlyseen
intheelderlyonthetrunk,
limbs,andflexuresdoesnot
usuallypresentwithoral
lesions

intercellularpattern
withunderlying
withintheepidermis neoplasms:non
reactantsatthedermal Hodgkinlymphoma
epidermaljunction.The (42%),chronic
combinationof
lymphocyticleukemia
intercellularand
(29%),Castleman
subepidermal
disease(10%)
depositionof
immunoreactantsisa
cluetothediagnosis.

Subcornealcollection
ofneutrophils
DIFshowsdeposition
ofintercellularIgAat
theepidermalsurfaces

Subepidermalbullae
withoutacantholysis
andwithprominent
eosinophils
DIFshowslinearIgG
depositionatthe
basementmembrane
zone
Subepidermalcleavage
withoutacantholysis

Mechanicallyinducedbullae
Epidermolysis
anderosionsmostlyon
bullosaacquisita extensorareasthathealwith
scarringandmilia

Cicatricial
pemphigoid

DIFshowsIgG
depositionatthe
basementmembrane
zonethatlocalizesto
thebaseonsaltsplit
skin

Newlydescribeddisease
withunknownfrequency

Oneofmostcommon
autoimmuneblistering
diseaseswithupto4.3
casesper100,000
personsperyear

Rarediseasewith
unknownfrequency
Canbeassociatedwith
inflammatorybowel
disease

Rarediseasewith
Histologyissimilarto estimatedincidenceof
0.9to1.1casesper
Presentswithbullae,erosions, bullouspemphigoid
millionpersonsperyear
milia,andscarringseenon
DIFmayreveal
mucousmembranesand
Increasedriskfor
patternssimilarto
conjunctivaeofmiddleagedto
malignancyinsome
bullouspemphigoid,
elderlypersonsoralmucosais
patients
linearIgAbullous
almostalwaysinvolved
dermatosis,or
conjunctivallesionsarealso
epidermolysisbullosa Prompttreatmentshould
common
beinitiatedtoavoid
acquisita
permanentocularand
oralscarring

Severelypruriticgrouped
Histologyshows
Commonblistering
vesiclesorerosionsonelbows, neutrophilicinfiltrateat
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Dermatitis
herpetiformis

LinearIgA
bullous
dermatosis

knees,back,scalp,and
thetipsofthedermal
buttockslesionsoccurin
papillaecausing
cropsandaresymmetrically subepidermal
distributedoftenthevesicles separation
arenotseenbecausethe
processissoitchythattheyare DIFshowsgranular
IgAdeposition
almostimmediatelybroken

Pruritic,discrete,orclustered
bullaeinaherpetiformpattern
(clusterofjewels)annular
orpolycycliclesionswith
vesiclesandbullaeatthe
peripheryarecommon

Subepidermalbullae
withneutrophils

diseasewith1011cases
per100,000personsper
year
Nearlyallpatientswith
dermatitisherpetiformis
willhaveceliacdisease

Inadults,theestimated
incidenceis0.6cases
per100,000personsper
year

Canbe
indistinguishablefrom Ocularinvolvementcan
DH,EBA,orbullous occur.
lupus
Avariantcanoccurin
DIFshowslinearIgA childrencalledchronic
deposition
bullousdermatosisof
childhood

Subepidermalbullae
withlittle
inflammationdermal
Erosionsandbullaeonhands papillaeprotrude
andforearms,andoccasionally upwardintotheblister
faceandfeetthathealwith
cavityandthickened
Porphyria
milia,hyperpigmentation,
upperdermalcapillary
cutaneatarda
hypopigmentedscars.
walls
(and
Porphyriacutaneatarda(but
pseudoporphyria)
notpseudoporphyria)canalso DIF:depositionof
presentwithhypertrichosison immunoglobulinsand
complementaroundthe
theface
dermalcapillariesand
linearatthebasement
membranezone

Commondisorderwith
estimatedincidenceof1
caseper25,000persons
peryear
Notatrueautoimmune
blisteringdisorderbut
shouldbeincludedin
thedifferentialdiagnosis
Canbeassociatedwith
hepatitisCinfection

DIF=directimmunofluorescenceIIF=indirectimmunofluorescenceDH=dermatitis
herpetiformisEBA=epidermolysisbullosaacquisitaPV=pemphigusvulgaris.
Identificationanddiagnosisofthesedisordersareimportantbecauseoftheassociatedmorbidityand
mortality.Althoughmostofthesediseasesareidiopathic,medicationscanalsocausevariantsof
almostallthedisorders(Table20),andathoroughmedicationhistoryandreviewareessential.
Referralforevaluationandoptimalmanagementisimportant.
Table20.OpeninNewWindowDrugInducedAutoimmuneBlisteringDisorders
Condition
Pemphigus

Medications
Thiolgroup(Dpenicillamine,captopril,gold,pyritinol)
Amoxicillin

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Ampicillin
Cephalosporins
Rifampin
Pemphigoid

Furosemide
Amoxicillin
Ampicillin
Phenacetin
Penicillin
Penicillamine
PUVA
Blockers
Terbinafine

Cicatricialpemphigoid

Penicillamine
Indomethacin
Practolol
Clonidine
Topicalpilocarpine

LinearIgAbullousdermatosis Vancomycin
Captopril
Amoxicillin

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Ampicillin
Diclofenac
Lithium
Pseudoporphyria

Furosemide
Naproxen
Oxaprozin
Tetracycline
Voriconazole

PUVA=psoralenultravioletAlight.

RecognitionandDiagnosis
RelatedQuestions
Question57
Question70
Autoimmuneblisteringdisordersshouldbesuspectedinanypatientwithpersistentorrecurrent
blistersinvolvingtheskin,eyes,ororalandgenitalmucosa.Theclinicalpresentationcanvary
dependingontheunderlyingdisorder,rangingfromlargeurticarialplaquestoflaccidblistersthat
mayalmostinstantlyruptureandappearaserosionstointacttensebullae.Theextentofbody
surfaceareainvolvedcanvaryinautoimmuneblisteringdisorders.Theremaybeminimal
involvementofonlylocalizedblistersontheextremitiestomoreextensiveinvolvementofnearly
theentirebodysurfacearea.Astheblistersresolve,erosions,hyperpigmentation,andinsome
patients,scarringcanoccur.Paincanpredominatewhenerosionsandbrokenskinarepresent.In
addition,somedisorders(bullouspemphigoid)canpresentwithsignificantpruritus.Thorough
examinationoftheeyes,oralmucosa,andgenital/perianalmucosashouldbeperformedbecause
permanentscarringcanresultleadingtoblindnessandvaginalororalcontractures.Mucosalvariants
alsocanoccur,andevaluationforanunderlyingautoimmuneconditionshouldbeconsideredin
patientswithpersistentmucosalerosions.Inpemphigus,theblistersareflaccidandresultinearly
blistererosionwithsubsequentsuperficialcrusting(Figure90),whereasinbullouspemphigoid,
urticariallikelesions,tensebullae,andaperipheraleosinophiliamaybepresent(Figure91).
Cicatricialpemphigoidcanbelocalizedtothescalpandcausesignificantscarring.Epidermolysis
bullosaacquisitaandporphyriacutaneatarda(andpseudoporphyria,whichpresentsthesameas
porphyriacutaneatardabutismedicationinduced)presentwithsmallblistersinareasoffriction
suchasthedorsalhands,andscarsandmiliaformwithresolutionofblisters(Figure92).
Figure90.OpeninNewWindow

Theflaccidintradermalblistersofpemphigusvulgarisarereadilybroken,leavinglargeweeping,
denudedlesionsandcrusting.

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Figure91.OpeninNewWindow

Tensebullaeonerythematousbasewithsomeareasoferodedskinareseeninbullouspemphigoid.

Figure92.OpeninNewWindow

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Achronicblisteringskindiseaseonsunexposedskinwitherythema,bullae,erosions,andsmall
milia,especiallythebackofthehands,consistentwithporphyriacutaneatarda.

Differentiationoftheautoimmuneblisteringdiseasescanbemadebasedonclinicalfeatures,but
definitivediagnosisrequireshistopathologicexaminationandinsomepatientsserologictestingfor
pathogenicantibodies.Dependingonthelocationofthetargetedantigen,flaccidortensebullaewill
bepresentclinically,andthecorrespondingseparationcanbeappreciatedusinghistopathology.In
pemphigus,flaccidblisterscorrespondwithsuprabasilarseparation(Figure93),whereastense
bullaecorrespondwithsubepidermalblistersinbullouspemphigoidandepidermolysisbullosa
acquisita.
Figure93.OpeninNewWindow

Thesuperficialblistersinpemphigusfoliaceusresultinmultipleerosionsandcrusting(similarto
cornflakes).Intactvesiclesarenotseenregularly.

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Twobiopsiesoftenareperformed:oneoflesionalskinforhistologyandoneofperilesionalnormal
skininordertoperformdirectimmunofluorescenceandidentificationofspecificimmunoglobulins
thatreactwiththeskin.Boththetypeofimmunoreactants(IgG,C3,IgA)andthepatternarehelpful
indiagnosis.
Serumfromaffectedpatientsalsocanassistindiagnosis.Thebloodcanbereactedwithdifferent
substratesandwilldetermineifcirculatingantibodiesarepresent(indirectimmunofluorescence).
Testssuchasserumenzymelinkedimmunosorbentassayshavebeendevelopedthatdetectthe
presenceofspecificantibodiesinpemphigusvulgaris,pemphigusfoliaceus,andbullouspemphigoid
andmaycorrelatewithdiseaseactivity.
Althoughmanyofthesedisordersareidiopathic,theymaybeassociatedwithotherdiseasesthat
needtobeconsidered.Pemphigus,bullouspemphigoid,andlinearIgAbullousdermatosishave
beenreportedinassociationwithotherautoimmunediseasesincludingdiabetesmellitus,
rheumatoidarthritis,andthyroiddisease.
Severalofthesedisordershavealsobeenassociatedwithmalignancy.Paraneoplasticpemphigusis
highlyassociatedwithunderlyingleukemia,lymphoma,andCastlemandisease.Cicatricial
pemphigoid,andmorerarelyepidermolysisbullosaacquisita,maybeseeninpatientswithan
underlyingcancer.Ageappropriatescreeningandathoroughreviewofsystemsareimportantin
thesepatients.Patientswithdermatitisherpetiformisalmostuniformlyhaveunderlyingceliac
disease,althoughitmaybeasymptomaticinuptoonethirdofpatients,andthisshouldbe
appropriatelyevaluated.Additionally,epidermolysisbullosaacquisitahasbeenreportedin
associationwithinflammatoryboweldisease.

Treatment
Managementofautoimmuneblisteringdisordersdependsontheextentofskinandmucosal
involvement,patientcomorbidities,andthespecificunderlyingblisteringdisorder.Medicationsthat
suppresstheimmunesystemareoftenrequired.Indruginducedcases,cessationofthecausative
medicationisessential,butadditionalimmunosuppressivetherapymaystillberequired.

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Forlimiteddisease,potenttopicalglucocorticoidsmaybesufficient.Inmostpatients,systemic
therapyisrequired,oftenwithmultipletherapies.Becauseofitsquickonsetofaction,prednisoneis
usuallytheinitialtherapy.Additionalmedications,includingimmunosuppressantssuchas
azathioprine,methotrexate,cyclophosphamide,andmycophenolatemofetilareoftennecessaryto
controlthedisease.Intravenousimmuneglobulinandantiinflammatoryagentssuchastetracycline
classantibioticsalsohavebeenused.Recently,rituximabhasbeenshowntobeeffectivein
pemphigusandcouldpotentiallybehelpfulinotherautoimmuneblisteringdiseases.Ocular
cicatricialpemphigoidoftenrequiresrapid,aggressivetherapy,orscarringcanquicklydevelop.
Dapsoneiseffectiveinconditionswithapredominanceofneutrophilsintheinflammatoryinfiltrate
includingdermatitisherpetiformis,IgApemphigus,andlinearIgAbullousdermatosis.Indermatitis
herpetiformis,aglutenfreedietisfirstlinetreatmentbecauseoftheassociationbetweendermatitis
herpetiformisandceliacdiseaseandanincreasedriskofbowellymphoma,butadditionaltherapy
oftenisrequired.
Diseaseremissionscanoccur,butlongtermimmunosuppressivetherapyoftenisrequired.Because
oftheerosionsandbreakdownintheskinbarrier,secondarybacterialandviralinfectionscanoccur
inthesepatients,andahighindexofsuspicionandculturesareoftennecessaryforevaluation.

KeyPoints
Theautoimmuneblisteringdiseasesarecharacterizedbypersistentpruritictopainfulblisters
witherosionsandvariablemucosalandocularinvolvementandscarring.
Medicationsthatsuppresstheimmunesystemareoftenrequiredtotreatautoimmune
blisteringdiseasesindruginducedcases,cessationofthecausativemedicationisessential,
butadditionalimmunosuppressanttherapymaystillberequired.

Bibliography
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11410196
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SchmidtE,BrckerEB,GoebelerM.Rituximabintreatmentresistantautoimmuneblistering
skindisorders.ClinRevAllergyImmunol.2008Feb34(1):5664.PMID:18270859
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ThiscontentwaslastupdatedinAugust2015.

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Chapter12
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AutoimmuneBlisteringDiseases
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