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UrticariaAReview
TasneemPoonawallaBrentKelly
AmJClinDermatol.200910(1):921.

AbstractandIntroduction
Abstract

Urticariaisoftenclassifiedasacute,chronic,orphysicalbasedondurationofsymptomsandthepresenceor
absenceofinducingstimuli.Urticarialvasculitis,contacturticaria,andspecialsyndromesarealsoincludedunder
thebroadheadingofurticaria.Recentadvancesinourunderstandingofthepathogenesisofchronicurticaria
includethefindingofautoantibodiestomastcellreceptorsinnearlyhalfofpatientswithchronicidiopathicurticaria.
Thesepatientsmayhavemoreseverediseaseandrequiremoreaggressivetherapies.Extensivelaboratory
evaluationforpatientswithchronicurticariaistypicallyunrevealingandtherearenocompellingdatathatassociate
urticariawithchronicinfectionsormalignancy.Pharmacologictherapyconsistsprimarilyoftheappropriateuseof
firstandsecondgenerationhistamineH1receptorantihistamines.Additionaltherapymayincludeleukotriene
receptorantagonists,corticosteroids,andimmunomodulatoryagentsforsevere,unremittingdisease.Despiteour
greaterunderstandingofthepathogenesisofurticaria,theconditionremainsafrustratingentityformanypatients,
particularlythosewithchronicurticaria.
Introduction

Urticaria,commonlycalled'hives,'hasalongandrichhistoryindocumentedmedicinedatingbackatleasttothe
10thcenturyB.C.whenitwascalled'FengYinZheng'inChina.[1]Manycultureshavedescribedurticariainsome
capacityandthedisorderhashadmanynames.Inthe4thcenturyB.C.,Hippocratesnotedthesimilaritiesbetween
urticaria,contactwithstingingnettles,andinsectbitesandcalledthecondition'cnidosis'(nettlerash).[2]'Uredo,'
'essera'(Arabicforelevation),'urticatio'(derivedfromtheLatinureretoburn),and'scarlatinaurticaria'haveallbeen
used.[2]Useoftheterm'morbusporcinus',whichmeanspig'sdisease,resultedfromatranslationalerrorofthe
intendedterm'morbuspocellaneus,'whichreferredtothewhitecolorofthecentralwheal.[3]WilliamCullenwas
probablythefirsttousethetermurticariain1769.
Nearlyasmanytheoriesaboutthepathogenesisofurticariahavebeendescribedincluding,amongothers,a
humoraltheory(relatingurticariatobody'humors'),ametereologictheoryin1823(suggestingthatallergywas
determinedbytheconstellationofthestars),andamenstrualtheoryin1864(proposingthaturticariawasrelatedto
endogenoushormones).[1]Itwasthediscoveryofthemastcellin1879byPaulEhrlichthatledtoourcurrent
understandingofallergypathogenesis,includingurticaria.However,despiteimprovementsinourunderstandingof
urticaria,theconditionremainsafrustratingdisorderformanypatients,particularlythosewithchronicurticaria.This
reviewattemptstoclassifyurticariaanddiscusstheevidencebasedpathogenesisandtreatmentoptionsavailable,
withparticularemphasisonchronicurticaria.
AMEDLINEsearchusingOvidwasperformedtoobtainthearticlesreviewed.Searchtermsincluded'urticaria'and
'hives'andwereappliedfrom1950tothedateofreview.Relevantarticles,particularlythoserelatingtohistory,
pathogenesis,andtreatment,wereincludedinthisreview.Articleswereexcludediftheydidnotaddtotheknown
knowledgebaseofthesubject.Additionalrelevantarticleswereobtainedfromcitationsinthereferencesectionsof
identifiedarticles.

ClinicalFeaturesandEpidemiology
Urticariaconsistsofrecurrentwhealsthatareusuallypruritic,pinktorededematousplaquesthatoftenhavepale
centers.Thewhealsaretransient,andinmosttypesofurticarialastfor<24hours.[4]Thewhealsrangeinsizefrom
afewmillimeterstoseveralcentimetersindiameter.Theycan,however,becomeconfluentandformplaques.
Urticarialwhealsaregenerallypalerthantheerythematoussurroundingskinbecauseofthecompressingeffectof
dermaledemaonpostcapillaryvenules.Whealsmayberoundorirregularandmayoccuranywhereontheskin,

includingthescalp,palms,andsoles.Theyarequitepruriticwithmaximalintensityintheeveningsandnighttime
andoccasionallymaybe'burning'or'pricking'inquality.Thisitchisuniqueinthatitisrelievedmoresobyrubbing
thanbyscratching,andpurpuraratherthanexcoriationsareamorecommonconsequenceofurticaria.[5]
Urticariaisaworldwidediseaseandmaypresentatanyage.Thelifetimeoccurrenceofurticariainthegeneral
populationrangesfrom1%to5%.[6,7]

Classification
Classificationofurticariaismostoftenbaseduponclinicalcharacteristicsratherthanetiology(see).Unfortunately,it
isoftendifficulttodeterminetheetiologyorpathogenesisofindividualcasesofurticariaandmanycasesremain
idiopathic.Sixweeksofdailyornearlydailysymptomsisasomewhatarbitrary,butnonethelessuseful,timeperiod
forseparatingacutefromchronicurticaria.Angioedemacan,andoftendoes,accompanytheurticariallesions.
Angioedemawithouturticaria,however,shouldraisesuspicionofanacquiredorhereditaryform(particularly
complement[C]1inhibitordeficiency),whichcanoftenbemoreseverewithlaryngealinvolvement.Othercategories
ofurticariaincludecontacturticaria,urticarialvasculitis,andphysicalurticaria.Physicalurticaria,auniqueandoften
debilitatingformofthedisorder,resultsfromaspecifictrigger.Subtypesincludeaquagenic,cholinergic,cold,
delayedpressure,dermatographismrelated,localizedheat,andsolarandvibratoryurticaria.[4,5]
TableI.ClassificationofUrticaria

Ordinaryurticarias

Acuteurticaria
Chronicurticaria
Contacturticaria
Physicalurticarias

Dermatographism
Immediate
Delayed
Cholinergicurticaria
Vibratoryangioedema
Exerciseinducedurticaria
Adrenergicurticaria
Delayedpressureurticaria
Solarurticaria
Aquagenicurticaria
Coldurticaria
Specialsyndromes

Schnitzlersyndrome
MuckleWellssyndrome
Pruriticurticarialpapulesandplaquesofpregnancy
Urticarialbullouspemphigoid
Urticarialvasculitis
AcuteUrticaria

Acuteurticaria,bydefinition,iswhealsoccurringfor<6weeks.Theindividuallesionstypicallyresolvein<24hours,
occurmorecommonlyinthepediatricpopulation,[4]andareoftenassociatedwithatopy.Between20%and30%of
patientswithacuteurticariaprogresstochronicorrecurrenturticaria.[8]Etiologicdatasuggestthatacuteurticariais
idiopathicinabout50%ofpatients,duetoupperrespiratorytractinfectionsin40%,todrugsin9%,andtofoodsin
1%.[4]Foodallergiesprobablycontributemoreoftenthanisreflectedinthesedata,butareunderrepresented
becausepatientsoftenselfdiagnoseandthenavoidtheoffendingagent.Acuteurticariaprecipitatedbyfoods,drugs
(mostnotably,lactamantibacterials),insects,contactwithanexternalagent,orparasitesisoftenIgEdependent.
Opioids,musclerelaxants,radiocontrastagents,andvancomycinoftencauseurticariaviadirectmastcell
degranulationandproinflammatorymediatorrelease.Complementmediatedacuteurticariacanbetriggeredby
serumsickness,transfusionreactions,andviralorbacterialinfections.Finally,acetylsalicylicacid(aspirin)and
NSAIDscancauseacuteurticariathroughtheireffectsonthemetabolismofarachidonicacid.[4]
ChronicUrticaria

Chronicurticariaisdefinedasthedevelopmentofcutaneouswhealsthatoccuronaregularbasis(usuallydaily)for
>6weekswithindividuallesionslastingfrom4to36hours.Thesymptomscanbesevereandcanimpairhealth
relatedqualityoflife.[9]Detailedepidemiologicstudiesarenotavailableandpublishedstudiesareproblematicin
thatsomeincludethephysicalurticariasandurticarialvasculitiswhileothersdonot.Additionally,establishingcause
andeffectisdifficultandmanycasesremainidiopathic.Bysomeestimates,thephysicalurticariasaccountfor
approximately35%ofallcasesofchronicurticaria,whileurticarialvasculitismakesupabout5%.[4]Asmall
percentageofchronicurticariaiscausedbyaninfectionorpseudoallergy.Althoughmanycasesofchronicurticaria
remainclassifiedasidiopathic,recentevidencesuggeststhatasignificantportionofthesocalledidiopathic
urticariasmayhaveanautoimmuneetiology.[4,5]Ingeneral,chronicurticariaismoreprevalentinfemalepatients,
occurringata2???1femaletomaleratio.[4]
ContactUrticaria

Contacturticariaisdefinedasthedevelopmentofurticarialwhealsatthesitewhereanexternalagentmakes
contactwithskinormucosa.Contacturticariascanbesubdividedintoallergic(involvingIgE)ornonallergic(IgE
independent)forms.IgEmediatedallergiccontacturticariaoccursinpersonssensitizedtoenvironmentallergens
suchasgrass,animals,orfoodsortooccupationalallergenssuchaslatexglovesinhealthcareworkers.Non
allergiccontacturticariaoccursasaresultofthedirecteffectsofurticantsonbloodvessels.Examplesofcommon
urticantsaresorbicacidineyesolutions,cinnamicaldehydeincosmetics,andchemicalsfromthestingingnettle
(Urticadioica),whichincludehistamine,acetylcholine,andserotonin.[4]
PhysicalUrticaria

Ofthevariousurticarialdisorders,thephysicalurticariasmayaffectqualityoflifemostseverely.[4]Thelesionsofthe
physicalurticariasaretypicallylocalizedtothestimulatedareaandresolvewithin2hourswiththeexceptionof
delayedpressureanddelayeddermatographism.[10]Ifapatienthasahistoryofwhealslastingfor<1hour,the
presenceofaphysicalurticariashouldbeconsidered.[4,5]Symptomaticdermatographismthemostcommonform
ofphysicalurticariaisnotassociatedwithsystemicdisease,atopy,foodallergy,orautoimmunity.[4]Conversely,
patientswithdelayedpressureurticariamaypresentwithsystemicsymptomssuchasmalaise,influenzalike
symptoms,andarthralgias.Delayedpressureurticariaisdistinguishedbythedevelopmentofdeeperythematous
swellingsatsitesofsustainedpressuretotheskinafteradelayof30minutestoaslongas12hours.Examplesof
sitestypicallyaffectedincludethewaistlineafterthewearingoftightclothingandtheareaofthelegsthatmakes
contactwiththeelasticbandofsocks.Manypatientswithdelayedpressureurticariaalsohaveconcurrentchronic
idiopathicurticaria.[5]Cholinergicurticariathesecondmostcommontypeofphysicalurticariaischaracterizedby
awhealsurroundedbyanobviousflareinresponsetophysicalexertion,hotbaths,orsuddenemotionalstress.[4]
Adrenergicurticaria,incontrasttocholinergicurticaria,ischaracterizedbyblanched,vasoconstrictedskin
surroundingsmallpinkwheals.Othercategoriesofphysicalurticariaincludecoldurticaria,solarurticaria,aquagenic
urticaria,pressureurticaria,andvibratingangioedema.
Challengetestingtoconfirmthediagnosisofaphysicalurticariacanbeperformedintheofficesetting.Cholinergic
urticariacanbediagnosedwithexerciseorhotbathtesting.Thelesionsofcoldurticariacanbeinducedwiththeice
cubetest.Aquagenicurticariacanbeconfirmedwithapplicationofwatercompresses.Testingforpressureurticaria
canbeperformedbyapplyingan8kgweighttothepatient'sthigh.[4]

canbeperformedbyapplyingan8kgweighttothepatient'sthigh.[4]
SpecialSyndromes

Schnitzlersyndromeisauniquevariantofchronicurticariacharacterizedbyrecurrentnonpruriticwheals,
intermittentfever,bonepain,arthralgiasorarthritis,anelevatederythrocytesedimentationrate(ESR),anda
monoclonalIgMgammopathy.IgMmayplayanimportantroleinwhealformationasithasbeendemonstrated
arounddermalvesselsandIgMautoantibodiesdirectedagainstskinhavebeenreported.[11]Someinvestigators
believethatSchnitzlersyndromemaybeavariantofurticarialvasculitisratherthanchronicurticaria.Interestingly,
Sauratetal.[12]foundthatpatientswithSchnitzlersyndromehadIgGantibodiesdirectedagainstthecytokine
interleukin(IL)1.BiopsiesoflesionsfrompatientswithclinicalfeaturesofSchnitzlersyndromeoftendemonstrate
anincreasedpolymorphonucleocytecountwithoccasionalleukocytoclasia.[13]
MuckleWellssyndrome,anautoinflammatorydisorderassociatedwithcoldinducedautoinflammatorysyndrome1
genemutations,isarareentitycharacterizedbyurticaria,arthralgias,progressivesensorineuraldeafness,and
amyloidosis.Familialcoldautoinflammatorysyndromeisasimilarentitythatseemstoberelatedtochangesin
temperature.[14]
Pruriticurticarialpapulesandplaquesofpregnancy(PUPPP),alsoknownaspolymorphiceruptionofpregnancy,is
themostcommondermatosisassociatedwithpregnancy.Itslesionsareoftenurticarialandinvolvethetrunk,
particularlyabdominalstriae.PUPPPtypicallyrunsabenign,selfresolvingcoursewithanonsetinthethird
trimester.Itisimportanttodifferentiatethisdisorderfromthemoreseriouspemphigoidgestationis,abullous
pemphigoidlikedisorderassociatedwithpregnancy.[15]
UrticarialVasculitis

Theclinicalpresentationofurticarialvasculitismaybeindistinguishablefromthatofchronicurticaria.Nonetheless,
thecharacteristicsofthewhealsmaybehelpfulindifferentiatingurticarialvasculitisfromchronicurticaria.In
contrasttochronicurticaria,thelesionsofurticarialvasculitistendtolastlongerthan24hoursandareassociated
withburningandpaininadditiontoitching.Theselesionsarealsodescribedashealingwithpurpuraorpetechiae
however,themostcommoncauseofpurpuraafterurticariaisprobablyscratching.[4,16]Inpatientswithsuspected
urticarialvasculitis,histologicexaminationofaskinbiopsyspecimentypicallyshowsevidenceofleukocytoclastic
vasculitis.Urticarialvasculitisisrare,withreportedrangesof110%inpatientswithchronicurticaria.[4,16]The
incidenceisprobablyclosestto1%inmostexperts'opinion.Whenitdoesoccur,urticarialvasculitisistypicallya
componentofachronicsystemicillnesssuchassystemiclupuserythematosus,hypocomplementemicurticarial
vasculitissyndrome,Sjgrensyndrome,ormixedcryoglobulinemia.[17]

Etiology
Unfortunately,mostcasesofchronicurticariaremainidiopathic.Recentdatasuggestthat3550%ofchronic
urticariacasesarerelatedtoautoimmunity,specificallythepresenceofautoantibodiestothehighaffinityIgE
constantfragmentreceptor1(FceR1)locatedonmastcells.[18]Thisresultsinchronicstimulationofthesemast
cellsandreleaseofvasoactivemediators.Althoughnotwidelyused,aninvivotestknownastheautologousserum
skintest(ASST)canseparatethesepatientsfromtheremainingidiopathiccases.TheASSTisamodifiedskin
allergytestusingthepatient'sownseruminjectedintradermallytoelicitwhealformation.[18,19]Thistestandthe
importanceofautoimmunechronicurticariaarediscussedfurtherinsection5.
Inadditiontoautoimmunecauses,otheridentifiablecausesofchronicurticariaincludeIgEdependent,complement
mediated,orimmunecomplexdeposition.Nonimmunologiccausesmayincludedirectmastcellrelease,vasoactive
stimuli,alterationsinprostaglandin(PG)pathwaysasaresultofintakeofacetylsalicylicacidandotherNSAIDs,
dietarypseudoallergens(rarely),andalterationsinthebradykininpathwayasaresultofuseofACEinhibitors.
[4,18,20]

Foodallergyandfoodadditivessuchaspreservativesandcoloringagentsdonotappeartobesignificantcausesof
chronicurticaria.[19]Itispossiblethatimpairedgastroduodenalbarrierfunctionmaybeofpathophysiologic
importanceinthedevelopmentofpseudoallergicreactions,anddespitetherareassociationofchronicurticariawith
foodallergies,somecliniciansrecommendthatpatientstryaneliminationdietatleastonceintheirlifetime.[13,21]

foodallergies,somecliniciansrecommendthatpatientstryaneliminationdietatleastonceintheirlifetime.[13,21]
Most,however,feelthatthisapproachisunnecessaryandthatfoodallergycanberuledoutasacausebythe
history.Foodallergiestypicallywouldcauseareactionwithin30minutesofingestion.[22]
BothHashimotothyroiditisandGravesdiseasehavebeenassociatedwithchronicurticaria.Antithyroidantibodies,
antimicrosomalantibodies,orbothhavebeenfoundinupto27%ofpatientswithchronicurticaria.[23,24]Arecent
studyshowedthatpatientswithchronicurticariawhohadapositiveASSTresulthadsignificantlymoreautoimmune
thyroiddiseaseandabnormalthyroidfunctionwithabnormalthyroidmicrosomalantibodiesandabnormalthyroid
stimulatinghormonethanASSTnegativepatients.[25]Also,otherinvestigatorshavefoundthatpatientswithchronic
autoimmuneurticariahavesignificantlymoreantithyroidperoxidaseantibodythanpatientswithchronicidiopathic
urticaria(p=0.03).[26]About19%ofpatientswithchronicurticariahaveabnormalthyroidfunction.[27]However,
thereisnoevidencethattheantibodiesinvolvedinthyroiddisordersplayaroleinthepathogenesisofchronic
urticariathisassociationmostlikelyrepresentsparallelbutunrelatedautoimmuneevents.[19]Additionally,thereis
onlyanecdotalevidencethatbothrefutesandsupportstreatmentofurticariawithlevothyroxinesodiumineuthyroid
patients.Inpatientswithbothchronicurticariaandautoimmunethyroiditis,theASSTcancontinuetobepositive
afterremissionofurticaria.ThissuggeststhatsomecomponentofthyroiddiseasecanenhanceapositiveASST.
AlmostallpatientswithautoimmunethyroiditisandnohistoryofurticariahaveanegativeASST,[28]whichcorrelates
ASSTmorewithchronicurticariathanwiththyroiditis.Thisphenomenonneedsfurtherstudytoverifythereliabilityof
apositiveASSTasasurrogatemarkerofcirculatingantiFceRIandantiIgEautoantibodiesinpatientswith
coexistingchronicurticariaandautoimmunethyroiditis.[28]Otherautoimmuneconditionsassociatedwithchronic
urticariaincludevitiligo,insulindependentdiabetesmellitus,rheumatoidarthritis,andperniciousanemia.[29,30]
IthasbeenproposedthatHelicobacterpylori,whichhasanimmunogeniccellenvelope,mayplayanindirectrolein
theetiologyofchronicautoimmuneurticariabyreducingimmunetoleranceandinducingautoantibodyformation,
suchasantiFceRI.[19,26]SomeinvestigatorshavefoundanincreasedfrequencyofH.pyloriIgGantibodiesin
patientswithchronicurticaria,[31]whileothershavenot.[32]WhethereradicationofH.pyloriiseffectiveinthe
treatmentofchronicurticariaisacontroversialissue,andthelimitednumberofstudiesofthisquestionhaveyielded
conflictingresults.[31]InasystematicreviewofpublishedstudiesoftheeffectsofH.pylorieradicationontherateof
remissionofchronicurticaria,Federmanetal.,[33]in2003,foundthaturticariawasmorelikelytoresolvewhen
antibacterialtherapysuccessfullyeradicatedH.pylorithanwheneradicationwasunsuccessful.Sincethen,data
havebothrefutedandconfirmedimprovementsinurticariawithsuccessfuleradicationofH.pylori.[3436]Although
manyexpertsarenotconvincedofacausativeroleofH.pyloriinchronicurticaria,anevaluationforitspresence
maystillbeconsidered,particularlysinceH.pyloriinfectionisalsoassociatedwithmucosaassociatedlymphoid
tissuelymphomaandgastricadenocarcinomaandaneffectivetreatmentisavailable.
Thereisnoassociationbetweenchronicurticariaandmalignancy.[37,38]Althoughanassociationbetweenurticaria
andoccultinfectionssuchasdentalabscessesorgastrointestinalcandidiasishasbeenproposed,thereislittle
supportingevidenceotherthananecdotalreports.[38]Afewcasereportshavedescribedresolutionofrecalcitrant
chronicurticariaaftertreatmentofdentalabscesses.[39]Parasiticinfectionssuchasintestinalstrongyloidiasismay
occasionallycausechronicurticariainendemicareas.[37]ThefishnematodeAnisakissimplexhasbeenimplicated
asacauseofchronicurticariabasedondetectionofIgG4antibodies.[40,41]Althoughastudy[42]fromJapan
suggestedapossiblelinkbetweenhepatitisCandchronicurticaria,otherinvestigations,includingalarge
prospectivestudy[43]conductedinFrance,havefoundnoassociationbetweenthehepatitisCvirusandurticaria.[37]
NoconclusiveevidenceisavailablelinkingchronicurticariawithhepatitisB,EpsteinBarrvirus,cytomegalovirus,or
HIV.[39]
Thereissomeevidencethatgeneticfactorsplayaroleinthepathogenesisofchronicurticaria.Inastudyofmore
than1300patientswithchronicidiopathicurticaria,Asero[44]foundthattheprevalenceofthediseasewasmuch
higheramongfirstdegreerelativesofthestudygroupthaninthegeneralpopulation.O'Donnelletal.[45]have
shownthat,comparedwithcontrolindividuals,patientswithchronicidiopathicurticariahaveanincreasedfrequency
ofHLADR4andHLAD8Q.HLADR4isstronglyassociatedwithautoimmunechronicurticaria.

Pathogenesis
Themastcellistheprincipaleffectorcellofurticaria.Mastcellsaredistributedthroughoutthebodybutvaryintheir

responsetostimuli.AllmastcellsexpresshighaffinityIgEreceptors(FceRIs)thatenabletheirinvolvementinIgE
dependentallergicreactions.TheconstantregiondomainofIgE,Ce3,isthemajorsiteofinteractionwiththeIgE
receptor.WhenIgEformsacomplexwithFceRIonthemastcelltowhichanallergenbinds,degranulationoccurs.
[20]Mastcelldegranulationalsooccursthroughavarietyofothermechanisms,includingcrosslinkingofadjacent
FceRI,bindingofreceptorboundIgEbyallergen,antiIgE,andantiFceRIantibodies.Nonimmunologicstimulisuch
asopioids,C5aanaphylotoxin,andstemcellfactoraswellasneuropeptidessuchassubstancePcancause
degranulationviadirectstimulation.Thesestimuliinitiatecalciumandenergydependentstepsthatcausestorage
granulestofusewiththecellmembraneandexternalizetheircontents,whichincludepreformedandnewly
synthesizedmediatorsofinflammation.FceRIstimulationalsoleadstoupregulationofthesynthesisandsecretion
ofproinflammatorymediators.[4,19,20]
Thekeymediatorishistamine.Preformedcytokines,includingtumornecrosisfactor(TNF)a,IL3,IL4,IL5,IL6,
IL8,IL13,andgranulocytemacrophagecolonystimulatingfactor(GMCSF),arealsoreleased.Newlysynthesized
mediatorsfromarachidonicacidincludePGD2andleukotrienesC4,D4,andE4.[4,19,20]LeukotrieneC4is1000
timesmorepotentthanhistamineincausingawhealandflarereactionandthuscanalsobeconsideredan
additionalmediatorofurticaria.[46]Histamine,TNFa,andIL8upregulatetheexpressionofadhesionmoleculeson
endothelialcellsandencouragemigrationofcirculatinginflammatorycellsfromthebloodintotheurticariallesion.[4]
IL4promotesfurtherIgEproductionthatcausespositivefeedback.Onestudyhasshownthattheserologicimmune
profileofpatientswithchronicautoimmuneurticariaisamixedThelper1(Th1)/Th2patternwithaslightTh2
predominanceduetoincreasedIL13production.[47]IL13sharesbiologicpropertieswithIL4andmayincrease
mastcellFceRIexpressionandmediatorrelease.Anotherstudyfoundevidenceforaprevalentroleoflymphocytes
withamixedTh1/Th2responsefocallyexpressinginterferon?andIL5inautologouswheals.[48]Theinvestigators
alsoreportedthatthemaininfiltratingpopulationwasneutrophilswithinvolvementofthechemokinepathway.
Additionally,theyfoundthatuninvolvedskininpersonswithchronicidiopathicurticariahadlatentinflammationwith
alymphocyticandgranulocyticcellularinfiltratewithmediatorupregulation,whichmayrepresentaprolongedand
widespreadurticarialstate.[48]
Histologyofchronicurticaria(bothidiopathicandautoimmune)demonstratesaperivascularnonnecrotizinginfiltrate
ofCD4+lymphocytesconsistingofamixtureofTh1andTh2subtypes,plusmonocytes,neutrophils,eosinophils,
andbasophils.[49]Otherobservationsincludeincreasedlevelsofmatrixmetalloproteinase9inpatientsafflictedwith
chronicurticaria,especiallythosewithseveredisease.Inaddition,thereisevidencethatCD4+Tcellsarehighly
activated,withincreasednuclearfactor?B(NF?B)expressionleadingtoincreasedBcelllymphoma(bcl)2
expressionintheTcellsofpatientswithchronicurticaria.[50]SubstancePdoesnotappeartoplayanoteworthyrole
inchronicurticaria,althoughitmayoccasionallyfunctionasanalternatemodeoftriggeringurticaria.[51]
InitialevidenceofautoimmuneinvolvementinchronicurticariawasreportedbyHideetal.[18]whoshowed
autoantibodiesoftheIgGsubclassagainstFceRIonmastcellsandbasophils.Onlypatientswithchronicurticaria
havebeenshowntomanifestfunctionalhistaminereleasingantiFceRIautoantibodies.Theseantibodiesdonot
occurinphysicalurticarias,atopiceczema,orotherdiseasesinvolvingactivatedmastcells.[5]About3540%of
patientswithchronicurticariahaveIgGantibodiestotheasubunitoftheFceRI,and510%haveIgGantibodiesto
IgEitself.Thoseautoantibodiesthatrecognizethea2domainontheFceRIcompetewithIgEforthebindingsite,
whereasnoncompetitiveautoantibodiesaredirectedagainstthea1domainandareabletobindeveninthe
presenceofIgE.[4,19]
AutoantibodiestomastcellsmayalsoinitiatecomplementactivationwithgenerationofC5aanaphylatoxinleadingto
degranulation.[52]TheantibodiesinvolvedareprimarilyIgG1andIgG3,whichareoftenconsideredtobeinvolvedin
complementactivation.IgG4isalsooccasionallyinvolved,although,unlikeIgG1andIgG3,itisnotcomplement
fixing.[53]ItisinterestingtonotethatonlyIgGinserawithcomplementwillreleasehistaminefromdermalmast
cells,whichindicatesthatthereleaseofhistaminefromdermalmastcellsbyFceRIismostlikelyaugmentedby
complementactivation.Thisfindingisfurthersupportedbythefactthatpatientswithsevereautoimmunechronic
urticariadonotexperiencebronchospasmbecauselungmastcells,unlikedermalmastcells,aredevoidof
complementreceptors.Onestudy,however,didshowthatpatientswithchronicurticariahadbronchialhyper
responsivenesstomethacholineprovocationonpulmonaryfunctiontests.[54]Thishyperresponsivenesswasnotas
severeasthatobservedintheasthmaticcontrolpatients.

Inadditiontoautoantibodies,itispossiblethatotherfactorsinseraorplasmamayalsocontributetomastcell
degranulationandurticariaformation.Forexample,somehavesuggestedthatonlyhalfofpatientswithapositive
ASSTareabletoinducehistaminereleasefrombasophilsinvitro.[55]Additionally,IgGdepletedserawerestillable
tomaintainawhealandflare.Somehavesuggestedthatcomponentsofthecoagulationcascade,particularly
thrombin,mayplayarole.[56]Thrombinhasbeenshowntoincreasevascularpermeability,[57]triggermastcell
degranulationand,indeed,maybeequipotenttoFceR1mediatedactivation.Autologousplasmaskintests(which
wouldstillincludeclottingfactors)aremorefrequentlypositivethanASSTinpatientswithchronicurticaria,and
serumlevelsofthrombinhavebeendirectlyrelatedtourticariaseverity.[58]

DiagnosisandWorkup
Studieshaveshownthattakingadetailedpatienthistoryisusuallyadequatetoestablishadiagnosisofchronic
urticaria.[4,38,5961]Iflaboratorytestsarewarranted,basedonthehistory,anESRandwhitebloodcellcountwith
differentialshouldbeconsidered.AlthoughtheASSTishelpfulindistinguishingsomecasesofchronicautoimmune
urticariafromchronicidiopathicurticaria,[4,38]thistestiscurrentlynotwidelyused.Ifacausefortheurticariaisnot
found,somecliniciansrecommendscreeningforH.pyloriinfection.Thyroidfunctiontestsandtestsforthyroid
antibodiesarenecessaryonlywhenclinicalfindingssuggestthepresenceofthyroiddisease.[37]Challengetesting
isindicatedwhenapatientisbeingevaluatedforaphysicalurticaria.Patientssuspectedofhavingurticarial
vasculitisshouldundergoaskinbiopsytoconfirmthediagnosis.Patientswithangioedemabutwithouturticaria
shouldhaveC4levelsmeasuredtoscreenforC1inhibitordeficiencyC1inhibitorlevelscanbemeasurediftheC4
levelislow.[4,37,38]
Distinguishingbetweenautoimmunechronicurticariaandidiopathicchronicurticariaisclinicallyimportantbecause
patientsafflictedwiththeautoimmuneformtypicallyhaveamoreaggressivediseasecourseandaremoreresistant
totreatment.Sabroeetal.[29]haveshownthatpatientswithautoantibodieshavemorewhealswithawider
distribution,higheritchscores,moresystemicsymptoms,andlowerserumIgElevelsthanpatientswithout
autoantibodies.Inaddition,theyaremorelikelytorequireandbenefitfromimmunosuppressivetherapy.
Establishingadiagnosisofautoimmunechronicurticariaisadifficulttaskbecausetherearenoreliablelaboratory
teststoaidtheclinician.Adecreaseinbasophils(basopenia)isacommonfeatureofchronicurticariaandmaybe
usefulforscreeningfortheautoimmuneformofthedisease.[62,63]However,therearenoconvenientand
reproduciblemethodsofcountingbasophilsintheperipheralcirculation.Unfortunately,noreliabledirectantibody
testisavailableandresultswithELISAandimmunobindingtechniqueshavebeendisappointing.[5]
CurrentlythemostusefultestforevaluatingchronicurticariaistheASST.Asampleofthepatient'sownserum
(collectedduringaflare)isinjectedintradermallyintouninvolvedskinoftheforearm.Salineandhistaminecontrols
areinjectedatthesametime.Aresultispositiveforautoimmunityifthediameterofthewhealattheseruminjected
siteis1.5mmgreaterthanthatoftheblebatthesalineinjectedsite.Thesensitivityofthistestisestimatedtobe
6581%andthespecificity7178%.[19]Ifapositivereactionisobserved,theresultshouldbeconfirmedbyinvitro
testing(thegoldstandard),whichdemonstrateshistaminereleasefromtargetbasophilsanddermalmastcellsfrom
healthydonors.[19]TheASSThasalsobeenshowntobeusefulinmonitoringthecourseofchronicurticaria,witha
positivetestbeingconsistentwithanexacerbationofsymptomsandanegativetestwithremissionofsymptoms.[28]
Thediagnosisofchronicidiopathicurticariaisestablishedwhenapatientdoesnothaveanyidentifiable
autoantibodiestomastcells.Inthesepatients,thelikelihoodofidentifyinganunderlyingcauseoftheurticariais
rare.Theclinicalfeaturesofautoimmunechronicurticariaareindistinguishablefromthoseofchronicidiopathic
urticaria.

Treatment
Themainstaysofmanagingurticariaincludegeneralmeasurestopreventoravoidtriggersandpharmacotherapy.
Managementcanbestratifiedintofirst,second,andthirdlinetherapies.
FirstlineTherapy

FirstlinetherapyincludespatienteducationandgeneralnondrugmeasuresfollowedbyatrialofhistamineH1
receptorantihistaminesifsymptomspersist.[4]Generalmeasuresincludeavoidanceofaggravatingfactorssuchas

receptorantihistaminesifsymptomspersist.[4]Generalmeasuresincludeavoidanceofaggravatingfactorssuchas
overheating,stress,andalcohol.[38]Avoidanceofacetylsalicylicacid,NSAIDs,andACEinhibitorsmayalsobe
advisable.[4,38]Coolingantipruriticlotionssuchas1%or2%mentholinaqueouscreamorcalaminelotionmaybe
helpful.[37,38]Itisimportanttokeeppatientswellinformedaboutthedisease,usingbothverbalandwritten
information.Specifically,patientsshouldbeinformedaboutthebenigncourseofthedisease,thelackofacure,and
thefactthatacauseoftencannotbefound.[38]
HistamineH1ReceptorAntihistamines.AntihistaminesareinverseagonistsatH1receptors.StimulationoftheH1
receptoractivatesGproteincoupledreceptorsthatinturnactivateinositoltriphosphateanddiacylglycerolin
additiontothetranscriptionfactorNF?B,whichpreventstheproductionofmanyimportantmediatorsof
inflammationsuchasPselectin,intercellularadhesionmolecule1,vascularcelladhesionmolecule1,inducible
nitricoxidesynthase,IL1,IL6,TNFa,andGMCSF.[64]Antihistamineshavethecapacitytoinhibithistamine
releaseandpreventtheactionsofmastcellandbasophilderivedhistamineonitstargetorgans.H1receptor
inhibitionalsoreducesallergeninducedeosinophilaccumulation.Investigatorswhoexaminedtheeffectsoftwo
secondgenerationH1receptorantihistamines,cetirizineandlevocetirizine,reportedthatbothdrugshavewell
documentedantiinflammatoryeffectsthatincludeinhibitionofplateletactivatingfactor(PAF)dependenteosinophil
chemotaxis,PAFdependenteosinophiladhesiontotheendothelium,andtransendothelialmigrationthroughdermal
endothelialcells.[65]CetirizinehasalsobeenshowntodownregulateNF?Bproduction.[65]Receptoroccupancyisa
conceptthatsuggeststhatpredictingtheefficacyofdrugsinhumansisafunctionnotonlyoftheinvitroaffinityofa
drugtoareceptoranditshalflife,butalsoofthedrugconcentrationatthereceptorsiteinvivo.Forexample,
investigatorshavefoundthatalthoughdesloratidinehasahigheraffinityforH1receptorsandalongerhalflifethan
bothfexofenadineandlevocetirizine,itsabilitytoinhibitawhealandflareresponsearediminishedbecauseof
decreasedreceptoroccupancyinvivo.[66]
Theefficacyofantihistaminesinalleviatingpruritusanddecreasingthenumberofhivesiswellestablished,although
notallpatientswillrespond.Ofpatientstreatedwithantihistaminesattertiarycareclinics,only40%experienced
completeclearingoftheirsymptoms.[4]Insomepatients,antihistaminesonlyreducetheseverityofpruritusand
decreasethenumberanddurationofwheals.[4]However,itisimportanttonotassumetherapeuticfailureifone
particularantihistaminedoesnotresolvetheurticariamorethanoneantihistamineshouldbetriedsinceefficacyis
patientspecific.Antihistaminesaremosteffectiveiftakendailyratherthanonanasneededbasis.[4,38]
FirstgenerationorclassicH1receptorantihistaminesincludehydroxyzine,diphenhydramine,cyproheptadine,and
chlorpheniramine(chlorphenamine).Theseantihistaminesarerarelyusedasmonotherapybecauseoftheiradverse
effectprofile,whichincludessedatingandanticholinergiceffects.However,theycanbevaluableadjunctivetherapy,
especiallyforpatientswhosesleepisdisturbedbysymptomsofurticaria.[4,38]Manybelievethattheadverseeffect
profileinpatientswithsignificanturticariaisattenuatedandbecomeslessapparentifthemedicationisusedlong
term(dailyformorethan1week)however,toourknowledge,thishasnotbeenshowninanywellconducted
studies.
AnumberofsecondgenerationH1receptorantihistamineshavebeendevelopedoverthelast15yearsandareas
efficaciousasfirstgenerationantihistamines.Theseincludecetirizine,levocetirizine,loratadine,desloratadine,
fexofenadine,ebastine,andmizolastine.Amajoradvantageofsecondgenerationantihistaminesistheirlackof
significantCNSandanticholinergicadverseeffects.Althoughantihistaminesareoftenprescribedatdoseshigher
thanthoserecommendedinthepackageinsertinanattempttoachieveadditionalantiallergenicandanti
inflammatoryeffects,thereisnoevidencetosupportthispractice.[67]Arecentstudyoffexofenadine,theactive
metaboliteofterfenadine,showedthattherecommendeddailydoseof180mgprovidedeffective,welltolerated
reliefforpatientswithchronicurticaria.[68]AdosefindingstudybyNelsonetal.[69]showedthatatwicedaily60mg
doseoffexofenadinewasonlyslightlylessefficaciousthanhigherdoses(120and240mg)inreducingpruritus
severityandnumberofwheals.FexofenadineisuniqueamongstsecondgenerationH1receptorantihistaminesin
thatitislipophobicanddoesnotpenetratethebloodbrainbarrierhence,itcanbeprescribedatdosesofup360
mg/daywithoutriskofsedation.[5]
Desloratadineisanactivemetaboliteofloratadineandhasmorepotentantihistaminicandantiinflammatory
propertiesthanloratadine.[70]Cetirizineisanactivecomponentofhydroxyzinewithsimilareffectsbutlesssedation.
[71]Levocetirizineistheactiveenantiomerofcetirizineandismorepotentthancetirizine.Ithasbeenshownto

[71]Levocetirizineistheactiveenantiomerofcetirizineandismorepotentthancetirizine.Ithasbeenshownto

providerapidreliefofpruritusandwhealsinpatientswithchronicurticaria.[72]Mizolastine,whichisunavailablein
theUS,shouldbeusedwithcautioninpatientsalsotakingcytochromeP450enzyme(CYP)inhibitorssuchas
cimetidine,cyclosporine(ciclosporin),andnifedipinebecauseofconcernaboutcardiacarrhythmias(QT
prolongation).[4]
H2ReceptorAntagonists.Because15%ofhistaminereceptorsintheskinareoftheH2type,[73]H2receptor
antihistamineshavebeenshowntobeahelpfuladditiontoH1receptorantihistaminesinsomepatientswithchronic
urticaria.[4,73,74]However,H2receptorantagonistsshouldnotbeusedalonesincetheyhaveonlyminimaleffects
onpruritus.H2receptorantagonistsincludecimetidine,ranitidine,nizatidine,andfamotidine.[4]Overall,data
supportingtheefficacyofH2receptorantagonistsarelimited.
SecondlineTherapy

Ifurticarialsymptomsarenotcontrolledbyantihistaminesalone,secondlinetherapiesshouldbeconsidered,
includingbothpharmacologicandnonpharmacologicmeasures.ResultsofphototherapywithUVlightor
photochemotherapy(psoralenplusPUVA[PUVA])havebeeninconclusive,althoughsomestudieshaveshown
increasedefficacyforPUVAinmanagingphysicalurticariasbutnotchronicurticaria.[75]Studiesofrelaxation
therapieshavealsoreportedinconclusiveresults.[38]Severalclassesofdrugsmaybeusefulinsecondlinetherapy,
includingantidepressants,corticosteroids,calciumchannelantagonists,levothyroxinesodiumsupplements,
leukotrienereceptorantagonists,andavarietyofotherdrugs.
Antidepressants.ThetricyclicantidepressantdoxepinhaspotentH1andH2receptorantagonistactivity[4,37]and
hasbeenshowntobemoreeffectiveandlesssedatingthandiphenhydramineinthetreatmentofchronicurticaria.
[76]However,Goldsobeletal.[77]reportedthatsedationisagreaterproblemfordoxepinthanfordiphenhydramine
orhydroxyzineandlimitstheusefulnessofthisantidepressant.Becauseofitssedatingproperties,doxepinworks
bestwhentakenatnight.Furthermore,becausedoxepinismetabolizedbytheCYPsystem,itshouldbeusedwith
cautionoravoidedinpatientstakingotherdrugsmetabolizedbythisenzyme,suchascimetidine,erythromycin,and
cyclosporine.Doxepinmaybeespeciallyusefulinpatientswithchronicurticariaandcoexistingdepression.[37]
Althoughthedosageofdoxepinforthetreatmentofdepressionmayvaryfrom25to150mg/day,only1030
mg/dayisrecommendedforchronicurticaria.Mirtazapineisanantidepressantthatdemonstratessignificanteffect
ontheH1receptorandhasantipruriticactivity.Ithasbeenreportedtobehelpfulinafewcasesofphysicalurticaria
anddelayedpressureurticariaatdosesof30mg/day.[78]
Corticosteroids.Shortcoursesofsystemiccorticosteroidscanbeprescribedforsevereurticarialsymptomswhen
thepatientneedsrapidandcompletediseasecontrol.Althoughthereisnodoubtabouttheefficacyof
corticosteroids,longtermtherapycannotberecommendedbecauseofthelikelihoodofdevelopingtoleranceand
numerousadverseeffectssuchashyperglycemia,osteoporosis,pepticulcers,andhypertension.Ifprolonged
corticosteroidtherapyisnecessary,itisimperativetousethelowesteffectivedoseandincorporatecorticosteroid
sparingimmunosuppressivemodalities.[4,37,38,74,79]Cliniciansshouldbeawarethatantihistaminedosages,
particularlyoffirstgenerationantihistaminesgivenuptofourtimesdaily,shouldbemaximizedinanattempttoavoid
corticosteroidcourses.
LeukotrieneReceptorAntagonists.Leukotrienes(C4,D4,E4)arepotentmediatorsofinflammationandhave
beenshowntoelicitwhealandflareresponsesbothinpatientswithchronicurticariaandinhealthyindividuals.[46]
Leukotrienereceptorantagonistssuchasmontelukast,zafirlukast,andzileutonhavebeenshowntobesuperiorto
placebointhetreatmentofpatientswithchronicurticaria.[80,81]Leukotrienereceptorantagonistssuchas
montelukastmayalsobeeffectiveincontrollingchronicurticariainpatientswhoareunresponsivetoantihistamines
alone.[74,82,83]ThereisalsoevidencethatleukotrienereceptorantagonistsmaypreventNSAIDinduced
exacerbationsinpatientswithchronicurticaria.[84]Anotherstudyshowedthatmontelukastincombinationwith
desloratadinewassuperiortodesloratadinealoneinmanagingthesymptomsofchronicurticaria.[85]Bagenstoseet
al.[86]alsoreportedthatadditionoftheleukotrienereceptorantagonistzafirlukasttocetirizinetherapywas
significantlymoreeffectivethancetirizinealoneinmanagingpatientswithchronicurticariawhowereASSTpositive,
butnotinthosewhowereASSTnegative.Despitethesepromisingresults,useofleukotrienereceptorantagonists

inthemanagementofurticariaremainscontroversialandnotalltrialshaveshownabeneficialeffect.Forexample,
inarecentdoubleblind,placebocontrolled,crossoverstudyof52patientswithchronicurticaria,monotherapywith
zafirlukast20mgtwicedailydidnotprovideanysignificantbenefitoverplacebo.[87]
Nifedipine.Nifedipinehasbeenreportedtobeeffectiveindecreasingpruritusandwhealinginpatientswithchronic
urticariawhenusedaloneorincombinationwithantihistamines.[88]Manyexperts,however,havefoundtheclinical
effectofnifedipinedisappointing.[38]Theproposedmechanismofactionismodificationofcalciuminfluxinto
cutaneousmastcells.Atrialofnifedipinemaybeareasonableoptioninpatientswithcomorbidhypertension,
particularlyifthepatientistakinganACEinhibitororcombinationtherapythatincludesanACEinhibitorandan
alternativeantihypertensiveisdesired.[4,38]
ThirdlineTherapy

Thirdlinetherapyforpatientswithurticariawhodonotrespondtofirstandsecondlinetreatmentstypicallyinvolves
theuseofimmunomodulatoryagents,whichincludecyclosporine,tacrolimus,methotrexate,cyclophosphamide,
mycophenolatemofetil,andintravenousimmunoglobulins(IVIG).Patientswhorequirethirdlinetherapyoftenhave
theautoimmuneformofchronicurticaria.Otherthirdlinetherapiesthatmaybebeneficialincludeplasmapheresis,
colchicine,dapsone,albuterol(salbutamol),tranexamicacid,terbutaline,sulfasalazine,hydroxychloroquine,and
warfarin.[4,16,37,38]
ImmunomodulatoryAgents.Severalstudieshaveshownthatcyclosporineiseffectiveintreatingpatientswith
refractorychronicurticaria.[5,89,90]Cyclosporine35mg/kg/dayappearstobenefitabouttwothirdsofpatientswith
chronicurticariawhodonotrespondtoantihistamines.[37]Inarandomized,doubleblindtrial,8of19patientswith
severechronicurticariahadapositiveresponsetocyclosporinetherapyversusnoneofthepatientstreatedwith
placebo.[90]TherewasalsoastatisticallysignificantdecreaseintheASSTresponsetoserumhistaminereleasing
activityaftercyclosporinetherapy.DiGioacchinoetal.[89]reportedsimilarresultswithcyclosporineinadoubleblind
studyof40patientswithchronicidiopathicurticariaandapositiveASST.Greaves[5]statesthat>75%ofpatients
thathetreatshaveanexcellentresponsetocyclosporinewithonethirdremaininginremissionafterwithdrawal,
onethirdhavingamildrelapse,andonethirdrelapsingtopretreatmentlevels.Duringtreatmentwithcyclosporine,
H1receptorantihistaminesshouldbecontinuedandbloodpressureandrenalfunctionshouldbemonitored
appropriately.Maintainingpatientsonlongtermcyclosporinetherapyshouldnotbetakenlightlybecauseofthe
numerousadverseeffectsofthedrug(e.g.hypertension,renaltoxicity)andthepotentialforreboundafter
discontinuation.[4,37,74]
Experiencewithotherimmunomodulatoryagents(tacrolimus,methotrexate,andcyclophosphamide)ismorelimited.
[37,74]Inarecentreviewoftheliterature,Stanaland[91]reportedexcellentresultswitha20g/mLdailydoseof
tacrolimusinthetreatmentofpatientswithcorticosteroiddependenturticaria.Arecentcasereportdescribedthe
useofintravenouscyclophosphamidetoachievecompleteclinicalremissioninapatientwithcorticosteroid
dependenturticaria.[92]MethotrexatehasbeenusedsuccessfullyinthemanagementoftwoASSTnegativepatients
withchronicurticariarefractorytoconventionaltherapies.[74,93]ArecentreportbyShaharetal.[94]documented
significantimprovementinninepatientswithchronicurticariatakingmycophenolatemofetilfor12weeks.All
patientswereabletostopprednisoneandnoseriousadverseeventswerenoted.
IVIGappeartobeeffectiveinthemanagementofpatientswithsevererefractoryautoimmunechronicurticaria.
[4,37,74]Althoughthemechanismofactioninvolvedisunclear,ithasbeenproposedthatIVIGmaycontainanti
idiotypicantibodiesthatcompetewithendogenousIgGforH1receptorsandblockhistaminereleaseorenhance
clearanceofendogenousIgG.[95]Whytheeffectwouldbesustainedafterinitialtherapyisnotknown.Inastudyby
O'Donnelletal.,[96]nineoftenpatientswithsevereautoimmunechronicurticariaexperiencedclinicalbenefitanda
reducedASSTresponseafter5daysofhighdoseIVIGtherapy.Threepatientshadprolongedremissionsof3
years.Anotherreportdescribedcompleteremissionofrefractoryautoimmuneurticariawithin48hoursafterahigh
doseinfusionofIVIG.[95]DespiteanegativeASSTat6months,thepatient'ssymptomsreturned7monthsafter
IVIGtherapy.Othershavenotfoundsignificantbenefit.[97]Expenseandpotentialmorbidityremainconcernstheuse
ofIVIG,andcontrolledstudieshavenotyetbeenconductedtoevaluatethistherapyforurticaria.[4,37,38,74]
Plasmapheresis.Plasmapheresishasbeenreportedtobebeneficialinthemanagementofseverechronic

autoimmuneurticaria.Inacaseseriesreport,plasmapheresisrelievedthesymptomsofsixofeightpatientswith
severe,treatmentresistantautoimmunechronicurticaria.[98]However,thisapproachcannotbeusedlongtermor
asmonotherapybecauseofexpense,potentialmorbidity,andearlyrelapseofurticaria.Plasmapheresisaloneis
insufficienttopreventreaccumulationofhistaminereleasingautoantibodiesandneedstobeinvestigatedin
conjunctionwithuseofimmunosuppressantpharmacotherapy.[4,37,38,74]
OtherDrugs.Dapsone[99,100]and/orcolchicine[4]maybebeneficialinmanagingurticariawhenpredominantly
neutrophilicinfiltratesareseenhistologically,butareprobablymostusefulforurticarialvasculitis.Limitedexperience
suggeststhatsulfasalazinemaybebeneficialinmanagingbothchronicidiopathicurticariaanddelayedpressure
urticaria[4,37]however,manyhavenotfoundthisagentusefulanditisprobablybestreservedforurticarial
vasculitis.Hydroxychloroquinehasalsoshownpromisingresultsinthetreatmentofchronicidiopathicurticariaand
hasbeenassociatedwithagoodresponseinhypocomplementemicurticarialvasculitis.[37,74,101]Althoughthe2
adrenoceptoragonistterbutalinehasbeenevaluatedformanagementofchronicurticaria,itsuseisgenerallynot
recommendedbecauseofadverseeffectssuchastachycardia,insomnia,andjitterinessthatarenotwelltolerated
bymanypatients.[79]Afewstudieshavefoundthatwarfarinappearstohavebeneficialeffectsinsomepatientswith
chronicurticaria[102,103]however,otherinvestigatorswerenotabletoreplicatethisfinding.[104]Inthesmall,
doubleblindstudyconductedbyParslewetal.,[103]warfarinproducedaresponseinsomepatientswithASST
negativechronicurticariaandangioedemawhowereresistanttoantihistamines.Theseresultssuggestthattheir
symptomswerenothistaminedependentbutmorerelatedtocoagulationdependentmediatorssuchaskinins.[74]

TheFuture
SpectorandTan[105]recentlyreportedonthreepatientswithchronicurticariawhorespondedtoomalizumab,a
humanizedmonoclonalantibodythatbindsfreeIgE.Interestingly,notallofthepatientshadelevatedIgElevelsprior
totherapy.TheinvestigatorsspeculatedthatdownregulationofIgEreceptorsimprovedsymptoms.Itwouldbe
interestingtoknowifpatientswithautoimmunechronicurticaria(patientswithantiFCeR1antibodies)would
respondsimilarly.
GimenezArnauetal.[106]reportedthattreatmentwithanovelnonsedatingH1receptorantihistamine,rupatadine,
wasassociatedwithsignificantsymptomimprovementin195patientswithchronicurticariacomparedwithcontrol
patients.Itisclaimedthatthisantihistaminehasadditionalantiinflammatoryeffectsasaresultofitsantiplatelet
activatingfactorpropertiesandhigheraffinityfortheH1receptor.
Recently,H4receptorsonmastcellshavebeendiscovered.Thesemaybemoreimportantinthepathogenesisof
itch.KnockoutmicefortheseH4receptorshaveanattenuateditchresponsetohistaminestimulation.Furthermore,
aselectiveH4receptorantihistamine,JNJ7777120,reduceditchinmicemoreeffectivelythanH1receptor
antihistamines.[107]

Conclusion
Urticariacanbediagnosedonthebasisoftheclinicalpresentationwithoutextensivelaboratoryinvestigationand
canbeclassifiedasidiopathicafterallergic,infectious,physical,anddrugrelatedcauseshavebeenruledout.
Historyandphysicalexaminationarecrucialwhileundirectedlaboratoryexaminationistypicallyfruitless.Although
acuteurticariaoftenhasanidentifiabletrigger(foods,drugs,virus),chronicurticariafrustratinglytendstoremain
idiopathic.About3540%ofpatientswithchronicidiopathicdiseaseappeartohaveanautoimmuneetiologyin
whichsettingtheASSTisasomewhatsensitiveandspecifictestforhistaminereleasingautoantibodies.These
patientswithautoimmunechronicurticariatendtofollowamoreaggressivecourseandoftenrequiremore
aggressivetherapy.NonsedatingH1receptorantihistaminesrepresentthefirstlinetherapyforurticaria,followedby
combinationsofH1receptorantihistamineswithotherentitiessuchassedatingantihistamines,antidepressants,or
leukotrienereceptorantagonists.Forsevere,recalcitrantchronicurticaria,shortcoursesofcorticosteroidscanbe
beneficialfollowedbyimmunosuppressanttherapiesforpatientswithdebilitatingdisease.
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