10/15/2015

Pityriasisrosealikeadversereaction:ReviewoftheliteratureandexperienceofanItaliandrugsurveillancecenter[eScholarship]

DermatologyOnlineJournal
UCDavis

Pityriasisrosealikeadversereaction:ReviewoftheliteratureandexperienceofanItaliandrugsurveillancecenter
LauraAtzoriMD,AnnaLuisaPinnaMD,CaterinaFerreliMD,NicolaAsteMD
DermatologyOnlineJournal12(1):1

DermatologyDepartment,CagliariUniversity,CagliariItaly.ATZORI09@lauraatzori.191.it

Abstract
Pityriasisroseaisacommon,acuteeruptionofuncertainetiology.Arashverysimilartothisidiopathicdiseaseisalsoattributedtoseveraldrugs,andrecovery,whichdependson
withdrawaloftheresponsibledrug,canbedelayedbyitslateidentification.Aprospectivestudytorecordallcasesofadversecutaneousreactionspresentingwithpityriasisrosea
likemanifestationswasconductedatthecenterfordrugsurveillanceofthedermatologydepartmentofCagliariUniversity.Wedevelopedanintensivesurveillanceprogramfrom
June2002toMay2005,adoptingtheWHOCollaboratingcenterforDrugMonitoringcausalityassessmentcriteriaandalgorithm.Eightcases,sixmaleandtwofemale,werestudied
ina3yearperiod.Nonehadpreviouslysufferedfromdrugintoleranceorallergy.Clinicalmanifestationswereverysimilartopityriasisrosea.Responsibledrugsweremainly
angiotensinconvertingenzymeinhibitors,aloneorincombinationwithhydrochlorothiazide,followedbyonecaseeachforhydrochlorothiazideplussartan,allopurinol,nimesulide,
acetylsalicylicacid.Recoverywasobtainedinallcaseswithdrugwithdrawal.Finalcausalityassessmentwasprobableforalleruptions.Frequencyofdrugpityriasisrosealike
eruptionsisprobablyunderreported.Themildnessoftheeruption,mimickingaverycommonandselflimitingdiseasedoesnotpromptphysicianstoverifytheuseofmedications
untilpersistence,severityoflesionsanditchingrequirereevaluationoftheoriginaldiagnosis.

Introduction
Skininvolvementinadversedrugreactionsisfrequentanddiagnosisisoftenintuitive,butuncommonpresentationsmaymimicandbemisdiagnosedforothermorefrequentskin
conditions,suchasGibert'sPityriasisrosea[1].Severaldrugshavebeenreportedasbeingresponsibleforarashsimilartotheidiopathicdisease[220],butthereareno
estimationsregardingthefrequencyofsuchevents.Recognitionoftheiatrogenicoriginoftheeruptioniscrucialtoavoidanextremelychroniccourseandalsotoexperimentarapid
recoverywiththesimplewithdrawaloftheresponsibledrug.
Aspartofanintensivedrugsurveillanceprogram,aprospectivestudywasconductedatthedermatologydepartmentofCagliariUniversitytorecordandanalyzeallcasesof
adversecutaneousreactionspresentingpityriasisrosealikefeatures.Severaldistinctivecriteriaweredepicted,whichcanhelpinthedifferentiationfromtheidiopathicdisease.

Materialsandmethods
FromJune2002toMay2005allcutaneousadversereactionstodrugswererecordedonmagneticsupport,includingoutpatients,patientsadmittedtothedermatologydepartment,
andpatientshospitalizedinotherdepartmentsofthecity(Cagliari,Italy).Diagnosiswasbasedonclinicalfeatures,circumstantialevidence,timerelationshipsbetweentakingthe
drugandonsetoftherash,andexclusionofalternativediagnoses.Accurateallergicandpharmacologicanamnesis,aswellashistoryofpreviousreactionstodrugswereobtained
fromthepatientsandgeneralpractitioners.Histologywasperformedinallcases.FinalcausalityassessmentfollowedtheWHOCollaboratingCenterforDrugMonitoring
internationalcriteriaandalgorithm[21].

Results
Ina3yearperiod,aspartoftheactivitiesofadermatologiccenterofdrugsurveillanceeightcasesoutof380(2%)adversecutaneous
reactionspresentedanerythematoussquamouseruptionmimickingGibert'spityriasisrosea.Meanagewasoverthe6thdecade(68.6years)
withaclearmaleprevalence(6M:2F)(Table1).Noneofthepatientsreportedaprevioushistoryofdrugintolerance.Clinicalmanifestations
weresimilarinallpatients,ablossomingofflat,roundorovalscalypatches,brightredtovioletincolor,andinvolvingthetrunk,abdomen,and
proximalaspectsofthelimbs(Figs.1,2).Thelesionsevolveinsuccessivecropsandthereisnotendencyofspontaneousremission.Thescaly
surfaceofsomelesionsshowedatypicalmarginalcollarette(Fig.3).Patientsreportedsevereitching,andthiswasunresponsiveto
antihistaminetreatment.Noprodromicsymptomswerereported.
Laboratoryinvestigationswerewithinnormalrange,exceptforaslightleukocytosisandeosinophilia(917%)insixcases.Hepaticandrenal
functionalitywerenormal,aswellastheelectrocardiogramandchestXray.Allbloodtestswerenegativeforpriororconcomitantinfections.
Figure1
Histologicalexaminationoncutaneousbiopsydemonstratedsimilarfeaturesinallcases,asuperficialperivasculardermatitis,withparakeratosis,
spongiosisandmarkededemaofthepapillarydermis.Theinflammatoryinfiltratewasmainlycomposedoflymphomonocytes,butwithfrequent Figure1.Enalaprileruption:
eosinophils.
numerousscatteredbrightred
violetscalingmaculesand
papulesconfinedtotheupper
partofthetrunk,abdomenand
proximalaspectsofthelimbs
afterstartingthisdrug.

Figure2A

Figure2B

Figures2.Acetylsalicylicacidpityriasisrosealikeeruptionina43
yearoldman:A)anterioraspectsofthetrunkB)lateralsurfaceof
thetrunk.

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Pityriasisrosealikeadversereaction:ReviewoftheliteratureandexperienceofanItaliandrugsurveillancecenter[eScholarship]
Figure3

Figure4

Figure3.Lisinoprileruption:surfacepatternofthelesionsonthe
back,withamarginalcollaretteofscales.
Figure4.Completeresolutionofthecasepresentedinfigure2,
aftersimplediscontinuationofthedrug.
Pharmacologicalanamnesiswassimplebecausenopatientwastakinganyotherdrugs.Responsibledrugsweremainlyangiotensinconvertingenzyme(ACE)inhibitors,aloneorin
combinationwithhydrochlorothiazide,followedbyonecaseeachforhydrochlorothiazideplussartan,allopurinol,nimesulide,acetylsalicylicacid.Timefromfirstdoseintaketoonset
oftheeruptionvariedfrom5to20daysthetimeforaspecialistdiagnosisoftheiatrogenicoriginrangedfrom13to50days.Suspecteddrugswerediscontinuedandtheclinical
manifestationsimprovedsoonafter,withcompleteresolutionwithin510days.Norelapseswereobservedina6monthfollowup.
FinalcausalityassessmentfollowingtheWHOprogramalgorithm[21]definedasprobablyrelatedtothedrugallcases,inabsenceofrechallengeinformation.

Discussion
Thedermatologist'scommitmentinadversedrugreactionsiscrucialbecausetheskinisaverycommontargetandanyskindisordercanbeimitated,inducedoraggravatedby
drugs.Constant,detailedattentionshasbeengiventouncommonpresentationsandpityriasisroselikeeruptionssinceaspecializedcenterdevotedtodrugsurveillancewas
createdinourdermatologydepartment.Isolatedcasereportsfordifferentmedicationhavebeenreportedincurrentliterature[220](Table2).Thefrequencyofpityriasisrosealike
eruptionsinourcasereports,comparedtotheoverallnumberofadversecutaneousreactions(2%)isremarkableandsuggestsunderreporting.Clinicalmanifestationsarevery
similartothepityriasisroseaofGibert.Inaddition,thefollowingdistinctivecharacteristicsfromtheidiopathicdiseasewerenoted:
Theabsenceofanevocative,single"herald"patch.
Themarkedinflammatorycolorofthelesions,tendingtobrightvioletred.
Theseverityofitching,andlackofresponsetoantihistaminetreatment.
Thepresenceofincreasedeosinophilsinthebloodandintheskininfiltrate.
Theclinicalsuspicionofaniatrogenicetiologywasconfirmedbythesuddenrecoveryafterwithdrawalofthedrug(dechallenge).Extentoferuptionandpatients'advancedage
requiredhospitalizationinthevastmajorityofcases(94%).ResponsibilityofACEinhibitorsseemstobemorefrequentthanthatofotherdrugs[3,4,5,6,7],butextensive
marketingoftheseantihypertensivedrugsinrecentyearsmayhaveplayedarole,especiallyconsideringthequiteobsoleteprescriptionofcertainmedicationreportedinthepast:
goldsalts,metronidazole,meprobamate,bismuth[1,2,15,16].Themechanismsofskininvolvementareunknownandvaryaccordingtothemolecules.FollowingWilkin's
hypothesis[3,4,5],ACEinhibitorsmightinduceincreasedplasmaandtissuelevelsofkinins,whosegenericproinflammatoryeffectsareimplicatedindifferentcutaneousadverse
reactions,includingpityriasisrosealikeeruptions.NSAIDsarealsoabletoevokecutaneousinflammation[8,9,10]theinhibitionofcyclooxygenasesmaycauseacollateral
availabilityoftheprostaglandinprecursor,arachidonicacid,whichactivateslypoxygenasepathwayandfinalleukotrienerelease.Nopreviousreportswerefoundregarding
administrationofallopurinolorhydrochlorthiazide(whoseresponsibilityincombinationwithACEinhibitorsorsartancannotbefullyexcluded).
Afterourfirstcasedescription[7]wehypothesizedthatthefrequencyofdrugrelatedpityriasisrosealikeeruptionsisunderreported,andweconductedaprospectivestudy
collectingallnewcasesobservedinourdepartment.Ina3yearperiod,2percentofallcutaneousadversedrugreactionspresentedthispeculiarmanifestation,confirmingour
impression.Themildnessoftheeruption,mimickingaverycommonandselflimiteddisease,probablydoesnotpromptphysicianstocheckfordrugassociationuntilpersistence,
severityoflesions,anditchingrequirereconsiderationoftheoriginaldiagnosis.ResponsibilityofACEinhibitors,aswellasNSAIDsmeritsfurtherinvestigationsandsuggest
analogiesamongproinflammatorypathwaysaffectingtheskin.Prevalenceamongoldpatientsonlongtermtreatmentisaninterestingfindingandmayrepresentadistinguishing
featurefromtheidiopathicdisease,whichischaracteristicofyoungadults[2].Misdiagnosisandconsequentwaitingforpityriasisroseaselfhealingshouldhavefurtherprolonged
illnessandcausedanotabledelayinadoptingthemoreimportantmeasure,whichisdiscontinuationofthedrug.

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