Erythrodermic psoriasis treated with ustekinumab: An Italian multicenter retrospective analysis

Letter

to

the

Editor

Erythrodermicpsoriasistreatedwith ustekinumab:AnItalianmulticenter retrospectiveanalysis

DearEditor,

Erythrodermic psoriasis (EP) is one of the most severe cutaneousconditionswhich mayleadtoseriousmorbidity and evenmortality.Thisconditionisoftendifficulttomanageand,due toitsrarity(estimatedprevalence1–2.25%ofpsoriaticpatients) there is a lack of high-quality medical literature examining treatmentoptions[1].

Dataon the useof biologicsin EP are very sparse because erythrodermarepresentedexclusioncriteriainallthemainstudies investigatingbiologicsefficacyandsafetyinpsoriasis[1,2].

Untilnowonlytworetrospectivestudieshavetriedtoassess theefficacyandsafetyofanti-TNF-

a

[3,4].

Here wereporttheresultsfromamulticenter, retrospective analysisofpatientswithEPtreatedwithustekinumabin9Italian DermatologyHospitalDepartments.

Data of 22 patients with EP (defined as a generalized, inflammatoryerythematousdermatosis,withorwithout associ-atedexfoliationlastingforatleast3monthsinvolvingatleast75% of thebody surfacearea, withthecharacteristic clinicaland/or histologicalfeatures of psoriasisand theexclusion oftheother main differential diagnoses for erythroderma)[1],treated with ustekinumab between February 2010 and July 2014, were included.EachpatienthasbeenevaluatedwiththePsoriasisArea andSeverityIndex(PASI),beforeandafter4,16and28weeksof treatment.

Baseline characteristicsof thestudy population are summa-rizedinTable1.

19 patients have a positive personal history of plaque type psoriasiswhile3experiencederythrodermasincethebeginningof thedisease.InthelattercasesdiagnosisofEPwasmadeexcluding otherpossiblecausesoferythroderma.

Patientsreceived ustekinumabatweeks0,4 andthenevery 12weeks.16patients(weighting100kg)receivedustekinumab 45mgwhile6(weighting>100kg)90mg.

JournalofDermatologicalScience78(2015)149–164

Keywords:

Psoriasis;Erythrodermicpsoriasis; Biologics;Ustekinumab;Safety; Efficacy

Table 1

Baselinecharacteristicsofthe22studiedpatients.

Patients Sex AgePso AgeEP PrevioustreatmentPso PrevioustreatmentEP BaselinePASI Ustekinumab dose(mg)

1 M 25 46 Cs,PUVA,ETA – 41.6 45

2 M 40 59 MTX,Cs,EFA,ETA CCS 59 45

3 F 13 53 Cs,MTX,EFA,ETA,INF CCS 40 45

4 M 23 45 Cs,MTX Ret,CCS 45 90

5 M 46 46 – Cs,Ret,CCS 49 90

6 M 49 67 UVB,MTX MTX,Cs,UVB 41 45

7 F 35 67 – Cs,MTX,Ret,ADA 48 90

8 M 46 63 Cs Cs,CCS,ADA 48.8 45

9 M 57 62 Ret,MTX,Cs Ret,Cs,ADA,ETA 63 45

10 M 29 46 Ret,MTX,Cs Ret,Cs,ETA 57.2 45

11 M 29 36 Cs Cs,CCS 37.8 45

12 F 49 54 Cs,Ret,ADA Cs,ETA,INF,CCS 45.2 45

13 F 15 15 – MTX,Cs,Ret,CCS 35 45

14 F 9 26 PUVA,MTX,Cs,EFA ADA,ETA 42 90

15 F 28 34 – MTX,Cs,INF 50 90

16 F 12 42 Cs,PUVA – 42.3 45

17 M 23 43 Ret,PUVA – 41.4 45

18 M 9 54 Cs,PUVA – 42.3 90

19 M 29 34 Cs,Ret,ADA,ETA CCS 38 45

20 M 38 61 UVB,Cs,MTX,Ret INF,ADA,ETA 42 45

21 M 56 66 UVB,MTX,Ret Cs,CCS 41 45

22 F 59 59 Cs,PUVA,Ret – 40.8 45

CCS:systemiccorticosteroids;Cs:ciclosporin;Ret:oralretinoids;MTX:methotrexate;PUVA:psoralenplusultravioletA;UVB:ultravioletB;ADA:adalimumab;EFA: efalizumab;ETA:etanercept;INF:infliximab.Topicaltherapiesnotincluded.

ContentslistsavailableatScienceDirect

Journal

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Dermatological

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Five patients received ustekinumabas firsttreatment at the onsetofEP.

Theremaining17patients receivedasfirsttreatmentforEP, prior toustekinumab, systemic steroids, conventional systemic treatments(acitretin,methotrexate,cyclosporine)phototherapy, otherbiologictherapies.

Theefficacyofustekinumabwasassessedbytheproportionof patientsreachinga50,75and90%improvementinPASI(PASI50, PASI75,PASI90)atdifferenttimepoints(Fig.1).

After 4 weeks of ustekinumab treatment more than half of patientsshowedaclinicalimprovementofatleast50%compared withbaselinePASIscorewhileafter16weeksabouttwothirdof patients reached PASI75.After 28 weeks of treatment 68.2% of patientsreachedPASI90,86.3%PASI75and90.9%PASI50.

Atthetimeofdatacollection,themedianfollow-upduration was60weeks(mean66.5,range24–120weeks)aftertheonsetof ustekinumabtreatment.

16 patientswere still receivingustekinumab witha median PASIof2.3(mean2,range0–8)attheendofthefollow-upperiod. CausesoftreatmentwithdrawalwerefailureinPASI50 achieve-ment after 28 weeks (2 patients) and clinical remission (4patients).

EPisoneoftheclinicalsubtypesofpsoriasisassociatedwith poorprognosisanddirectmortality[1].

EP mostcommonly arisesfrom a pre-existing long-standing chronicpsoriasisvulgarisor,morerarely,itcanoccurabruptlyas theinitialpresentationofpsoriasis.

CurrentevidencesupportingtheuseofbiologicsinEPislimited tocasereportsandcaseseries[1].

Tothebestofourknowledgethisisthelargestretrospective study investigating the efficacy and safety of ustekinumab in patientswithEP.

SuccessfuluseofustekinumabinEPwasreportedinvarious casereports[5–10] underliningitsefficacyeven afterfailureof variousanti-TNFagents.

ThelargerevaluationofustekinumabinEPcurrentlyavailable isanAsiancaseseriesof8patientswith75%,50%and37.5%of patientsreachingrespectivelyPASI50,PASI75andPASI90atweek 28 [10]. In this study ustekinumab 45mg was given only at baselineandafter4weeks;thiscouldexplaintheirdisappointing results.Moreover,itseemsthatbiologicstreatmentforpsoriasis

mayhavealessimpressiveresponseinAsianraces,asstatedalso bythesameauthors.InarecentFrenchmulticenterretrospective studyonthesafetyandefficacyofdifferentbiologictreatmentsin EP,3patients weretreatedwithustekinumabwithonlylimited efficacyreported[3].Howevertheauthorsunderscoredthatinthe reportedcasesustekinumabtreatmentwasprescribedasa fourth-line biological treatment in all cases,and thesewere themost recalcitrantones.

Our case series highlight the efficacy of ustekinumab in EPwitha percentageofpatientsreachingPASI75closeto70% at week 16 weeks. This percentage increases more than 80% at week 28. In terms of time related clinical improvement (PASIreduction)ourresults areequaltoorgreaterthanthose obtainedwithothersbiologics[2,3].Thefourpatientswhohave withdrawalustekinumabafterreaching clinicalremissionhave maintainedthisconditionthroughouttheendofthefollow-up period.

Ustekinumabwasgenerallywelltoleratedandpatientswere compliantandsatisfied.

No severe infection, injection site reaction, or drug-related laboratoryabnormalitieshavebeenreportedamongthesubjects enrolledinthisstudy.

We didn’tfindanyrelationamong anyclinicalfactors(BMI, previoustreatments,durationofEP,smokinghabit)andqualityof response (efficacy, quick onset of response) to ustekinumab treatment.Thismaybeduetothelimitednumberofpatientsof ourstudy.

Ourretrospectiveanalysisdemonstratesthatustekinumabisa highlyeffectivetreatmentforEP,providingrapidandsignificant clinicalresponseassociatedwithanexcellentsafetyprofile.

The limitation of the current study is that the efficacy of ustekinumabwasinvestigatedretrospectively.Anotherlimitation shouldbethesmallnumberofpatientsincludedbuttalkingabout EPtreatmentwithonebiologicthisrepresentsthelongestseriesup tonow.

Even if there is a clear need for dedicated and prospective comparativeclinicaltrialstoassesswhicharethesafestandmost efficacioustherapies for themanagement ofEP, therapidity of clearance and theexcellent safety profile observed in ourcase seriessuggeststhatustekinumabcanplayanimportantroleinits management.

Fig.1.ImprovementofPASIofthe22studiedpatientsatdifferenttimelines. LetterstotheEditor/JournalofDermatologicalScience78(2015)149–164 150

Funding None. References

[1]RosenbachM,HsuS, KormanNJ,LebwohlMG,Young M,BeboBF,etal. Treatmentoferythrodermicpsoriasis:fromthemedicalboardoftheNational PsoriasisFoundation.JAmAcadDermatol2010;62(4):655–62.

[2]LevinEC,DebbanehM,KooJ,LiaoW.Biologictherapyinerythrodermicand pustularpsoriasis.JDrugsDermatol2014;13(3):342–54.

[3]ViguierM,Page`sC,AubinF,DelaporteE,DescampsV,LokC,etal.Efficacyand safetyofbiologicsinerythrodermicpsoriasis:amulticentre,retrospective study.BrJDermatol2012;167(2):417–23.

[4]Esposito M,Mazzotta A,deFelice C,PapoutsakiM,ChimentiS.Treatment oferythrodermicpsoriasiswithetanercept.BrJDermatol2006;155(July(1)): 156–9.

[5]SaracenoR,TalamontiM,GalluzzoM,ChiricozziA,CostanzoA,ChimentiS. Ustekinumabtreatmentoferythrodermicpsoriasisoccurringafterphysical stress:areportoftwocases.CaseRepDermatol2013;5(3):254–9.

[6]BuggianiG,D’ErmeAM,KrysenkaA,PescitelliL,LottiT,PrignanoF.Efficacyof ustekinumabinsub-erythrodermicpsoriasis:whenTNF-blockersfail. Derma-tolTher2012;25(3):283–5.

[7]Castin˜ eirasI, Ferna´ndez-DiazL, Jua´rezY, LueiroM.Sustainedefficacyof ustekinumabinrefractoryerythrodermicpsoriasisafterfailureofantitumor necrosisfactortherapies.JDermatol2012;39(8):730–7.

[8]Santos-JuanesJ,Coto-SeguraP,Mas-VidalA,GalacheOsunaC.Ustekinumab inducesrapidclearingoferythrodermicpsoriasisafterfailureofantitumour necrosisfactortherapies.BrJDermatol2010;162(5):1144–6.

[9]StincoG,PiccirilloA,ErrichettiE,BergamoS,PatroneP.Treatmentofrecalcitrant erythrodermicpsoriasiswithustekinumab.EurJDermatol2014;24(3):387–90.

[10]WangTS,TsaiTF.Clinicalexperienceofustekinumabinthetreatmentof erythrodermicpsoriasis:acaseseries.JDermatol2011;38:1–4.

LeonardoPescitellia_{,ValentinaDini}b_{,PaoloGisondi}c_, FrancescoLoconsoled,StefanoPiasericoe,AngeloPiccirillof, GiuseppeStincog_{,EnzoErrichetti}g_{,MarinaTalamonti}h_,LaraTripoa_, WalterVolpia_{,FrancescaPrignano}a,_*

a

DivisionofClinical,Preventive,andOncologicDermatology, DepartmentofSurgeryandTranslationalMedicine,

UniversityofFlorence,Florence,Italy;

b_{DepartmentofDermatology,UniversityofPisa,Pisa,Italy;} c_{SectionofDermatologyandVenereology,DepartmentofMedicine,} UniversityofVerona,Verona,Italy;

d_{DermatologyandVenereologyUnit,DepartmentofBiomedical} SciencesandHumanOncology,UniversityofBari,Bari,Italy; e_{DermatologyUnit,DepartmentofMedicine,UniversityofPadova,} Padova,Italy;

f

DepartmentofDermatology,SanCarloHospital,Potenza,Italy; g_{InstituteofDermatology,DepartmentofExperimentalandClinical} Medicine,UniversityofUdine,Udine,Italy;

h

DepartmentofDermatology,UniversityofRomeTorVergata,Rome, Italy

*Correspondingauthorat:VialeMichelangelo41,50125Florence, Italy.Tel.:+390556939624;fax:+390556939625

E-mailaddress:francesca.prignano@unifi.it(F.Prignano). Received4November2014

http://dx.doi.org/10.1016/j.jdermsci.2015.01.005

Letter

to

the

Editor

Atopicdermatitis-likedermatitisemerges unevenlyondifferentsitesinflakytailmice

TotheEditor,

Flaky tail mice (FTM; ma/ma, Flgft/ft_{) have two pathogenic} geneticabnormalitiesrelatedtocutaneouspermeabilitybarrier homeostasis, namely, gene mutations in filaggrin (Flgft_{) and} matted(ma),andareknowntoexhibitatopicdermatitis (AD)-likedermatitis‘‘spontaneously’’andthespontaneousemergence ismainlyattributedtothemattedmutation[1–4].AlthoughFTM hasbeenusedas oneof themurineAD models,whethersuch spontaneousemergenceisconsistentwiththepathogenesisof human AD, in which genetic abnormalities are not the sole determinantbutthecombinationofgenetic abnormalitiesand environmental factors is the most important characteristic, remains questionable. In the present study, we determined whether site-dependent emergence of skin manifestations, whichis oneofclinicalcharacteristicsofhumanAD,isseenin FTM.

TheseverityofdermatitisandageofonsetinFTMdifferamong laboratories[1,2,5,6].Suchinconsistencymightberelatedtothe presenceorabsenceofthemattedmutationand/ortovariationsin thegeneticbackgroundofindividualstrainsandinenvironmental factors[2,7].Inourlaboratory,youngFTM(7–8weeksold)didnot

haveanyclinicalorhistologicalsymptomsofdermatitis[8].FTM agedover40weeks(oldFTM)developedmarkeddermatitisonthe ears,eyelids,cheeksandneckaccompaniedbyelevationofserum IgElevels(Fig.1,SupplementaryFigs.S1–S3).Thedermatitisonthe

Keywords:

Atopicdermatitis;Flakytailmice

Fig.1.Physiologicalandhistologicalfindings.Transepidermalwaterloss(TEWL,A), stratumcorneum(SC)pH(B),andepidermalthickness(C)werecomparedateach sitebetweenoldC57BL/6(WT)andflakytailmice(FTM)(40-to90-week-old),as describedinthesupplementaryfile.N=7–9inA,N=5–8inB,andN=6–10inC.NS, notsignificant,*P<0.05,**P<0.01.