what’s new, what’s true? · genetic advances allowed reclassification of a subset of gpp as...
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PediatricPsoriasis:What’sNew,What’sTrue?
KellyM.Cordoro,M.D.AssociateProfessorofDermatologyandPediatrics
UniversityofCalifornia,SanFrancisco
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Disclosures
ConsultantforPfizer,CelgeneandValeant.
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What’sNew,What’sTrue?
TheStrepStory
ComorbiditiesandScreening
MonogenicVariants
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EnvironmentalFactors
GeneticSusceptibility
Adaptive and Innate Immune
Responses
HLA-Cw6dominant
suscept allele.~50%ofheritability,earlyonsetpso.
Guttatepsoriasis,severity,chronicity.
39 geneticlocimaptoimmunepathogenesispathways(TNF,IL-12,IL-23R,IL-17).
Psoriasis:complex
inflammatorydisease
Lu Y et al. 2013
Identifiabletriggers
commoninkids,
especiallyinfections.
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Strepasatriggermay impartfavorableprognosis.
Koetal.JDermatol2010:-Precedingstreppharyngitispredictedguttatemorphologyandeventualresolution
Mercyetal.PediatrDermatol2013:-Precedingstreppharyngitispredictedguttatemorphologybutnotseverity
-Initialguttatemorphologyinabsenceofstreppredictedprogressiontoseverepso
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Pediatr Dermatol. 2013 Jul-Aug;30(4):424-8.
Clinical Approach: Guttate Psoriasis
Strep may impart a favorable prognosis, look for and treat it.
Consider more aggressive management in strep negative cases
given risk of progression to severe disease.
Especially FHx +
Thorleifsdottir RH J Immunol 2012
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Strep and Psoriasis
…for patients with recurrent guttate psoriasis or chronic plaque psoriasis,
there is to date no good evidence that antibiotics or tonsillectomy are beneficial.
Published Online: 24 APR 2000
Notallstrepisinthetonsils.
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PediatricPsoriasisComorbidityUpdate
• 1/3ofpatientsdeveloppsoriasisbeforeage20– Manybeforeage2
• Doesthecomorbidityclockstarttickinginchildhood?
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High riskbehavior
Quality of Life
Mood Disorders
Arthritis Lymphoma?
Autoimmune Diseases/IBD
Metabolic Syndrome
CVD?
Obesity
Pediatric Psoriasis
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Quality of Life
Mood Disordersanxiety/depression
Obesity
Best Evidence
PalleretalNEJM2008
Koebnick etalJPediatr2011
CordoroetalInProg 2017
Boccardi etalBJD2009
Augustin BJD2010
ZhuetalJDermatol 2012
PalleretalJAMADerm 2013
Kimballetal.JAAD2012
DeJager etalBJD2010
Bilgic etal.Ped Derm 2010
TollefsonMM.PCNA2014
Remrod etal.BJD2013
Kimetal.Ped Derm 2015
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Metabolic SyndromeLess
Evidence
HypertensionDyslipidemia
InsulinResistance/DM
In absence of obesity,less evidence for association with
other components of metabolic syndrome.
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Metabolic Syndrome
At risk for CVD?
Obesity
?HypertensionDyslipidemia
InsulinResistance/DM
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Psoriasisconfersanindependentrisk foratherosclerosis,MI,stroke
andearlyCV-relatedmortality.
Neimann.JAAD2006.GelfandJM.ArchDerm2007.Prodanovitch.ArchDerm.2009.
Persistentsystemicinflammationisproposedtocontributetothisassociation.
Brauchli2008;Spah,BJD2008;Ahlehoff- DanishStudy,2011.
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SeverePsoriasis
SystemicInflammation
Atherosclerosis
EndothelialDysfunction
InsulinResistance
ThromboticEventMI/Stroke
Boehnckeetal.ExpDermatol2011Boehncke&SchönLancetMay2015
PsoriaticMarchConceptproposedtoexplainhowseverepsoriasisdrives
CVmorbidity/mortality.
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OBESITY
SystemicInflammation
Atherosclerosis
EndothelialDysfunction
InsulinResistance
ThromboticEventMI/Stroke
Boehnckeetal.ExpDermatol2011Boehncke&SchönLancetMay2015
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Ifthepsoriaticmarchisreal,wemaybeabletopreventtheprogressionbymodifyingpsoriasisseverityandobesity.
NijstenT,WakkeeM.JID2009.Horreauetal.JEADV2013.Dowlatshahietal.JID201. Wooton,BJD2013.
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Finally!1st systemictherapyapprovedtotreat
pediatricpsoriasis.
11/4/16:FDAapprovesEnbreltotreatchildrenwithplaquepsoriasis4+.
• Otherbiologicapprovalsareonthehorizon– UstekinumabsubmittedtoFDA
– IL-17inhibitorsandPDE4(apremilast)inpediatrictrialscurrently
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BilgicetalPediDerm2010KimetalPediDerm2010KimballetalJAAD2012TodbergTetalBJD2016TollefsonetalJAAD2017
Psychiatric and Emotional Comorbidities
AnxietyDepression
Bipolar disorderEating disordersSocial isolation
Risky behavior (drugs, alcohol)Poor QOL
Caregiver QOL
Situationaland intrinsic.
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Depression
Obesity
Psoriasis
Reciprocalexacerbatingfactors.
Eachrepresentsaninsulttoself-esteemandoverallwell-being.
Highstresslevels. Poorqualityoflife.
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Whattodoingeneral?
Remainvigilantateachvisit.
Identifythoseatgreatestrisk.Overweightandobese;severedisease;lowmood,riskybehaviors.
Refertorelevantexpertsforhelp.Obesity/nutritionexperts
Psychologists,therapists,psychiatrists
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– Overweight,Obesity– Hypertension– Dyslipidemia– Type2Diabetes– NAFLD
– InflammatoryBowelDisease– PsoriaticArthritis– DepressionandAnxiety– SubstanceAbuse– QualityofLife
Drs.EOsier,AWang,LEichenfield- UCSD
Amultidisciplinaryinitiativetocreateaguidancedocumentforpractitionersbasedonthebestavailableevidence.
NPFandPeDRACSI:ComorbidityScreeningInitiative
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CSI:ScreeningforPsoriasisPatientsAged2-21
• Bloodpressure
• BMI(bodymassindex)
• Arthritisscreen– Jointpain/swelling/inflammation– Jointstiffnessafterrestorsleep– Limp
• Mooddisordersscreen– Anxiety,depression,substanceabuse
AnnualAdditionalscreeningforDM,dyslipidemiaandfattyliverbasedonweight,otherrisk
factors.
Key:ScreeningguidelinesdonotexceedAAPorEUage-
basedscreeningrecs.
Osieretal.JAMADerm 2017.
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Whattodospecifically?
InvolveprimarycareMD.Psoriasiscomorbidityscreeningrecsdonotdepartfrom
AAPorEUage-basedrecs.
JAMA Dermatol. Published online 5/17/17.
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ClinicalVariantsofPustularPsoriasis
PustularPsoriasis
Palmoplantar Pustular
GPP without Plaque
GPP with Plaque
Neonatal Onset GPP
AcrodermContinuaHallopeau
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GeneticAdvanceshaveReclassifiedaSubsetofGPPasMonogenicAutoinflammatory Disorders
PustularPsoriasis
Palmoplantar Pustular
GPP without Plaque
GPP with Plaque
Neonatal Onset GPP
AcrodermContinuaHallopeau
ARMutationsinIL36RNDITRA
IL36RN
IL36RN
CARD14
ARMutationsinIL1RNDIRA
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PustularPsoriasis
GPP without Plaque
Neonatal Onset GPP
ARMutationsinIL36RNDITRA
ARMutationsinIL1RNDIRA
lead to unopposed pro-inflammatory signaling
by IL -1 α and β.
lead to unopposed pro-inflammatory signaling
by IL36 α β and γ.
MonogenicAutoinflammatory DisordersDuetoMutationsinGeneswithintheIL-1Superfamily
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Sugiura et al. JAAD 2014.
DITRA:Def ofIL-36RAntagonist.IL36inepithelial(skin,GI)tissues.
InfantoradultonsetGPP;ofteninabsenceofpsoriasisvulgaris.
IL-1Rantagonistmaywork.
DIRA:DefofIL-1RAntagonist.
IL1αactiveinepithelia,bone,CNS.
PerinatalonsetGPP,multifocalasepticosteomyelitis,periostitis.
IL-1Rantagonistseffective.
Cowen E. JAMA Derm, 2012.
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Sugiura et al. JAAD Vol 71;5, 2014.
DITRA: Def of IL36 R Antagonist.Inherited and sporadic cases reported.
Range of phenotypes is evolving. Definitive Rx not yet identified.
Response to Anakinra (2 months only).Rossi-Semerano et al. Pediatrics 2013;132:e1043
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HolyGrail:PersonalizedMedicine
Cordoro et al. JAAD 2017.
DecreasedexpressionofIL-17+CD4+ andCD8+ Tcellscomparedtoadultpsoriasis
IncreasedexpressionofIL-22+CD4+ andCD8+ Tcellscomparedtoadultpsoriasis
Pediatric Psoriasis Tissue Immunophenotype
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KeyMessages:PrognosisandComorbidities
Identifyat-riskpatients,optimizephysicalandmentalhealthtohaltprogression/preventdownstreameffects.
Recentdatasuggestcourse/severityimpactedby+/- strep,ageofpsoriasisonsetandfamilyhx ofpsoriasis.
Obesityandpsychosocialimpairmentaredominantcomorbidites.Inabsenceofsigns/sx,evidencedoesnotsupportlabscreeningbeyond
standardizedage-basedpediatricguidelines.
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KeyMessages:MonogenicVariantsofGPP
Utilizeacollaborativeapproachonyourpatient’sbehalf.Youmayhelpyourpatientandlearnsomething.
GeneticadvancesallowedreclassificationofasubsetofGPPasmonogenicAIdiseases.SpecificRxbygenotype(DIRA).
Moleculartechniquescanclarifyaffectedtissueimmunephenotypesandindividualizetherapychoices.