PediatricPsoriasis:What’sNew,What’sTrue?

KellyM.Cordoro,M.D.AssociateProfessorofDermatologyandPediatrics

UniversityofCalifornia,SanFrancisco

Kelly.cordoro@ucsf.edu

Disclosures

ConsultantforPfizer,CelgeneandValeant.

What’sNew,What’sTrue?

TheStrepStory

ComorbiditiesandScreening

MonogenicVariants

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.

Strepasatriggermay impartfavorableprognosis.

Koetal.JDermatol2010:-Precedingstreppharyngitispredictedguttatemorphologyandeventualresolution

Mercyetal.PediatrDermatol2013:-Precedingstreppharyngitispredictedguttatemorphologybutnotseverity

-Initialguttatemorphologyinabsenceofstreppredictedprogressiontoseverepso

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

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.

PediatricPsoriasisComorbidityUpdate

• 1/3ofpatientsdeveloppsoriasisbeforeage20– Manybeforeage2

• Doesthecomorbidityclockstarttickinginchildhood?

High riskbehavior

Quality of Life

Mood Disorders

Arthritis Lymphoma?

Autoimmune Diseases/IBD

Metabolic Syndrome

CVD?

Obesity

Pediatric Psoriasis

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

Metabolic SyndromeLess

Evidence

HypertensionDyslipidemia

InsulinResistance/DM

In absence of obesity,less evidence for association with

other components of metabolic syndrome.

Metabolic Syndrome

At risk for CVD?

Obesity

?HypertensionDyslipidemia

InsulinResistance/DM

Psoriasisconfersanindependentrisk foratherosclerosis,MI,stroke

andearlyCV-relatedmortality.

Neimann.JAAD2006.GelfandJM.ArchDerm2007.Prodanovitch.ArchDerm.2009.

Persistentsystemicinflammationisproposedtocontributetothisassociation.

Brauchli2008;Spah,BJD2008;Ahlehoff- DanishStudy,2011.

SeverePsoriasis

SystemicInflammation

Atherosclerosis

EndothelialDysfunction

InsulinResistance

ThromboticEventMI/Stroke

Boehnckeetal.ExpDermatol2011Boehncke&SchönLancetMay2015

PsoriaticMarchConceptproposedtoexplainhowseverepsoriasisdrives

CVmorbidity/mortality.

OBESITY

SystemicInflammation

Atherosclerosis

EndothelialDysfunction

InsulinResistance

ThromboticEventMI/Stroke

Boehnckeetal.ExpDermatol2011Boehncke&SchönLancetMay2015

Ifthepsoriaticmarchisreal,wemaybeabletopreventtheprogressionbymodifyingpsoriasisseverityandobesity.

NijstenT,WakkeeM.JID2009.Horreauetal.JEADV2013.Dowlatshahietal.JID201. Wooton,BJD2013.

Finally!1st systemictherapyapprovedtotreat

pediatricpsoriasis.

11/4/16:FDAapprovesEnbreltotreatchildrenwithplaquepsoriasis4+.

• Otherbiologicapprovalsareonthehorizon– UstekinumabsubmittedtoFDA

– IL-17inhibitorsandPDE4(apremilast)inpediatrictrialscurrently

BilgicetalPediDerm2010KimetalPediDerm2010KimballetalJAAD2012TodbergTetalBJD2016TollefsonetalJAAD2017

Psychiatric and Emotional Comorbidities

AnxietyDepression

Bipolar disorderEating disordersSocial isolation

Risky behavior (drugs, alcohol)Poor QOL

Caregiver QOL

Situationaland intrinsic.

Depression

Obesity

Psoriasis

Reciprocalexacerbatingfactors.

Eachrepresentsaninsulttoself-esteemandoverallwell-being.

Highstresslevels. Poorqualityoflife.

Whattodoingeneral?

Remainvigilantateachvisit.

Identifythoseatgreatestrisk.Overweightandobese;severedisease;lowmood,riskybehaviors.

Refertorelevantexpertsforhelp.Obesity/nutritionexperts

Psychologists,therapists,psychiatrists

– Overweight,Obesity– Hypertension– Dyslipidemia– Type2Diabetes– NAFLD

– InflammatoryBowelDisease– PsoriaticArthritis– DepressionandAnxiety– SubstanceAbuse– QualityofLife

Drs.EOsier,AWang,LEichenfield- UCSD

Amultidisciplinaryinitiativetocreateaguidancedocumentforpractitionersbasedonthebestavailableevidence.

NPFandPeDRACSI:ComorbidityScreeningInitiative

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.

Whattodospecifically?

InvolveprimarycareMD.Psoriasiscomorbidityscreeningrecsdonotdepartfrom

AAPorEUage-basedrecs.

JAMA Dermatol. Published online 5/17/17.

ClinicalVariantsofPustularPsoriasis

PustularPsoriasis

Palmoplantar Pustular

GPP without Plaque

GPP with Plaque

Neonatal Onset GPP

AcrodermContinuaHallopeau

GeneticAdvanceshaveReclassifiedaSubsetofGPPasMonogenicAutoinflammatory Disorders

PustularPsoriasis

Palmoplantar Pustular

GPP without Plaque

GPP with Plaque

Neonatal Onset GPP

AcrodermContinuaHallopeau

ARMutationsinIL36RNDITRA

IL36RN

IL36RN

CARD14

ARMutationsinIL1RNDIRA

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

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.

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

HolyGrail:PersonalizedMedicine

Cordoro et al. JAAD 2017.

DecreasedexpressionofIL-17+CD4+ andCD8+ Tcellscomparedtoadultpsoriasis

IncreasedexpressionofIL-22+CD4+ andCD8+ Tcellscomparedtoadultpsoriasis

Pediatric Psoriasis Tissue Immunophenotype

KeyMessages:PrognosisandComorbidities

Identifyat-riskpatients,optimizephysicalandmentalhealthtohaltprogression/preventdownstreameffects.

Recentdatasuggestcourse/severityimpactedby+/- strep,ageofpsoriasisonsetandfamilyhx ofpsoriasis.

Obesityandpsychosocialimpairmentaredominantcomorbidites.Inabsenceofsigns/sx,evidencedoesnotsupportlabscreeningbeyond

standardizedage-basedpediatricguidelines.

KeyMessages:MonogenicVariantsofGPP

Utilizeacollaborativeapproachonyourpatient’sbehalf.Youmayhelpyourpatientandlearnsomething.

GeneticadvancesallowedreclassificationofasubsetofGPPasmonogenicAIdiseases.SpecificRxbygenotype(DIRA).

Moleculartechniquescanclarifyaffectedtissueimmunephenotypesandindividualizetherapychoices.

Thankyou!kelly.cordoro@ucsf.edu