what’s new, what’s true? · genetic advances allowed reclassification of a subset of gpp as...
TRANSCRIPT
PediatricPsoriasis:What’sNew,What’sTrue?
KellyM.Cordoro,M.D.AssociateProfessorofDermatologyandPediatrics
UniversityofCalifornia,SanFrancisco
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.