Lupusnephri+s
NephrologyforGeneralPaediatricsManchester,24thJune2016
Dr.LouiseOniNIHRClinicalAcademicLecturerPaediatricNephrology
AlderHeyChildren’sNHSFoundaAonTrustHospital&UniversityofLiverpool,Liverpool
Whydoesageneralpaediatricianneedtoknowaboutlupus…
SessionAims• Gainawarenessof
– JuvenileSystemicLupusErythematosus(SLE)inchildren– Introduc+ontoLupusnephri+s– Importanceofearlydiagnosis
• JSLEasadifferen+aldiagnosisinanypa+entwho‘doesn’tquitefitthebox’
Juvenile-onsetSystemicLupusErythematosus(JSLEorpaediatriclupus)
• Rare-incidence:0.3-0.9/100,000(SSNS3casesper100,000;IDDM207casesper100,000)
• Paediatric:15-20%ofalllupus• Ethnicvaria+on:morecommonAsian,BlackAfrican• F:Mra+o,5.6:1• Moresevere&moreac+vethanadultdisease
Tuckeretal,Lupus2008;Huangetal,ClinExpRheumatol2004;Huemeretal,JRheumatol2001;Bowyer,JRheumatol1995;Mallesonetal,JRheumatol1996
Ae+ology
GENETICSUSCEPTIBILITY
ABNORMALIMMUNESYSTEM
ENVIRONMENTALTRIGGERS
SLE
UVLIGHTEXPOSUREVIRUSES(EBV)
CIGARETTESMOKINGOCCUPATIONALHAZARDS
SEXHORMONESVITAMINDDEFICIENCY
TYPE1IFNCOMPLEMENTDEFICIENCESTNFPATHWAYSCYTOKINEBALANCES
UNSTABLE,DYSREGULATED,OVERACTIVE
Leeetal,Lupus2010,Cooperetal,Rheum2010
Coagulation pathway, red cell agglutination
Cell death and self nucleic material
Dendritic cell antigen presentation to B cells
Cytokines,chemokines,growthfactors
Toll like receptor activation T cell activation
Macrophage activation
YY
Y
Formation of autoimmune complexes
Cytokines
Interferon-α,β,γ
Liver
AcutephasereactantsChemokines
Complement pathway
Vasodila+on,+ssueinflamma+on,cellinfiltra+on,celldeath
Pathophysiologyoflupus
CNS• Asep+cmeningi+s• Cerebrovasculardisease• Demyelina+ngsyndrome• Movementdisorders• Myelopathy• Seizuredisorder• Acuteconfusion• Anxietydisorder• Cogni+vedysfunc+on• Mooddisorder• Psychosis
PeripheralNS• Guillain-Barre• Autonomicneuropathy• Mononeuropathy• Myastheniagravis• Cranialneuropathy• Plexopathy• Polyneuropathy
• Pleuritis • Pneumonitis • Pulmonary haemorrhage • Pulmonary embolism • Pleural effusions • Pulmonary hypertension • Interstitial lung disease • Myocarditis • Pericarditis / tamponade • Arrhythmias
• Autoimmunehepa++s
• Proteinloosingenteri+s
• Cholecys++s• pancrea++s
• Haemoly+canaemia• Thrombocytopenia• Lymphopenia• Leucopenia
MULTI-ORGANINVOLVEMENT
Diagnosis
Wongetal,ACR2004;Petrietal,ArthRheum2012
Tips for ANA results Can be positive in healthy kids ANA+54%healthycohort;43%1:40,1:80diluAon Present in 99% of JSLE cases Correlate clinically
Tips for dsDNA VeryspecificforJSLESeenin75%ofcasesHighvalue=ac+vedisease
Any4outof11criteriarequired
Recogni9oncanbedifficult!
• Ini+allymaynotfulfill
“diagnos+ccriteria”
• Widevaria+onofseverity
• Widedifferen+aldiagnosis
• Varietyofspecialists– Referralandmanagement
TypicalfeaturesofJSLEatpresenta+on
Renal
Haematological
Mucocutaneous
Cons+tu+onal
Musculoskeletal
Neurological
Cardiorespiratory
Gastrointes+nal
Ophthalmology
DatafromUKJSLECohortStudy,Watsonetal,2012
N=232UKpaAents
Pathophysiologyoflupusnephri+s
YYY
Cytokines
Cytokines,chemokines,growthfactors
Macrophage activation
Immune cell TLR activation
Cell death and nucleic material
Dendritic cell activation, antigen presentation to B cells
T cell activation
Interferon-α,β,γ
Formation of immune complexes
Y Y YYVasodila+on,+ssueinflamma+on,cellinfiltra+on,celldeath
Lupusnephri+spresen+ngfeatures
Weeningetal,JASN2004;15(2):241-250,VanTellingenetal,NethJMed2012;70(4):199-207
Noconsensusna+onally/interna+onally1. Diagnos+cuncertainty2. Renalindices:
• Ac+veurinesediment:pyuria(>5WCC/hpf),haematuria(>5RCC/hpf)orredcellcasts
• Proteinuria• Hypertension• Renalimpairment
WhentodoarenalbiopsyinLupus?
Hahnetal,ArthCareRes2013;64(6):797-808,VanTellingenetal,NethJMed2012;70(4):199-207
Ifques+oningrenalinvolvement
Biopsy
• Class I: Normal Glomeruli • Class II: Pure mesangial alterations • Class III: Focal Segmental GN • Class IV: Diffuse GN • Class V: Membranous GN
⇒ Severe Renal Disease
Lupusnephri+shistology
0
5
10
15
20
I II III IV V VI
Num
bero
fpa+e
nts
ISN/RPSLupusnephri+s
Lupusinves+ga+ons
Hollanderetal,ArthrRheum2013
Lupusmanagement
KDIGOclinicalprac+ceguidelineGN
ACRguidelinesforscreening,treatmentandmanagementofLN
EULAR/ERA-EDTAmanagementLN Consensustreatment
plansforinduc+onLN
Management:majororganInduc+onphaseCor+costeroids
IV30mg/kg(max1g)x3,PO≈1mg/kg/dayplus
Cyclophosphamide(0.5-0.75g/m2IVx6)or
MMF600mg/m2bd(max1.5gbd)
Maintenancephase
Cor+costeroids(<0.5mg/kg/day)plus
MMForAZA(2mg/kg/day)
Noresponse2ndline: Rituximab
3rdline: Ciclosporin,orTacrolimus,plusCor+costeroids Otherbiologics
NoresponseSwapinduc+on
therapy
ConsiderRituximab
Abou-Rayaetal.JRheumatol2013;40(3):265-72,Bacaetal.Lupus2006;15(8):490-5
6months
24+months
Defini+ons
• AimforcompleterenalresponsewithuPCR<50mg/mmolandnormalrenalfunc+on
• Par+alresponse:stabilisa+onorimprovementofcrea+nine,plus>50%decreaseinuPCR– ifnephro+crange<300mg/mmol
OutcomeAcutemortality• Infec+on• Disease:neurological,renal• Macrophageac+va+onsyndrome
Long-termoutcome• Mortality:1950’s~50%,Current:10yr~20%.• Damage~50-60%• Worseoutcome:Childhoodonset,male,renaldisease
Miegunenetal,JRheum2004;31(8):1650-4,Vachvanichsanongetal.ArchDisChild.2011;96(1):44-9,Vachvanichsanongetal.NDT.2009;24(9):2729-34,Faurschouetal,ArthCareRes,2010;62(6):873-880,Mahmoudetal.RheumatolInt.
2012;32(1):47-51
Renaloutcomes• 10-yearrenalsurvival83%
• Ethnicvaria+onUKcohort:19%Caucasians,62%BlackAfricanESRD
• Renalinvolvementindependentlylinkedtomortality
• Predictorsofpoorrenaloutcome• Non-responder• Elevatedbaselinecrea+nine• Persistentproteinuria• Delayintreatment
Miegunenetal,JRheum2004;31(8):1650-4,Vachvanichsanongetal.ArchDisChild.2011;96(1):44-9,Vachvanichsanongetal.NDT.2009;24(9):2729-34,Faurschouetal,ArthCareRes,2010;62(6):873-880,Mahmoudetal.RheumatolInt.
2012;32(1):47-51;Moketal,ArthrRheum2013
Whyisearlierdiagnosisimportant?
• Delaytodiagnosislinkedtoirreversibledamage
• SLEpa+entshave4.9xincreasedmortality– Acceleratedatherosclerosisseeneveninchildren– HighCVmorbidity
• Earlyintensivetreatmentcorrelateswithabeyerlong-termrenaloutcome.
LateefA,PetriM2012
DelayindiagnosisinUKchildren
0.00 2.50 5.00 7.50 10.00 12.50 15.00
Symptomonset
Presenta+ontoPaedRheum
Lupusdiagnosis
Meanpa+entage(years)
~2years10.8years
12.3years
12.5years
DatacourtesyoftheUKJSLECohortStudy,June2016
Meanageofsymptomonset,presenta+onanddiagnosisinJSLEpa+ents(N=430)
Lupuspresentstomanydifferentprofessionals
GPPaediatricianSub-specialistA&EAdultRheumNotspecified
52%
June2016;N=430
DatacourtesyoftheUKJSLECohortStudy,June2016
Clinicalcaseexample
• 15ygirl• May2012
– Nosebleeds,plateletcountof3-ITP• Aug2012
– Bleedingfrommouth– Bruising,petechialrash,+redness– Plt5,Hb14.1,WCC5.6– TreatedwithIVIG/steroids,plateletstransientlyup(68)– Nofurtherinves+ga+ons– SeenbyHaemadvisedmonthlyFBCorifsymptoma+c
Sept2012…
• Re-admiyed– Poormobility,+red,kneepain– Platelets5– Bonemarrow–ITP– CAMHSreview– Amitriptyline,codeine,pred(50mg,weaning)
Dec2012…– Bilateralfootdrop– Seenbyneurology– Nerveconduc+onstudies–distalmotor/sensoryneuropathy
– An+bodyscreensent:Highposi+veANA(>1:640),posi+vean+dsDNA,an+RoandLa,an+cardiolipinIgG
– ESR75– Platelets8
Jan2013rheumatology
• Mouthulcers• Urinedips+ck3+protein,2+blood
– Urinealbumin:crea+ninera+o75• Photosensi+verashappearing• Steroidtoxic• Lupusdiagnosis…8monthslater• Renalbiopsy:ClassIIILN• Steroidsparingtreatment
– Rituximab,Hydroxychloroquine,MMFDiseaseresponded,platelets>275,– proteinuriaresolved
x
x
x
x
x
x
Keylearningpoints• Diagnosiscanevolve…pastsymptomsimportant
• Cluestodiagnosisrequirespecificinves+ga+ons– UACR,auto-anAbodies
• Remainsuspiciousof‘atypical’cases
– Evenifunderspecialists,canquerydiagnosis
• Averageageatpresenta+onisduringteenageyears– ManyhaveseenCAMHSpriortodiagnosis
ThefutureforJSLE….
« Newbiologicmedica+ons« JSLEclinicaltrials« JSLECohortdata
« Lupusspecialists
« Transla+onalresearch
Whydoesageneralpaediatricianneedtoknowaboutlupus…
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Conclusion
• Lupusinchildrenisrare• Diagnosis:difficult,clinical&laboratory• >50%presenttotheirlocalpaediatrician• Diagnos+cdelay:common,worseoutcome
• Lupusnephri+s:requiresurinetes+ng,commonlyseen,linkedtomortality
• Futureispromising
AcknowledgementsUniLiverpool/AlderHeyChildren’sHospital• ProfMichaelBeresford• DrCarolineJones&colleagues• DrAngelaMidgley• OliviaLloyd• EmilyWilson• EveSmith• AprilVernon• TomMorgan• SunilSampath• DrGavinCleary• DrLizaMcCann• DrEileenBaildam• DrClarePain• RachelCorkhill• GrahamJeffers• CarlaRoberts
GreatOrmondStreetHospital• DrClarissaPilkington• DrKjellTullus• DrSteveMarksOther• Collabora+ngUKcentres
All the patients and families who participate in the study, along with ALL the clinicians,
nurses and healthcare professionals who are involved: THANK YOU!!
Benefactors (patients & families) who have so generously donated or fund raised
