Date post: | 11-Apr-2017 |
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Pediatric Vasculitis Initiative
March 2017CORD Vancouver
David Cabral, Pediatric Rheumatologist PI
Co-‐investigators: Susanne Benseler; Dirk Foell; Jinko Graham:Bob Hancock; Raashid Luqmani; Colin Ross
A CIHR Emerging Team Grant in Rare Disease (2012)
Multifactorial / polygenic Autoimmune / Inflammatory
Several diseases
Severe, treatable, relapsingØ Toxic++ treatments
Very rare in childhood
CHRONIC VASCULITIS
Single organ vasculitisPACNSCutaneous Vascultiis
Multifactorial / polygenic Autoimmune / Inflammatory
Several diseases
Severe, treatable, relapsingØ Toxic++ treatments
Very rare in childhood
CHRONIC VASCULITIS
AAV: ANCA associated vasculitisGPA: Granulomatosis with polyangitisMPA: Microscopic polyangiitis
PACN: Primary angiitis of the central nervous system
Single organ vasculitisPACNSCutaneous Vascultiis
Is Childhood Vasculitis the same as in Adults?Ø What is the outcome for kids?
Which type of vasculitis is it?Ø Does it matter?
Do we always need the most toxic treatment?
When do we stop /restart medicines?
from Doctors & families
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Feb 2012: PedVas Grant
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Feb 2013: First biosamples
DATA48 sites,10 countries
Patients485 systemic
vasculitis(263 CNS vasculitis)
BIOLOGICAL SAMPLES ` 21 sites, 7 countriesPatients165 kids(RNA, DNA, serum, plasma, urine)277 adults DNA (17 with RNA)
PedVas cumulative data & samples
2006ArchiveLaunchVF
ChallengesDifficulties in cIinical data versus biosamples!
• ethics approval 2-‐12 months- blood collection & cross border shipping
• contract negotiations 1-‐13 months- between universities because of funding provided
• workload (& costs) - for training, blood versus saliva-‐sampling & shipping
• Some countries sites prohibit release of biosamples
Average Study start-‐up taking up to 12 months per site (ethics approval, contract negotiation, laboratory set-‐up, training)
Comparing presenting clinical features of 48 children with MPA against 183 having GPA• Evaluating new adult GPA classification in children• Gene expression & targeted SNP to distinguish GPA / MPA
Early Outcomes in Children with GPA/MPA • Predicting early outcome and damage esp. kidney failure
Inflammatory signatures /biomarkers
PROJECTS
…PROJECTS
Clinician Needs Assessment Survey: Towards developing consensus treatment plans for GPA/MPA • Developing web-‐based online teaching modules for physicians• Establishing consensus treatments for GPA/MPA • Comparing old and new treatments within our registry
COLLABORATIONSCARRACANCVASCDCAVAS
Supports existing vasculitis registries to collect & analyse clinical data, biological samples & KT.
• Initial focus GPA, MPA, & PACNS
PedVas
Nonprogressive,Angiography-‐positive CNS vasculitisN=180
Progressive,Angiography-positive CNS vasculitis N=37
Small vessel Angiography-negative CNS vasculitis N=94
Secondary CNS vasculitisN=59
AB mediated IBrainDN=69
• Clinical phenotypes
• Treatment• Outcome
in 397 children with CNS vasculitis
Search for CNS vasculitis biomarkers
Von Willebrand Factor Antigen
Gene expression profiles in brain tissue
http://www.sickkids.ca/Research/Brainworks/Welcome/Welcome.html…or google childhood CNS vasculitis
BrainWorks
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500Prior to 20
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0920
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1120
1220
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1420
1520
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Feb 2012: PedVas Grant
awarded
Feb 2013: First biosamples
PedVas cumulative data & samples
2006Archivelaunch
Challenges Clinical vs clinical data collection
National policies prohibitive
workload (& costs) • Training bio-‐sampling, shipping
ethics approval • biosamples, cross border
shipping• 2-‐12months
contract negotiations • Because of funding • 1-‐13 months
Av startup 12 months
Current StatusSite recruitment – 48 sites from 10 countries contributing clinical data– 21 sites from 7 countries with ethics for biosampling
Clinical data – 485 systemic vasculitis patients– 263 primary CNS vasculitis patients
Biological samples – 165 pediatric patients contributed (RNA, DNA, serum, plasma, urine)
– 277 adults with vasculitis contributed DNA samples (17 with RNA)
Comparing presenting clinical features of 48 children with MPA against 183 having GPA• Evaluating new adult GPA classification in children• Gene expression & targeted SNP to distinguish GPA / MPA
Early Outcomes in Children with GPA/MPA
• Predicting early outcome and damage • Renal Trajectories and Outcomes
• Evaluating disease activity biomarkers (CRP, platelets,S100A12, Anti-‐LAMP2 antibodies)
• Gene expression identifying persisting inflammatory signatures in patients in clinical remission
Preliminary Data: Biological Measures of Disease Activity
S100A12 measured healthy people and children with vasculitis
Serum S100A12 levels are highest at the time of diagnosis when vasculitis is most active. (More sensitive than ESR & CRP)
Levels decline after treatment, but rarely reaches levels measured in serum from healthy individuals
Preliminary data suggest that vasculitis remains active after treatment and when clinical measures might suggest otherwise.
Preliminary Data: Biological Measures of Disease Activity
Blood cells from healthy people and children with vasculitis are analyzed for similar patterns of gene expression;; samples that are most similar are closest together on the plot
Preliminary data reveals abundance of active inflammatory genes in blood cells from children with vasculitis.
Many of these genes remain expressed 12 months post diagnosis when there are few overt symptoms of disease.
PROJECTSClinical• Comparing presenting clinical features of 48 children with
MPA against 183 having GPA
• Early Outcomes in Children with MPA/GPA
• Clinician Needs Assessment Survey: Towards developing consensus treatment plans for MPA/GPA
• Incorporation of established treatment protocols to Brainworks CNS vasculitis website
• Distinct Phenotype Clusters in Childhood Inflammatory Brain Diseases: Implications for Diagnostic Evaluation
In ProgressClinical• Evaluating new adult GPA classification in pediatric cohort• Predicting early outcome and damage for ANCA Vasculitis• Renal Trajectories and Outcomes in Pediatric ANCA Vasculitis• Developing web-‐based online teaching modules for physicians• Health-‐related quality of life in children with primary CNS vasculitis
Biological• Gene expression & targeted SNP to distinguish GPA / MPA• Assessing S100A12 with other routine inflammatory biomarkers to
improve disease activity assessment• Anti-‐LAMP2 antibody -‐associated disease activity in pediatric vasculitis• Gene expression identifying persisting inflammatory signatures in
patients in clinical remission• Genotype-‐phenotype relationship in PAN patients with ADA2 deficiency• In vitro modeling of vascular endothelial homeostasis and activation