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)

-­‐ a bad disease!

CHRONIC

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 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

Inflammatory signatures /biomarkers

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

BrainWorks website

Information sharing -­ Knowledge translation

http://www.sickkids.ca/Research/Brainworks/Welcome/Welcome.html…or google childhood CNS vasculitis

BrainWorks

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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