Leading transformational change: inner and outer skills
RDD Conf Day 2: Pediatric Vasculitis Initiative, David Cabral, British Columbia Children’s Hospital
1. Pediatric
Vasculitis Initiative
March
2017
CORD
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)
3. Multifactorial
/
polygenic
Autoimmune
/
Inflammatory
Several
diseases
Severe,
treatable,
relapsing
Ø Toxic++ treatments
Very
rare
in
childhood
CHRONIC VASCULITIS
Single organ vasculitis
PACNS
Cutaneous Vascultiis
4. Multifactorial
/
polygenic
Autoimmune
/
Inflammatory
Several
diseases
Severe,
treatable,
relapsing
Ø Toxic++ treatments
Very
rare
in
childhood
CHRONIC VASCULITIS
AAV: ANCA associated vasculitis
GPA: Granulomatosis with polyangitis
MPA: Microscopic polyangiitis
PACN: Primary angiitis of the central nervous system
Single organ vasculitis
PACNS
Cutaneous Vascultiis
5. 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
6. 0
50
100
150
200
250
300
350
400
450
500 Prior
to
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Feb
2012:
PedVas
Grant
awarded
Feb
2013:
First
biosamples
DATA
48 sites,10 countries
Patients
485 systemic
vasculitis
(263 CNS vasculitis)
BIOLOGICAL
SAMPLES
` 21 sites, 7 countries
Patients
165 kids
(RNA, DNA, serum,
plasma, urine)
277 adults
DNA (17 with RNA)
PedVas cumulative data & samples
2006
Archive
Launch
VF
7. Challenges
Difficulties
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)
8. 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
9. …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
COLLABORATIONS
CARRA
CANCVASC
DCAVAS
20. 0
50
100
150
200
250
300
350
400
450
500 Prior
to
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Feb
2012:
PedVas
Grant
awarded
Feb
2013:
First
biosamples
PedVas cumulative data & samples
2006
Archive
launch
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
21. Current
Status
Site
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)
22. 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
23. 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.
24. 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.
25. PROJECTS
Clinical
• 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
26. In
Progress
Clinical
• 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