Exciting developments  : how to choose the right medicine in JIA and how to predict response to the treatment.

1. Exci%ng
developments
:
how
to
choose
the
right
medicine
in
JIA
and
how
to
predict
response
to
the
treatment.
Lucy R Wedderburn
Professor of Paediatric Rheumatology,
Director, Arthritis Research UK Centre for Adolescent Rheumatology
UCL GOS Institute for Child Health
PReS ENCA meeting
Genoa Italy
September 2016

2. Disclosures:
• Pfizer
led
symposium
PRES
2016
• Contribu%ons
to
CHART-­‐JIA
Consor%um
–
Janssen,
Pfizer
and
Roche
• Abbvie
– Expert
Panel
on
JIA
– Support
for
mee%ng
London,
March
2016

3. “JIA” is an umbrella term
oligo
persistent
poly
RF+ve
ERA
psoria%c
systemic
poly
RF-­‐ve
Oligo
extended
JIA:
• Affects 1 in 1000 children
• Starts before age of 16 yr
• Arthritis in one or more
joint for > 6 weeks
• Of no known cause

4. Immune
cells

5. An%-­‐TNF
An%-­‐IL-­‐6
An%-­‐
IL-­‐1
An%-­‐CD20
The ‘arsenal’ of inflammation

6. Drug
name Trade
name Type
of
molecule Target
Etanercept Enbrel
Soluble
p75
TNF
receptor,
as
fusion
protein
to
Ig
TNFa
Infliximab Remicade Monoclonal
Ab
to
TNF,
chimeric TNFa
Adalimumab Humira
Monoclonal
Ab
to
TNF,
humanised
TNFa
Anakinra Kineret
Human
receptor
antagonist
IL-­‐1Ra
IL-­‐1
Canakinumab Ilaris
Monoclonal
Ab
to
IL-­‐1,
humanised
IL-­‐1
Tocilizumab Roactemra
Monoclonal
Ab
to
IL-­‐6R,
humanised
Il-­‐6
Rituximab Rituxan
Monoclonal
Ab
to
CD20,
chimeric
B
cells
Abatacept Orencia
Human
CTLA4
as
fusion
protein
(CTLA4-­‐Ig)
CD80/86

7. Quality of
life
Toxicity,
disability
Time
Fail
DRUG
A
DRUG
B
Fail
Fail
DRUG
C
DRUG
D
Genotype
RESPONDERS
Variation in response to medication

8. How
can
we
switch
off
the
arthri%s
?

9. The example of systemic JIA
1990s
blood
serum
IL-­‐6
and
IL-­‐1
are
high
in
sJIA
2000s
a
drug
to
block
an%
IL-­‐6
is
available
2005,
2008:
an%
IL-­‐6
effec%ve
in
sJIA
2012
big
study
of
an%-­‐IL6R
in
sJIA
Approval
for
an%
IL-­‐6
therapy
Now
widely
in
use
in
sJIA…
Rooney
et
al
1995

10. Problem: not all children with sJIA need Tocilizumab,
not all respond to Tocilizumab,
some need Anakinra, some get MAS

11. How
can
we
switch
off
the
arthri%s
?
BLOOD JOINT
IL-­‐17
making
cells
Healthy
Arthri%s
Arthri%s
blood
joint
Nistala
et
al
Arth
and
Rheum
2008

12. Extended-to-be JIA: predicting how the
arthritis will develop from the joint fluid

13. Extended-to-be JIA: predicting how the
arthritis will develop from the joint fluid
Hunter
et
al,
Arthri%s
and
Rheum,
2010
severe
(extended)
Oligo-
Articular
arthritis
One year
Diagnosis Outcome
Sample
mild
(persistent)

14. Extended-to-be JIA: can we predict how the
arthritis will develop from the joint fluid
Persistent Extended-to-be
0 +2.7-2.7
Genes expressed
Hunter
et
al,
Arthri%s
and
Rheum,
2010
p
e
r
s
i
s
t
e
n
t
e
x
t
e
n
d
e
d
-
t
o
-
b
e
0
.
0
0
.
5
1
.
0
1
.
5
2
.
0
2
.
5
3
.
0
3
.
5
Ratio CD8:4 cells

15. How can we predict response ?
JIA
Predict
response
to
treatment
Start
drug
Predict
effect
of
stopping
treatment
Measure
response

16. The
use
of
tools
or
biomarkers
to
group
pa%ents
by
chance
of
responding
to
a
treatment
or
medicine,
chance
of
a
side
effect,
or
mechanism
of
disease,
to
help
decide
treatment
choice
Stratified medicine

17. What makes a good biomarker for
predicting response to treatment
• Reliably
predicts
the
future
• Easy
to
measure
• Available
without
causing
upset
to
child
• Economical
to
test

18. How can we progress towards
stratified medicine ?
6 (4-8)0 months
Start drug
Data, sample Data, sample
Define
response:
…..
Offer
the
chance
to
be
in
research
to
all
families

19. Biomarkers in serum for JIA:
prediction of flare after stopping MTX
Foell
et
al,
J
Amer
Med
Assn
2010
Outcome after stopping MTX
MRP8/14serumlevelbeforestoppingMTX

20. Biomarkers
in
serum
for
JIA:
predic%on
of
response
S100A8/A9 ( MRP8/14)
(ng/ml)
NR/ACR30 ACR50/ACR70
An%-­‐TNF
Moncrieffe
et
al,
Rheumatology
2013;
Anink
et
al,
Arth
Res
Therapy,
2015

21. Stratified medicine in JIA in the UK
!
CHildhood Arthritis Response to Treatment Consortium
Childhood
arthri%s
prospec%ve
study
CHARMS
Childhood
arthri%s
response
to
medica%on
study

22. Stratified medicine meeting in JIA, 2016
!CHildhood Arthritis Response to Treatment Consortium
CARRA
Pharmachild
PRCSG
PRINTO
CCHMC
BIKER
Jumbo
ReachOut
CAPRI
Clarity
CHARMS
CAPS
BCRD
BSPAR
Etanercept
Study
25 World
experts
from
17 ins%tu%ons
and
18 8
countries
including
the
following
studies………………

23. What do we need to achieve stratified medicine
1. Family
and
pa%ent
voice
is
KEY
!
2. All
children
need
to
have
standardised
data
collected
3. Agree
upon
targets
of
treatment
(subtype
specific)
4. Parallel
specimens
stored
where
possible
5. Trials
to
include
bio-­‐specimens
pre
drug
6. Strong
interna%onal
collabora%ons

24. THANK
YOU
for
listening
and
lets
discuss
!