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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
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
“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
Immune cells
An%-‐TNF An%-‐IL-‐6 An%-‐ IL-‐1 An%-‐CD20
The ‘arsenal’ of inflammation
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
Quality of lifeToxicity, disability
Time
Fail
DRUG A
DRUG B
Fail
Fail
DRUG C
DRUG D
Geno
type
RESPONDERS
Variation in response to medication
How can we switch off the arthri%s ?
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
Problem: not all children with sJIA need Tocilizumab, not all respond to Tocilizumab,
some need Anakinra, some get MAS
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
Extended-to-be JIA: predicting how the arthritis will develop from the joint fluid
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)
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
How can we predict response ?
JIA Predict
response to treatment
Start drug
Predict effect of stopping treatment
Measure response
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
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
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
Biomarkers in serum for JIA: prediction of flare after stopping MTX
Foell et al, J Amer Med Assn 2010
Outcome after stopping MTX
MR
P8/
14 s
erum
lev
el b
efor
e st
oppi
ng M
TX
Biomarkers in serum for JIA: predic%on of response
S100A8/A9 ( MRP8/14)
(ng/
ml)
NR/ACR30 ACR50/ACR70
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An%-‐TNF
Moncrieffe et al, Rheumatology 2013; Anink et al, Arth Res Therapy, 2015
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
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………………
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
THANK YOU for listening and lets
discuss !