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    !