similarities and discrepancies between adult and ... · no difference in clinical trials nor...
TRANSCRIPT
Similarities and discrepancies between adult and paediatric disease and differential drug
effects
Frank M. Ruemmele IBD Clinics and Mucosal Immunology Program
Pediatric Gastroenterology Hôpital Necker-Enfants Malades, Paris
INSERM U1163 Université Paris Descartes, Sorbonne Paris Cité
CONFLICT OF INTEREST
NONE for this report
But Research Funding and Speaker fees
from AbbVie, Celegen, Centocor, Danone, Ferring, J&J, Mead Johnson,
MSD, Nestlé, Shering-Plough
Paediatric or adult-onset IBD ?
What signifies starting IBD 10-20 years earlier ?
What signifies starting IBD 10-20 years earlier ?
Molinié et al, Gut 2004
EPIMAD Registry
What signifies starting IBD 10-20 years earlier ?
Molinié et al, Gut 2004
EPIMAD Registry
What signifies starting IBD 10-20 years earlier ?
What signifies starting IBD 10-20 years earlier ?
Genetic Defects
Environnemental factors
Maximal = monogenetic
multiple - polygenetic
adult-onset pediatric-onset early-onset very
early-onset
Crohns disease IL10 KO etc.
birth 2 years 8-16 years adulthood
Genetic background and IBD
5p13
10q21
ATG16L
PTPN2
NKX2-3
IRGM
3p21
7p12 ICOSLG
6q27 21q21
6q21 17q21
CDKAL1 17q21
IL12B 13q14
1q32 12q12
1q24 c11orf30
1q23 10p11
1q13 9p24
8q24
IL23R TNFSF15 IBD5
NOD2
2007 2008 2006 2005 2000
Prior to GWAS WTCCC GWAS
Early GWAS GWAS meta-analysis
~20% genetic risk ~ 10% overall risk
Pediatric Specific Genes ? Kugathasan et al. Nature Genetics 2008 2 loci (DcR3?) Imielinski et al. Nature Genetics 2009 5 loci (IL27?)
Genetic background and IBD
No !
Genetic susceptibility is not
different between pediatric
and adult-onset IBD
Genetic background and IBD
Pediatric versus adult-onset IBD
Score 0:0
Adult IBD
Pediatric IBD
Is it just a matter of size
??
F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité
Frank Rümmele, Université Sorbonne Paris
Disease presentation at diagnosis
36% 48%
Vernier-Massouille et al Gastro 2008 Van Limbergen J et al. Gastro 2008
60% 10%
Frank Rümmele, Université Sorbonne Paris
Disease presentation
Disease presentation at diagnosis
De Bie C IBD 2013, Israeli et al CGH 2014
Disease presentation at diagnosis
36% 48%
Vernier-Massouille et al Gastro 2008 Van Limbergen J et al. Gastro 2008
60% 10%
Disease presentation at diagnosis
Yes and No!
Disease presentation is not different
between pediatric and adult onset IBD
but there is a trend to a more frequent
panenteric presentation in children
Frank Rümmele, Université Sorbonne Paris
Disease presentation at diagnosis
Score 1:1
Frank Rümmele, Université Sorbonne Paris
Predictors for severe disease evolution
N=1759 N=175 N=115
Lazarev M et al Am J Gastro 2013
Predictors for severe disease evolution
Vernier-Massouille et al Gastro 2008
Pigneur et al IBD 2009
N= 206 N= 412
Differing natural history
F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité
Disease Evolution
Frank Rümmele, Université Sorbonne Paris
Lovasz B et al WJG 2013
Differing natural history
F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité
Disease Evolution
Frank Rümmele, Université Sorbonne Paris
Disease Evolution
Van Limbergen J et al Gastro 2008 Frank Rümmele, Université Sorbonne Paris
Disease Evolution
Frank Rümmele, Université Sorbonne Paris
Yes and No!
Several studies indicate a more severe
disease evolution in pediatric versus
adult onset IBD, but not all
Disease Evolution
Score 2:2
Frank Rümmele, Université Sorbonne Paris
Efficacy and Effectiveness data
Markowitz J et al., Gastroenterology 2000
6MP
placebo
Frank Rümmele, Université Sorbonne Paris
Riello et al. IBD 2011
0 6 12 18 240
25
50
75
100 late
early
time (months)Pa
tient
s in
rem
issi
on (%
)
Clinical trial Cohort data
Efficacy and Effectiveness data
Frank Rümmele, Université Sorbonne Paris
56 65 68
28
56
01020304050607080
2.2 y
8 y
Efficacy/effectiveness
No!
No difference in clinical trials nor
real-world cohorts for the drug
responses between child- or
adulthood onset IBD
Frank Rümmele, Université Sorbonne Paris
Efficacy/effectiveness
Score 3:3
PK/PD?
Frank Rümmele, Université Sorbonne Paris Kelsen JR et al. JPGN 2014
PK/PD?
Frank Rümmele, Université Sorbonne Paris
Dosing ?
Frank Rümmele, Université Sorbonne Paris
PK/PD
Frank Rümmele, Université Sorbonne Paris
Score 4:3
Side effects/safety
Imagine 1 vs Classic 1
Hyams Gastro 2012, Hanauer Gastro 2006
Side effects/safety
CHARM
Colombel et al Gastro 2007
Side effects/safety
REACH vs ACCENT
Side effects/safety:HSTCL
Data on file, Centocor (PSUR 24, July 2011) See also: Mackey AC, et al. J Pediatr Gastroenterol Nutr. 2007;44:265-267; Rosh JR, et al. IBD. 2007;13:1024-1030; Shale M, et al. Gut. 2008;57: 1639-1641; Cucchiara S, et al. J Pediatr Gastroenterol Nutr. 2009;48:257-267.
• Infliximab treatment duration ranged from < 6 months to more than 5 years of therapy
• 87% (27/31 cases) were in males and 67% (20/30 known cases) were ≤ 30 years
HSTL cases, N
Deaths due to HSTL,
n/N
Underlying pathology
Exposure to AZA or 6-MP,
n/N
Exposure to biologic, n/N
31 26/31
CD – 25/31 UC – 4/31 IC – 1/31 Unknown – 1/31
30/31 (Unknown – 1/31)
IFX – 23/31 Other anti-TNFα – 6/31 Natalizumab – 1/31 Unknown – 1/31
• Reporting period: August 1998 – June 2011
Frank Rümmele, Université Sorbonne Paris
Side Effects/Safety
Frank Rümmele, Université Sorbonne Paris
No doubt !
There is a clear difference
between paediatric and adult-
onset IBD
Side Effects/Safety
Frank Rümmele, Université Sorbonne Paris
Score 5:3
Conclusion
Frank Rümmele, Université Sorbonne Paris
Pediatric and adult-onset IBD are to > 90%
the same diseases, but
• Children probably have a more
extensive and more aggressive disease
Urgent need for efficient medication
Conclusion
Frank Rümmele, Université Sorbonne Paris
Data from RCT in adult IBD cohorts
• Can easily be extrapolated to children
with IBD
• Should help to design appropriate
paediatric IBD trials
• Addressing PK/PD issues
• Safety issues
