similarities and discrepancies between adult and ... · no difference in clinical trials nor...

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

frank.ruemmele@nck.aphp.fr

Thank you !