Similarities and discrepancies between adult and paediatric disease - - PowerPoint PPT Presentation

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Similarities and discrepancies between adult and paediatric disease - - PowerPoint PPT Presentation

Apr 10, 2024 126 likes •565 views

Similarities and discrepancies between adult and paediatric disease and differential drug effects Frank M. Ruemmele IBD Clinics and Mucosal Immunology Program Pediatric Gastroenterology Hpital Necker-Enfants Malades, Paris INSERM U1163

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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

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SLIDE 2

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

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Paediatric or adult-onset IBD ?

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What signifies starting IBD 10-20 years earlier ?

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What signifies starting IBD 10-20 years earlier ?

Molinié et al, Gut 2004

EPIMAD Registry

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What signifies starting IBD 10-20 years earlier ?

Molinié et al, Gut 2004

EPIMAD Registry

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What signifies starting IBD 10-20 years earlier ?

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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

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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?)

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Genetic background and IBD

No ! Genetic susceptibility is not different between pediatric and adult-onset IBD

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Genetic background and IBD

Pediatric versus adult-onset IBD

Score 0:0

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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
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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%

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Frank Rümmele, Université Sorbonne Paris

Disease presentation

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Disease presentation at diagnosis

De Bie C IBD 2013, Israeli et al CGH 2014

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Disease presentation at diagnosis

36% 48% Vernier-Massouille et al Gastro 2008 Van Limbergen J et al. Gastro 2008 60% 10%

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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

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Disease presentation at diagnosis

Score 1:1

Frank Rümmele, Université Sorbonne Paris

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Predictors for severe disease evolution

N=1759 N=175 N=115

Lazarev M et al Am J Gastro 2013

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Predictors for severe disease evolution

Vernier-Massouille et al Gastro 2008

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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

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Lovasz B et al WJG 2013

Differing natural history

  • F. Ruemmele, Necker, Université Descartes, Sorbonne Paris Cité

Disease Evolution

Frank Rümmele, Université Sorbonne Paris

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Disease Evolution

Van Limbergen J et al Gastro 2008

Frank Rümmele, Université Sorbonne Paris

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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

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Disease Evolution

Score 2:2

Frank Rümmele, Université Sorbonne Paris

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Efficacy and Effectiveness data

Markowitz J et al., Gastroenterology 2000 6MP placebo

Frank Rümmele, Université Sorbonne Paris

Riello et al. IBD 2011

6 12 18 24 25 50 75 100

late early time (months) Patients in remission (%)

Clinical trial Cohort data

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Efficacy and Effectiveness data

Frank Rümmele, Université Sorbonne Paris

56 65 68 28 56 10 20 30 40 50 60 70 80 2.2 y 8 y

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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

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Efficacy/effectiveness

Score 3:3

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PK/PD?

Frank Rümmele, Université Sorbonne Paris

Kelsen JR et al. JPGN 2014

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PK/PD?

Frank Rümmele, Université Sorbonne Paris

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Dosing ?

Frank Rümmele, Université Sorbonne Paris

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PK/PD

Frank Rümmele, Université Sorbonne Paris

Score 4:3

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Side effects/safety

Imagine 1 vs Classic 1

Hyams Gastro 2012, Hanauer Gastro 2006

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Side effects/safety

CHARM Colombel et al Gastro 2007

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Side effects/safety

REACH vs ACCENT

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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

  • r 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

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Side Effects/Safety

Frank Rümmele, Université Sorbonne Paris

No doubt ! There is a clear difference between paediatric and adult-

  • nset IBD
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Side Effects/Safety

Frank Rümmele, Université Sorbonne Paris

Score 5:3

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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

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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
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frank.ruemmele@nck.aphp.fr

Thank you !