paediatric inflammatory bowel disease
TRANSCRIPT
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Paediatric Inflammatory Bowel Disease
Prof Andrew Day Paediatric Gastroenterologist
Christchurch, NZ
PIBD
Case reports What is IBD all about Approaching and diagnosing IBD Management principles The future
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JF 13 year old boy
Presents with 18 m abdo pain, weight loss (7 kg),
lethargy 12 m no increase in height 6 m loose motions (mucousy)
JF
No longer swimming Missing school ++ Mother Crohn’s colitis from 18 y Uncle & cousin Coeliac disease
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JF
ESR 55 Albumin 27 Platelets 558 Hb 97 CRP 43 ? IBD - scopes & small bowel imaging
BM Follow Through Wall thickening Irregularity TI stricture
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JF UGIE: erythematous stomach: granulomatous
gastritis Colonoscopy: aphthoid ulceration ileo-caecal
region, active and chronic inflammatory changes
JF Long history pain, diarrhoea, weight loss Ileocolonic CD with upper gut involvement
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JF
Commenced on Exclusive Enteral Nutrition 9 drinks daily 8 weeks
Commenced Azathioprine week 2
Full dose week 4
JF
Week 2 CRP 17, Weight gain 1.2 kg Back to school, energy improved
Week 8 CRP 4, ESR 13, Alb 36 Weight gain 5.3 kg
Ongoing followup…
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CH – 12 year old boy
Diarrhoea 6 weeks 3-4 day/ 1-2 nocte Bloody, loose, mucous occ vomit intermittent pain weight loss (1-2 kg) anorexia, lethargy
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CH
Stools (x4) WBC+++ No Clostridium, no pathogens
Calprotectin >500 ESR 2, CRP<3 Platelets & Albumin normal
CH
Normal upper gut Rectum to splenic - ulceration, exudate, loss
of markings, friable Proximal colon and TI normal
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CH
CH
Upper gut histology normal Active chronic colitis (rectum to splenic),
with cryptitis, crypt destruction. No granulomata.
Proximal colon/TI normal
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CH
Short history Left sided colitis, no other involvement Ulcerative colitis
CH
Oral pentasa Rectal pentasa enemas Progressive improvement over first 7-10 days Back to school, improved energy Ongoing followup
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Soranus of Ephesus
AD130 Described diarrhoeal
disease
Description of IBD
Dr. Dalziel
“I can only regret that the aetiology of the condition remains in obscurity but I trust that ere long further consideration will clear up the difficulty.” BMJ, 1913
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Crohn et al
Initial description of what is now known as Crohn’s disease in 1932 Crohn BB, Ginzburg L, Oppenheimer GD. Regional Ileitis, a pathologic and clinical entity JAMA,1932; 99
What is IBD?
Relapsing/remitting, chronic (life-long) gut inflammation
Crohn’s disease (CD) - throughout gut Ulcerative colitis (UC) – colon only also IBD Unclassified (IBDU)
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Pathogenesis of IBD
Interactions between bacteria and gut epithelium in a genetically susceptible host
leads to dysregulated immune response
GENETICS BACTERIA
IMMUNE RESPONSE
Triggering event
Genes Environment Intestinal bacteria
Immune system Non-immune defenses
INTESTINAL INFLAMMATION
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BACTERIA
NOD 2
INFLAMMATORY RESPONSE
Early onset genes
TNF-α promotor IL-10 receptor Others…
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IBD: family history common
Children 20-25% family history (adults 10-15%)
Twins identical 30-35%, non-identical 8%
Relatives 1st degree relatives 8-10% non-relatives 1:1000
Ethnicity
Intestinal flora central to health
1013 bacterial cells: ~ 1.5 kg 1012 cells in human body Individual profile of bacteria
unique
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Putative infectious agents
Mycobacterium tuberculosis Listeria monocytogenes Shigella sp. Yersinia sp. Bacteroides vulgatus Measles virus Escherichia coli subtypes
Mucous-associated bacteria may play role in gut inflammation
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Kaakoush et al, PlosOne 2011
Gut Bacteria & IBD
Not specific infection ? Bacterial component(s) ? Different response to a bacteria that we all
have Variation in bacterial patterns between IBD
and non-IBD
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Which kids get IBD ?
Most common second decade - but can be
ANY AGE Boys slightly more often than girls
Age at diagnosis APAIBD 0-18yr 1996 - 2006
0
25
50
75
100
125
150
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17AGE AT DIAGNOSIS (years)
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Increasing rates of IBD
CD continues to increase Decreasing age Increasing in new countries
Are children
little adults??
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NO!!
Disease location: CD
PAEDS ADULTS Ileal 6 16 Colonic 36 45 IleoColonic 53 39 Upper Gut 62 5
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Disease location: UC
PAEDS ADULTS Proctitis 4 38 Left sided 17 43
PanColonic 71 13
Upper gut in children
86 children with new IBD (55 CD) 50% upper gut findings 9 diagnosed solely on UGIE 13 with CD diagnosed correctly with UGIE Lemberg et al, J Gastro Hepatol 2005
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Crohn’s disease presentation
Abdominal pain
Diarrhea
Weight Loss
Loss of appetite
Fever & Fatigue
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Prevalence of symptoms at presentation (1990-9)
CD UC (n=386) % (n=195) %
Pain 86 69 Diarrhoea 78 93 Blood 49 95 Weight loss 80 55 Joint symptoms 17 8
AM Griffiths, HSC
Typical CD Presentations HSC 1980-9 (n=299)
Classical 78.6 % Growth Failure 3.3 Extraintestinal 8.4 Anaemia 2.7 Perianal disease 3.7 Anorexia 2.0 Operation for pain 1.3
Griffiths AM, Adolescent Med 1995
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Delayed Presentation in Australia
677 children 12.6 yrs 405 CD, 85 IC, 187 UC. Delay 26 (12-52) wks CD
21 (11-40) wks IC 12 (8-26) wks UC (p<0.0001)
Time to diagnosis inversely proportional to age
Growth and nutrition in children with IBD
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Nutritional consequences in Paediatric IBD
Weight loss in 85 % CD and 65 % UC at
presentation (Seidman et al, JPGN, 1991)
Decreased oral intake (pain, anorexia)
Malabsorption Increased expenditure
Growth and Paediatric IBD
Chronic malnutrition may lead to impaired linear growth and delayed pubertal development
CD more than UC Especially in early adolescence (usual rapid
growth) Boys > girls (later and longer puberty)
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Approach to ?IBD
Exclude other causes of symptoms: define inflammatory markers
Diagnostic features:
radiological endoscopic histological features
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Standard Markers in IBD
Hb, Alb, ESR & Platelets in 526 children All 4 normal in 21% CD & 54% mild UC 4% normal in moderate-severe CD/UC ESR normal in 26%: Hb 32%: platelets 50%:
Albumin 60%
Mack et al, Pediatrics 2007
CRP, ESR, Albumin or Platelets?
Number of Abnormal tests
0 1 2 3 4 __________________________________________________________________ CD (n=144) 19 25 26 24 52 UC (n=27) 4 7 5 3 8 IBDU (n=28) 10 5 8 2 3
Day et al, Unpublished data
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Porto Criteria
Management of Paediatric IBD
Paediatric setting
Child and family focused
Multi-disciplinary input
Cater to all aspects
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IBD
Growth Nutrition
Education
Social Puberty
QOL
Treatment
Family
Induction of Remission
Enteral feeds (EEN) Steroids Salicylates /ASA (UC) Antibiotics Tacrolimus (or Cyclosporin) Biologics Surgery
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Maintenance of remission
ASA (UC) Imuran/6MP Methotrexate Maintenance Enteral Nutrition Biologics Other
EEN and IBD 1
Initial report: Elemental feeds in adult CD O’Morain BMJ 1984
Polymeric shown to be as effective Exclusive administration important
Murphy JPGN 2001
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EEN and IBD 2
More effective in children than adults More effective in primary than secondary Less effective for colitis alone As good as steroids (in children)
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EEN
Polymeric formula Exclusive 8 weeks Predominantly oral Support/encouragement etc Few side-effects
EEN
Induction of remission Improved disease activity Weight gains Many more benefits…
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EEN & mucosal healing
RCT of polymeric EEN vs steroids Mucosal healing at week 10
74% of EEN group 33% of steroid group
Borrelli et al. Clin Gastro Hepatol 2006; 4: 744
Control CD Baseline CD Post EEN0
1
2
3
4
p=0.002p=0.0003p>0.05
Seru
m C
ross
Laps
(ng/
ml)
Less bone resorption (Crosslaps) & EEN
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Biologic therapies
As more of the complex puzzle of immune system in gut is explained, more places to focus new therapies:
Development of biologic therapies
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Infliximab
First biological agent to be used in Crohn’s Given to > 1 million people worldwide in last
decade Indications: Severe, unresponsive disease
Fistulizing disease
Dosing: 5 mg/kg at 0, 2, and 6 weeks
Structure of Infliximab
Native (mouse) Antibody
Humanized (Primatized™)
Chimeric
Infliximab - a chimeric antibody (25% mouse derived, 75% human protein)
Human Protein
Mouse Protein
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Infliximab: Mechanism of Action Binds & neutralizes soluble & membrane bound TNFα - inhibits further activity
Receptor
Nucleus
NFκB transcription
No Signal
= TNFα
Adalimumab
Humanised anti-TNF Subcutaneous – fortnightly
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Natalizumab
Α4β1 Integrin inhibitor (CNS and gut) IV injection CD (and MS) Associated PML
Vedolizumab
Gut selective integrin antagonist α4β7 integrin
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Certolizumab
Pegylated anti-TNF inhibitor (Cimzia) Monthly s.c. injections CD
Others on the horizon…
Mongersen – oral, enhances TGF-β Golimumab – human IgG1 monoclonal TNFα Tofacitinib – JAK inhibitor Ustekinumab – IL-12/IL-23 (p40) inhibitor Faecal Transplant – cautious anticipation Mesenchymal stem cells
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Worm therapy The Hygiene Hypothesis
Less exposure to infections including parasites
Infections impt in development of immune
system in gut ? Different responses without early priming
“Worm therapy”
Pig whip-worm (Tricuris suis) Infects pigs: no human infection Trials with eggs (TSO): transiently live in gut Change type of response in the gut
Prevent release of inflammation-causing proteins Promote release of protective proteins
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“Worm therapy” in adults
UC: 13 of 30 (43.4 %) got better with TSO over 12 weeks (controlled with placebo).
CD: 21 of 29 (72.4%) under control at 12 and 24 weeks
Treatment safe in short term No long-term data Subsequent data less clear