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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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Alfred the Great

AD 850 King Alfred Long-term GI illness ? witchcraft CD

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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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Crohn’s disease

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Crohn’s

Crohn’s disease

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UC - pancolitis

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Ulcerative Colitis

Ulcerative Colitis

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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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# 16: CARD 15/NOD 2

30 % CD: 5 % UC: 5% Controls

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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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Who gets 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

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