final evolution of ibd 2012 naspghan

12/13/2012

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Subra Kugathasan, MDProfessor of Pediatrics & Human genetics

Marcus Professor of Pediatric Gastroenterology

Emory University & Children’s Healthcare of Atlanta

Evolution of IBD: Research Lessons Learned

I have the following financial relationships to disclose:JanssenUCB

IBD: The Pediatric Burden & the impact of Pediatric IBD research

• 1.2 million people with IBD in the US, estimated 80‐100,000 children with IBD

• About 20‐25% of all IBD is diagnosed during the pediatric age

• Identification of BIOTYPE = Genotype + Phenotype+ Immunotype + Bacteriotype + ??? clearest in pediatric IBD leading to Risk stratification and personalized therapy in IBD.

• The cause of IBD !• Differential diagnosis between CD and UC (colonic disease)

• Limited endoscopic approaches & lack of good small bowel imaging

• Surgery: the only answer to failure of medical therapy (sulfasalazine and steroid)

• Complete lack of studies in the pediatric age group while knowing pediatric disease is different from adult disease?

• Inability to induce long lasting remission (& mucosal healing)

Major Issues in IBD Diagnosis and TherapyPlagued us over the last few decades!

• IBD epidemiology & natural history

• Pediatric disease activity index: PCDAI & PUCAI

• TNF in stool leading to discovery of anti‐TNF as groundbreaking therapy in IBD

• Gene discoveries and therapeutic targets

• Microbiome, diet and intestinal inflammation

• Risk Prognostication in IBD

• Evolution of collaborative research in pediatrics compared to single center/investigator effort

Evolution of IBD:What have we learned in the last 50 years?

Agenda for the talk

Evolution of IBD epidemiology and natural History

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Rising Incidence‐global trends

Crohn’s disease Ulcerative Colitis

Molodecky, Gastroenterology, 2012

Worldwide IncidenceCrohn’s disease Ulcerative colitis

Benchimol, Inflamm Bowel Dis, 2011

Rising Incidence, becoming stablein Omstead county, MN

•Incidence rates of CD and UC increased after 1940•Incidence stable recently

Crohn’s disease Ulcerative Colitis

Loftus, Inflamm Bowel Dis, 2007

Incidence: Pediatric IBD

Overall incidence of IBD: 9.5 per 100,000 Incidence stable over last 8 years

Adamiak, Inflamm Bowel Disease, in press 2012

Rising incidence of UC in Korea

Yang S‐K et al, J Gastroenterol Hepatol, 2000

• Incidence in Korea increased 3‐4 decades after North America and Western Europe• Might this be due to “Westernization”?

Incidence in Indian Migrants to UK

Probert CS, et al. Gut, 1992 Jayanthi et al, Quarterly J of Medicine, 1992Carr I, Am Journal of Gastroenterol Yang S, Inflamm Bowel Dis, 2001

IBD incidence in South Asian migrants ≥ Western‐born population

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Regional Variation: Crohn’s disease prevalence

200 (192‐209) * 213 (206‐220) * 211 (204‐217) *

180 (174‐186)

Kappelman, Clin Gastroenterol Hepatol, 2007

Evolution of IBD epidemiology and natural History

Research Lessons learned• World-wide increase in IBD

• Globally, IBD is still raising• Incidence stabilized in western countries!• Increasing in developing countries & new

populations – where the research should be targeted!!

Development of Pediatric Disease Activity Indices:

PCDAI & PUCAI

ITEM POINTS

1. Abdominal pain No pain Pain can be ignored Pain cannot be ignored

0 5 10

2. Rectal bleeding None Small amount only in < 50% of stools Small amount with most stools Large amount (>50% of the stool content)

0 10 20 30

3. Stool consistency of most stools Formed Partially formed Completely unformed

0 5 10

4. Number of stools per 24 hours 0-2 3-5 6-8 >8

0 5 10 15

5. Nocturnal bowel movement (any diarrhea episode causing wakening)

No Yes

0 10

6. Activity level No limitation of activity Occasional limitation of activity Severe restricted activity

0 5 10

SUM OF PUCAI (0-85)

The PUCAI

Turner et al; Gastroenterology 2007;133:423‐432

• Abdominal pain (0‐10)• Stools/bleeding (0‐10)• Functioning/well being (0‐10)• Laboratory:

• Hct (0‐5• ESR (0‐5)• Albumin (0‐10)

• Weight (0‐10)• Height velocity (z score) (0‐10)• Abdominal exam (0‐10)• Perirectal disease (0‐10)• EIM (0‐10)

The PCDAI

Hyams et al. JPGN 1991;12:439 Turner et al. Gastroenterology 2007;133:423‐432

r=0.78; n=76

Gastroenterology 2007;133:423–432 and unpublished data (DT)

Colonoscopic Score

(0‐15)

PUCAI score

Correlation of the PUCAI with colonoscopy

Studies evaluating the PCDAI & PUCAI in different scenarios

• Inflamm Bowel Dis 2011; 17(8):1726‐30

• JPGN 2011;52: 708–713

• Gut 2010;59(9):1207‐1212

• Gastroenterology 2010;138(7):2282‐2291


• J Clin Epidemiol 2010; 63(1):28‐36

• Clin Gastroenterol Hepatol2009;7(10):1081‐8


• J Clin Epidemiol 2009;62(4):374‐379

• J Clin Epidemiol 2009;62(7):738‐744

• Gut 2008; 57:331‐338

• Gastroenterology 2007;133:423‐432


(Pediatric Infliximab trial)


(Pediatric Adalilumab trial)

• J Pediatr Gastroenterol Nutr2007;44:185‐91

(Pediatric Natalizumab trial)

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TNF in stool leading to discovery of anti‐TNF as groundbreaking

therapy in IBD

Different anti‐TNF: comparable results(Years 2000 to 2006)

Response† Remission Response‡ Remission Response‡ Remission

27.0

51.0

21.0

39.0

Hanauer SB et al. Lancet. 2002;359:1541–1549.Colombel J et al. Gastroenterology. 2006;131:950.Schreiber S et al. NEJM. 2007;357:239‐50.

Week 26–30

26.0

52.0

17.0

40.0

62.8

36.2

47.9

28.6

Infliximab 5 mg/kg

ACCENT 1n = 113

CHARMn = 172

PRECiSE 2n = 215

Adalimumab 40 mg EOW Certolizumab pegol 400 mg every 4 weeks

Placebo Placebo Placebo

*

**

***

***

***

***

REACH: Pediatric CD infliximab trialAnti‐TNF therapy is highly efficacious in inducing remission

88

64

33

59 56

24

0102030405060708090

100

Week 10 Week 54 q8 Week 54 q12

Response Remission% of Patients

n = 99 n = 66 n = 29n = 33 n = 17 n = 12

p = 0.002

p < 0.001

Hyams J, et al. Gastro 2007;132:863‐873

Early aggressive biologic therapy induced more mucosal healing than conventional management of Crohn’s disease

(n=26)Early aggressive

(n=23)Conventional therapy

p=0.003

% Patients with m

ucosal healing

73

30

0

100

D’Haens G, et al. Lancet 2008;371:660‐7.

Lichtenstein GR, et al. Gastroenterology 2005;128:862

Anti‐TNF: fewer surgeries and post‐surgical recurrence

100

125 Placebo maintenance (n=99)

Cumulative number of surgeries and procedures

Weeks

Randomization0

25

50

75

2 6 14 22 30 38 46 54

Infliximab 5 mg/kg maintenance (n=96)

RegueiroM, et al. Gastroenterol 2009;136:441‐450.

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• 10 year old presented with rectal bleeding, perianal pain

• Growth failure and iron deficiency anemia

• Exam under anesthesia & MRI: recto‐labial fistula and perianal fistulae

• Endoscopy: severe left sided Crohn’s colitis & inflammation

• Induction with ‘top down’ biologic therapy rather than ‘step up’ therapy

Before After

Anti‐TNF: ‘Top down’ Evolution in the initial approach in pediatric IBD Crohn’s disease: therapeutic evolution

1979 SulfasalazineSteroids

1980Antibiotics6‐MP

1993 5‐ASA

1994Budesonide

1995 Methotrexate

1998 Infliximab

2005Second‐

generationbiologicals

Adapted from Rutgeerts PJ. Rev Gastroenterol Disord. 2004;4(suppl 3):S3‐S9.

1980 1990 2000

Steroids vs 6-MP for maintenance of remission in pediatric Crohn’s

30

40

50

60

70

80

90

100

0 50 100 150 200 250 300 350 400 450 500 550 600

Days Since Remission Induction

% o

f P

atie

nts

in

Re

mis

sio

n

P<.007

91%

53%

At baseline, patients received prednisone plus either 6‐MP or placebo. Steroids were tapered after induction of remission.

Markowitz J et al. Gastroenterology. 2000;119:895.

Steroids & 6‐MP

Steroids only

Pediatric CD Registry and Wisconsin population-based cohort study

Time point N % on AZA/

6-MP/MTX

At diagnosis 578 21%

30 days 525 41%

3 months 515 56%

1 year 410 69%

2 years 276 76%

Adamiak et al. Inf lammatory Bowel Diseases 2012 (in press)

Increased time‐dependent exposure to immunomodulators

and anti‐TNF agents in pediatric IBD (2002‐2007)

Markowitz J et al. Clin Gastroenterol Hepatol. 2006;4:1124

Crohn’s disease

Ulcerative colitis

Infliximab: Cumulative Commercial Patient exposure by Indication

PSUR 23: August 24, 2010 – February 23, 2011

Total Patients TreatedWorldwide: 1,537,395

Hepatosplenic T‐cell Lymphoma in Infliximab‐treated Patients: Cumulative Review

• 27 reported/possible cases

– All were reported between 2002 and February 2011

– All patients had reported exposure to azathioprineor 6‐mercaptopurine

– 5 cases with another anti‐TNF‐α antagonist

– 26 confirmed cases reported to be HSTCL, all in IBD (22 CD, 4 UC)

– 23 cases have been fatal

Data on File, Janssen Biotech, Inc.

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The therapeutic “pendulum”

2004 – everyoneon combinationtherapy

2008 – everyone onbiologic or Immunomodulatormonotherapy

2012 – more use of combination therapy

Pediatric IBD; impact of HSTCLis HUGE

What we have:Fatal form of lymphoma Large, population-based FDA mandated

registry (DEVELOP -short and long-term) is ongoing.

What we need:More follow upRisk stratification and translational studies

Genetics of IBD and therapeutic targets

Timeline of genetic discoveries in IBD

1988 20011996 2006‐7 2012 beyond2008‐9 2010

Twin studies

Linkage studiesIDB1; IBD2

NOD2IBD5

CD GWASTNFSF15, IL23R;ATG16L1; IRMG;

NKX2.3

1st CD meta‐analysis:30 confirmed CD loci

UC GWAS: IL10, IFNγ, HNF4α Pediatric GWAS: IL27, CAPN10

2nd CD meta‐analysis:71 confirmed CD loci

1st UC meta‐analysis:47 confirmed CD loci99 confirmed IBD loci

Innate Immunity (CD)

• Th17 pathway (IBD)• Autophagy (CD)• Defective barrier

function (UC)

• Fine mapping of existing loci• Missing heritability• Genotype‐phenotype correlation• Metagenetics• Disease biology• Biomarker of disease severity• Pharmacogenomics• Genomic‐based therapeutic targets

Immunochip163 confirmed IBD lociloci overlap with mycobacterial infection.Pathways are shared with host response

Tysk et al. Gut 1988;29:990‐996Hugot JP et al. Nature 1996;379:821–3Ogura Y et al. Nature 2001;411:603–6Barrett JC et al. Nat. Genet; 40:955‐962Franke A et al. Nat. Genet; 42:1118‐25Anderson CA et al. Nat. Genet; 43:246‐52

Many loci are shared, few are specificLoci segregates specific disease mechanism

CDIBD

UC

Innate ImmunityNOD2; LRRK2

Function not clearly definedNKX2‐3; CREM; C11Orf30; ORMDL3; RTEL1; PTGER4; KIF21B; CDKAL1; ZNF365

Receptor Signaling pathwayMST1; IL10; CARD9; REL; PRDM1; TNFSF15; IL1R2; YDJC; SMAD3; PTPN2

Adaptive immunityIL‐23 /Th17 pathwayIL23R; IL12B; TNFSF15; TYK2; JAK2; ICOSLG; STAT3; IL21

HLADRB103

Epithelial barrier

ECM1HNF4ACDH1LAMB1GNA12

AutophagyNOD2ATG16L1IRGM

Epithelial BarrierMUC19ITLN1

Cell migration

ARPC2LSP1

AAMP

Less organ‐specific, More mechanism/pathway oriented

Lees et al Gut 2011

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Clinical and therapeutic valueof genetic discoveries in IBD

Gut 2009;58:1612

Inflamm Bowel Dis 2010;16:2090

Inflamm Bowel Dis 2010;16:1357 Inflamm Bowel Dis 2011;17:179

Children carrying 34 or more of the common CD risk

alleles have a ~13-fold increased risk of developing CD,

and children carrying 20 or more of the common UC risk

alleles have a ~7-fold increased risk of developing UC

Imielinski M et al. Nat Genetics 2009;41:1335

Inflamm Bowel Dis 2011;17:1830

These initial findings need replication in large, well phenotyped and prospective cohorts

These initial findings need replication in large, well phenotyped and prospective cohorts

From gene discovery to IBD pathways

Gut 2011;60:1739‐1753

AutophagyNOD2; ATG16L1; IRGM; LRRK2PARK7; DAP

ER stressCPEB4; SERINC3

Cell migrationARPC2; LSP1; AAMP

Apoptosis /necroptosisFASLG; THADA; DAP

Oxidative stressPRDX5; BACH2; ADO; GPX4; GPX1; SLC22A4; LRRK2; NOD2HSPA6; DLO; PARK7

Epithelial barrierMUC19; ITLN1GNA12; HNF4A; CDH1; ERRF11

RestitutionSTAT3;PLA2G2A/E; HNF4A; ERRF11

Paneth cellsITLN1; NOD2; ATG16L1

Innate mucosal defenseNOD2; ITLN1; SLC11A1; FCGR2A/B

Antigen presentationERAP2; LNPEP; DENND18

IL‐23 / Th17STAT3; IL21

T‐cell regulationNDFIP1; TAGAP; IL2RIL2; TNFRSF9; PIM3; IL7R; TNFSFB; IFNG

B‐cell regulationIL5; IK2F1; BACH2;IL7R; IRF5

Immune toleranceIL27; SBNO2; NOD2; IL1R1 / IL1R2

Main pathways identified so far

Drug-mediated modulation of autophagy

Rubinzstein D et al. Nat Rev Drug Discovery. 2007;6:304

Massey D et al. Gut 2008;57:1294

Use of sirolimus (rapamycin) to treat refractory Crohn’s disease

Gene discovery can help in diagnosis and therapy

Allogeneic bone marrow transplantation could cure severe & early onset IBD

Gut 2012;61:7 1028‐1035

Glocker EO et al. The NEJM 2009;361:2033-2045

Muise, Snapper, Kugathasan. Gastroenterology, 2012

Evolution of IBD Genetics and therapeutic targets

Research Lessons learned

• CD and UC are very closely related.

• Genetics of IBD is shared with many other complex disorders. The genetic research has become less organ-specific, but focuses of molecular level and common pathways.

• Identification of clusters of ‘Bio-types’ can be used to target specific biological pathways.

• Firm genomic diagnosis can be used for definitive therapies to reverse the IBD

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Microbiome, diet and intestinal inflammation

Evidence for gut microbial dysbiosis in IBD

R Balfour Sartor and Sarkis K Mazmanian. Am J Gastroenterol 2012

Our environment determines the compositionof the gut microbiota

http://www.springerimages.com/Images/RSS/1‐10.1007_s12263‐011‐0226‐x‐0

Westernized lifestyle

Decreased microbial exposure

Reduced microbiota diversity

Chronic inflammatory diseases

Dysregulation of the immune system

Susceptible host

The hygiene hypothesis

Manichanh, C. et al. Nat. Rev. Gastroenterol. Hepatol. 9, 599‐608 (October 2012)

Changes in lifestyle alter the gut microbiota

Modern lifestyle in year 2012 !

Lifestyle: 50 yrs ago in Western world

Antibiotics and Pediatric IBD

Case control of all children born in Finland between 1994‐2008. • IBD diagnoses and antibiotic

ascertained through national registries

• For CD, repeated exposure increased risk

• No risk of abx during 1st year of life

Virta, Am. J. Epidemiology, 2012

CDN=233

UCN=362

Adjusted OR 2.1 (1.0‐4.4) 1.1 (0.7‐1.8)“Dirty” pigs

(Outdoor environment)

“Clean” pigs(Indoor environment + antibiotics)

Gut floraMore Firmicutes,

mostly LactobacillaceaeLess enterobacteria

Gut floraLess Firmicutes,

fewer LactobacillaceaeMore enterobacteriaGene expressioninflammation,

cholesterol synthesis

Gene expressionBalanced immunity

Mulder Iet al. BMC Biol 2009;7:79

Experimental evidence supporting the hygiene hypothesis

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Summary of gut microbiota main composition in IBD

Mulder I. et al. BMC Biol 2009;7:79

Phylotype Healthy Disease (IBD) ‘Clean’ Pigs ‘Dirty’ pigs

Firmicutes

Bacteroidetes

Proteobacteria

Frank et al PNAS 2007 Manichanh C et al Gut. 2006:205‐11

Diet shapes the gut microbiota

Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14691‐6

Rural Africa (Burkina Faso)

Urban Europe (Florence, Italy)

High carbohydrate, fiber and non‐animal protein Children breast‐fed up to the age of 2

Typical western diet high in animal protein.Children breast‐fed for up to age of 1.

Dietary patterns are associatedwith specific gut microbial patterns

Wu G et al. Sciencexpress / September 1, 2011 / 10.1126/science.1208344

CarbohydratesProtein & animal fat

Nickerson & McDonald (unpublished data)

Western diet (malto +)Normal diet (malto -)

FL82 AIEC biofilm formation

Maltodextrin: a common additive that improvestexture and palatability found in many foods, sweeteners (Splenda), drugs, cosmetics, etc.

Intestinal epithelial cells (HT29) infected with salmonella in the absence (normal diet) and presence (Western diet)of matodextrin: malto suppresses autophagy ➞ less killing ➞ more residual colonies ➞excess of bacteria

Modulation of bacterial function

by food additives

Different bacterial species induce different phenotypes of colitis in IL-10-deficient mice

Kim et al. Gastroenterology 2005

Germ-freeNo colitis

Commensal bacteria Pancolitis(Right sided)Onset 1 wk

E. faecalis Left sided10-12 wks

E. coli Right sided3 weeks

E. coli + E. faecalis Pancolitis1 week

D’ Haens G et al., Gastroenterology 114:262, 1998

Recurrence of ileal Crohn’s diseasebefore and after infusion of intestinal contents

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Evolution of collaborative researchin pediatrics compared to

single center/investigator effort

From single center/investigators to

multi‐center, multi‐investigator studies

Risk Stratification (Prognostication) in IBD

Frequency of Disease Behavior %

Number of immune responses (serology)

More antibody types, more disease risk

Inflammatory

Penetrating

Stricture

0N=199

1N=262

2N=194

3N=57

Surgery

Dubinsky MC et al CGH 2008;6:1105

Study:

Genetic makeup

Bacteria in bowel

Serology (reactive to bacteria, food, infections, etc)

Environmental exposures

1200 children with Crohn’sdisease at diagnosis

3 year follow up160 – 200 patients with complication / surgery

ControlCD

Preliminary microbial analysis from the RISK cohort

• MiSeq 16S rRNA gene sequencing (V4)

• ~10k filtered seqs/sample

• 61 CD, 31 control

• CD: 51 no complications, 10 w/ complications

RISK study team & PROKIIDS consortiaBroad: Dirk Gevers, Rob Knight, Ramnik Xavier and Curtis Huttenhower

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In patients with ileal CD Ruminococcaceae, and Faecalibacterium were dramatically decreasedcompared to control subjects

Fusobacteria - Fusobacteria - Fusobacteriales - Fusobacteriaceae - Fusobacterium

In patients with ileal CD Fusobacteria were dramatically increasedcompared to control subjects

Preliminary microbial analysis show bothdecreased and increased taxa in risk cohort Fecal microbiota transplant for IBD

17 case series: 41 patients with IBD (27 UC)

• reduction of symptoms: 76%

• cessation of IBD medications: 76%

• disease remission: 63%

• resolution of concurrent C. difficile: 100%

Anderson et al, Aliment Pharmacol Ther. 2012

Perhaps, we can do selective FMT based on individual's flora and genetics

Can the host’s mucosal gene expression at the time of diagnosis predict complications?

– Non IBD (control)Red – Inflammatory (B1)Blue – Stricturing and penetrating (B2/B3)

Clusters

Ted Denson & RISK study team

Evolution of IBD Risk Stratification

Research Lessons learned

• Small proportion (20%) of CD accounts for 80% of complicated disease (and healthcare needs)

• These high risk patients are identifiable at the time of diagnosis with relatively low cost

• Individualized care based on RISK• Best approach for risk/benefit ratio• Reduce overall cost in long term

Remember the Key note speech delivered by Dr Clark

IBD: The Pediatric Burden & the impact of Pediatric IBD research

• 1.2 million people with IBD in the US, estimated 80‐100,000 children with IBD

• About 20‐25% of all IBD is diagnosed during the pediatric age

• Identification of BIOTYPE = Genotype + Phenotype+ Immunotype + Bacteriotype + ??? Future of IBD management.

ImmuneResponse

I

ImmuneResponse

ll

ImmuneResponse

lll

Immune responses

Outcomebiotypes

IBD l

IBD ll

IBDlll

Hypothesis: IBD biotypes drive the IBD phenotype and outcome

Bacterial

Bacteriall

Bacterialll

Gene l

Genell

Genelll

Genetic variability

Microbial variability

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Exposome

Metabolome

Transcriptome

Epigenome

Proteome

MicrobiomeEpimmunome

Inflammasome

Genome

Resolvome

Apoptosome Phenome

Responsome

Antibodome

IBD patientand associated“omes” network

IBD patientand associated“omes” network

“How Everything is Connected to Everything”A-L Barabási. Plume Books 2003

The interactomeThe interactome

Stead WW. Beyond expert-based practice. IOM Institute of Medicine. Evidence-based medicine and the changing nature of health care:The National Academies Press 2008

Clinical featuresDeep ulcerations etc.

Microbiome

Genetic variationand gene expression

Serology / immunotypes

RISK Stratification in the puzzle

of pediatric IBD

Close integration of 4 in‐depth

critical components

The Future

ACKNOWLEDGEMENT

Topics and contents I have chosen for the talk were suggested by the following IBD’ologists and scientists:

Francisco SylvesterJoel RoshJeff HyamsJim MarkowitzMarla DubinskyTed DensonAlex MuiseTim BoyleClaudio Fiocchi

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Timing as a critical factor in IBD:early life stress, “sensitive period”,

and IBD evolution

Life with IBDEarly disease Late disease

Less plasticity, “insensitive” period

Life before IBD

Trigger

Clinicalsymptoms,diagnosis

Exposome, GXG, GXE,epigenetics, etc.

Life after IBD

Therapy

Unknownultimateoutcome

Remissionrecurrencesmedications

hospitalizationsoperations

cancer, etc.

Response / no responseto therapy

?

Sensitive period

Early life events: fetal development, exposome contact, immune priming, GXG and GXE interactions, epigenetics, etc.

Conception

Birth

final evolution of ibd 2012 naspghan

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