Disease behavior in adult patientsDisease behavior in adult patients--are there predictors for stricture or are there predictors for stricture or

fistula formation?fistula formation?Falk Symposium 168, Madrid, SpainFalk Symposium 168, Madrid, Spain

Iris Dotan, M.D.,Iris Dotan, M.D.,Head, IBD Center,Head, IBD Center,

Department of Gastroenterology and Liver Diseases,Department of Gastroenterology and Liver Diseases,Tel Aviv Sourasky Medical Center,Tel Aviv Sourasky Medical Center,

Tel Aviv, IsraelTel Aviv, Israel

CrohnCrohn’’s disease behavior:s disease behavior:Vienna and Montreal classificationsVienna and Montreal classifications

• Age at dianosis (A)– A1<16 yr– A2 17–40 yr– A3 >40yr

• Location (L)– L1 ileal– L2 colonic– L3 ileocolonic– L4 isolated upper

• Behavior (B)– B1 nonstricturing-

nonpenetrating– B2 stricturing– B3 penetrating– P perianal disease

Inflammatory

Stricturing

Penetrating

Silverberg MS, et al. Can J Gastroenterol 2005; 9 Suppl A:5-36Gasche C, et al. Inflamm Bowel Dis 200;6:8-15

• Age at Diagnosis (A)– A1< 40 yr

– A2 ≥ 40 yr

• Location (L)– L1 terminal ileum – L2 colonic – L3 ileocolonic

– L4 upper gastrointestinal

• Behavior (B)– B1 nonstricturing-

nonpenetrating– B2 stricturing– B3 penetrating

Cosnes J, et al. Inflamm Bowel Dis 2002;8:244–250

Wolters F, et al EC-IBD. Scand J Gastroenterol 2006

Natural history of CrohnNatural history of Crohn’’s disease: s disease: 90% of patients develop stricturing 90% of patients develop stricturing

or penetrating complicationsor penetrating complicationsDisease behavior is not a stable given.More than 70% of CD patients develop complications within 10 y

2402161921681441209672482400

20

40

60

80

100

Prob

abili

ty (%

)

Months

PenetratingPenetrating

StricturingStricturingInflammatoryInflammatory

Changes in CrohnChanges in Crohn’’s disease s disease behavior and locationbehavior and location

Louis E, et al. Gut 2001;49:777–782

0 1 3 5 10 15 20 25Years from diagnosis

0

Patie

nts

(%)

20

40

60

80

100

B1 inflammatoryB1 inflammatory

B2 stenosingB2 stenosing

B3 penetratingB3 penetrating

Behavior

= L4 upper GI

0 1 3 5 10 15 20 25Years from diagnosis

0

Patie

nts

(%)

20

40

60

80

100

L3 ileocolonL3 ileocolon

Disease location

L2 colonL2 colon

L1 ilealL1 ileal

Stricture or fistula both Stricture or fistula both reflectreflectand and predictpredict severe/aggressive severe/aggressive

diseasedisease• Adults: 361 CD patients

– HR of ~2.1 for strictures and severe CD

• Pediatric population: 989 CD patients median follow-up 2.8 y– HR of ~2.5 for stricture or fistula and

the risk for surgery

Loly C, Scand J Gastroenterol 2008;43:948-954Gupta N, et al. Gastroenterol 2006;130:1069-1077

Predicting Predicting severesevere CrohnCrohn’’s disease s disease [the development of non reversible serious lesions[the development of non reversible serious lesions]]

Loly C, et al. Scand J Gastroenterol 2008;43:948-954

0 10 20 30 40

Time (years)

Non

sev

ere

Cro

hn’s

dis

ease

0

0.2

0.4

0.6

0.8

1.0

Non B2 and no weight lossNon B2 and weight lossB2 and no weight lossB2 and weight lossB2 and weight loss

Stricture or fistula are Stricture or fistula are associated with an increased associated with an increased

risk for surgeryrisk for surgery• 60% of patients require surgery within 10 years

Veloso FT, et al. Inflamm Bowel Dis 2001;7:306–313

0Years after diagnosis

0

Prob

abili

ty (%

)

20

40

60

80

100

2 4 6 8 10 12 14 16 0Years after diagnosis

0

Prob

abili

ty (%

)20

40

60

80

100

2 4 6 8 10 12 14 16

Second surgeryPenetrating

StricturingFirst surgery

Inflammatory

Stricture or fistula at Stricture or fistula at diagnosis predict surgerydiagnosis predict surgery

• Population-based study, 476 CD patients, diagnosed in 12y• Mean age at CD diagnosis 34, 71% diagnosed before 40 y• Inflammatory disease behavior in 76%• Perianal fistula prevalence:

4.8% within 6 months, 10.3% at final follow up• Predictors for surgery stricturing and penetrating

phenotypes• Predictors for disease recurrence:

– Small bowel localization– Stricturing disease– Young age<40y

Romberg-Camps MJL et al, Am J Gastroenterol 2009;104:371-383

Why do we need disease course Why do we need disease course and behavior prediction?and behavior prediction?

• Patient information• Closer follow-up of patients with

worse prognosis• Top down therapy suggested for patients

with predicted aggressive course,may modulate disease course in adult and pediatric CD

Baert F, et al. Dig Dis 2007;25:260-6Gupta N, et al. Gastroenterol 2006;130:1069-1077

How can we predict disease How can we predict disease behavior?behavior?

•• ClinicalClinical[Endoscopic][Endoscopic]

•• SerologicSerologic•• GeneticGenetic

Clinical factors associated with Clinical factors associated with development of stricture or fistuladevelopment of stricture or fistula

Fistula

• Age <40 yr – (HR 1.3 [1–1.5])

• Non-caucasian – (HR 1.3 [1.1–1.6])

• Anoperineal lesions – (HR 2.6 [2.3–3.0])

• No oesophagogastroduodenal involvement – (HR 1.4 [1.1–1.9])

Stricture• Recent diagnosis

(after 1987)– (HR 1.3 [1–1.6])

• Jejunal involvement – (HR 3.2 [2.2–4.7])

• Ileal involvement – (HR 2.5 [1.9–3.3])

• No colonic involvement – (HR 2.0 [1.6–2.4])

• No anoperineal disease – (HR 1.4 [1.1–1.8])

Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244–50

55--year year disablingdisabling CrohnCrohn’’s diseases disease

0

20

40

60

80

100

St-Antoine(Paris)

Olmsted County CHU Liège

Disabling Non-disabling

Beaugerie L, et al. Gastroenterology 2006;130:650-656Seksik, et al. Gastroenterology 2007; 132 a17.80Loly C, Scand J Gastroenterol 2008;43:948-954

% o

f pat

ient

s

Predictors of Predictors of disablingdisablingCrohnCrohn’’s diseases disease

Beaugerie L, et al. Gastroenterol 2006;130:650-656

Score is based on the number of predictive factors at diagnosis:age <40, steroid treatment, perianal lesions

0102030405060708090

100

Proportion of pts Positive predictive value

Score 0Score 1Score 2Score 3

Prop

ortio

n of

pat

ient

s&

pos

itive

pre

dict

ive

valu

e

Deep colonic ulcers are risk Deep colonic ulcers are risk factors for colectomy factors for colectomy

in Crohnin Crohn’’s diseases diseaseProbability of colectomy in patients with or without

Severe Endoscopic Lesions (SELs) defined by deep ulcerscovering >10% of at least 1 colonic segment

Allez M, et al. Am J Gastroenterol 2002;97:947-953

Perc

ent

0

10

20

30

40

50

60

70

1 year 2 year 3 year

SELsNo SELs

Mucosal healing predicts remissionMucosal healing predicts remission• In patients with CD,

fever at diagnosis andmedical treatmentwithout steroids weresignificant predictorsfor mucosal healing

• Mucosal healingsignificantly associatedwith less inflammationafter 5 years

– p = 0.02Froslie KS. Gastroenterology 2007;133:412

0 1 2 3 4 5 6 7Time in years after 1 year visit

0.6

0.7

0.8

0.9

1.0

Prop

ortio

n of

CD

pat

ient

sno

t res

ecte

d

Mucosal healingat 1 year

No mucosalhealing

Clinical predictors of Clinical predictors of stricture or fistulastricture or fistula

• Age<40• Disease location (small bowel-strictures)• Perianal disease• Steroid use

• [No mucosal healing?]

Antibody Directed against Sensitivity/specificity (%)

pANCA Neutrophil cytoplasm (colonic bacteria?)

60-70 in UC90

ASCA Mannans, Saccharomyces cerevisiae

60-70(can be as low as 35)95

Young diagnosis ageNeed for surgeryFS, IPNOD2 association

OmpC Outer membrane porin C, E coli

31-55% IP disease, need for surgeryLonger duration

Anti-I2 I2 protein, Pseudomonas fluorescens

FS disease, need for surgery

CBir1 Flagellin of commensal bacteria (clostridium?)

SB IP FSpANCA+CD>pANCA+UC

Rump JA, Immunobiology, 1990Duerr RH, Gastroenterology 1991Rutgeerts P, Gastroenterology 1998Sendid B, Clin Diagn Lab Immunol 1996Vermeire S, Gastroenterology 2001

Cohavy O, Infect Immun 2000Landers CJ, Gastroenterology 2002Lodes MJ, JCI 2005Targan SR, Gastroenterology 2005Papp M, Am J Gastroenterol 2008Amre DK, Am J Gastroenterol 2006Forcione DG, et al. GUT 2004 Gupta N, et al. Gastroenterol 2006

Serologic response Serologic response can predict disease behaviorcan predict disease behavior

Antibody Directed against Sensitivity/specificity (%)

gASCA covalently-bound mannan

50-56 Young diagnosis ageShorter durationperianal diseaseAZA useFS/IPNOD2 association

ALCA Laminaribioside 15-27 Young diagnosis ageFS/IP

ACCA Chitobioside 11-20 Longer duration (high levels)non inflammatory behavior

AMCA Mannobioside 11-28 NOD2 associationShorter duration

Dotan I, Gastroenterology 2006;131:366-378Ferrante M, GUT 2007;56:1394-1403Papp M, Am J Gastroenterol 2008;103:665-681

CrohnCrohn’’s disease stratification: s disease stratification: itit’’s quality s quality andand quantityquantity……

Cumulative reactivities (higher levels/more markers) were associated with:Stricturing or penetrating disease behavior in adultand pediatric populationssmall bowel locationneed for surgeryrelapsing course of pediatric CDNOD2 and TLR4 variants (controversy)

Dotan I, Gastroenterology 2006;131:366-378:Ferrante M,GUT 2007;56:1394–1403.Dubinsky MC, Am J Gastroenterol 2006;101:360-367Forcione DG, GUT 2004;53:1117-22

Desir B, CGH 2004;2:139-46Henckaerts L, GUT 2007;56:1536-42Dassopoulos T, Inflamm Bowel Dis 2007;13:143-151Papp M, Am J Gastroenterol 2008;103:665-681

CrohnCrohn’’s disease progression: s disease progression: Serologic response predicts timingSerologic response predicts timing

Israeli E, Gastroenterology 2006 (abstr)Amre DK, Am J Gastroenterol 2006;101:645-52Dassopoulos T, Inflamm Bowel Dis 2007;13:143-51Dubinsky MC, Am J Gastroenterol 2006;101:360-367

AMCA

44

ACCAgASCA

6279

91

37 3845 47

5766

76 7796.6

ACCA

71.736.723.0

107.6

54.5

ALCAgASCA

Before disease onsetAfter disease onset

Average level of serologic markers before and after diagnosis

Antibodies (gASCA, ALCA) appear >10 yearsbefore CDonset in CD but not control patients

Steady increase in antibody levels as disease progresses

0-3 years (n=98)4-9 years (n=103)10-15 years (n=82)>15 years (n=90)

Serologic markers units by year post onset

Time to first complication (fistula or abscess)Shorter for ASCA+ vs ASCA-Shorter for pANCA- vs pANCA+

Ferrante M, et al. Gut 2007;56:1394–1403.Dubinsky MC, et al. Am J Gastroenterol 2006;101:360-7

Serologic predictors ofSerologic predictors ofstricture or fistulastricture or fistula

Children:ASCA, Omp, I2, CBir1

Freq

uenc

y of

dise

ase

beha

viou

r0

20

40

60

80

100 p trend = 0.002

0(n=40)

*1.9

Score<1.5

83.2

Score1.5

or 2.0

Score2.5

or 3.0

Score>3.0

71.756.0

42.0

1(n=60)

2(n=42)

3(n=29)

4(n=12)

Number of immune responses

*2.3

*5.5

*11.0

NPNSPP onlyIPS only

OR: 1.76p=0.006

OR: 2.00p=0.001

OR: 1.96p=0.010

Prop

ortio

n of

pat

ient

s

0

20

40

60

80

100

913 Adult CD patientsALCA ACCA AMCA gASCA OmpCScore 0=no serologic markersScore 5-all markers positive

GenotypeGenotype--phenotype phenotype correlationscorrelations

Presence of NOD2 variants determinedseroreactivitygASCA, ALCA, AMCA associated with NOD2NOD2 genotype and seroreactivity synergismin predicting fibrostenotic diseaseDose response between the number of mutantNOD2 alleles and ASCA prevalence and titers

DevIin SM, Gastroenterology 2007Papp M, Am J Gastroenterol 2008;103:665-681Ferrante M, GUT 2007;56:1394-1403.Ippoliti AF, Gastroenterol 2006 (abstr)Dassopoulos T, Inflamm Bowel Dis 2007;13:143-51

GenotypeGenotype--phenotype phenotype correlationscorrelations

0Mutation type 1 2

33%45% 47%

0Mutation type 1 2

50%64%

72%

Degree of genetic mutationlow high

% ALCA positivity in CD patients with NOD2/CARD15 variantsn=800, p=0.002

Titers 41 vs 47 U p=0.003

% gASCA positivity in CD patients with NOD2/CARD15 variantsn=850, p<0.0001,Titers 62 vs 84 U p<0.0001

% ACCA positivity in CD patients with TLR4 variantsn=791, p=0.003 0Mutation type 1 2

34%25%

9%

Henckaerts L, et al. GUT 2007;56:1536-42

Genetics predictors ofGenetics predictors ofstricture or fistulastricture or fistula

• 1684 CD patients, The Netherlands:NOD2, IBD5, DLG5, ATG16L1, IL23R

• CD patients with stricturing or penetrating disease-significantly more risk alleles

• Patients needing surgical intervention-more risk alleles

• ATG16L1 -associated with stricturing and perianal disease

Weersma RK, et al. GUT 2009;58:388-395

Risk stratified approach Risk stratified approach for treatment decisionsfor treatment decisions

Top Down: early treatment with immunomodulators

“Complication Risk Test”: combined clinical, serologic, genetic factors• May assist in deciding whom to treat top down vs. step up• May enable improved matching of aggressive, expensivetreatment specifically to potentially complicated patients

• Prevent complications• Increase patients quality of life

5ASAAntibiotics AZA/MTXSteroids Biologics Surgery

Step up

Biologics AZA/MTX Surgery

Top Down

Steroids

Summary Summary Disease behavior in adult patientsDisease behavior in adult patients--are there are there predictors for stricture or fistula formation? predictors for stricture or fistula formation?

• Stricture or fistula are complicated CD phenotypes• Stricture or fistula are aggressive CD,

and predict disabling/complicated CD• Stricture or fistula may be predicted using clinical,

serologic and genetic markers• Combined serologic and genetic markers

and higher titers- predict disease aggressiveness, behavior,rate of development

• Long term, prospective studies are required

ConclusionsConclusionsDisease behavior in adult patientsDisease behavior in adult patients--are there are there predictors for stricture or fistula formation? predictors for stricture or fistula formation?

•• Should we predict disease course? Should we predict disease course? Yes we shouldYes we should

•• Can we predict disease course Can we predict disease course Yes we canYes we can……(as good as it gets..)(as good as it gets..)

•• Future perspectives: better Future perspectives: better combination of clinical, genetic and combination of clinical, genetic and serologic indices for a prospectively serologic indices for a prospectively effective risk score effective risk score

Thank You!Thank You!