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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!