MICI: classification et nosologiele point de vue du clinicien
Edouard Louis
Service de Gastroentérologie, CHU Liège
GIGAresearch, Université de Liège
Disease phenotypes in IBDwhy to bother ?
IBD
CD
UC
IC
CD1CD2CDx
UC1UC2UCx
1. Different pathogenesis ?2. Different natural history ?3. Different response to treatment ?
To answer these questions, classifications must be tested to
be validated
1. Rome, 1991
2. Vienne, 1998
3. Montreal, 2005
CD: Vienne Montreal
• Vienne• Age at diagnosis
– A1 <40– A2 >40
• Location– L1 Ileal– L2 Colonic– L3 Ileocolonic– L4 upper GI
• Behaviour– B1 non-stricturing non-fistulizing– B2 stricturing– B3 fistulizing
• Montreal• Age at diagnosis
– A1 <16– A2 16-40– A3 >40
• Location– L1 Ileal– L2 Colonic + L4 upper GI– L3 Ileocolonic– L4 upper GI
• Behaviour (disease duration)– B1 non-stricturing non-fistulizing– B2 stricturing– B3 intraabdominal penetrating
+ P perianal disease
Age at diagnosis
• <16 yrs: pediatric CD– Increasing incidence– More upper GI CD– More extensive CD
• 16-40 yrs: classical CD
• >40 yrs: CD in the elederly– More colonic disease– Differential diagnosis with ischemia
CD: Vienne Montreal
• Vienne• Age at diagnosis
– A1 <40– A2 >40
• Location– L1 Ileal– L2 Colonic– L3 Ileocolonic– L4 upper GI
• Behaviour– B1 non-stricturing non-fistulizing– B2 stricturing– B3 fistulizing
• Montreal• Age at diagnosis
– A1 <16– A2 16-40– A3 >40
• Location– L1 Ileal– L2 Colonic + L4 upper
GI– L3 Ileocolonic– L4 upper GI
• Behaviour (disease duration)– B1 non-stricturing non-fistulizing– B2 stricturing– B3 intraabdominal penetrating
+ P perianal disease
Upper GI CD: L4
• Location proximal to the terminal ileum
• Specific problems and particular natural history
• Rarely isolated
• Prevalence depends on the techniques used for the diagnosis
Prevalence of small bowel CD with VCE Results of a meta-analysis
-10
0
10
20
30
40
50
60
70
IncrementalYield of VCE
(%)
SBFTN=9
P<0.001
ileoscopN=4
P=0.02
MRIN=1
P=0.16
EnteroscN=2
P<0.001
CT enteroN=3
P=0.001
Triester et al. Am J Gastroenterol 2006;101:954
CD: Vienne Montreal
• Vienne• Age at diagnosis
– A1 <40– A2 >40
• Location– L1 Ileal– L2 Colonic– L3 Ileocolonic– L4 upper GI
• Behaviour– B1 non-stricturing non-fistulizing– B2 stricturing– B3 fistulizing
• Montreal• Age at diagnosis
– A1 <16– A2 16-40– A3 >40
• Location– L1 Ileal– L2 Colonic + L4 upper GI– L3 Ileocolonic– L4 upper GI
• Behaviour (disease duration)– B1 non-stricturing non-
fistulizing– B2 stricturing– B3 intraabdominal penetrating
+ P perianal disease
Penetrating CD: heterogeneous entityAssociation between perianal CD and internal
fistulizing CD according to disease location
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
• Database records of 5491 CD pts from 6 centers
• No consistency for association in 1686 ileal CD (RR=0.8-2.2)
• Significant association in 1655 colonic CD
Sachar et al. Am J Gastroenterol 2005; 100: 1547
RR of association betweenPerianal and internal fistulizingDisease in colonic CD
P<0.0001
Development of stricturing and fistulizing CD over the course of the disease
0102030405060708090
100
diag 1 3 5 10 15 20 25
B3B2B1
Time (years)Louis et al. Gut 2001
Patients at risk. N= 297 259 218 187 125 74 47 32
%
Development of stricturing and fistulizing CD over the course of the disease
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve P
rob
abili
ty (
%)
Patients at risk:Months
2002 552 229 95 37N =
Penetrating
Stricturing
Inflammatory
A classification for Ulcerative colitis
• By extent– E1: proctitis– E2: left-sided colitis– E3: extensive colitis– Particular cases: periappendiceal infllammation,
PSC-associated colitis
• By severity – S0: inactive– S1: mild– S2: moderate– S3: severe
Indeterminate colitis
• Diagnosis based on surgical specimen– Overlapping features of both CD and UC
Indeterminate colitis• Diagnosis based on endoscopy with
biopsies– Chronic IBD, only colon involvement,non
conclusive endoscopy, no infection, no microscopic feature specific for UC or CD
Chronic IBD type unclassified
Drawbacks of current classification
• Definition of a phenotype depends on the techniques used to explore the patient: X-Ray, medical imaging, endoscopy, histology, biology.
• Instability over time of behaviour of CD, severity of UC and location of CD and UC
• Overlap between phenotypes: almost all fistulizing CD are associated with downstream strictures
Significant inflammation in macroscopically normal mucosa in CD
Reimund et al. Gut 1996;39:684.
How to define a stricturing CD
• In Vienna classification: associated with symptoms or proximal dilatation
• Persistent stricture
• Inflammatory vs fibrotic stricture
Subobstructive CD 8 w. after Ifx
Drawbacks of current classification
• Definition of a phenotype depends on the techniques used to explore the patient: X-Ray, medical imaging, endoscopy, histology, biology.
• Instability over time of behaviour of CD, severity of UC and location of CD and UC
• Overlap between phenotypes: almost all fistulizing CD are associated with downstream strictures
Development of stricturing and fistulizing CD over the course of the disease
0102030405060708090
100
diag 1 3 5 10 15 20 25
B3B2B1
Time (years)Louis et al. Gut 2001
Patients at risk. N= 297 259 218 187 125 74 47 32
%
Behaviour of CD is a dynamic multifactorial polygenic character• There is not really a time-limit after
which a phenotype remains stable
• Genetic and environmental factors may influence the speed at which a phenotype develops
• Influence of genetic or environmental factors must be studied through multivariate analysis
Speed of development of stricturing CD
time
stri
ctu
re
Drawbacks of current classification
• Definition of a phenotype depends on the techniques used to explore the patient: X-Ray, medical imaging, endoscopy, histology, biology.
• Instability over time of behaviour of CD, severity of UC and location of CD and UC
• Overlap between phenotypes: almost all fistulizing CD are associated with downstream strictures
Origin of non perianal fistulas in Crohn’s disease
• 60 specimens with fistulas, including 44 in first excisions– 62% located at proximal end of a stricture– 31% within a stricture– 7% not associated with a stricture
Kelly et al. J Clin Gastroenterol 1989;11: 193
Fistulizing CD: a mechanical theory
Intraluminal hyperpressure
Are different phenotypes driven by different pathophysiology ?
This would imply that a stable general phenotype exists for
each patient
Influence of smoking of the phenotype of CD
0
1
2
3
4
5
6
Ileal location B1 behaviour
Brant et al. Inflamm Bowel Dis 2003 Picco et al. Am J Gastro 2003
Impact of disease phenotype on natural history
That is mainly the phenotype at diagnosis which is important
Crohn’s disease location is the main factor influencing the development of complications
CD behaviour 5 years after diagnosis
0
10
20
30
40
50
60
70
80
90
L1 (n=74) L2 (n=45) L3 (n=36) L4 (n=8)
B1
B2
B3
Louis et al. Gut 2003
Subtype of penetrating CD after 5 years according to location of disease at diagnosis
0
10
20
30
40
50
60
70
L1 L2 L3 L4
B3P
Intrabdominal penetrating disease was mainly associatedwith ileal location and perianal with colonic location (p<0.0001)
Louis et al. Gut 2003
Perianal Crohn’s disease
• Cumulative frequency of 12% at 1 year, 15% at 5 ys, 26% at 20 ysSchwartz et al. Gastroenterology 2002; 122:875
• Occurs in 12% of ileal CD, 41% of colonic CD, 92% in case of rectal involvementHellers et al. Gut 1980; 21: 525
Recurrence rate in newly diagnosed CD
Wolters et al. Gut 2006; 55: 1124.The only factor independently associated with all recurrences was L4 location (P<0.01)
Predictors of disabling CDProportion of patients and predictive positive value of
having a disabling CD in the 5-yr period after diagnosis. Score is based on the number of predictive factors at
diagnosis: age<40, steroid treatment, perianal lesions.
0
10
20
30
40
50
60
70
80
90
100
proportion of pts positive predict value
score 0
score 1
score 2
score 3
Beaugerie et al. Gastroenterology 2006; 130: 650.
Mortality over 10 years in newly diagnosed CD
Wolters et al. Gut 2006; 55: 447.
Increasing age was the only independent risk factor for both total and CD related mortality causes
Colectomy in UC after 5 years
0
5
10
15
20
25
30
35
proctitis left-sided colitis extensive colitis
%
Langholz et al. Gastroenterology 1992;103:1444
Colorectal cancer in UC after 30 years
0
5
10
15
20
25
30
35
40
45
50
proctitis left-sided colitis extensive colitis
%
Devroede et al. N Engl J Med 1971;285:17
Standard mortality ratio in UC
0
0,5
1
1,5
2
2,5
proctitis left-sided colitis extensive colitis
SMR
Ekbom et al. Gastroenterology 1992;103:954
Impact of disease phenotype on response to treatments
That is mainly the phenotype at the time you treat the patient
which is important
5ASA and UC extent
• 5ASA suppositories for proctitis
• 5ASA enemas for left colitis
• 5ASA tablets for extensive colitis» Seksik et al. Gastroenterol Clin Biol 2004;28:964» Beaugerie et al. Gastroenterol Clin Biol 2004;28:974
Budesonide and CD location
Logistic regression of clinical factors associated with response to infliximab in CD
Favours non-response Favours Response
YoungAge
Colonicdisease
Immuno-suppressants
0
0,5
1
1,5
2
2,5
3
3,5
-4 -2 0 2 4 6 8
Odds Ratio
0.94
1.9
2.3
Vermeire et al, DDW 2001
Symptomatic luminal stricture underlies infliximab non-response
in CD
• 95 patients treated with infliximab and evaluated after 6 months
• 45/95 did not respond or lost response and were explored
• 30/45 had underlying stricture or obstruction (28 small bowel and 2 colon)
Prajapati et al. Gastroenterology 2002; 122:
A777
Week 26 Response to Certolizumab pegol in precise 2
by Duration of Crohn’s Disease90%
75%
62%57%
33%36%
50%
37%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<1 Year 1-<2 years 2-<5 years ≥5 years
% in
CD
AI R
es
po
ns
e o
r R
em
iss
ion
Certolizumab pegol Placebo
Steroids may favour abdominal or pelvic abscesses
• Retrospective case-control study of 432 CD patients
• 29 patients with abscess and 57 with perforating disease without abscess– Adjusted OR for systemic steroid for abscess
development: 18.84 (2.32-152.73)• 12 patients with initial non-perforating phenotype
developping abscess over follow up vs 24 persisting non-perforating phenotype– OR for systemic steroid for abscess development:
9.31 (1.03-83.91)
Agrawal et al. Clin Gastroenterol Hepatol 2005; 3: 1215.
Conclusions
• Defining relevant phenotypes is a difficult task• Phenotype definitions must be tested and
validated with specific aims• Different phenotypes of CD or UC have at least
partly different pathophysiology• Different phenotypes of CD and UC have
different natural history• Different phenotypes of CD and UC have
different response to treatment
Research agenda
• Difference of composition of the fecal stream at different level of the colon in UC
• Characteristics of the inflammatory reaction at different GI levels in CD
• Difference in the characteristics of the lesions in early vs old CD and UC
• When studying biology of stricturing or fistulizing CD– Take time into account– Study the stricturing pattern by comparing B2+B3 to
B1 and then fistulizing pattern by comparing B2 to B3