MICI: classification et nosologie le point de vue du clinicien Edouard Louis Service de Gastroentérologie, CHU Liège GIGAresearch, Université de Liège.

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