MICI: classification et nosologie le point de vue du clinicien

1
MICI classification et nosologiele point de vue
du clinicien

• Edouard Louis
• Service de Gastroentérologie, CHU Liège
• GIGAresearch, Université de Liège

2
Disease phenotypes in IBDwhy to bother ?
CD1 CD2 CDx UC1 UC2 UCx
CD
IBD
UC
IC

1. Different pathogenesis ?
2. Different natural history ?
3. Different response to treatment ?

3
To answer these questions, classifications must
be tested to be validated

1. Rome, 1991
2. Vienne, 1998
3. Montreal, 2005

4
CD Vienne ? Montreal

• Vienne
• Age at diagnosis
• A1 lt40
• A2 gt40
• 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 lt16
• A2 16-40
• A3 gt40
• 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

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Age at diagnosis

• lt16 yrs pediatric CD
• Increasing incidence
• More upper GI CD
• More extensive CD
• 16-40 yrs classical CD
• gt40 yrs CD in the elederly
• More colonic disease
• Differential diagnosis with ischemia

6
CD Vienne ? Montreal

• Vienne
• Age at diagnosis
• A1 lt40
• A2 gt40
• 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 lt16
• A2 16-40
• A3 gt40
• 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

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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

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Prevalence of small bowel CD with VCE Results of
a meta-analysis
Triester et al. Am J Gastroenterol 2006101954
Incremental Yield of VCE ()
ileoscop N4 P0.02
MRI N1 P0.16
Enterosc N2 Plt0.001
SBFT N9 Plt0.001
CT entero N3 P0.001
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CD Vienne ? Montreal

• Vienne
• Age at diagnosis
• A1 lt40
• A2 gt40
• 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 lt16
• A2 16-40
• A3 gt40
• 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

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Penetrating CD heterogeneous entityAssociation
between perianal CD and internal fistulizing CD
according to disease location

• Database records of 5491 CD pts from 6 centers
• No consistency for association in 1686 ileal CD
  (RR0.8-2.2)
• Significant association in 1655 colonic CD

Plt0.0001
RR of association between Perianal and internal
fistulizing Disease in colonic CD
Sachar et al. Am J Gastroenterol 2005 100 1547
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Development of stricturing and fistulizing CD
over the course of the disease

Patients at risk. N 297 259 218
187 125 74 47
32
Time (years)
Louis et al. Gut 2001
12
Development of stricturing and fistulizing CD
over the course of the disease
100
90
80
70
Penetrating
60
50
Cumulative Probability ()
40
30
Stricturing
20
Inflammatory
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
2002
552
229
95
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244
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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

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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

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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

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Significant inflammation in macroscopically
normal mucosa in CD
Reimund et al. Gut 199639684.
17

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How to define a stricturing CD

• In Vienna classification associated with
  symptoms or proximal dilatation
• Persistent stricture
• Inflammatory vs fibrotic stricture

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Subobstructive CD 8
w. after Ifx
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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

21
Development of stricturing and fistulizing CD
over the course of the disease

Patients at risk. N 297 259 218
187 125 74 47
32
Time (years)
Louis et al. Gut 2001
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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

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Speed of development of stricturing CD
stricture
time
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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

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Origin of non perianal fistulas in Crohns 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 198911 193
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Fistulizing CD a mechanical theory
Intraluminal hyperpressure
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Are different phenotypes driven by different
pathophysiology ?

• This would imply that a stable general phenotype
  exists for each patient

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Influence of smoking of the phenotype of CD
Brant et al. Inflamm Bowel Dis 2003
Picco et al. Am J Gastro 2003
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Impact of disease phenotype on natural history

• That is mainly the phenotype at diagnosis which
  is important

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Crohns disease location is the main factor
influencing the development of complicationsCD
behaviour 5 years after diagnosis
Louis et al. Gut 2003
31
Subtype of penetrating CD after 5 years according
to location of disease at diagnosis
Intrabdominal penetrating disease was mainly
associated with ileal location and perianal with
colonic location (plt0.0001)
Louis et al. Gut 2003
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Perianal Crohns disease

• Cumulative frequency of 12 at 1 year, 15 at 5
  ys, 26 at 20 ys Schwartz et al. Gastroenterology
  2002 122875
• Occurs in 12 of ileal CD, 41 of colonic CD, 92
  in case of rectal involvement
• Hellers et al. Gut 1980 21 525

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Recurrence rate in newly diagnosed CD
The only factor independently associated with all
recurrences was L4 location (Plt0.01)
Wolters et al. Gut 2006 55 1124.
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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 agelt40, steroid treatment,
perianal lesions.
Beaugerie et al. Gastroenterology 2006 130 650.
35
Mortality over 10 years in newly diagnosed CD
Increasing age was the only independent risk
factor for both total and CD related mortality
causes
Wolters et al. Gut 2006 55 447.
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Colectomy in UC after 5 years

Langholz et al. Gastroenterology 19921031444
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Colorectal cancer in UC after 30 years

Devroede et al. N Engl J Med 197128517
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Standard mortality ratio in UC
SMR
Ekbom et al. Gastroenterology 1992103954
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Impact of disease phenotype on response to
treatments

• That is mainly the phenotype at the time you
  treat the patient which is important

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5ASA and UC extent

• 5ASA suppositories for proctitis
• 5ASA enemas for left colitis
• 5ASA tablets for extensive colitis
• Seksik et al. Gastroenterol Clin Biol 200428964
• Beaugerie et al. Gastroenterol Clin Biol
  200428974

Budesonide and CD location
41
(No Transcript)
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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

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Week 26 Response to Certolizumab pegol in precise
2 by Duration of Crohns Disease
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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.

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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

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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 B2B3
  to B1 and then fistulizing pattern by comparing
  B2 to B3