Diagnostic,

présentation clinique et

histoire naturelle des MICI

Prof Yoram Bouhnik

Gastroentérologie et Assistance Nutritive

Université Paris VII

Hôpital Beaujon, Clichy

DU Médecine interne, Novembre 2013

The burden of IBD

• Prevalence of IBD is 1% in North America and some European countries

• Incidence of Crohn’s disease is still increasing in these countries

• Rapid increases in the incidence of IBD are now being observed in Japan, South Korea, Australia, New Zealand and some regions of India and China

• IBD will emerge as a worldwide epidemic in the coming years

Elkjaer M et al. Gut 2010;59:1652–61 Molodecky NA, et al. Gastroenterology 2012;142:46–54

global map of inflammatory bowel disease

Worldwide IBD incidence and/or prevalence rates for countries reporting

data (A) before 1960; (B) from 1960 to 1979; (C) after 1980.

Before 1960

1960-1979

≥ 1980

Molodecky et al. Gastroenterology 2012;142 (Jan):46-54

UC CD

Molodecky et al. Gastroenterology 2012

Temporal trends of incidence rates for studies that reported at least 10 years

of data and with at least 3 time points for CD

Data from France The EPIMAD registry: Northern France

6 million inhabitants (9.3% of french population)

242 adult gastroenterologists, 12 pediatric gastroenterologists, 6733 GPs

22,976cases recorded by the Registry (1988-2012)

4

5

6

7

8

9

Total

Femmes

Hommes

Incidence /105

Incidence of Crohn’s disease in Northern France (1988-2008)

Chouraki V et al. Aliment Pharmacol Ther 2011 (maj 2012)

5,3

4,5

6,1

7,6

6,4

8,8

0

2

4

6

8

10

12

0-19

0-9

10-19

Age at diagnosis

Incidence /105

Incidence variation for CD in children and adolescents in Northern France (1988-2008)

Chouraki V et al. Aliment Pharmacol Ther 2011 (maj 2012)

3,5

0,5

6,5 7,1

1,2

12,9

Crohn’s Disease Incidence according to gender & age

0

2

4

6

8

10

12

14

16

18

20

0-9

10-19

20-29

30-39

40-49

50-59

60-69

70-79

>=80

Age

incid

en

ce

Males

Females

Incidence /100 000 26 years (median age at diagnosis)

0%

20%

40%

60%

80%

100%

< 17 ans 17-39 ans 40-59 ans > 60 ans

E3 (PANCOLITE)

E2 (COLITE GAUCHE)

E1 (RECTITE)

Présentation de la RCH selon l'âge

• Étude prospective

• 5 253 cas incidents en population

• Registre EPIMAD de 1988 et 2010

Incidence

Localisation au diagnostic

Symptômes au diagnostic

0

20

40

60

80

100

douleurs abdominales perte de poids syndrome rectal manifestations

extraintestinales

< 17 ans

17-39 ans

40-59 ans

> 60 ans

ATCD Familiaux

13 % 3 % p < 10-4 * p < 10-4

• Conclusion : Présentations cliniques différentes en fonction de l’âge probablement reflet d’une pathogénie différente (poids des facteurs environnementaux et génétiques)

Charpentier C et al. DDW 2012. Abstract 102

p < 10-4

Facteurs environnementaux protecteurs

RR de développer une RCH :

•fumeur = 0,4

•ex-fumeur = 1,7

Ex-fumeur :

•aggravation de la maladie

•extension des lésions

•augmentation du risque de RCH

réfractaire et de colectomie.

Facteurs Causalité

Tabac +++

Appendicectomie +++

Infections intestinales ++

Antibiothérapie +

Hygiène +

OP ou THS +

Alimentation +

Polluants ?

Soleil ?

Chaîne du froid ?

Ulcerative colitis Crohn’s disease

Crohn’s disease

• CD is a relapsing, transmural inflammatory disease of the GI mucosa that can affect the entire GIT from the mouth to the anus.

• Typical presentations include the discontinuous involvement

of various portions of the GIT and the development of complications including strictures, abscesses, or fistulas.

• The clinical presentation is largely dependent on disease

location and can include diarrhoea, abdominal pain, fever, clinical signs of bowel obstruction, as well as passage of blood or mucus or both.

From mouth to anus

Rare

Perianal fistula:

One fourth of patients

after 20 years

Small bowel and colon (30%)

Colon (40%)

Small bowel (30%)

Upper GI tract (<5 %)

Ulcerative colitis

• UC is a relapsing non-transmural inflammatory disease that is restricted to the colon

• Patients typically present with bloody diarrhoea (often nocturnal and postprandial), passage of pus, mucus, or both, and abdominal cramping during bowel movements.

• Severe symptoms are less common in left-sided colitis and proctitis.

Left sided

colitis

(20%) Extensive

colitis

(30%)

Proctitis (50%)

Differential diagnosis of UC and CD

Up to 25% patients with CD and UC will develop EIM

Ileocolonoscopy with biopsies is the 1st

line investigation to diagnose IBD

Le diagnostic repose sur l’endoscopie et les biopsies

Small intestinal Crohn’s disease

as seen by capsule endoscopy

Detects erosions in suspected Crohn’s disease with negative SBFT /

colonoscopy

Recent imaging to explore the SB in IBD

CT-based (left) and MRI-based (right) enterography showing an ileocaecal-sigmoid fistula in patient with Crohn’s disease

Histoire naturelle RCH

Représentation de l’histoire naturelle

de la rectocolite hémorragique

Torres J et al. Inflamm Bowel Dis 2012 ; 18 : 1356-63

Ac

tivité

infla

mm

ato

ire

(Ma

yo

sco

re, U

CEIS

)

Premiers

Symptômes

Diagnostic RCH

précoce

RCH

tardive

De

stru

ctio

n in

test

ina

le

Atteinte

Epithéliale

Dysplasie

/Cancer

Extension

Perte de

compliance

Chirurgie

Poussées

sévères

Profil évolutif de la RCH

Solberg, Scand J Gastro 2009; 44: 431

amélioration

progressive

aggravation

progressive

chronique

continu

chronique

intermittent

55% 1% 37% 6%

Cohorte d'inclusion danoise (IBSEN study), n=423/519, suivi 10 ans

Principales complications

associées à la RCH

Complications Commentaires

Colite grave 15%

Hémorragie 10%, cause fréquente d’anémie

Mégacôlon toxique,

perforation

5%

Sténose colique 2 -10%, avec risque tumoral +++

Hépatobiliaires CSP avec risque de cholangiocarcinome (X

100-800)

Thrombovasculaires FDR indépendant accident + récidive (x 3,5

vs population générale (veineuses+++)

– Risque de complications/mégacolon toxique,

péritonite, hémorragie

– Risque de chirurgie / Risque morbimortalité

– Risque de cancer colorectal

– Qualité de vie / handicap fonctionnel

Risques particuliers des formes

sévères/compliquées de RCH

(E3 > E1-E2)

Cu

mu

lati

ve p

rob

abili

ty (

%)

Cohorte de 1161 patients au Danemark (1962–87)

Langholz E et al. Scand J Gastroenterol 1996;31:260–6

Recto-sigmoidite

L’étendue des lésions progresse avec le temps

chez 50% des patients atteints de RCH

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Années après le diagnostic

Progression

Une maladie destructrice au cours du temps

• Relation entre augmentation de la largeur de

l’espace présacré et la durée de la maladie :

– augmentation du dépôt de graisse en avant

du sacrum

– rétrecissement de la lumière rectale

– épaississement de la paroi rectale

– affaissement de la graisse périrectale

Torres J et al. Gut 2011;Jul 11:Epub ahead of print

% cumulé de CCR

Risque élevé de cancer colorectal

dans la RCH

Double méta-analyse : CCR et RCH

Lutgens et al. Gut 2008 ; 57 :A131. Eaden et al. Gut 2001;48:526-35

1% à 10 ans 4% à 20 ans 14% à 30 ans

Adherence to endoscopy guidelines

CESAME cohort: prevalence of colonoscopic surveillance of IBD in patients with longstanding (>7 years) extensive colitis

0

20

40

60

80

100

Pro

po

rtio

n o

f p

atie

nts

su

rvey

ed

(%

)

Study centre (academic)

All UC + IBDU Crohn’s colitis

1 2 3 4 5 6 7 8 All 9

Vienne A, et al. Aliment Pharmacol Ther 2011;34:188–95

Vingt et 30% des patients RCH ont une

colectomie après 10 et 25 ans d’évolution

Langholz E et al. Gastroenterology. 1994

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24

Années après le diagnostic

% d

e p

ati

en

ts

Colectomie

Maladie active

Rémission

Status at any given timepoint

Méthode : étude en population (Manitoba) depuis 1984 (suivi maximal de 25 ans)

– facteurs de risque de colectomie • sexe masculin : HR = 1,34, p < 0,0064 • âge > 65 ans : HR = 0,63, p < 0,0001 • hospitalisation au diagnostic : HR = 2,01, p < 0,0001

Chirurgie au cours de la RCH

DDW 2011 – Targownik L.E. et al. CO631

0 0 2 4 6 8 10 12 14 16 18 20

5

10

15

Taux global de colectomie

(%)

15,4

10,5

7,7 1,8

à 90 jours

Années après le diagnostic

0 0 5 10 15 20

5

10

15

20 1987-91 1992-96 1997-2001 2002-08

(%) Taux de colectomie par périodes

Années après le diagnostic

p<0.0001

Meucci G, et al. Gastroenterology 2006;130(4 Suppl. 2):Abstract S1302

% R

ech

ute

à 1

2 m

ois

90

80

70

60

50

40

30

20

10

0 Rémission clinique

et endoscopique à S6

(n=54)

Rémission clinique

mais non endoscopique à S6

(n=5)

L’objectif thérapeutique dans la RCH est la rémission clinique et endoscopique

ECCO consensus

La rémission endoscopique est définie

par le score Mayo endoscopique

RE = sous-score

endoscopique ≤ 1

Pineton de Chambrun, G. et al. NRGH 2010; 7:15–29

La cicatrisation muqueuse à un an

diminue le risque de colectomie

Froslie K.F et al Gastroenterology, 2007; 133: 412-22

Suivi prospectif d’une cohorte

Norvégienne recrutée entre 1990-94

(avant biothérapies)

354 RCH avec évaluation

endoscopique à 1 an : 175 MH+, 163

MH -

Réévaluation clinique à 5 ans

MH+: 3 colectomies /178 (2%)

MH -:13 colectomies /176 (7%)

p= 0,02

MH-

MH+

Colombel JF et al. Gastro 2011;141:1194–1201

Une colon d’aspect normal est associé à un risque

plus faible de dysplasie/cancer au cours de la RCH

À l’endoscopie Groupe OR (IC95% ) p

Pseudo-polypes inflammatoires

NON

OUI

1

2, 29 (1,28-4,11) 0,005

Sténose du colon NON

OUI

1

4,62 (1,03-20,08) 0,05

Inflammation histologique sévère

NON

OUI

1

5,13 (2,36-11,14) 0,001

Colon d’aspect normal NON

OUI

1

0, 38 (0,19-0,73) 0,003

Rutter MD et al. Gut 2004 ; 53 : 1813-6

Rutter MD et al. Gastroenterology 2004 ; 56 : 451-9

Histoire naturelle MC

Crohn’s disease as a progressive disease

Progression of digestive damage and inflammatory activity in a theoretical patient with Crohn’s disease

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

Inflam

mato

ry activity (C

DA

I, CD

EIS, CR

P)

Surgery

Stricture

Stricture

Fistula/abscess

Disease onset

Diagnosis Early disease

Profil évolutif des MICI maladie de Crohn

Solberg, CGH 2007; 5: 1430

amélioration

rapide

aggravation

tardive

chronique

continue

chronique

intermittente

43% 3% 32% 19%

Cohorte d'inclusion danoise (IBSEN study), n=197/237, suivi 10 ans

Peyrin-Biroulet L, et al. Gut 2010;59:141–7

Genetic and environmental

factors, intestinal microflora Symptoms Criteria for diagnosis of

Crohn’s disease fulfilled

Time

Early Crohn’s disease

Inflammation (clinical, biological,

endoscopic, radiologic evidence

of disease activity)

No fistula, abscess or stricture

Late Crohn’s disease

Bowel damage (stricture, fistula,

abscess,

Impairment of GI functioning

Colorectal cancer

Preclinical phase

Subclinical inflammation

(immune response and

histologic lesions)

Early CD

Rutgeerts P, et al. Gastroenterology 1990;99:956-63

Endoscopic lesions precede clinical

relapse • Prospective trial with 89 patients having had ileal resection

• Endoscopical diagnosis 1 year after surgery predicts future relapse

i0: no lesions

i1: <5 aphthous lesions

i2: >5, but normal

mucosa between lesions

i3: diffuse and diffusely

inflamed between lesions

i4: diffuse inflammation

and large ulcers,

narrowing, etc.

0

0.2

0.4

0.6

0.8

1.0

Sym

pto

m-f

ree s

urv

ival (%

)

0 1 2 3 4 5 6 7 8

i4

i3

i2

i0 + i1

Follow up (years)

Anatomic Evolution

Rutgeerts P, et al. Gastroenterology 1990;99:956-63

Inflammation

Stricture

Fistula/

abscess

At diagnosis After 10 years

80% 50%

20% 50%

Disease behaviour over time

Montreal classification

Montreal

Age at diagnosis A1 below 16 y

A2 between 17 and 40 y

A3 above 40 y

Location L1 ileal

L2 colonic

L3 ileocolonic

L4 isolated upper

disease*

Behaviour B1 non‐stricturing,

non‐penetrating

B2 stricturing

B3 penetrating

p perianal disease

modifier†

*L4 is a modifier that can be added to L1–L3 when concomitant upper gastrointestinal disease is present.

†“p” is added to B1–B3 when concomitant perianal disease is present.

Cumulative rate of remaining free of intestinal penetrating or stricturing complications in ileal (left) and colonic (right) CD

Data were obtained from the studies at St-Antoine hospital that included 1448 patients with ileal disease (L1) and 1129 patients

with colonic disease (L2).

CD evolution relates to disease location

Long term disease course in CD

Ileal

Colon

Ileocolon

Proximal

Penetrating

Stricturing

Inflammatory

Louis E et al Gut 2001; 49:777-32

%

years years

Behaviour Location

Schwartz et al. Gastroenterology 2002

Perianal fistulas

Penetrating complications

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30

Years from Crohn’s disease diagnosis

Cu

mu

lati

ve p

rob

ab

ilit

y

of

co

mp

licati

on

s

Penetrating or stricturing complications

Stricturing complications

52

Long-term evolution of Crohn’s disease behaviour

(population-based study)

Thia KT, et al. Gastroenterol 2010;139:1147–55

American population-based cohort of individuals diagnosed with Crohn’s disease 1970–2004 (n=306);

evaluated for initial phenotype and cumulative probability of complications estimated using Kaplan-Meier

Hospitalisations Taux annuel: 20 %

Chirurgie abdominale majeure

(Comté d’Olmsted, 1970-2004, n=310)

Peyrin-Biroulet L et al. Soumis

Perc

en

t

0

20

40

60

80

100

Years

0 5 10 15 20 25 30

310 166 92 54 33 20 7# at risk

Cumulative Probability of First Major Abdominal Surgery

Récidive post-opératoire

(Comté d’Olmsted, 1970-2004, n=310)

Peyrin-Biroulet L et al. DDW 2010

Phenotype recurrence after surgery

Indications for first

resection

Perforating

(n=195)

Non-

perforating

(n=150)

Indications

for second

resection

Perforating 64(77%) 24(29%)

Non-

perforating

19(23%) 60(71%)

Total 83 84

Greenstein et al. Gut, 1988, 29, 588-592

Work disability in IBD C

D p

atie

nts

re

ceiv

ing

DP

(%

)

0

10

20

30

50

18–29 40–49 60–67 50–59 30–39

40

Age (years) U

C p

atie

nts

re

ceiv

ing

DP

(%

) 0

10

20

30

50

18–29 40–49 60–67 50–59 30–39

40

DP because of CD

DP because of other diagnosis

DP in background population

DP because of UC

DP because of other diagnosis

DP in background population

Age (years)

Norwegian population-based study of IBD patients (n=518) receiving disability pension (DP)

RR for DP: 2.0 (95% CI 1.4–2.7)

RR for DP: 1.8 (95% CI 1.4–2.3)

Hoivik M, et al. Gut 2012 [Epub ahead of print: doi:10.1136/gutjnl-2012-302311]

Crohn’s disease Ulcerative colitis

Estimates of mortality in IBD

Mortality increased in the first year after diagnosis

Intermediate and long-term mortality increased by 10% in UC and 50% in CD

Mortality from UC decreased from 1982 to 2010, because of reduced mortalities from gastrointestinal disorders and colorectal cancer

Mortality from CD did not change

Risk of dying according to age at, and time since, IBD diagnosis (Denmark 1982–2010) 36,080 UC and 15,361 CD vs 2,858,096 matched controls

Jess T, et al. Clin Gastroenterol Hepatol 2013;11:43–8

0 25 50

100

0 5 10 15 20 25

80+ years old

0 25 50

100

0 5 10 15 20 25

60–79 years old

0

20

40

0 5 10 15 20 25

40–59 years old

0 5

10 15

0 5 10 15 20 25

20–39 years old

0

2

4

0 5 10 15 20 25

0–19 years old

Time since IBD diagnosis / date of matching (years)

Ris

k o

f d

eat

h (

%)

Control persons

Ulcerative colitis

Crohn’s disease

Inflam

mato

ry activity

Surgery

Stricture

Stricture

Fistula/abscess

Disease onset

Dig

est

ive

dam

age

Diagnosis Early disease

New goal of treatment: Blocking disease progression and damage

Adapted from Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

New goal of treatment: Blocking disease progression and damage

Adapted from Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

Inflam

mato

ry activity

Disease onset

Dig

est

ive

dam

age

Diagnosis Early disease

Réponse

clinique

Rémission

clinique Réponse ET

rémission

clinique

Rémission

clinique Rémission

clinique

sans

corticoïdes

1997

Targan

2006

Hanauer

CLASSIC-I

2002

Hanauer

ACCENT 1

2007

Colombel

CHARM

2010

Colombel

SONIC

Cicatrisation

muqueuse

2012

Rutgeerts

EXTEND

Critère de jugement principal dans les

essais randomisés contrôlés dans la MC

Emerging concepts in IBD therapy

Treat to target (beyond symptoms)

Early intervention

Monitoring (tight control)

Profiling disease course

Personalizing (precision medicine)

Take home messages • Incidence et prévalence des MICI ont augmenté ces 4

dernières décades, parallèlement à l’industrialisation du mode de vie

• Maladies chroniques inflammatoires à manifestations digestives et extradigestives évoluant par poussées de pronostic imprévisible

• Diagnostic relativement facile si on y pense (iléocoloscopie+++)

• Risque chirurgical majeur

• Objectif thérapeutique actuel = rémission profonde soutenue pour modifier histoire naturelle