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

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Presentation on theme: "MICI: classification et nosologie le point de vue du clinicien Edouard Louis Service de Gastroentérologie, CHU Liège GIGAresearch, Université de Liège."— Presentation transcript:

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

2 Disease phenotypes in IBD why to bother ? IBD CD UC IC CD1 CD2 CDx UC1 UC2 UCx 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, Vienne, Montreal, 2005

4 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 –A –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

5 Age at diagnosis <16 yrs: pediatric CD –Increasing incidence –More upper GI CD –More extensive CD yrs: classical CD >40 yrs: CD in the elederly –More colonic disease –Differential diagnosis with ischemia

6 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 –A –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

7 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

8 Prevalence of small bowel CD with VCE Results of a meta-analysis Incremental Yield of VCE (%) SBFT N=9 P<0.001 ileoscop N=4 P=0.02 MRI N=1 P=0.16 Enterosc N=2 P<0.001 CT entero N=3 P=0.001 Triester et al. Am J Gastroenterol 2006;101:954

9 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 –A –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

10 Penetrating CD: heterogeneous entity Association 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 (RR= ) Significant association in 1655 colonic CD Sachar et al. Am J Gastroenterol 2005; 100: 1547 RR of association between Perianal and internal fistulizing Disease in colonic CD P<0.0001

11 Development of stricturing and fistulizing CD over the course of the disease Time (years) Louis et al. Gut 2001 Patients at risk. N= %

12 Development of stricturing and fistulizing CD over the course of the disease Cosnes J et al. Inflamm Bowel Dis. 2002;8: Cumulative Probability (%) Patients at risk: Months N = Penetrating Stricturing Inflammatory

13 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

14 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

15 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

16 Significant inflammation in macroscopically normal mucosa in CD Reimund et al. Gut 1996;39:684.

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18 How to define a stricturing CD In Vienna classification: associated with symptoms or proximal dilatation Persistent stricture Inflammatory vs fibrotic stricture

19 Subobstructive CD 8 w. after Ifx

20 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 Time (years) Louis et al. Gut 2001 Patients at risk. N= %

22 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

23 Speed of development of stricturing CD time stricture

24 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

25 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 1989;11: 193

26 Fistulizing CD: a mechanical theory Intraluminal hyperpressure

27 Are different phenotypes driven by different pathophysiology ? This would imply that a stable general phenotype exists for each patient

28 Influence of smoking of the phenotype of CD Brant et al. Inflamm Bowel Dis 2003 Picco et al. Am J Gastro 2003

29 Impact of disease phenotype on natural history That is mainly the phenotype at diagnosis which is important

30 Crohns disease location is the main factor influencing the development of complications CD 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 (p<0.0001) Louis et al. Gut 2003

32 Perianal Crohns disease Cumulative frequency of 12% at 1 year, 15% at 5 ys, 26% at 20 ys Schwartz et al. Gastroenterology 2002; 122:875 Occurs in 12% of ileal CD, 41% of colonic CD, 92% in case of rectal involvement Hellers et al. Gut 1980; 21: 525

33 Recurrence rate in newly diagnosed CD Wolters et al. Gut 2006; 55: The only factor independently associated with all recurrences was L4 location (P<0.01)

34 Predictors of disabling CD Proportion 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. Beaugerie et al. Gastroenterology 2006; 130: 650.

35 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

36 Colectomy in UC after 5 years % Langholz et al. Gastroenterology 1992;103:1444

37 Colorectal cancer in UC after 30 years % Devroede et al. N Engl J Med 1971;285:17

38 Standard mortality ratio in UC SMR Ekbom et al. Gastroenterology 1992;103:954

39 Impact of disease phenotype on response to treatments That is mainly the phenotype at the time you treat the patient which is important

40 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

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42 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

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

44 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: ( ) 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 ( ) Agrawal et al. Clin Gastroenterol Hepatol 2005; 3: 1215.

45 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

46 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


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