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 ?

3. To answer these questions, classifications must be tested to be validated Rome, 1991 Vienne, 1998 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 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

5. 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

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 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

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

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 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

10. 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 (RR=0.8-2.2) Significant association in 1655 colonic CD

11. Development of stricturing and fistulizing CD over the course of the disease

12. Development of stricturing and fistulizing CD over the course of the disease

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

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

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

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

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 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

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

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

30. Crohn’s disease location is the main factor influencing the development of complicationsCD behaviour 5 years after diagnosis

31. Subtype of penetrating CD after 5 years according to location of disease at diagnosis

32. Perianal Crohn’s 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

34. 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.

35. Mortality over 10 years in newly diagnosed CD

36. Colectomy in UC after 5 years

37. Colorectal cancer in UC after 30 years

38. Standard mortality ratio in UC

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

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 Crohn’s 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: 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.

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