Activity and Endoscopic measures : Crohn s disease. Jean-Frederic COLOMBEL Justin Cote-Daigneault Icahn Medical School at Mount Sinai, New York

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1 Activity and Endoscopic measures : Crohn s disease Jean-Frederic COLOMBEL Justin Cote-Daigneault Icahn Medical School at Mount Sinai, New York

2 J-F Colombel has served as consultant or advisory board member for Abbvie, ABScience, Amgen, Bristol Meyers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Medimmune, Merck & Co., Millenium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co. J-F Colombel has served as speaker for Abbvie, Falk, Ferring, Janssen, Merck & Co., Nutrition Science Partners Ltd., Takeda.

3 The origin

4 The CDEIS Deep ulcerations 12 points Superficial Ulcerations* 6 points Surface of ulcerations (0-10 cm) Surface of lesions (0-10 cm) Ileum 0 or 12 0 or Right colon 0 or 12 0 or Transverse 0 or 12 0 or Left colon 0 or 12 0 or Rectum 0 or 12 0 or TOTAL (sum of all cases) TOTAL/number of explored segments N/ if ulcerated stenosis if nonulcerated stenosis 0-3 CDEIS : 0 to 44 N * : excluding aphtous ulcers Mary JY et al. Gut 1989

5 CDEIS definitions Ulcerated surface includes: Aphtous ulcerations Superficial ulcerations Deep ulcerations Ulcerated stenosis Affected surface includes: Aphtous ulcerations Superficial ulcerations Deep ulcerations Pseudopolyps Erythema Frankly swollen mucosa Non-ulcerated stenosis Ulcerated stenosis Healed ulceration

6 Development of SES-CD The Simple Endoscopic Score for Crohn s Disease (SES-CD), was developed in 2004 and was: an attempt to simplify the CDEIS based on importance and reproducibility of the most relevant endoscopic characteristics of CD. SES-CD included only characteristics that were: contributing to clinical symptomatology showing good reproducibility in the GETAID studies Daperno M et al. Gastrointest. Endosc

7 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Definition - scoring of elementary lesions considered SES-CD values (evaluated for each of the 5 ileo-colonic segments) Variable Size of ulcers None Ulcerated surface Affected surface Presence of narrowings None Unaffected segment None Daperno et al. Gastrointest Endosc

8 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Definition - scoring of elementary lesions considered SES-CD values (evaluated for each of the 5 ileo-colonic segments) Variable Size of ulcers None Aphtous ulcers ( 0.1 to 0.5 cm) Large ulcers ( 0.5 to 2 cm) Very large ulcers ( >2 cm) Ulcerated surface None Affected surface Unaffected segment Presence of narrowings None Daperno et al. Gastrointest Endosc 2004

9 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Definition - scoring of elementary lesions considered SES-CD values (evaluated for each of the 5 ileo-colonic segments) Variable Size of ulcers None Aphtous ulcers ( 0.1 to 0.5 cm) Large ulcers ( 0.5 to 2 cm) Very large ulcers ( >2 cm) Ulcerated surface None <10% 10-30% >30% Affected surface Presence of narrowings Unaffected segment None Daperno et al. Gastrointest Endosc 2004

10 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Definition - scoring of elementary lesions considered SES-CD values (evaluated for each of the 5 ileo-colonic segments) Variable Size of ulcers None Aphtous ulcers ( 0.1 to 0.5 cm) Large ulcers ( 0.5 to 2 cm) Very large ulcers ( >2 cm) Ulcerated surface None <10% 10-30% >30% Affected surface Presence of narrowings Unaffected segment None <50% 50-75% >75% Daperno et al. Gastrointest Endosc 2004

11 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Definition - scoring of elementary lesions considered SES-CD values (evaluated for each of the 5 ileo-colonic segments) Variable Size of ulcers None Aphtous ulcers ( 0.1 to 0.5 cm) Large ulcers ( 0.5 to 2 cm) Very large ulcers ( >2 cm) Ulcerated surface None <10% 10-30% >30% Affected surface Unaffected segment <50% 50-75% >75% Presence of narrowings None Single, can be passed Multiple, can be passed Cannot be passed Daperno et al. Gastrointest Endosc 2004 Daperno et al. Gastrointest Endosc 2004; 60:505-12

12 THE SIMPLE ENDOSCOPIC SCORE FOR CD (SES-CD) Ileum Right colon Transverse colon Left colon Rectum Total Presence and size of ulcers (0-3) Extent of ulcerated surface (0-3) Extent of affected surface (0-3) Presence and type of narrowings (0-3) SES-CD = 0-56 Daperno et al. Gastrointest Endosc 2004

13 Correlation between CDEIS and SES-CD Sipponen T et al. Inflam Bowel Dis

14 SES-CD grading vs CDEIS grading SES-CD overestimates severity vs CDEIS in inactive / mild CD Sipponen T et al. Inflam Bowel Dis

15 Correlation between CDEIS, SES-CD and CDAI Cellier C et al. Gut 1994 Daperno et al. Gastrointest Endosc 2004

16 Definition of endoscopic severity using SES-CD Endoscopic severity with SES-CD (in 4 of 11 studies)* : remission (inactive) (0-2) mild inflammation (3-6) moderate inflammation (7-15) severe inflammation (> or =16) * In total 6 different cut-off definitions, but 6 of 11 studies used similar cutoffs Vuitton L et al. Gut

17 Definition of endoscopic response with SES-CD Authors Journal Year Definition of response Sipponen et al. Scand J Gastroenterol 2010 A partial response as a one-class change in the SES-CD (inactive 0-2; mild 3-6; moderate 7-15; severe > or =16) Ferrante et al. (SONIC post hoc) Gastroenterology 2013 Decrease from baseline in SES-CD of at least 50%. Grover et al. J Gastroenterol 2014 Absolute score SES-CD 0-3 was defined as a response 17

18 Endoscopic response at wk 26 predicts corticoid-free remission at wk 50 in CD (SONIC) Roc Curve for detecting corticoid-free remission at wk 50 using the SES-CD % reduction from baseline to wk 26 Roc Curve for detecting corticoid-free remission at wk 50 using the CDEIS % reduction from baseline to wk 26 Mucosal healing and endoscopic response (defined as a decrease from baseline in SES-CD or CDEIS of at least 50%) at week 26 identified patients most likely to be in CFREM at week 50 Ferrante M, et al. Gastroenterology;

19 Definition of endoscopic remission using SES-CD Authors Journal Year Definition of Remission Moskovitz et al. Gastroenterology 2007 score 0 Sipponen et al. Aliment Pharmacol Ther 2008 score <3 Baert et al. Gastroenterology 2010 score 0 Sipponen et al. Scand J Gastroenterol 2010 score 0 2 or a two- or three-class decrease in the SES-CD from the baseline score ( i.e. change from endoscopically severely active disease to mildly active or inactive or from moderately active to inactive). Aomatsu et al. Aliment Pharmacol Ther 2011 score 0 Aomatsu et al. Dig Dis Sci 2011 score 0 af Björkesten et al. Scand J Gastroenterol 2013 score 0-2 Molander et al. J Crohns Colitis 2013 score 0-2 Beigel et al. PLoS One 2014 score 0 Fukuchi et al. BMC Gastroenterol 2014 score 0 Yüksel et al. Turk J Gastroenterol 2014 score 0-2 Yu et al. J Dig Dis 2014 score 0 Schaffer et al. J Crohns Colitis 2014 score 0-3 Dignass et al. J Crohns Colitis 2014 score 0 19

20 Definition of endoscopic remission/mh using SES-CD Endoscopic remission/mh most frequently defined as* SES-CD score 0 (8 studies) or SES-CD score 0-2 (4 studies) * In total 4 different cut-off definitions in 14 studies

21 IOIBD technical review on endoscopic indices for Crohn's disease clinical trials Endoscopic response definition >50% decrease in SES-CD or CDEIS Endoscopic remission definition SES-CD = 0-2 Vuitton L et al. Gut 2016

22 Who should read and score the procedures in clinical trials Central readers vs local endoscopist Local endoscopist could overestimate the endoscopic activity to include their patients in the trial 1 Inter-observer variability could affect data interpretation 1 However, recent data showed 2 : Good agreement between local live readings and central readings using CDEIS and SES-CD Good agreement between local live readings and delayed live video-recorded readings using CDEIS and SES-CD 1. Panes et al. JCC Cote-Daigneault et al Abstract ECCO 2017

23 Remaining questions Validation of cut-offs When to measure? Technical issues : What is the length of ileum that should be intubated to score the SESCD? Definition of ulcerations and lesions Definition of narrowing that cannot be passed How to use SES-CD or CDEIS in patients with past history of surgery (not validated)

24 Endoscopic recurrence after surgery : Rutgeerts s score i0: no lesions i1: < 5 aphthous lesions i2: > 5 aphthous lesions with normal intervening mucosa i3: diffuse aphthous ileitis with diffusely inflamed mucosa i4: diffuse inflammation with large ulcers, nodules, and/or narrowing Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:

25 Marteau P et al. JCC 2016