How Should We be Assessing and Documenting Endoscopies in IBD: Incorporating Standard Scoring Systems into Patient Care Gary R Lichtenstein, MD Director, Center for IBD University of Pennsylvania School of Medicine Hospital of the University of PA Philadelphia, PA

Uses of Endoscopy in IBD Diagnosis Disease extent Prognostication Assessment of Activity/Healing Stricture evaluation and dilation Dysplasia Surveillance Diagnose/Control Bleeding Pouch Evaluation Endoscopic Ultrasound Video Capsule Endoscopy

I. Mucosal Healing UC and Crohn’s disease characterized by the presence of gut inflammation accompanied by areas of ulceration Mucosal healing is becoming increasingly important in the clinical management of UC and Crohn’s disease, as well as being used as an end point in clinical trials. Achieving mucosal healing has unequivocally been associated with better outcomes, and for these reasons, it has become an important treatment goal.

I. Mucosal Healing Multiple methods to score endoscopic disease activity in both UC and Crohn’s disease. Those used most frequently or that have been validated: Mayo Endoscopic Score Ulcerative Colitis Endoscopic Index of Severity (UCEIS) Crohn’s Disease Endoscopic Index of Severity (CDEIS), Simple Endoscopic Score for Crohn’s Disease (SES-CD), Rutgeerts Postoperative Endoscopic Index for Crohn’s disease.

II. Definition of Mucosal Healing Mucosal healing in the context of IBD refers to the endoscopic assessment of disease activity. Simply stated, mucosal healing should imply the absence of ulceration and erosions. There is currently no validated definition of mucosal healing in IBD.

III. Inflammation in UC The pattern of inflammation in UC is associated with several mucosal changes, initially vascular congestion, erythema, and granularity. As inflammation becomes more severe, friability (bleeding to light touch), spontaneous bleeding, and erosions and ulcers develop.

What Is the Definition of Mucosal Healing?

AGA Consensus on Efficacy End Points: Endoscopic Healing in Ulcerative Colitis “Absence of friability, blood, erosions, and ulcers in all visualized segments are the required components of genuine endoscopic healing.” D’Haens G et al. Gastroenterology 2007;132(2):763–86. 8

Mucosal Healing in Ulcerative Colitis Disease: The Issues What is the definition of mucosal healing? Depends on finding a scoring system of your choice some studies allow erythema and friability in the definition of mucosal healing 1 Many different endoscopic indices for UC have been used in clinical trials, only one UCEIS - validated in prospective studies; this creates problems when comparing trials. 1.) Dave M, et al Gastroenterol Hepatol 2012;8(1):29–38. 9

Mucosal Abnormalities in Crohn’s Disease The SB has limited ways to demonstrate injury: Mucosal Disruption Erosions Ulcers Erythema Villous Blunting Strictures These findings are easily captured by capsule endoscopy, but are not pathognomonic of IBD.

Hypothesis Erythema and Villous Blunting Aphthous Ulcers VCE + Superficial Ulceration Serpiginous or Linear Ulcers Rad + Cobblestone Appearance Transmural Inflammation Strictures, Fistulas Carucci LR et al: GI Clinics NA 31:93-117, 2002

What Is the Definition of Mucosal Healing in Crohn’s Disease? CDEIS: Deep ulceration, superficial ulceration, and inflammation1 Complex (many variables and scores range from 0 to 44) Experience is required Difficult to use in clinical practice No validated definition of mucosal healing SES-CD: Ulcers, inflammation, and narrowing2 Validated in only 1 study Scores range from 0 to 60 Rutgeerts Score: Aphthoid lesions, inflammation, ulcers, nodules, and narrowing3 Only applicable to postoperative recurrence No endpoint for endoscopic remission in the trials CDAI = Crohn’s Disease Activity Index; SES-CD = Simple Endoscopic Score for Crohn's Disease. 1. Mary JY et al. Gut. 1989;30:983-989; 2. Daperno M et al. Gastroenterology. 2002;122:A216; 3. Rutgeerts P et al. Gastroenterology. 1990;99:956-963. 12

Limitations of Endoscopic Scores of Bowel Lesions in Crohn’s Disease? No validated endpoints for: Endoscopic response Endoscopic remission Complete mucosal healing = total disappearance of all ulcers Does the mucosal activity reflect transmural damage? No controlled studies have evaluated endoscopic score correlation with the entire thickness of the intestinal wall What is the spontaneous variation of endoscopic activity in Crohn’s disease? Study of the placebo effect 13

Limitations of Endoscopic Scores of Bowel Lesions in Crohn’s Disease? Does not access small bowel other than terminal ileum Makes assumption that changes to the lesions in terminal ileum reflect what transpires in remainder of the small bowel 14

Actual Endoscopic Indices Ulcerative Colitis Mayo Score UCIEIS Crohn’s Disease UCEIS SES-CD Rutgeerts Score 15

UC Endoscopic Indices Table Source- Walsh A, et al. Gastrointest. Endoscopy Clin. N. Am. 2014; 24: 367–378 16

Mayo Scoring System1 for Assessment of UC Activity Stool frequency: 0 = Normal number of stools for this patient 1 = 1 to 2 stools more than normal 2 = 3 to 4 stools more than normal 3 = 5 or more stools more than normal Rectal bleeding: 0 = None 1 = Streaks of blood with stool less than half the time 2 = Obvious blood with stool most of the time 3 = Blood alone passes Endoscopic findings: 0 = Normal or inactive disease 1 = Mild disease (redness, decreased vascular pattern visible, friability) 2 = Moderate disease (redness, no vascular pattern visible, friability, erosions) 3 = Severe disease (bleeding, ulceration) Physician’s global assessment of disease activity: 0 (normal) to 3 (severe) Schroeder KW, et al. N Engl J Med. 1987;317(26):1625-1629.

Mayo Score: Practical Points Overlap in the features of the different levels of this endoscopic index, which causes high interobserver variation. The most troublesome component of this index is friability, as this is subjective and leads to inconsistent results.1 This inconsistency has lead to an adaptation of the index to remove friability. 2,3 1.) D’Haens G, et al Gastroenterology2012;143(6):1461–9. 2.) Kamm MA, et al. Gastroenterology2007;132(1):66–75. 3.) Lichtenstein GR, et al Clinical Gastroenterol Hepatol. 2007; 2007;5: 95–102. 18

Mayo Score: Practical Points The value of this index is its widespread use in clinical trials. Mucosal healing – 0 or 1- or a deceases from the subscores of 2 or 3.1 In Active Ulcerative Colitis Trials, patients with a post-treatment Mayo score of grade 1 were no more likely to undergo a colectomy than those with a score of 0. 1 1.) Rutgeerts P , et al N Engl J Med 2005;353(23):2462–76. 19

UCEIS for Assessment of UC Activity Table Source- Walsh A, et al. Gastrointest. Endoscopy Clin. N. Am. 2014; 24: 367–378

UCEIS: Practical Points In practical terms, the most severely affected part of the mucosa is scored. Limitations- Thresholds for remission and mild, moderate, and severe disease have yet to be set. The extent to which full colonoscopy may influence the score compared with the flexible sigmoidoscopy on which it was based, has only started to be evaluated .1 1- Thia KT et al, Inflamm Bowel Dis. 2011;17(6):1257–64. 21

UCEIS: Practical Points Knowledge of symptoms does not materially influence the score, and a comparison with the Mayo Clinic endoscopy subscore shows that the UCEIS is less subject to variation by a central reader. UCEIS is simple enough to use in clinical practice and should achieve its goal of reducing variation in endoscopic assessment of activity between observers. Patients admitted with acute severe colitis with a score of 7 or 8 (out of 8) on admission predicted an inadequate response to intravenous steroids and the need for rescue therapy with cyclosporine or infliximab1. Easy for in office use 1.) Conte CJ, et al. Gastroenterology 2013; 144(5): S-102. 22

Crohn’s Disease: Endoscopy Table Source- Walsh A, et al. Gastrointest. Endoscopy Clin. N. Am. 2014; 24: 367–378 23

Crohn’s Disease Endoscopic Index of Severity Prospectively developed instrument constructed to detect changes in disease activity1. Examines 4 endoscopic variables In each of the following locations: rectum, sigmoid and left colon, transverse colon, and right colon and ileum CDEIS scores range from 0 to 44. Mary JY, et al. Gut 1989;30(7): 983–9. 24

Crohn’s Disease Endoscopic Index of Severity CDEIS Evaluates: Deep ulcerations: score 0 if absent or 12 if present. Superficial ulcerations: score 0 if absent or 6 if present. Length of ulcerated mucosa (0-10cm): score 0 to 10 according to length in centimeters Length of diseased mucosa (0-10cm): score 0 to 10 according to length in centimeters. 1.) Conte CJ, et al. Gastroenterology 2013; 144(5): S-102
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Crohn’s Disease Endoscopic Index of Severity The numbers are added up in each segment and divided by the number of segments evaluated. An additional 3 points is given if an ulcerated stenosis is present, and a further 3 points if a nonulcerated stenosis is present. Mary JY, et al. Gut 1989;30(7): 983–9. 26

Crohn’s Disease Endoscopic Index of Severity Table Source- Walsh A, et al. Gastrointest. Endoscopy Clin. N. Am. 2014; 24: 367–378 27

Crohn’s Disease Endoscopic Index of Severity CDEIS Definitions: Endoscopic remission (minor or no lesions) is defined as a CDEIS score less than or equal to 6 or less than or equal to 7 Complete endoscopic remission (mucosal healing, i.e., no lesions at all or scarred lesions only) is defined as a CDEIS score less than or equal to 3 or less than or equal to 4. Endoscopic response is a decrease from baseline CDEIS score of at least 4 or 5 points.
. Mary JY, et al. Gut 1989;30(7): 983–9. 28

Crohn’s Disease Endoscopic Index of Severity Critque: It is the standard index and it is reproducible. It is complex Requires training and experience To estimate ulcerated or disease mucosal surface areas To distinguish between superficial and deep ulcerations. It is cumbersome to use in clinical practice. Mary JY, et al. Gut 1989;30(7): 983–9. 29

Simplified Endoscopic Score for Crohn’s Disease Daperno M, et al. Gastrointest Endoscopy 2004; 60: 505-512. 30

Crohn’s Disease Endoscopic Index of Severity Critque: The SES-CD correlates well with the CDEIS Correlation coefficient (r=0.920) Interobserver reliability (kappa- 0.791-1.000) Easy to use Less complex than the CDEIS No cutoff values have been determined for this Mucosal healing not defined. Daperno M, et al. Gastrointest Endoscopy 2004; 60: 505-512. 31

The Natural Course of Postop CD Recurrence is clinically silent initially Histologic Endoscopic Radiologic Clinical Surgical 30% 3 yr 60% 5 yr Within 1 week 70-90% by 1 yr Tissue damage 50% by 5 yrs Surgery [1] D’Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114:262-267. [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33:331-335. [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983. [4] Sachar DB. Med Clin North Am 1990;74:183-188.

Endoscopic Recurrence Score Endoscopic Remission 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 Endoscopic Recurrence Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983.

>70% of Pts Have i2,3,4 Recurrence 1 Year after Surgery – Rutgeerts et al Gastro 1990 i0 and i1 remission -low likelihood of progression i,3 i4 i2,i3,i4 recurrence Likely progression to another surgery

Actuarial Rate of Symptomatic Recurrence Those individuals with grade 3 and 4 lesions at one year postoperatively during colonoscopy were more likely to have symptomatic recurrences earlier than those with individuals with grade 1 and 2 lesions. 1.0 Grade 0 and Grade 1 0.8 % symptom free survival 0.6 Grade 2 0.4 0.2 Grade 4 Grade 3 1 1 2 3 4 5 6 7 8 9 10 Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99:956-983.

POCER Study: Postoperative Crohn’s Disease Endoscopic Recurrence Methods: Multicentre RCT No Endoscopy (“Standard”) Risk driven best drug therapy 1/3 of patients All patients: Metronidazole: 0-3 months Randomization Low risk: No further treatment High risk: Thiopurine or adalimumab if thiopurine intolerant 18 Month Colonoscopy RISK Stratification: Low or High (High risk: smoker, ≥ second operation, perforating disease) 2/3 of patients 6 Month Colonoscopy Step up Rx if ≥ i2 on Rutgeerts scale Endoscopic Intervention (“Active”) SURGERY: Curative resection De Cruz P, et al. Presented at DDW; May 21 2013. Abstract 925J.

POCER Study: Postoperative Crohn’s Disease Endoscopic Recurrence Results: 32% dropout rate; no difference between both study arms 174 randomized: 122 Active/ 52 Standard 6-month (short-term) endoscopic recurrence: ADA better than thiopurine in high-risk patients (P=0.028) Stepping up at 6 months if ≥i2 brought 39% into endoscopic remission at 18 months Remission at 6 months colonoscopy, 39% endoscopic recurrence at 18 months Conclusions regarding postoperative recurrence of Crohn’s: Treatment according to risk of recurrence at 6 month colonoscopy, is superior to drug therapy alone Step-up with anti-TNF therapy, based on colonoscopy findings at 6 months, is a viable strategy in high-risk patients Rutgeerts ≤ i2 at 18 months Active Care (n=122) 62/122 (51%) P= 0.028 Standard Care (n=52) 17/52 (33%) Adalimumab Immediately Postop (n=28) 16/28 (57%) P = 0.2 Adalimumab Initiated if i≥2 at 6 Months (n=32) 13/32 (41%) De Cruz P, et al. Presented at DDW; May 21, 2013. Abstract 925J.

CONCLUSION The colonoscopic assessment of mucosal inflammation and healing is important for assessment of patients with UC and CD All clinicians should try to achieve mucosal healing in patients with IBD Multiple endoscopic indices for UC exist but only one, the UCEIS is validated The CDEIS and SES-CD are validated in CD The Rutgeerts postoperative endoscopic index is useful for predicting the clinical course in patients with ileocecal CD undergoing ileocecal resections 38