Newsletter

Recommendations

Société Française d'Endoscopie Digestive (SFED)

Endoscopy in inflammatory bowel disease: recommendations from the IBD Committee of the French Society of Digestive Endoscopy (SFED) Laurent Peyrin-Biroulet1, Guillaume Bonnaud2, Arnaud Bourreille3, Jean-Baptiste Chevaux1, Patrick Faure4, Jérôme Filippi5, David Laharie6, Lucine Vuitton7, Philippe Bulois8, Florent Gonzalez9, Caroline Trang3, Stéphane Koch7, David Bernardini10, Christophe Cellier11 1 Inserm U954 and Department of Hepato-Gastroenterology, University Hospital of Nancy-Brabois, Université Henri Poincaré 1, 54511 Vandoeuvrelès-Nancy 2 Department of Gastroenterology, Clinique des Cèdres, 31700 Cornebarrieu 3 Institut des Maladies de l’Appareil Digestif, Nantes 4 Clinique Saint Jean Languedoc, 20 route de Revel 31400 Toulouse 5 Department of gastroenterology and nutrition, Archet 2 Hospital, Nice 6 CHU de Bordeaux, Hôpital HautLévêque, Service d’Hépato-gastroentérologie, Pessac, F-33600 7 Department of Gastroenterology, University hospital of Besançon, 25000 Besançon Cedex 8 Cabinet de Gastroentérologie, 20 rue du Ballon, 59000 Lille 9 Department of Gastroenterology, Polyclinique du Grand Sud, 30000 Nîmes 10 Service d’Hépato-gastroentérologie, Hôpital Sainte Musse, Avenue Sainte Claire Deville, 83056 Toulon Cedex 11 Service d’Hépato-gastroentérologie et Endoscopie, Hôpital Européen Georges Pompidou, 20 rue Leblanc 75015 Paris

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Corresponding author Prof. Laurent Peyrin-Biroulet, MD, PhD Inserm U954 and Department of Hepato-Gastroenterology University Hospital of Nancy-Brabois Université Henri Poincaré 1 Allée du Morvan 54511 Vandoeuvre-lès-Nancy France Phone + 33 3 83 15 36 31 Fax + 33 3 83 15 36 33 [email protected]

veillance is now well defined by the European Crohn’s and Colitis Organisation (ECCO) and includes an increasing use of chromoendoscopy, at least by experienced endoscopists. The classification of dysplastic lesions has been revised recently and the terms “Adenoma-like raised lesions’ (ALRL)” and ‘Non adenoma-like raised lesions’ (NALRL)” have replaced the terms “adenoma-like masses’ (ALM)” and “dysplasia-associated lesions or masses’ (DALM)”. About 3 out of 10 patients with CD will develop intestinal stricture during disease course and some patients with ulcerative colitis will experience colonic strictures. After ileocecal resection, 40 % of patients will need a second surgery, in most cases for anastomotic stricture; endoscopic dilatation is a good option in these patients, being effective and safe in the vast majority of cases. These recommendations from the IBD Committee of the French Society of Digestive Endoscopy (SFED) may be used to guide decision making in our clinical practice.

Key words endoscopy; inflammatory bowel disease. Fundings: None; Writing assistance: none

Small Bowel and Colonic Capsule Endoscopy in Inflammatory Bowel Disease (IBD) or suspected IBD !

Introduction !

In the biologics era, diagnosing inflammatory bowel disease (IBD) can still be challenging. The diagnosis of IBD is based on a combination of clinical, biological, radiological and histological markers. Enteroscopy and capsule endoscopy (CE) may be useful in patients with suspected Crohn’s disease (CD) or IBD-unclassified. Recently, mucosal healing (MH) has emerged as a major therapeutic goal in IBD. Accumulating evidence indicates that MH may change the natural course of the disease by decreasing the need for surgery and reducing hospitalization rates in both UC and CD. Crohn’s Disease Endoscopic Index of Severity (CDEIS) for CD and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) for UC are the only validated endoscopic scores. These scores are still underused in clinical practice. The absence of MH is associated with an increased risk of dysplasia and colorectal cancer (CRC) in IBD. Even though recent reports found a dramatic decrease in colorectal cancer risk, it remains a dreaded complication in IBD. Endoscopic sur-

In order to provide a worldwide perspective on the use of CE, a consensus has been published in 2009 jointly by the ECCO and the Organisation Mondiale d’Endoscopie Digestive (OMED) [1].

Small bowel capsule endoscopy (SBCE) in suspected Crohn’s disease CE is superior to all current forms of radiological testing of small-bowel in detecting mucosal lesions of non-stricturing CD. However the specificity is poor (2) and, in the absence of a validated index, a diagnosis of CD should not be based only on CE appearances [EL5, RG D]. Other limitations of CE in CD include the inability to take tissue samples and the lack of evaluation of transmural lesions (bowel damage). Small-bowel cross-sectional imaging should generally precede CE (EL 5, RG D). Magnetic resonance imaging should be preferred if possible as it is radiation-free. Total blood count, biochemical or fecal markers of inflammation, and serological markers should precede the use of CE when CD is suspected and conventional endoscopy and cross-sectional imaging are normal or inconclusive. Abnormal findings increase the diagnostic yield of CE. Normal capsule endoscopy has a high

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negative predictive value for active small bowel CD [EL4, RG D] [1].

Small bowel capsule endoscopy in established Crohn’s disease Defining active CD when ileocolonoscopy and cross-sectional imaging are inconclusive For patients with established CD, CE is better at identifying small bowel mucosal lesions than barium, CT, and MR enterography or enteroclysis [EL3a, RG C], but the clinical relevance of this difference has yet to be determined. The main drawback remains its low specificity and thus the risk to overdiagnose active CD, leading to unnecessary escalation of therapy [3]. The role of SBCE in patients with established CD should focus on patients with unexplained symptoms when other investigations are inconclusive, if this will alter management [EL 5, RG D] [1]. Cross sectional imaging should precede SBCE to identify obstructive strictures, extra-luminal disease and the anatomical distribution of lesions.

Assessing disease extent and severity Several activity indexes have been developed to access the severity and extension of small bowel CD [4, 5]. Unfortunately, none of them has been independently validated [6]. Jejunal lesions were reported in more than half of patients with CD having CE [7]. As jejunal lesions were associated with an increased risk of clinical relapse, it may be regarded as a poor prognostic factor [7].

Evaluation of postoperative recurrence CE should only be considered if ileocolonoscopy is contraindicated or unsuccessful [EL 4, RG C] [1].

Evaluation of mucosal healing CE has a potential role in the assessment of mucosal healing after drug therapy [EL 4, RG C] [1]. However, this will require further investigation.

Capsule endoscopy in IBD-unclassified (IBD-U) In patients with IBD-U, small bowel CE can be helpful in identifying those with small bowel mucosal lesions compatible with CD. However, a negative CE does not exclude a future diagnosis of CD [5EL3b, RG C] [8].

Complications Capsule retention in the small bowel is the most frequent complication of CE, observed in 1 % – 2.5 % of patients with suspected CD. This is similar to what has been reported in the general population, but this rate can increase up to 13 % in patients with established diagnosis of CD. A normal imaging study cannot entirely prevent the risk of small bowel capsule retention. The use of a patency capsule may predict safe transit of CE of identical or lesser size [9].

Ulcerative colitis The presence of visible lesions has no clear meaning after ileoanal anastomosis [EL3b, RG C]. Before ileoanal anastomosis, the presence of lesions at CE is not predictive of postoperative complications course. Colonic CE is not recommended in UC even though preliminary studies are encouraging [10 – 13].

Take-home messages CE is increasingly used in CD, particularly in IBD-U and suspected CD. It use should be restricted to selected patients as the risk of overtreating CD solely based on lesions found with CE remains its major limitation. It role in assessing postoperative CD recurrence and mucosal healing will require further investigation as there is no validated index. Its role in assessing disease activity and severity in UC has yet to be determined despite some encouraging results.

References 1 Boureille A, Ignjatovic A, Aabakken L et al. Role of small-bowel endoscopy in the management of patients with inflammatory bowel disease: an international OMED- ECCO consensus. Endoscopy 2009; 41: 618 – 37. 2 Solem CA, Loftus EV Jr, Fletcher JG et al. Small-bowel imaging in Crohn’s disease: a prospective, blinded, 4-way comparison trial. Gastrointest Endosc 2008; 68: 255 – 266 3 Doherty GA, Moss AC, Cheifetz AS. Capsule endoscopy for small-bowel evaluation in Crohn's disease. Gastrointest Endosc 2011; 74: 167 – 75. 4 Kornbluth A, Legnani P, Lewis BS. Video capsule endoscopy in inflammatory bowel disease: past, present, and

future. Inflamm Bowel Dis 2004; 10: 278 – 85. 5 Gal E, Geller A, Fraser G, Levi Z, Niv Y. Assessment and validation of the new capsule endoscopy Crohn's disease activity index (CECDAI). Dig Dis Sci 2008; 53: 1933 – 1937. 6 Chevaux JB, Fiorino G, Frédéric M et al. Capsule endoscopy in Crohn’s disease. Current drug targets 2012; 13: 1261 – 1267. 7 Flamant M, Trang C; Maillard O et al. The prevalence and outcome of jejunal lesions visualized by small bowel capsule endoscopy in Crohn’s disease. Inflammatory Bowel Disease 2012, In press. 8 Maunoury V, Savoye G, Bourreille A et al. Value of wireless capsule endoscopy in patients with indeterminate colitis (inflammatory bowel disease type unclassified). Inflamm Bowel Dis 2007; 13: 152 – 155. 9 Yadav A, Heigh RI, Hara AK et al. Performance of the patency capsule compared with nonenteroclysis radiologic examinations in patients with known or suspected intestinal strictures. Gastrointest Endosc 2011; 74: 834 – 839. 10 Hosoe N, Matsuoka K, Naganuma M et al. Applicability of second-generation colon capsule endoscope to ulcerative colitis: A clinical feasibility study. J Gastroenterol Hepatol 2013; 28: 1174 – 1179. 11 Meister T, Heinzow HS, Domagk D et al. Colon capsule endoscopy versus standard colonoscopy in assessing disease activity of ulcerative colitis: a prospective trial. Tech Coloproctol 2013. [Epub ahead of print]. 12 Ye CA, Gao YJ, Ge ZZ, et al. PillCam colon capsule endoscopy versus conventional colonoscopy for the detection of severity and extent of ulcerative colitis. J Dig Dis 2013;14:117 – 124. 13 Sung J, Ho KY, Chiu HM et al. The use of Pillcam Colon in assessing mucosal inflammation in ulcerative colitis: a multicenter study. Endoscopy 2012; 44: 754 – 758.

Enteroscopy in inflammatory bowel disease !

Suspected Crohn’s disease A recent meta-analysis of 11 studies showed that capsule endoscopy and double balloon enteroscopy (DBE) have comparable diagnostic yields in small bowel disease (60 % and 57 %, respectively), in-

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cluding CD (18 % and 16 %, respectively) [EL2a, RG B] [1]. DBE can be used to diagnose small bowel CD when biopsies are required or to analyze a non-typical lesion (OMED-ECCO statement 2G [EL5, RG D] [2]. Two studies with a low number of patients have showed improved diagnosis with DBE between 30 and 48 % in patients with suspected CD [EL4, RG C] [3]. A third study suggested that DBE and MRI are complementary techniques: DBE for the analysis of superficial lesions requiring histologic confirmation by targeted biopsies, and MRI to obtain some information on possible extra-luminal disease [EL4, RG C] [4]. In patients with suspected small bowel disease and a negative initial investigation (gastroscopy upper GI endoscopy with duodenal biopsies, ileo-colonoscopy with biopsies, or CT) a non-invasive diagnostic procedure such as CE should be preferred. Depending on the nature and location of the lesions seen at CE, an upper enteroscopy could be performed if lesions are present in the first two thirds of the CE procedure. However, if a stricure is suspected on radiological assessment, enteroscopy should be preferred because of the risk of CE retention and to allow biopsies or a therapeutic procedure such as dilation. Recommendations of the 2009 OMED-ECCO consensus are in line with these statements. The decision to perform a CE or device assisted enteroscopy (DAE) as first-line will depend on the nature and of lesion location in the small intestine, but also of local expertise and available resources [2].

Established Crohn’s disease Several studies have evaluated the role of DBE in established small bowel CD. In the study by Oshitani et al. [EL4, RG C] [5] enrolling 40 Japanese patients with established CD (38 for disease assessment, two for mild GI bleeding), a Small Bowel Barium Study (SBBS) was performed in 30 patients. Hemorrhagic ileal ulcers were identified in two patients but no hemostatic treatment was deemed necessary in these patients. The procedure failed in two patients: one because of colonic stenosis and the other because of adhesions. Endoscopic findings were divided into three groups: 1) aphthae, erosions, and small ulcers; 2) longitudinal and deep ulcers; 3) strictures. Small mucosal lesions were found in nine patients on DBE, while none of these lesions were detected on SBBS. Longitudinal and deep ulcers were found in 12 patients using DBE and in 12

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patients with SBS. DBE was superior to radiological study to detect aphthae, erosions, and small ulcers in the ileum. Ileal strictures were found in five patients with DBE and one patient with SBBS. One ileal perforation occurred after 53 examinations (1.9 %) [EL4, RG C] [5]. In another Italian study including 37 patients with CD [EL4, RG C] [6], the majority of procedures were performed for first diagnosis/ staging (43 %), obscure bleeding (27 %), or suspected strictures (19 %). DBE revealed at least one small bowel lesion in 18 (49 %) patients. The diagnostic yield was highly related to the indication (100 % for suspected strictures and 40 % in case of obscure bleeding). There were no reported complications. A limitation of DBE procedure was ileocecal valve intubation that waspossible in only 61.5 % of patients. In a Dutch retrospective study of 40 patients, DBE allowed the detection of small bowel lesions in 60 % of patients (leading to a therapeutic adjustment in 75 % of them), whereas half of these lesions could not be assessed by conventional endoscopy [EL4, RG C] [7].

Strictures dilation Pohl et al. [EL4, RG C] [8] reported initial results from a series of 19 consecutive patients with CD and known or suspected small-bowel strictures who underwent DBE. Fourteen patients had accessible strictures. Dilation therapy was successful in 79 % of patients. The St Mark’s Group has also reported their experience, with 13 DBE performed among 11 patients with CD [EL4, RG C] [9]. Ten of these patients had previous resection surgery. Eighteen small bowel stricture dilations were performed in 9 out of 11 patients. In two patients, stricture dilation was not performed because structure could not be reached due to adhesions. One patient suffered a delayed perforation. In the remaining eight patients, stricture dilation was successful, with no patients requiring surgery during a mean follow-up period of 20.5 months. Two patients required repeated dilation at 6.5 and 13 months [9]. In Japon, Ohmiya et al. [EL4, RG C] [10] evaluated the outcome of 66 patients with small bowel obstruction. Of 16 patients with CD, 69 % remained asymptomatic during follow-up. Another study from Hirai et al. [EL4, RG C] (11) reported the assessment of 25 patients with CD who underwent DBE for small bowel strictures. This procedure was successfully conducted in 72 % of cases, and compli-

cations were observed in 2 patients (8 %). The cumulative surgery-free rate was 83 % at 6 months and 72 % at 1 year.

Complications Complications reported with DBE are rare, occurring in less than 1 % of patients regardless of indication, although active CD or history of digestive surgery increase the risk of perforation [EL 3b, RG C] [2]. In a recent study reporting 2478 DBE procedures, the rate of complications appeared to be 10-fold higher than with a conventional colonoscopy [12]. The most reported complications are post-procedure abdominal pain, bleeding and perforation [EL4, RG C] [13, 14].

Take-home messages For suspected small bowel CD where other investigations are inconclusive, CE is generally preferred. If a stricture is suspected on imaging studies, DBE should be preferred because of the risk of CE retention. The advantages of DBE over CE are its therapeutic capabilities, allowing mucosal biopsy and the possibility of stricture dilation. In 2013, the most frequent indications for DBE are the need to obtain small bowel biopsies (suspicion of CD or small bowel dysplasia, and looking for a differential diagnosis) and to perform endoscopic dilation. Complications of DBE are rare, but this risk may be increased in CD.

References 1 Pasha SF, Leighton JA, Das A et al. Double-balloon enteroscopy and capsule endoscopy have comparable diagnostic yield in small-bowel disease: a meta-analysis. Clin Gastroenterol Hepatol 2008; 6: 671 – 676. 2 Boureille A, Ignjatovic A, Aabakken L et al. Role of small-bowel endoscopy in the management of IBD patients: an international OMED-ECCO consensus. Endoscopy 2009; 41: 618 – 637. 3 Heine GD, Hadithi M, Groenen MJ et al. Double-balloon enteroscopy: indications, diagnostic yield, and complications in a series of 275 patients with suspected small-bowel disease. Endoscopy 2006; 38: 42 – 48. 4 Seiderer J, Hermann K, Diepolder H et al. Double-balloon enteroscopy versus

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Mucosal healing in inflammatory bowel disease !

The prognostic value of MH was first established in the setting of postoperative recurrence of CD more than 20 years ago [1]. Accumulating evidence suggests that MH is desirable in both CD and UC.

Definition of mucosal healing and available indexes There is no validated definition for MH neither in CD nor in UC in 2013. In CD, the disappearance of all mucosal ulcerations has been considered as MH in many controlled trials. This criterion appears simple and easy to use clinical practice. However, such a binary outcome – healed/not healed – does not reflect the great variety of endoscopic CD activity. Two endoscopic quantitative scoring systems have been elaborated with this aim. The CDEIS developed by the GETAID is the sole endoscopic index ever validated in CD [2]. It defines five bowel segments – i. e. terminal ileum, right colon, transverse colon, left colon and rectum – and takes into account four types of elementary lesions (deep ulcerations, superficial ulcerations, inflammatory lesions and stenosis). Values are ranging from 0 to 44 points. Two cut-offs have been validated for defining endoscopic remission when CDEIS < 6, and complete endoscopic remission when CDEIS < 4. A CDEIS decrease of at least 6 points is defining CD endoscopic response [3]. Despite its complexity and the learning curve required, the CDEIS is considered as the gold standard for endoscopic assessment in CD. The Leuven group proposed another index– namely the Simplified Endoscopic Score for Crohn’s Disease (SES-CD) – that is well correlated to the CDEIS but has never been validated [4]. No SES-CD thresholds defining endoscopic remission or response have been established so far. Concerning the CD postoperative recurrence on the neo-terminal ileum, Rutgeerts and colleagues have proposed in 1990 an endoscopic index ranging from 0 (no lesions) to 4 (severe lesions), which is now widely used in daily practice even though it lacks validation [1]. Despite the absence of validation and its poor reproducibility, the Mayo endoscopic subscore is the most commonly index used in practice and controlled trials [5]. An arbitrary definition of MH in UC based on this index– MH corresponding to subscores 0 and 1 – has been proposed. Importantly, such a definition has never

been validated and interobservator variability is high, mainly for the subscores 1 and 2. Recently, a new and more reproducible index, namely the UCEIS, has been developed and validated [6]. UCEIS takes into account the three most reproducible UC elementary lesions – vascular pattern, bleeding and ulcerations including severe lesions endoscopic. Importantly, UCEIS has intra-and inter-investigator reliability ratios of 0.96 and 0.88, respectively. At the moment and as suggested by an international expert committee, MH in UC could be better defined as diseappearance of any bleeding, erosion or ulceration in acceptance with mild decrease vascular pattern [7].

Mucosal healing and IBD outcomes Patients with MH seem to have better CD outcomes. However, few prospective data are available so far. According to results from the Norwegian IBSEN cohort, CD patients achieving MH experienced less surgeries within five years (22 % vs. 12 %; P = 0.10) [8]. This trend has been confirmed in the Leuven cohort of CD patients treated with infliximab: among patients achieving MH, 14 % had major abdominal surgery as compared to 38 % in those without MH (P < 0.0001) [9]. Similarly, fewer hospitalizations were observed in patients with MH in a post hoc analysis of the ACCENT 1 trial [10]. Finally, a subgroup of 46 patients recruited in the landmark step-up top-down trial having an endoscopic assessment at the end of the study period was prospectively followed

Take-home messages Absence of any ulceration has been proposed to define MH in CD (grade D). Endoscopic indexes provide a thinner assessment of the mucosal disease activity (grade B). Mayo endoscopic subscore 0 or 1 has been proposed to define mucosal healing in UC (grade D). The UCEIS has been recently validated and has better reproducibility. Mucosal healing is associated with better disease outcomes in both CD and UC (grade B). The definition of MH in IBD as well as the optimal timing (6 months in CD and 2 – 3 months in UC?) for controlling MH after the initiation of diseasemodifying agents such as thiopurines and anti-Tumour Necrosis Factor (TNF) agents have yet to be determined.

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magnetic resonance enteroclysis in diagnosing suspected small-bowel Crohn’s disease: results of a pilot study. Scand J Gastroenterol 2007; 42: 1376 – 1385. 5 Oshitani N, Yukawa T, Yamagami H et al. Evaluation of deep small bowel involvement by double-balloon enteroscopy in Crohn’s disease. Am J Gastroenterol 2006; 101: 1484 – 1489. 6 Manes G, Imbesi V, Ardizzone S et al. Use of double-balloon enteroscopy in the management of patients with Crohn’s disease: feasibility and diagnostic yield in a high-volume centre for inflammatory bowel disease. Surg Endosc 2009; 23: 2790 – 2795. 7 Mensink PB, Groenen MJ, van Buuren HR, et al. Double-balloon enteroscopy in Crohn’s disease patients suspected of small bowel activity: findings and clinical impact. J Gastroenterol 2009; 44: 271 – 276. 8 Pohl J, May A, Nachbar L et al. Diagnostic and therapeutic yield of push-and pull enteroscopy for symptomatic small bowel Crohn’s disease strictures. Eur J Gastroenterol Hepatol 2007; 19: 529 – 534. 9 Despott EJ, Gupta A, Burling D et al. Effective dilation of ileo-bowel strictures by double-balloon enteroscopy in patients with symptomatic Crohn’s disease (with video). Gastrointest Endosc 2009; 70: 1030 – 1036. 20 Ohmiya N, Arakawa D, Nakamura M et al. Small-bowel obstruction: diagnostic comparison between double-balloon endoscopy and fluoroscopic enteroclysis, and the outcome of enteroscopic treatment. Gastrointest Endosc 2009; 69: 84 – 93. 11 Hirai F, Beppu T, Sou S et al. endoscopic balloon dilatation using double-balloon endoscopy is a useful and safe treatment for small intestinal strictures in Crohn’s disease. Dig Endosc 2010; 22: 200 – 204. 12 Gerson LB, Tokar J, Chiorean M et al. Complications associated with double balloon enteroscopy at nine US centers. Clin Gastroenterol Hepatol 2009; 7: 1177 – 1182. 13 Landi B, Cellier C, Fayemendy L et al. Duodenal perforation occurring during push enteroscopy. Gastrointest Endosc 1996; 43: 631. 14 Jarbandhan SV, van Weyenberg SJ van der Veer WM, et al. Double balloon endoscopy associated pancreatitis: A description of six cases. World J Gastroenterol 2008; 14: 720 – 724.

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up two additional years; proportions of remission off steroids were 71 % among patients who achieved complete MH as compared to 27 % among the others (P = 0.036) [11]. Similar observations were made in UC. Among the 354 UC patients from the IBSEN cohort, early MH was associated with significant less colectomies (P = 0.02) [8]. A post hoc analysis from controlled studies and cohort studies confirmed that an early MH achieved with infliximab was associated with fewer hospitalisations and less surgeries within one year and beyond [12, 13].

References 1 Rutgeerts P, Geboes K, Vantrappen G et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology. 1990; 99: 956 – 963. 2 Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989; 30: 983 – 989. 3 Hebuterne X, Lemann M, Bouhnik Y et al. Endoscopic improvement of mucosal lesions in patients with moderate to severe ileocolonic Crohn's disease following treatment with certolizumab pegol. Gut 2012; 62: 201 – 8. 4 Daperno M, D'Haens G, Van Assche G et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc 2004; 60: 505 – 512. 5 Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987; 317: 1625 – 1629. 6 Travis SP, Schnell D, Krzeski P et al. Reliability and Initial Validation of the Ulcerative Colitis Endoscopic Index of Severity. Gastroenterology 2013 [epub ahead of print]. 7 D'Haens G, Sandborn WJ, Feagan BG et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007; 132: 763 – 86. 8 Froslie KF, Jahnsen J, Moum BA et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007; 133: 412 – 422.

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9 Schnitzler F, Fidder H, Ferrante M et al. Mucosal healing predicts long-term outcome of maintenance therapy with infliximab in Crohn's disease. Inflamm Bowel Dis 2009; 15: 1295 – 1301. 10 Rutgeerts P, Diamond RH, Bala M et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointest Endosc 2006; 63: 433 – 442. 11 Baert F, Moortgat L, Van Assche G et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology 2010; 138: 463 – 468. 12 Colombel JF, Rutgeerts P, Reinisch W et al. Early mucosal healing with infliximab is associated with improved longterm clinical outcomes in ulcerative colitis. Gastroenterology 2011; 141: 1194 – 1201. 13 Laharie D, Filippi J, Roblin X et al. Impact of mucosal healing on long-term outcomes in ulcerative colitis treated with infliximab: a multicenter experience. Aliment Pharm Ther 2013; 37: 998 – 1004.

Endoscopic surveillance for colorectal dysplasia in inflammatory bowel disease !

Endoscopic surveillance in clinical practice When to perform endoscopic surveillance? It is now recommended to perform a screening colonoscopy in any inflammatory colitis whatever its initial location, after a 6 to 8 year-time course of the disease [EL 5, RG D]. Biopsies throughout the colon should be performed to assess the microscopic extension, which is better correlated to dysplasia and CRC risk than that determined by visual examination only. The maximum extent during follow-up will be selected as reference colon level for the patient’s surveillance. Based on the last recommendations enacted by the ECCO, each patient’s follow-up is thus adapted to his/her own risk level [1]. In patients with primary sclerosing cholangitis (PSC), a yearly colonoscopy is mandatory, from the point of PSC diagnosis, irrespective of disease extent and activity and is also mandatory after liver transplantation [EL3a, RG B]. In patients without PSC, colonoscopy schedule depends on the presence of 4 risk factors (1 point per fac-

tor): 1 / pan-colitis; 2 / severe endoscopic and/or histological inflammation; 3 / colon pseudopolyps and/or stenosis; and 4 / CRC in a first-degree relative [EL2b, RG B]. Colonoscopy should be performed every 1 – 2 years in high-risk patients (score = 3 – 4); and every 3 – 4 years in mild-risk patients (score = 0 – 2) [1] [EL5, RG D] " Table 1). (●

How to perform colonoscopy and biopsies? Whenever possible, follow-up colonoscopy should be performed during a remission period; if not, histological differential diagnosis between inflammation and dysplasia is difficult [EL5, RG D]. As for CRC screening in general population, perfect bowel preparation is crucial, since it directly interferes with lesion detection. The use of split regimens and endoscopic irrigation pumps is highly recommended [2]. The low yield of random biopsies in terms of dysplasia screening remains a challenge. Significantly higher number of intra-epithelial carcinomas are diagnosed by using indigo-carmine blue chromoendoscopy (CE) than targeted biopsies [3 – 6]. The role of high definition virtual chromoendoscopy (NBI, i-SCAN, FICE) has yet to be determined. Current data are not sufficient to recommend these procedures [1]. Based on these results, the European ECCO consensus recommends CE with targeted-biopsies as the procedure of choice for well-trained endoscopists [EL1b, RG B]. If CE is not available, random biopsies (four-quadrant biopsies every 10 cm throughout the colon) should be added to targeted biopsies on any visible lesion [EL3, RG B] [1].

Description of dysplastic lesions Macroscopic features A new dichotomized and simplified classification is emerging, and will replace the previously proposed expressions such as ALM and DALM: ▶ Adenoma-like raised lesions (ALRL) represent non-necrotic, well limited Kudo pit-pattern III or IV, sessile or pediculate lesions, and are usually accessible to endoscopic treatment. ▶ Non adenoma-like raised lesions (NALRL) are described as velvet-like patches, irregular nodules, condylomalike mucosal thickness, stenosing lesions, and broad-based masses [7, 8]. Such lesions correspond to the ‘DALM’ described in 1981 [9], and are usually not accessible to endoscopic treatment.

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Association with PSC

Yearly

Personal history of dysplasia

Yearly

3 – 4 points : high-risk patients

Every 1 – 2yrs

1 – 2 points : mild-risk patients

Every 3 – 4yrs

PSC : primary sclerosing cholangitis

Microscopic features There are significant discrepancies in the histological interpretation of low-grade versus high-grade dysplasia between pathologists, even between experienced professionals [10]. For this reason, double reading by independent pathologists is highly recommended to assess diagnosis.

Management of dysplasia How to manage visible dysplastic lesions? Adenoma-like raised lesions. Several studies showed a favorable outcome when these lesions were endoscopically resected in UC patients [3, 11, 12]. ALRL in inflammatory lesions may thus be resected using mucosectomy or dissection if the lesion is totally resected and resection margins are in healthy mucosa. However, biopsies in flat peripheral areas are mandatory to confirm the absence of flat dysplasia. Non adenoma-like raised lesion. There is a very strong association (38 – 83 % depending on the study) between the occurrence of NALRL and that of metachronic or synchronic CRC [13]. It is the reason why colectomy is usually recommended in these patients, whatever the dysplasia grade. Adenomas occurring outside areas of colitis. Adenomas that occur outside (generally upstream) bowel segments with macroscopically and/or histologically proven inflammatory lesions should be managed like sporadic adenomas. Endoscopic treatment and surveillance modalities and time schedule after resection are the same as those of sporadic adenomas [11, 12].

How to manage dysplasia without visible lesion (‘flat dysplasia’)? High Grade Intra-Epithelial Neoplasia (HE IEN). The question is difficult to answer from available data as ‘flat dysplasia’ and absence of macroscopic lesions are often put together in the same entity. Based on previous data showing a high correlation between HG IEN and the occurrence of CRC [7, 14] most of scientific societies

(ECCO, British Society of Gastroenterology, American Gastroenterology Association) recommend proposing total colectomy to patients without visible lesions but with HG IEN confirmed by 2 independent pathologists. Low Grade Intra-Epithelial Neoplasia (LG IEN). Data from the literature are controversial. A meta-analysis of 20 surveillance studies indicated a 22 % positive predictive value of low-grade dysplasia for synchronic CRC occurrence [15]. By contrast a Swedish prospective study found no case of CRC and only 2 cases of high-level dysplasia occurrence over a 10-yr period of follow-up [16]. It is thus difficult to conclude regarding the benefit/risk ratio of total colectomy in such patients. Nevertheless, if surgery does not seem to be mandatory, it is necessary to initiate a close follow-up of such patients by yearly colonoscopy.

References 1 Van Assche G, Dignass A, Bokemeyer B et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 3: special situations. J Crohns Colitis 2013; 7: 1 – 33. 2 Hassan C, Bretthauer M, Kaminski MF et al. Bowel preparation for colonoscopy: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 2013; 45: 142 – 150. 3 Rutter MD, Saunders BP, Wilkinson KH et al. Most dysplasia in ulcerative colitis is visible at colonoscopy. Gastrointest Endosc 2004; 60: 334 – 339. 4 Kiesslich R, Fritsch J, Holtmann M et al. Methylene blue-aided chromoendoscopy for the detection of intraepithelial neoplasia and colon cancer in ulcerative colitis. Gastroenterology 2003; 124: 880 – 888. 5 Awais D, Siegel CA, Higgins PDR. Modelling dysplasia detection in ulcerative colitis: clinical implications of surveillance intensity. Gut 2009; 58: 1498 – 1503.

Take-home messages Endoscopic surveillance should begin 6 to 8 years after colitis diagnosis. In patients with PSC, a yearly colonoscopy is mandatory. Otherwise colonoscopy schedule depends on the presence of " Table 1). Chromoendosrisk factors (● copy allows targeted-biopsies of the lesions and surrounding area and should be performed whenever possible during remission periods. If chromo-endoscopy is unavailable, quadrant random biopsies should be used. Histological diagnosis of dysplasia must be confirmed by two independent pathologists. Adenoma-like raised lesions can be endoscopically resected. Non adenoma-like raised lesions are rarely accessible to endoscopic treatment and colectomy is usually recommended. High grade dysplasia on flat mucosa or on random biopsies requires total colectomy. For low grade dysplasia in that case there is no consensus on management (total colectomy or yearly surveillance can be discussed).

6 Hurlstone DP, Sanders DS, Lobo AJ et al. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis: a prospective evaluation. Endoscopy 2005; 37: 1186 – 1192. 7 Odze RD. Adenomas and adenoma-like DALMs in chronic ulcerative colitis: a clinical, pathological, and molecular review. Am J Gastroenterol 1999; 94: 1746 – 1750. 8 Farraye FA, Odze RD, Eaden J, Itzkowitz SH. AGA technical review on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease. Gastroenterology 2010; 138: 746 – 774. 9 Blackstone MO, Riddell RH, Rogers BH, Levin B. Dysplasia-associated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: an indication for colectomy. Gastroenterology 1981; 80: 366 – 374. 10 Odze RD, Goldblum J, Noffsinger A et al. Interobserver variability in the diagnosis of ulcerative colitis-associated dysplasia by telepathology. Mod Pathol 2002; 15: 379 – 386. 11 Vieth M, Behrens H, Stolte M. Sporadic adenoma in ulcerative colitis: endoscopic resection is an adequate treatment. Gut 2006; 55: 1151 – 1155. Newsletter … Endoscopy 2013; 45: 936–943

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Table 1 Colonoscopic surveillance for dysplasia in inflammatory bowel disease. Colonoscopy schedule depends on the presence of 4 risk factors (1 point per factor): pan-colitis; severe endoscopic and/or histological inflammation; colon pseudopolyps and/or stenosis; and colorectal cancer in a first-degree relative.

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12 Odze RD, Farraye FA, Hecht JL, Hornick JL. Long-term follow-up after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis. Clin Gastroenterol Hepatol 2004; 2: 534 – 541. 13 Hurlstone DP, Sanders DS, Atkinson R et al. Endoscopic mucosal resection for flat neoplasia in chronic ulcerative colitis: can we change the endoscopic management paradigm? Gut 2007; 56: 838 – 846. 14 Rutter MD, Saunders BP, Wilkinson KH et al. Thirty-year analysis of a colonoscopic surveillance program for neoplasia in ulcerative colitis. Gastroenterology 2006; 130: 1030 – 1038. 15 Thomas T, Abrams KA, Robinson RJ, Mayberry JF. Meta-analysis: cancer risk of low-grade dysplasia in chronic ulcerative colitis. Aliment Pharmacol Ther 2007; 25: 657 – 668. 16 Befrits R, Ljung T, Jaramillo E, Rubio C. Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study. Dis Colon Rectum 2002; 45: 615 – 620.

enrolling 347 CD patients, EBD was mainly used for postsurgical strictures, being technically successful in 86 % of cases [2]. In all studies, the shorter the stricture was, the better were the results [2, 3]. A stricture length less or equal to 4 cm is associated with a better outcome [2]. By contrast, few data are available for colonic strictures in CD. Short strictures could be managed by EBD only if associated neoplasia has been ruled out. In all other cases, surgery must be discussed.

after EBD of CD ileocolonic anastomotic strictures and there was even a trend toward a worse outcome [8]. Recently, in a single-center prospective, randomized, double-blind, controlled trial enrolling 29 paediatric CD patients with stricture, intralesional corticosteroid injection after EBD was an effective strategy for reducing the need for both re-dilation (p = 0.02) and surgery (p = 0.04) [9]. Overall, evidence is weak and local corticosteroid injections cannot be recommended routinely.

Endoscopic balloon dilatation Technique

Self-expandable metal stent (SEMS)

Available data are heterogeneous and rely on expert opinions. Hydrostatic balloon dilatators are passed through the stricture under endoscopic or fluoroscopic control in case of angulated narrowing. EBD should be progressive until calibre 18 mm which is a good compromise between efficacy and complications [4]. Passing scope through the stricture is not mandatory although this was an endpoint in several studies [2].

Results Endoscopic management of strictures complicating inflammatory bowel disease !

Cross-sectional imaging for evaluation of IBD strictures is essential. Indeed location, number, diameter, activity, extension, prestenotic dilatation and associated complications (fistula, abscess) should be assessed. Endoscopic balloon dilatation (EBD) was first described in the eighties. Unfortunately, most of available studies on this technique are observational, retrospective, small, and/or uncontrolled, using various procedures.

Indications For active inflammatory strictures (appreciated on clinical, biological and radiological data), medical treatment should be optimised [1]. For symptomatic fibrotic strictures, EBD or surgery should be proposed. According to the ECCO consensus, localised ileocaecal CD with obstructive symptoms, but no significant evidence of active inflammation, should be treated by surgery [Evidence Level (EL) 2b, Recommendation Grade (RG) C] [1]. However EBD of strictures in CD is a preferred technique for the management of accessible short strictures, especially for recurrence after ileocolonic resection [EL 2a, RG B] [1]. In a systematic review of 13 studies

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More than thirty uncontrolled series have been published since the early eighties. In a systematic review long-term clinical efficacy was achieved in 58 % of the patients [2]; 22 % of patients needed a second EBD and 19 % three or more [2]. The authors concluded that EBD is effective and safe, especially for anastomotic recurrence after ileocolonic resections, delaying surgery by a mean of 3 years [2]. Another systematic review enrolling 23 studies reported technical success in 90 % of patients with a need for surgery in 27.6 % after a 21 months median follow-up [5]. Predictive factors for long-term outcomes of EBD are not clearly identified. Smoking cessation after a first EBD could reduce the need for surgery [6] and for a new dilatation [7].

Complications Complications rate varies from 0 % to 15 %, major complications (perforation or excessive bleeding) occurring in 2 % to 3 % of cases [2, 5]. No death has been reported.

Endoscopic corticosteroid injection Several uncontrolled studies found less stricture recurrence after local corticosteroid injections associated with EBD. However, in a randomised pilot study involving 13 CD patients, a single treatment of intralesional triamcinolone injection did not reduce the time to re-dilatation

Different SEMS have been tested in CD strictures. Results are promising. A new asymmetric, partially covered stent is under evaluation [10]. This will require further investigation.

Ulcerative colitis !

In UC, colonic stricture is associated with a risk of neoplasia [11]. Hence, endoscopic evaluation and histologic analysis must be very performed carefully in order to rule out neoplasia and a surgical option should always be discussed, particularly in longstanding UC (EL 5, RG D) [12].

Take home messages Endoscopic management of strictures in CD EBD of strictures in CD is a preferred technique for the management of accessible short (< 4 cm) strictures especially for recurrence after ileocolonic resections [EL 2a] EBD should be progressive until calibre 18 mm that is a good compromise between efficacy and side effects [EL 3a] EBD is effective, safe with high technical success rate. Major complications (perforation or excessive bleeding) occurred in 2 % to 3 % of cases. Local corticosteroid injections after EBD cannot be recommended routinely for adult [EL 3a]. Different self-expandable metal stents are under evaluation in this situation. Endoscopic management of strictures in UC In longstanding UC strictures, endoscopic and histologic analyses must be very careful and a surgical option should be sought [EL 5]

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1 Dignass A, Van Assche G, Lindsay JO et al. The second European evidencebased Consensus on the diagnosis and management of Crohn’s disease: Current management. J Crohns Colitis 2010; 4: 28 – 62 2 Hassan C, Zullo A, De Francesco V et al. Systematic review: Endoscopic dilatation in Crohn’s disease. Aliment Pharmacol Ther 2007; 26: 1457 – 1464 3 Thienpont C, D’Hoore A, Vermeire S et al. Long-term outcome of endoscopic dilatation in patients with Crohn’s disease is not affected by disease activity or medical therapy. Gut 2010; 59: 320 – 324 4 Breysem Y, Janssens JF, Coremans G et al. Endoscopic balloon dilation of colonic and ileo-colonic Crohn’s strictures: long-term results. Gastrointest Endosc 1992; 38: 142 – 147 5 Wibmer AG, Kroesen AJ, Gröne J et al. Comparison of strictureplasty and endoscopic balloon dilatation for stricturing Crohn’s disease–review of the

literature. Int J Colorectal Dis 2010; 25: 1149 – 1157 6 Sabaté J-M, Villarejo J, Bouhnik Y et al. Hydrostatic balloon dilatation of Crohn’s strictures. Aliment Pharmacol Ther 2003; 18: 409 – 413 7 Hoffmann JC, Heller F, Faiss S et al. Through the endoscope balloon dilation of ileocolonic strictures: prognostic factors, complications, and effectiveness. Int J Colorectal Dis 2008; 23: 689 – 696 8 East JE, Brooker JC, Rutter MD et al. A pilot study of intrastricture steroid versus placebo injection after balloon dilatation of Crohn’s strictures. Clin Gastroenterol Hepatol 2007; 5: 1065 – 1069 9 Di Nardo G, Oliva S, Passariello M et al. Intralesional steroid injection after endoscopic balloon dilation in pediatric Crohn’s disease with stricture: a prospective, randomized, double-blind, controlled trial. Gastrointest Endosc 2010; 72: 1201 – 1208

10 Branche J, Attar A, Vernier-Massouille G et al. Extractible self-expandable metal stent in the treatment of Crohn’s disease anastomotic strictures. Endoscopy 2012; 44: E325 – 326 11 Yamazaki Y, Ribeiro MB, Sachar DB et al. Malignant colorectal strictures in Crohn's disease. Am J Gastroenterol 1991; 86: 882 – 885 12 Dignass A, Eliakim R, Magro F et al. Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 1: definitions and diagnosis. J Crohns Colitis 2012; 6: 965 – 990 Conflicts of interest: LPB, consulting and/ or lecture fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Takeda. CC, consulting and/or lecture fees from Vifor, Norgine, MSD. The other authors declare no conflicts of interest.

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References

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Endoscopy in inflammatory bowel disease: recommendations from the IBD Committee of the French Society of Digestive Endoscopy (SFED).

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