Alimentary Pharmacology and Therapeutics Randomised clinical trial: delayed-release oral mesalazine 4.8 g day vs. 2.4 g day in endoscopic mucosal healing ASCEND I and II combined analysis G. R. Lichtenstein*, D. Ramsey & D. T. Rubin à *Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. Procter & Gamble Company, Mason Business Center, Mason, OH, USA. à University of Chicago Inflammatory Bowel Diseases Center, Chicago, IL, USA. Correspondence to: Dr G. R. Lichtenstein, Gastroenterology Division, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, 3rd Floor Ravdin Building, 34 Spruce Street, Philadelphia, PA 1914-4283, USA. E-mail: grl@uphs.upenn.edu Publication data Submitted 3 July 21 First decision made 3 August 21 Resubmitted 6 December 21 Accepted 29 December 21 EV Pub Online 23 January 211 SUMMARY Background Recent studies have focused on the importance of mucosal healing in ulcerative colitis (UC). However, it was still unclear whether higher doses of delayed-release mesalazine (mesalamine) could provide additional benefit. Aim To examine how two doses of delayed-release mesalazine (4.8 g day and 2.4 g day) from ASCEND I and II compare in their relative ability to heal colonic mucosa over time. Methods Primary data from two prospective 6-week, double-blind, randomised studies in patients with mildly to moderately active UC were pooled and analysed retrospectively. The mucosal healing analysis focuses on moderately active UC patients (n = 391), comprising a majority of patients (84%). Additional analyses examined the relationship between mucosal healing and dose, clinical response to therapy and patient quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ). Results At week 3, mucosal healing (endoscopy subscore of or 1) was achieved in 65% of moderately active UC patients on 4.8 g day and 58% of patients on 2.4 g day (P =.219). At week 6, this increased to 8% for 4.8 g day and 68% for 2.4 g day (P =.12). Healing rates with the higher dose were also greater across all extents of disease and in patients with prior steroid use. At 6 weeks, clinical response to therapy and mucosal healing were found to be well correlated (kappa =.694). Likewise, the change in IBDQ at week 6 showed a significant relationship with mucosal healing (P <.1). Conclusion Mucosal healing rates in UC achieved at 6 weeks were statistically significantly higher with delayed-release mesalazine at 4.8 g day vs. 2.4 g day (Clinicaltrials.gov: NCT577473, NCT7321). Aliment Pharmacol Ther 211; 33: 672 678 672 doi:1.1111/j.1365-236.21.4575.x
Randomised clinical trial: mucosal healing with delayed-release mesalazine INTRODUCTION Ulcerative colitis (UC) is a chronic disease characterised by diffuse mucosal inflammation limited to the colon, typically originating in the rectum and extending proximally. 1 In clinical practice, the primary goal of therapy for ulcerative colitis is the elimination of clinical symptoms such as rectal bleeding and increased stool frequency, which clearly adversely affect a patient s quality of life. Studies are now emerging that focus on the importance of more objective markers of mucosal improvement and mucosal healing. In ulcerative colitis, characteristic mucosal changes include loss of the typical vascular pattern, granularity, friability and ulceration. 1 Investigators have long felt that an effective therapy for ulcerative colitis should control symptoms in addition to restoring maintaining the integrity of the bowel mucosa. As such, mucosal healing has become increasingly common as a secondary measure of therapy success in ulcerative colitis trials, although its correlation to patient quality of life is not known. Furthermore, it is unclear whether a higher dose of mesalazine (mesalamine) (a first-line therapy in mildly to moderately active ulcerative colitis) provides incremental benefits for mucosal healing. As shown in the ASCEND I and II trials, moderately active ulcerative colitis patients taking mesalazine 4.8 g day achieved significantly higher rates of overall improvement (the primary endpoint) as compared with 2.4 g day at 6 weeks, whereas mildly active ulcerative colitis patients received the same benefit with both doses. The primary goal of this analysis is to examine the difference in effect of a higher and lower dose of delayed-release mesalazine on mucosal healing in patients with moderately active ulcerative colitis from the ASCEND I and II studies (ASCEND Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA). Although there is currently no standardised definition of mucosal healing, it is commonly defined as a sigmoidoscopy score of or 1, 2 but may also be measured differently in other trials. 3 As such, this post hoc analysis will examine the data using two definitions available. It will also aim to investigate the relationship between mucosal healing and response to therapy via clinical measures and also quality of life measures (as measured by the Inflammatory Bowel Disease Questionnaire, or IBDQ). METHODS To determine the effect of delayed-release mesalazine dosed at 4.8 g day compared with 2.4 g day on endoscopically measured mucosal healing, data from two prospective 6-week double-blind, randomised, multi-site studies conducted in patients with mildly to moderately active ulcerative colitis (ASCEND I and II; NCT577473 and NCT7321) were pooled and analysed retrospectively. The ASCEND I and II studies were of similar design, assessing the efficacy and safety of oral delayed-release mesalazine given at doses of 4.8 g day (using 8 mg tablet, Asacol 8 [Canada and the UK], Asacol HD [US], Warner Chilcott) and 2.4 g day (using Asacol, 4 mg tablet, Warner Chilcott) in mildly to moderately active ulcerative colitis. Details of the study design, methods and results have been previously published elsewhere. 4, 5 A third study of similar design (ASCEND III) was not included in the present analysis. The authors of ASCEND III indicated that a novel technique, the contact friability test (CFT), had been incorporated in this study, but has not been performed in previous studies evaluating sigmoidoscopic improvement and mucosal healing in the modern era. This technique, which was performed using closed biopsy forceps passed through the therapeutic channel of a flexible sigmoidoscope, was included in the definition of sigmoidoscopy improvement. However, the technique may have had the effect of overestimating friability (and thus underestimating sigmoidoscopy improvement) as compared with the usual technique of assessing contact friability caused by normal passage of the flexible sigmoidoscope. For this reason, rates of sigmoidoscopy improvement reported in the ASCEND III trial cannot be compared with those reported in other ulcerative colitis studies. 6 The Mayo Score of Endoscopic Disease was used in these studies to measure mucosal healing. It is a four-point scale with scores from (endoscopically normal mucosa) to 3 (severely inflamed, spontaneously bleeding and ulcerated mucosa) (Figure 1). The mucosal healing analysis included patients with moderately active ulcerative colitis with a baseline endoscopy score of 2. Mucosal healing was defined as an endoscopy subscore of or 1, a definition that has previously been used in other ulcerative colitis clinical studies, and also an endoscopy subscore of only. 2, 3, 7 In addition, data from this population were analysed in order to determine mucosal healing rates with delayed-release oral mesalazine 4.8 g day and 2.4 g day across disease extents (proctitis, proctosigmoiditis, leftsided colitis, pancolitis), as well as for patients with mildly active ulcerative colitis with a baseline endoscopy score of 2. Finally, the relationship between mucosal healing with clinical response to therapy (overall improvement) and quality of life was examined. The Inflammatory Bowel Disease Questionnaire (IBDQ) was developed in order to examine disease- Aliment Pharmacol Ther 211; 33: 672 678 673
G. R. Lichtenstein et al. Score Endoscopy (Mayo index) Rectal bleeding Stool frequency Normal stool frequency per day PFA No friability or granularity; intact vascular pattern No blood seen Generally well 1 Erythema; diminished or absent vascular markings; mild granularity Streaks of blood with stool less than half of the time 1 to 2 stools greater than normal per day Fair 2 Marked erythema; absent vascular markings; granularity; bleeds with minimal trauma (friability); no ulcerations Obvious blood with stool most of the time 3 to 4 stools greater than normal per day Poor 3 Marked erythema; absent vascular markings; granularity; friability; spontaneous bleeding in the lumen; ulcerations Blood alone passed 5 or more stools greater than normal per day Terrible Figure 1 Clinical assessment scoring system. related dysfunction in IBD patients and to assess patient quality of life (QoL). 8 1 This questionnaire consists of 32 questions grouped into four domains (bowel symptoms, systemic symptoms, emotional function, social function). Scores range from 32 to 224, with higher scores indicating better QoL, and increase in the total IBDQ score greater than or equal to 16 points (1 2 point per question) or 32 points (1 point per question) indicate a clinically relevant improvement in QoL. Since its development in the late 198s, the IBDQ has been shown to be a valid, reliable and responsive measure of therapeutic outcome in a number of IBD studies, including large trials in ulcerative colitis 8, 11 13 patients. Statistical analysis for mucosal healing Patients with moderately active ulcerative colitis fulfilling eligibility criteria to the original ASCEND I and II studies and a baseline endoscopy subscore of 2 were included in the analyses assessing mucosal healing and evaluating its relationship to clinical response to therapy and quality of life. Pooled study analyses used the Cochran-Mantel- Haenszel test stratified by study to compare treatment groups. Individual study treatment comparisons were performed using Chi-square test computed separately for each clinical study. Kappa statistics were computed to assess the level of agreement (correlation) between mucosal healing and clinical response to therapy. Logistic regression analyses were carried out to compare the relationship between mucosal healing and change from baseline IBDQ while also including term for dose in the model. RESULTS Patient characteristics Of the 448 patients with moderately active ulcerative colitis at baseline of the two original studies 391 patients 674 Aliment Pharmacol Ther 211; 33: 672 678
Randomised clinical trial: mucosal healing with delayed-release mesalazine Table 1 Baseline demographics and treatment history Parameter 2.4 g day (N = 235) n (%) 4.8 g day (N = 213) n (%) Mean age (years) 42.6 43.4 18 64 years 214 (91) 194 (91) >64 years 21 (9) 19 (9) Gender Male 16 (45) 94 (44) Female 129 (55) 119 (56) Race Caucasian 182 (77) 158 (74) Black 23 (1) 26 (12) Hispanic 24 (1) 18 (8) Other 6 (3) 11 (5) Smoking history Never smoked 139 (59) 118 (55) Used to smoke 82 (35) 74 (35) Currently smoke 14 (6) 21 (1) Disease extent Proctitis 35 (15) 32 (15) Proctosigmoiditis 75 (32) 54 (25) Left-sided colitis 72 (31) 8 (38) Pancolitis 53 (23) 47 (22) Prior treatment Steroids (oral or IV) 8 (34) 68 (32) Immunomodulators 1 (4) 9 (4) Sulfasalazine 89 (38) 65 (31) Sulfa-free oral 5-ASAs 93 (4) 96 (45) Any oral 5-ASAs 142 () 127 () Rectal therapies 94 (4) 86 (4) Length of disease history <1 year 91 (39) 72 (34) 1 to 5 years 49 (21) 55 (26) >5 to 1 years 38 (16) 4 (19) >1 years 54 (23) 44 (21) Unknown 3 (1) 2 (1) Baseline sigmoidoscopy score (Normal) () () 1 (Mild) 26 (11) 31 (15) 2 (Moderate) 181 (77) 157 (74) 3 (Severe) 28 (12) 25 (12) qualified (endoscopy score of 2) for the analyses of mucosal healing and correlation between mucosal healing and clinical response to therapy. Baseline and demographic characteristics, disease history and disease state characterised were similar between the 2.4 g day group and the 4.8 g day groups (Table 1). Mucosal healing in moderate UC At week 3, mucosal healing was achieved by 65% of patients receiving delayed-release mesalazine 4.8 g day (8 mg tablet) compared with 58% of those receiving 2.4 g day (4 mg tablet) (P =.219). At week 6, mucosal healing rates were higher in patients receiving 4.8 g day compared with those receiving 2.4 g day (8% vs. 68%, respectively) (P =.12) (Figure 2). The mucosal healing rates for ASCEND I and ASCEND II analysed separately were found to be similar (Figure 3). At week 6, an endoscopy subscore of zero was achieved % patients with mucosal healing** % patients with mucosal healing 9 8 7 4 3 2 1 9 8 7 4 3 2 1 2.4 g/day 4.8 g/day 2.4 g/day 4.8 g/day 58 n = 172 n = 156 n = 169 n = 153 Week 3 Week 6 64 65 Figure 2 Mucosal healing at weeks 3 and 6; *P <.5 between 2.4 g day and 4.8 g day at week 6. 67 * 84 n = 7 n = 58 n = 69 n = 58 n = 12 n = 98 n = 1 n = 95 Week 3 Week 6 Week 3 Week 6 ASCEND I ASCEND II Figure 3 Mucosal healing at weeks 3 and 6 for ASCEND I and ASCEND II studies; *P <.5 between 2.4 g day and 4.8 g day at week 6. 57 68 65 8 * 69 78 Aliment Pharmacol Ther 211; 33: 672 678 675
G. R. Lichtenstein et al. 1 2.4 g/day 9 4.8 g/day * 82 86 8 79 76 73 71 7 63 67 4 3 2 1 n = 25 n = 24 n = 51 n = 37 n = 51 n = 57 n = 42 n = 35 Proctitis Proctosigmoiditis Left-sided Pancolitis colitis Extent of disease % patients with mucosal healing Figure 4 Mucosal healing at week 6 by extent of disease; *P <.5 between 2.4 g day and 4.8 g day for left-sided disease. in 32% of patients in the 4.8 g day group compared with 24% in the 2.4 g day group (P =.125). Mucosal healing by disease extent and prior therapy Among 18 moderately active ulcerative colitis patients with left-sided colitis, mucosal healing rates were higher in those receiving 4.8 g day compared with 2.4 g day (82% vs. 63%, respectively; P=.2) (Figure 4). Mucosal healing rates were also directionally higher in patients treated with 4.8 g day in comparison to 2.4 g day across other disease extents (proctitis, proctosigmoiditis, pancolitis), but these differences were not statistically significant. Mucosal healing rates in the subgroup of moderately active ulcerative colitis patients with prior steroid therapy (oral or intravenous) were also consistent with the overall population, with higher rates in those receiving 4.8 g day compared with 2.4 g day (at week 3: 68% and 46%, respectively, P=.3; at week 6: 85% and 65%, respectively, P=.19). Mucosal healing in mild UC At week 3, mucosal healing was achieved by 79% of mildly active ulcerative colitis patients receiving delayedrelease mesalazine 4.8 g day compared with 8% of those receiving 2.4 g day (P =.8). At week 6, mucosal healing rates were 84% in patients receiving 4.8 g day compared with 88% in those receiving 2.4 g day (P =.765). At week 6, an endoscopy subscore of zero was achieved in 44% of patients in the 4.8 g day group compared with 42% in the 2.4 g day group (P =.64). Percentile 4 3 2 1 No mucosal healing Mucosal healing 4 4 8 12 1 1 Week 6 change from baseline IBDQ Figure 5 Relationship in the change from baseline IBDQ at 6 weeks in patients who achieved mucosal healing vs. patients who did not achieve mucosal healing. Relationship of mucosal healing with clinical response to therapy and inflammatory bowel disease questionnaire At 6 weeks, clinical responses to therapy and mucosal healing (defined as an endoscopic score of or 1) were found to be well correlated (Kappa =.694), with 67% of moderately active ulcerative colitis patients achieving both endpoints. This finding was consistent regardless of dose of 2.4 g day or 4.8 g day (Kappa =.745 and.5, respectively) and was also consistent at the 3-week time point (Kappa =.717). In a logistic regression analysis, change in Total IBDQ score at week 6 showed a significant relationship with mucosal healing (P <.1) (Figure 5). To put the results in clinical perspective, a change in the IBDQ of 16 points (1 2 point mean increase per question) multiplies the odds of mucosal healing by 1.455. Likewise a change in the IBDQ of 32 points (1 point mean increase per question) multiplies the odds of mucosal healing by 2.118. The results were also highly significant when examined at the individual domain level (bowel, systemic, emotional and social function) P.1. At the week 3 time point, results were significant for change in total IBDQ (P =.57), as well as for the bowel and emotional domains. The logistic regression model for mucosal healing included terms for dose and change in the IBDQ. The logistic regression analysis confirmed the effect previously mentioned at week 6 regarding dose as for patients taking 4.8 g day the odds of being mucosal healed are multiplied by 1.859 relative to the 2.4 g day patients. DISCUSSION The results from this pooled analysis of the ASCEND I and ASCEND II trials demonstrated that initiation of a 7 8 9 Percentile 676 Aliment Pharmacol Ther 211; 33: 672 678
Randomised clinical trial: mucosal healing with delayed-release mesalazine 4.8 g day delayed-release mesalazine dosing regimen achieves significantly higher mucosal healing rates than a 2.4 g day dosing regimen in patients with moderately active ulcerative colitis at 6 weeks. The data also demonstrated that regardless of dose and as early as 3 weeks (in the ASCEND trials, this was the first post-treatment assessment visit), delayed-release mesalazine induced endoscopically measured mucosal healing in patients with moderately active ulcerative colitis. Compared with 2.4 g day, mucosal healing rates achieved with 4.8 g day were numerically higher across all extents of disease and statistically greater among patients with left-sided disease and with prior steroid use. The higher mesalazine dose was also associated with significantly greater improvement in sigmoidoscopy at 6 weeks compared with 2.4 g day. In mildly active ulcerative colitis patients, there was no significant benefit of the higher dose, as both doses achieved high levels of mucosal healing. The ability of mesalazine to achieve mucosal healing in patients with ulcerative colitis may be an important clinical benefit as data increasingly suggest that mucosal healing is an important therapeutic endpoint for ulcerative colitis. Other studies have indicated that mucosal healing may be associated with lower long-term risk of cancer, 14 16 reduced risk of relapse 17 and reduced colectomy rate in ulcerative colitis patients. 18, 19 Certain histologic findings (e.g. basal plasmacytosis) have also been found to be independently associated with a shorter time to relapse in ulcerative colitis patients. 17 Given these data and observations that endoscopic findings frequently, 2, 21 but not always 22 correlate with histologic findings, mucosal healing may be an important marker for stable disease response. A recent retrospective analysis 18 demonstrated that achievement of mucosal healing in ulcerative colitis was significantly associated with low risk of future colectomy, but did not predict disease activity, inflammatory activity, need for steroids or disease extension. Of particular interest are recent data suggesting that mucosal healing may be a strong predictor of reduced cancer risk among ulcerative colitis patients. In a case control study of patients with long-standing extensive ulcerative colitis, the degree of histologic inflammatory activity was identified as a strong predictor of colorectal cancer risk. 14 Data from a follow-up case control study determined that severe active inflammation, features indicative of previous severe inflammation (e.g. postinflammatory polyps), 23 and features indicative of chronic active colitis (e.g. shortened or tubular colon, stricture formation) are associated with a significant risk of colorectal neoplasia 23, 24 in ulcerative colitis patients. Moreover, a normal colonoscopic appearance correlated strongly with reduced risk of neoplasia, with a macroscopically normal colonoscopy returning the cancer risk to that of the general population. It is well accepted that symptom resolution is correlated with improved QoL. However, the impact of mucosal healing on QoL has not yet been established. In fact, there is an ongoing debate as to whether active disease can be present if the mucosa is healed. Discrepancies between clinical symptoms and endoscopic findings have been noted in ulcerative colitis patients 22 who may suffer from functional complaints despite complete mucosal healing. 25, 26 The results of this analysis offer new insight into this relationship, demonstrating that mucosal healing has a strong relationship with QoL increases (as measured by the IBDQ). Although further studies are needed to elucidate better the relationship between mucosal healing and the status of clinical symptoms, these findings suggest that mucosal healing is strongly related to clinical response to therapy, and impacts patient-defined improvement. In conclusion, the results from this pooled analysis indicated that 4.8 g day mesalazine provides statistically significantly higher rates of mucosal healing and sigmoidoscopic improvement within a 6-week period when compared with a 2.4 g day dosing regimen in patients with moderately active ulcerative colitis. Furthermore, mucosal healing was found to have a strong relationship with clinical response to therapy, as well as with patient quality of life. ACKNOWLEDGEMENTS Declaration of personal interests: Dr Gary R. Lichtenstein has served as a consultant for Abbott Corporation, Alaven, Centocor, Inc., Elan, Ferring, Millenium Pharmaceuticals, Procter & Gamble Pharmaceuticals/Warner Chilcott, Salix Pharmaceuticals, Schering-Plough Corporation, Shire Pharmaceuticals, UCB and Wyeth. He has done research for Bristol-Myers Squibb, Centocor, Inc., Ferring, Procter & Gamble Pharmaceuticals/Warner Chilcott, Prometheus Laboratories, Inc., Salix Pharmaceuticals, Shire Pharmaceuticals and UCB. Dr David T. Rubin has served as a consultant for Salix Pharmaceuticals, Prometheus Pharmaceuticals, Abbott Immunology, UCB Pharma, Shire, Centocor, Elan Pharmaceuticals, Takeda-Millenium, Schering-Plough Merck and Given. He has received grant support from Procter & Gamble Pharmaceuticals Warner Chilcott, Salix Pharmaceuticals, Prometheus Pharmaceuticals, Abbott Immunology (Registry) and Aliment Pharmacol Ther 211; 33: 672 678 677
G. R. Lichtenstein et al. Elan Pharmaceuticals. He is the co-founder of Cornerstones Health, Inc. (nonprofit medical education company). David Ramsey is an employee and shareholder of Procter & Gamble. Declaration of funding interests: The studies and drafting of this manuscript were funded by Warner Chilcott (formerly Procter & Gamble Pharmaceuticals). Medical writing support was provided by Erica Leung of Warner Chilcott. REFERENCES 1. Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 24; 99: 1371 85. 2. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 25 8; 353: 2462 76. 3. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily, high-concentration MMX mesalamine in active ulcerative colitis. Gastroenterology 27; 132: 66 75. 4. Hanauer SB, Sandborn WJ, Kornbluth A, et al. Delayed-release oral mesalamine at 4.8g day (8mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 25; 1: 2478 85. 5. Hanauer SB, Sandborn WJ, Dallaire C, et al. Delayed-release oral mesalamine 4.8g day (8mg tablets) compared with 2.4g day (4mg tablets) for the treatment of mildly to moderately active ulcerative colitis: the ASCEND I trial. Can J Gastroenterol 27; 21: 827 34. 6. Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8g day (8mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 29; 137: 1934 43. 7. Sandborn WJ, Kamm MA, Lichtenstein GR, et al. MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebocontrolled trials. Aliment Pharmacol Ther 27; 26: 25 15. 8. Guyatt G, Mitchell A, Irvine EJ, et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology 1989; 96: 84 1. 9. Higgins PD, Schwartz M, Mapili J, Krokos I, Leung J, Zimmermann EM. Patient defined dichotomous end points for remission and clinical improvement in ulcerative colitis. Gut 25; 54: 782 8. 1. Irvine EJ. Quality of life of patients with ulcerative colitis: past, present, and future. Inflamm Bowel Dis 27; 13: 1 11. 11. Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn s Relapse Prevention Trial Study Group. Gastroenterology 1994; 16: 287 96. 12. Feagan BG, Reinisch W, Rutgeerts P, et al. The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients. Am J Gastroenterol 27; 12: 794 82. 13. Han SW, McColl E, Steen N, Barton JR, Welfare MR. The Inflammatory Bowel Disease Questionnaire: a valid and reliable measure in ulcerative colitis patients in the North East of England. Scand J Gastroenterol 1998; 33: 961 6. 14. Rutter MD, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 24; 126: 451 9. 15. Rubin DT. The changing face of colorectal cancer in inflammatory bowel disease: progress at last. Gastroenterology 26; 13: 13 2. 16. Bansal R, Itzkowitz S, Harpaz H, et al. Severity of inflammation predicts progression to colorectal neoplasia in ulcerative colitis. Am J Gastroenterol 25; 1: S-289 [Abstract #778]. 17. Bitton A, Peppercorn MA, Antonioli DA, et al. Clinical, biological, and histological parameters as predictors of relapse in ulcerative colitis. Gastroenterology 21; 12: 13 2. 18. Froslie KF, Jahnsen J, Mourn BA, et al. Mucosal healing in inflammatory bowel disease results from a Norwegian population-based cohort. Gastroenterology 27; 133: 412 22. 19. Sandborn WJ, Rutgeerts P, Feagan BG, et al. Colectomy rate comparison after treatment of ulcerative colitis with placebo or infliximab. Gastroenterology 29; 137: 12. 2. Powell-Tuck J, Day DW, Buckell NA, et al. Correlations between defined sigmoidoscopic appearances and other measures of disease activity in ulcerative colitis. Dig Dis Sci 1982; 27: 533 7. 21. Binder V. A comparison between clinical state, macroscopic and microscopic appearances of rectal mucosa and cytologic picture of mucosal exudate in ulcerative colitis. Scand J Gastroenterol 197; 5: 627 32. 22. Shen B, Achkar JP, Lashner BA, et al. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology 21; 121: 261 7. 23. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a population-based study from Olmsted County, Minnestoa. Gastroenterology 26; 13: 139 46. 24. Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 24; 53: 1813 6. 25. Mahadevan U. Mucosal healing in Crohn s disease: what you see is what you get? Gastrointest Endosc 26; 63: 443 4. 26. Lichtenstein GR, Rutgeerts P. Importance of mucosal healing in ulcerative colitis. Inflamm Bowel Dis 21; 16: 338 46. 678 Aliment Pharmacol Ther 211; 33: 672 678