Treatment Algorithms in Ulcerative Colitis Gary R. Lichtenstein, M.D. Professor of Medicine University of Pennsylvan

1.  Treatment Algorithms in Ulcerative Colitis Gary R. Lichtenstein, M.D.Professor of MedicineUniversity of Pennsylvania School of MedicineHospital of the University of PAPhiladelphiaPennsylvania

2. Premise and Preview In Most Clinical Scenarios ofUlcerative Colitis

3. Goals of Therapy for IBD Inducing remission Maintaining remission Restoring and maintaining nutrition Maintaining patient’s quality of life Surgical intervention (selection of optimal time for surgery)

4. Referral Population Cohort:Disease Distribution at Presentation Slide 5 In a study conducted between 1960 and 1983 of 1,116 Cleveland Clinic Foundation patients with a confirmed UC diagnosis for whom follow-up was at least 5 years, the characteristics of the disease were reported as follows: Disease location could be defined in one of three categories: Proctosigmoiditis (46.2%) Pancolitis (36.7%) Left-sided colitis (17%) The mean age at diagnosis was 32 years. Early complications (within two years of diagnosis) included: colonic hemorrhage (16.7%) and toxic colitis (12.7%). Complications were highest among patients with pancolitis. Surgery was required for 37.6% of the patients. Disease extended in 53.8% of cases. References Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. Dig Dis Sci 1993;38(6):1137-1146.Slide 5 In a study conducted between 1960 and 1983 of 1,116 Cleveland Clinic Foundation patients with a confirmed UC diagnosis for whom follow-up was at least 5 years, the characteristics of the disease were reported as follows: Disease location could be defined in one of three categories: Proctosigmoiditis (46.2%) Pancolitis (36.7%) Left-sided colitis (17%) The mean age at diagnosis was 32 years. Early complications (within two years of diagnosis) included: colonic hemorrhage (16.7%) and toxic colitis (12.7%). Complications were highest among patients with pancolitis. Surgery was required for 37.6% of the patients. Disease extended in 53.8% of cases. References Farmer RG, Easley KA, Rankin GB. Clinical patterns, natural history, and progression of ulcerative colitis. Dig Dis Sci 1993;38(6):1137-1146.

5. Colitis Activity Assessment Slide 7 In patients with UC, disease activity is assessed primarily on the basis of clinical features most often using the criteria of Truelove and Witts. These criteria are clinically useful, although many patients have features that fall between those classified as mild and those classified as severe. Disease activity can also be assessed endoscopically. The histologic findings loosely parallel the endoscopic features. References Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996;334(13):841-848.Slide 7 In patients with UC, disease activity is assessed primarily on the basis of clinical features most often using the criteria of Truelove and Witts. These criteria are clinically useful, although many patients have features that fall between those classified as mild and those classified as severe. Disease activity can also be assessed endoscopically. The histologic findings loosely parallel the endoscopic features. References Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996;334(13):841-848.

6. UC: Natural History Slide 6 The prognosis of UC including survival, colectomy rate, activity of disease, and working capacity was estimated from a follow-up study of 783 patients with UC comprising all patients from the county of Copenhagen. The period of observation ranged from 1 to 18 years with a mean of 6.7 years. The following observations were made: The survival rate of woman did not differ from that of the general population. At diagnosis, men over age 40 had a slight excess mortality rate in the first 2 years after diagnosis. Colon cancer was seen in only 7 of 783 patients. Annual risk was 0.07%. The colectomy rate was 9.6% in first year of diagnosis. After 10 years, the colectomy rate was 23%. After 18 years, the colectomy rate was 31%. At 3 years after diagnosis, the capacity to work including those with colectomy was not different from that of the general population. The study also indicated that, at any given time, 50% of those with UC were without symptoms, 30% had low disease activity, and 20% had moderate to high disease activity. Within 10 years of diagnosis, 97% of patients experienced at least one relapse. References Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis – based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26:158-163.Slide 6 The prognosis of UC including survival, colectomy rate, activity of disease, and working capacity was estimated from a follow-up study of 783 patients with UC comprising all patients from the county of Copenhagen. The period of observation ranged from 1 to 18 years with a mean of 6.7 years. The following observations were made: The survival rate of woman did not differ from that of the general population. At diagnosis, men over age 40 had a slight excess mortality rate in the first 2 years after diagnosis. Colon cancer was seen in only 7 of 783 patients. Annual risk was 0.07%. The colectomy rate was 9.6% in first year of diagnosis. After 10 years, the colectomy rate was 23%. After 18 years, the colectomy rate was 31%. At 3 years after diagnosis, the capacity to work including those with colectomy was not different from that of the general population. The study also indicated that, at any given time, 50% of those with UC were without symptoms, 30% had low disease activity, and 20% had moderate to high disease activity. Within 10 years of diagnosis, 97% of patients experienced at least one relapse. References Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis – based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26:158-163.

7. UC Natural History

8. Natural Course of Ulcerative Colitis

9. The therapeutic pyramid is based upon clinical trials that have evaluated single agents for specified disease activity.The therapeutic pyramid is based upon clinical trials that have evaluated single agents for specified disease activity.

10. Sequential Indications Induction of remission Treatment of acute disease Maintenance of remission Medical maintenance Steroid-sparing

11. Ulcerative Colitis: Induction of Remission Mild disease Aminosalicylate Topical therapy (distal disease) Oral therapy (extensive disease)

13. Oral 5-ASA Release Sites Slide 12 Release Site: Mesalamine 5-ASA (Ethylcellulose granules) in the proximal jejunum to colon (Pentasa). Timed release Mesalamine 5-ASA (Eudragit-S coating) in the distal ileum to the colon (Asacol). pH dependent release Balsalazide 5-ASA + 4-aminobenzoyl-beta-alanine in the colon (COLAZAL). Azo bond cleavage by bacterial azoreductase in the colonSlide 12 Release Site: Mesalamine 5-ASA (Ethylcellulose granules) in the proximal jejunum to colon (Pentasa). Timed release Mesalamine 5-ASA (Eudragit-S coating) in the distal ileum to the colon (Asacol). pH dependent release Balsalazide 5-ASA + 4-aminobenzoyl-beta-alanine in the colon (COLAZAL). Azo bond cleavage by bacterial azoreductase in the colon

14. Comparative Doses:Mild to Moderate UC

15. 5-ASA Delivery Systems

16. SPD476 uses MMX technology to deliver 5-ASA to the entire colon Delayed and extended drug release formulation containing 1.2g 5-ASA Highest 5-ASA drugloading per tablet SPD476 is a novel, high-strength, once-daily formulation of 5-aminosalicylic acid (5-ASA) using the MMX Multi Matrix System™ (MMX), for the treatment of acute, mild-to-moderate ulcerative colitis (UC). The tablet core consists of 5-ASA incorporated into microparticles of a lipophilic matrix that are dispersed within a hydrophilic matrix. The tablet is coated with a gastro-resistant polymer film which breaks down at pH7 in the terminal ileum. Here the hydrophilic matrix begins to erode and 5-ASA diffuses out of the lipophilic matrix, delivering 5-ASA to the entire colon and creating the potential for once-daily administration. Each tablet contains 1.2g of 5-ASA, a higher drug loading per tablet than any of those currently available (highest available to date is 800mg). Once-daily administration of SPD476 is likely to increase patient convenience and compliance and thus improve treatment outcomes. SPD476 is a novel, high-strength, once-daily formulation of 5-aminosalicylic acid (5-ASA) using the MMX Multi Matrix System™ (MMX), for the treatment of acute, mild-to-moderate ulcerative colitis (UC). The tablet core consists of 5-ASA incorporated into microparticles of a lipophilic matrix that are dispersed within a hydrophilic matrix. The tablet is coated with a gastro-resistant polymer film which breaks down at pH7 in the terminal ileum. Here the hydrophilic matrix begins to erode and 5-ASA diffuses out of the lipophilic matrix, delivering 5-ASA to the entire colon and creating the potential for once-daily administration. Each tablet contains 1.2g of 5-ASA, a higher drug loading per tablet than any of those currently available (highest available to date is 800mg). Once-daily administration of SPD476 is likely to increase patient convenience and compliance and thus improve treatment outcomes.

17. Sulfasalazine Dose/Toxicity

18. Aminosalicylate Dosing for Reductionof Signs/Symptoms

19. ASCEND I & II:Pooled Data Two Phase III, multi-center, randomized, double-blind controlled studies 423 analyzable patients with moderately active UC randomized to oral mesalamine – 4.8 g/day (800 mg tablets) or 2.4 g/day (400 mg tablets) x 6 weeks Treatment with 4.8 g/day provided a statistically significant efficacy benefit over 2.4 g/day in moderately active disease Both doses of mesalamine had similar safety profiles, and both were well tolerated

20. ASCEND I & II:Treatment Success at Weeks 3 & 6

21. Oral (2.4 g) vs. Rectal (4 g)Mesalamine for Distal UC

22. Addition of Rectal Mesalamine to Oral Mesalamine in PancolitisMarteau, P et al. Gut 2005;54:960-965 Percentage of patients achieving remission (ulcerative colitis disease activity index (UCDAI) of 0 or 1) or improvement (decrease in UCDAI >2 points).

24. Maintenance Therapies for Ulcerative Colitis Aminosalicylates Azathioprine/6-MP

25. Aminosalicylate: Maintenance Therapy Sulfasalazine Dose-response limited by intolerance Conventional dose-reduction based on balance of efficacy/toxicity

26. Oral Mesalamine Dosingfor UC Maintenance

27. Oral vs. Topical Mesalaminefor Maintenance of Distal UC

28. Frequency of Topical Mesalamine for Maintenance of Distal UC

29. Combined Oral + Topical Mesalamine for Maintenance of Distal UC

30. AZA in Severe UC: 1 Yr Placebo-Controlled Trial - Results See publication for definition of response and remission. Sood: OBJECTIVE: To investigate the efficacy of azathioprine in treating patients with severe ulcerative colitis. DESIGN: One-year, randomized, placebo-controlled trial. SUBJECTS: 83 patients with severe ulcerative colitis were enrolled. Fifty patients who relapsed within two months on corticosteroid withdrawal were randomized into two groups. The azathioprine group received oral sulfasalazine (6-8 g/day), oral prednisolone (1 mg/Kg/day) and oral azathioprine (2 mg/Kg/day). The placebo group received oral sulfasalazine (6-8 g/day), oral prednisolone (1 mg/Kg/day) and placebo. Corticosteroids were tapered over 12-16 weeks. See publication for definition of response and remission. Sood: OBJECTIVE: To investigate the efficacy of azathioprine in treating patients with severe ulcerative colitis. DESIGN: One-year, randomized, placebo-controlled trial. SUBJECTS: 83 patients with severe ulcerative colitis were enrolled. Fifty patients who relapsed within two months on corticosteroid withdrawal were randomized into two groups. The azathioprine group received oral sulfasalazine (6-8 g/day), oral prednisolone (1 mg/Kg/day) and oral azathioprine (2 mg/Kg/day). The placebo group received oral sulfasalazine (6-8 g/day), oral prednisolone (1 mg/Kg/day) and placebo. Corticosteroids were tapered over 12-16 weeks.

31. Controlled Trial of AZA in Management of Chronic UC - Results Rosenberg: To determine the efficacy of azathioprine in the treatment of ulcerative colitis, a 6-month double blind trial was carried out. Thirty patients with chronic ulcerative colitis who required the equivalent of at least 10 mg of prednisone per day over the 3 months prior to entering the study were randomized into placebo and azathioprine (1.5 mg per kg) treatment groups. Reduction of steriods was a major objective of the trial. Rosenberg: To determine the efficacy of azathioprine in the treatment of ulcerative colitis, a 6-month double blind trial was carried out. Thirty patients with chronic ulcerative colitis who required the equivalent of at least 10 mg of prednisone per day over the 3 months prior to entering the study were randomized into placebo and azathioprine (1.5 mg per kg) treatment groups. Reduction of steriods was a major objective of the trial.

32. Controlled Trial of AZA in Management of Chronic UC - Results Kirk: A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Kirk: A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed.

33. Methotrexate for Active UC and Induction of Remission Oren: BACKGROUND & AIMS: Uncontrolled studies have suggested that methotrexate may be effective in patients with active ulcerative colitis. The aim of this study was to evaluate the effectiveness of oral methotrexate in chronic steroid-dependent ulcerative colitis in a randomized, double-blind multicenter trial. METHODS: Patients with active ulcerative colitis who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months with a current Mayo Clinic score of > or = 7 were included in the study. Methotrexate (12.5 mg) or placebo was added to their treatment once weekly for 9 months. Oren: BACKGROUND & AIMS: Uncontrolled studies have suggested that methotrexate may be effective in patients with active ulcerative colitis. The aim of this study was to evaluate the effectiveness of oral methotrexate in chronic steroid-dependent ulcerative colitis in a randomized, double-blind multicenter trial. METHODS: Patients with active ulcerative colitis who have received steroids and/or immunosuppressives for at least 4 months during the preceding 12 months with a current Mayo Clinic score of > or = 7 were included in the study. Methotrexate (12.5 mg) or placebo was added to their treatment once weekly for 9 months.

34. Complications of Surgery: Ileal Pouch-Anal Anastomosis (IPAA) Pelvic sepsis Leakage Incontinence Intestinal obstruction Anastomotic strictures Sexual dysfunction Pouchitis Female infertility The results for Ileal Pouch-Anal Anastomosis (IPAA) procedure are generally excellent and patient satisfaction is high. However, there can be significant morbidity after IPAA. Perioperative complications can occur with an IPAA as with any abdominal or pelvic operation. Short-term complications such as pelvic sepsis and leakage from the anastomosis or pouch do occur. Postoperative sepsis usually occurs in the setting of an anastomotic leak and is certainly one of the more serious complications of IPAA. The rate of sepsis is 6% to 37%, and treatment may require antibiotics, drainage, or prolonged ileostomy. Pelvic sepsis is one of the more common causes of pouch failure. Long-term complications like intestinal obstruction, anastomotic strictures, sexual dysfunction, and pouchitis also occur. The results for Ileal Pouch-Anal Anastomosis (IPAA) procedure are generally excellent and patient satisfaction is high. However, there can be significant morbidity after IPAA. Perioperative complications can occur with an IPAA as with any abdominal or pelvic operation. Short-term complications such as pelvic sepsis and leakage from the anastomosis or pouch do occur. Postoperative sepsis usually occurs in the setting of an anastomotic leak and is certainly one of the more serious complications of IPAA. The rate of sepsis is 6% to 37%, and treatment may require antibiotics, drainage, or prolonged ileostomy. Pelvic sepsis is one of the more common causes of pouch failure. Long-term complications like intestinal obstruction, anastomotic strictures, sexual dysfunction, and pouchitis also occur.

35. Complications of UC Surgery Mortality (<0.5%)1 3-10 stools/24 hrs so bowel pattern not normal1 Impotence (1.5%)2 Pouchitis (10-60%)1 Small bowel obstruction (20%)1 Decrease in female fertility (56-98%)3-5 Pouch-vaginal fistula (4%)1 Read slideRead slide

36. Ileal Pouch –Functional Outcome UC patients who undergo proctocolectomy and reconstruction with an ileal pouch are still at risk for a higher number of bowel movements per day, as well as incontinence. delaney: OBJECTIVE: To evaluate how age affects functional outcome and quality of life after ileal pouch anal anastomosis (IPAA).SUMMARY BACKGROUND DATA Because of the limited number of older patients undergoing IPAA, it has been difficult to assess functional outcome and quality of life stratified by age. METHODS: IPAA was performed in 1895 patients. Patients were stratified by age into <45 (n = 1410), 46-55 (n = 289), 56-65 (n = 154), and more than 65 years (n = 42). Outcome was assessed prospectively. Results are presented at 1, 3, 5, and 10 years after surgery.UC patients who undergo proctocolectomy and reconstruction with an ileal pouch are still at risk for a higher number of bowel movements per day, as well as incontinence. delaney: OBJECTIVE: To evaluate how age affects functional outcome and quality of life after ileal pouch anal anastomosis (IPAA).SUMMARY BACKGROUND DATA Because of the limited number of older patients undergoing IPAA, it has been difficult to assess functional outcome and quality of life stratified by age. METHODS: IPAA was performed in 1895 patients. Patients were stratified by age into <45 (n = 1410), 46-55 (n = 289), 56-65 (n = 154), and more than 65 years (n = 42). Outcome was assessed prospectively. Results are presented at 1, 3, 5, and 10 years after surgery.

37. Ileal Pouch: Cumulative Incidences Pregnancy BACKGROUND & AIMS: Women with ulcerative colitis generally have normal fertility. The aim of this study was to compare patients' fecundability before and after restorative proctocolectomy with ileal pouch-anal anastomosis with the fecundability of the general population. METHODS: Historical follow-up was performed on 343 consecutive female patients aged 10.6-40.5 years at surgery and a reference population of 1200 women aged 25-40 years. A total of 290 (85%) patients and 661 (55%) women in the reference population agreed to participate in a structured telephone interview concerning reproductive behavior and waiting times to pregnancy. Cox regression and Kaplan-Meier plots were used for analysis. BACKGROUND & AIMS: Women with ulcerative colitis generally have normal fertility. The aim of this study was to compare patients' fecundability before and after restorative proctocolectomy with ileal pouch-anal anastomosis with the fecundability of the general population. METHODS: Historical follow-up was performed on 343 consecutive female patients aged 10.6-40.5 years at surgery and a reference population of 1200 women aged 25-40 years. A total of 290 (85%) patients and 661 (55%) women in the reference population agreed to participate in a structured telephone interview concerning reproductive behavior and waiting times to pregnancy. Cox regression and Kaplan-Meier plots were used for analysis.

39. IV Cyclosporine: Major Toxicity Renal insufficiency 23% Infection 20% Seizures 3% Deaths 2% Anaphylaxis 1%

40. Study Design Multicenter, randomized, double-blind, placebo-controlled, parallel-treatment group trial Conducted globally at 62 sites 364 subjects with moderately to severely active ulcerative colitis were randomized and treated: 121 in the placebo treatment group 121 in the REMICADE® (infliximab) 5 mg/kg treatment group 122 in the REMICADE 10 mg/kg treatment group Multicenter, randomized, double-blind, placebo-controlled, parallel-treatment group trial. 364 patients with moderately to severely active colitis were enrolled at 62 sites. Patients were randomized into three treatment groups: 121 in the placebo treatment group 121 in the REMICADE 5 mg/kg treatment group 122 in the REMICADE 10 mg/kg treatment group Multicenter, randomized, double-blind, placebo-controlled, parallel-treatment group trial. 364 patients with moderately to severely active colitis were enrolled at 62 sites. Patients were randomized into three treatment groups: 121 in the placebo treatment group 121 in the REMICADE 5 mg/kg treatment group 122 in the REMICADE 10 mg/kg treatment group

41. Patient Population Subjects with: Moderately to severely active ulcerative colitis (UC): Mayo score ? 6 points (on 12 point scale) Endoscopy subscore ? 2 points Subjects must meet at least 1 of the following criteria: Current treatment with = 1 of the following: Oral corticosteroids, 6-mercaptopurine (6-MP), or azathioprine (AZA) Have failed to successfully taper, tolerate, or respond to corticosteroids within the past 18 months Have failed to tolerate or respond to 6-MP or AZA within the previous 5 years The inclusion criteria included: 1. Evidence of moderate-to-severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2. The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment . 2. AND either concurrent treatment with corticosteroids, azathioprine and/or 6-MP OR failure to tolerate or respond to at least one of the aforementioned therapies. The inclusion criteria included: 1. Evidence of moderate-to-severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2. The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment . 2. AND either concurrent treatment with corticosteroids, azathioprine and/or 6-MP OR failure to tolerate or respond to at least one of the aforementioned therapies.

42. Study Design All patients were randomized into three treatment arms of placebo, 5 mg/kg REMICADE, or 10 mg/kg REMICADE in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 8 and Week 30, followed by the Final evaluation at Week 54. Only 30 Week data available to date. All treatment groups received concomitant therapies, which were required to be stable at the baseline visit and throughout the trial. Following Week 8, tapering the daily dose of corticosteroids in subjects who demonstrated clinical improvement was allowed. All patients were randomized into three treatment arms of placebo, 5 mg/kg REMICADE, or 10 mg/kg REMICADE in a 1:1:1 ratio. They received infusions at Week 0, 2, and 6, and then every 8 weeks thereafter through Week 46 for a total of eight infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 8 and Week 30, followed by the Final evaluation at Week 54. Only 30 Week data available to date. All treatment groups received concomitant therapies, which were required to be stable at the baseline visit and throughout the trial. Following Week 8, tapering the daily dose of corticosteroids in subjects who demonstrated clinical improvement was allowed.

43. Clinical Response at Week 8 and Week 30 There was a significant difference in clinical response for the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 69% of the patients receiving 5 mg/kg and 62% receiving 10 mg/kg achieved clinical response at Week 8 vs. 37% of the placebo patients. 52% of the patients receiving 5 mg/kg and 51% receiving 10 mg/kg achieved clinical response at Week 30 vs. 30% of the placebo patients. There was a significant difference in clinical response for the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 69% of the patients receiving 5 mg/kg and 62% receiving 10 mg/kg achieved clinical response at Week 8 vs. 37% of the placebo patients. 52% of the patients receiving 5 mg/kg and 51% receiving 10 mg/kg achieved clinical response at Week 30 vs. 30% of the placebo patients.

44. Clinical Response at Week 8 by Corticosteroid Refractory Status In a subgroup analysis, there was a significant difference in the proportion of corticosteroid-refractory subjects achieving clinical response at Week 8 in the REMICADE-treated subjects compared to the placebo-treated subjects: 77.4% of subjects receiving 5 mg/kg and 67.7% receiving 10 mg/kg achieved clinical response vs. 35.3% of placebo subjects Similarly, there was also a significant difference in the proportion of noncorticosteroid refractory subjects achieving clinical response at Week 8 in the REMICADE-treated subjects compared to the placebo-treated subjects: 66.7% of subjects receiving 5 mg/kg and 59.3% receiving 10 mg/kg achieved clinical response vs. 37.9% of placebo subjectsIn a subgroup analysis, there was a significant difference in the proportion of corticosteroid-refractory subjects achieving clinical response at Week 8 in the REMICADE-treated subjects compared to the placebo-treated subjects: 77.4% of subjects receiving 5 mg/kg and 67.7% receiving 10 mg/kg achieved clinical response vs. 35.3% of placebo subjects Similarly, there was also a significant difference in the proportion of noncorticosteroid refractory subjects achieving clinical response at Week 8 in the REMICADE-treated subjects compared to the placebo-treated subjects: 66.7% of subjects receiving 5 mg/kg and 59.3% receiving 10 mg/kg achieved clinical response vs. 37.9% of placebo subjects

45. Clinical Remission at Week 8 and Week 30 There was a significant difference in the proportion of patients achieving clinical remission in the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 39% of the patients receiving 5 mg/kg and 32% receiving 10 mg/kg achieved clinical remission at Week 8 vs. 15% of the placebo patients. 34% of the patients receiving 5 mg/kg and 37% receiving 10 mg/kg achieved clinical remission at Week 30 vs. 16% of the placebo patients. There was a significant difference in the proportion of patients achieving clinical remission in the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 39% of the patients receiving 5 mg/kg and 32% receiving 10 mg/kg achieved clinical remission at Week 8 vs. 15% of the placebo patients. 34% of the patients receiving 5 mg/kg and 37% receiving 10 mg/kg achieved clinical remission at Week 30 vs. 16% of the placebo patients.

46. Mucosal Healing at Week 8 and Week 30 There was a significant difference in the proportion of patients who experienced mucosal healing (defined as an endoscopic subscore of 0 or 1) in the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 62% of the patients receiving 5 mg/kg and 59% receiving 10 mg/kg achieved mucosal healing at Week 8 vs. 34% of the placebo patients. 50% of the patients receiving 5 mg/kg and 49% receiving 10 mg/kg achieved mucosal healing at Week 30 vs. 25% of the placebo patients. There was a significant difference in the proportion of patients who experienced mucosal healing (defined as an endoscopic subscore of 0 or 1) in the REMICADE-treated patients compared to the placebo-treated patients at both Week 8 and Week 30. 62% of the patients receiving 5 mg/kg and 59% receiving 10 mg/kg achieved mucosal healing at Week 8 vs. 34% of the placebo patients. 50% of the patients receiving 5 mg/kg and 49% receiving 10 mg/kg achieved mucosal healing at Week 30 vs. 25% of the placebo patients.

47. Clinical Remission Without Corticosteroids at Week 30 The proportion of patients achieving clinical remission without corticosteroids at week 30 was significantly higher in the combined REMICADE group than in the placebo-treated patients (22% vs. 10%, respectively). The proportion of patients achieving clinical remission without corticosteroids at week 30 was significantly higher in the combined REMICADE group than in the placebo-treated patients (22% vs. 10%, respectively).

48. Relatively fewer options exist for the treatment of ulcerative colitis at present. For patients with disease confined to the bowel distal to the splenic flexure, topical therapy delivered by enema, particularly mesalamine enema, may be highly effective. For those patients who do not respond to enemas, the addition or substitution of an oral 5-aminosalicylate may be effective. Oral delivery is needed for patients with more extensive disease. Although dose ranging studies have not uniformly detected a robust dose response, some patients may respond to dose escalation. Patients who fail to respond to 5-ASA will require a course of steroids, and by definition have disease of at least moderate severity.Relatively fewer options exist for the treatment of ulcerative colitis at present. For patients with disease confined to the bowel distal to the splenic flexure, topical therapy delivered by enema, particularly mesalamine enema, may be highly effective. For those patients who do not respond to enemas, the addition or substitution of an oral 5-aminosalicylate may be effective. Oral delivery is needed for patients with more extensive disease. Although dose ranging studies have not uniformly detected a robust dose response, some patients may respond to dose escalation. Patients who fail to respond to 5-ASA will require a course of steroids, and by definition have disease of at least moderate severity.

49. Patients with moderate flare symptoms may be treated with a course of oral steroids, while those with more severe symptoms will require intravenous steroids. Patients who are steroid dependent or refractory may be treated with 6MP or azathioprine. Patients unresponsive to intravenous steroids may be considered for treatment with cyclosporine or colectomy.Patients with moderate flare symptoms may be treated with a course of oral steroids, while those with more severe symptoms will require intravenous steroids. Patients who are steroid dependent or refractory may be treated with 6MP or azathioprine. Patients unresponsive to intravenous steroids may be considered for treatment with cyclosporine or colectomy.

50. Final Points There is no “one size fits all” to IBD therapy Therapy and decision making are tailored to the individual Algorithms are based upon available evidence Evidence is in constant flux Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome Skillful application of medical therapy makes all the difference in outcomes