Dilemmas In Ulcerative Colitis

1. Dilemmas In Ulcerative Colitis

2. Traditional Approach To Therapy For Ulcerative Colitis

3. Case 1: Musician With L-UC Started by referring MD on mesalamine enemas with initial success Switched to oral mesalamine 2.4g for flare Steroids 40, then 60 begun for subsequent flares Empiric course of metronidzole Still has 8 BM/day, malaise without fever. Works but wants to feel good and get it on the good foot. NL vital signs in clinic. Mild anemia Good God! Now what??

4. The Walking (working) WoundedHow Do We Optimize Care?

5. ASA: More is Better

6. 181. ORAL VERSUS RECTAL MESALAMINE VERSUS COMBINATION THERAPY IN ACTIVE DISTAL ULCERATIVE COLITIS The efficacy of nightly mesalamine enemas alone, (Rowasa®) 2.4 gm/d of oral mesalamine (Asacol®) alone, and the combination of enemas and tablets were compared in 60 patients with active distal ulcerative colitis. Patients with combination therapy reported cessation of rectal bleeding sooner; at all visits (week 1, 3, & 6), the combination group had the highest percentage of patients with no blood in their stools. This difference was statistically significant at six weeks. It was concluded that the combination of oral and rectal mesalamine therapy was well-tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone. • Safdi M, DeMicco M, Sininsky C et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92:1867-71181. ORAL VERSUS RECTAL MESALAMINE VERSUS COMBINATION THERAPY IN ACTIVE DISTAL ULCERATIVE COLITIS The efficacy of nightly mesalamine enemas alone, (Rowasa®) 2.4 gm/d of oral mesalamine (Asacol®) alone, and the combination of enemas and tablets were compared in 60 patients with active distal ulcerative colitis. Patients with combination therapy reported cessation of rectal bleeding sooner; at all visits (week 1, 3, & 6), the combination group had the highest percentage of patients with no blood in their stools. This difference was statistically significant at six weeks. It was concluded that the combination of oral and rectal mesalamine therapy was well-tolerated and produced earlier and more complete relief of rectal bleeding than oral or rectal therapy alone. • Safdi M, DeMicco M, Sininsky C et al. A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis. Am J Gastroenterol 1997;92:1867-71

7. Corticosteroids: Dependency: Short and Long Term Efficacy See publication for definition of steroid response and remission. Faubion: BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. Prednisone dose ranged from 40-60 mg/day. Taper was attempted over a variable period of 3-6 months.See publication for definition of steroid response and remission. Faubion: BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. Prednisone dose ranged from 40-60 mg/day. Taper was attempted over a variable period of 3-6 months.

8. Risk of Resection in UC After 1st Course of Steroids: An Indication for CRS Consultation Faubion: BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. Prednisone dose ranged from 40-60 mg/day. Taper was attempted over a variable period of 3-6 months. Faubion: BACKGROUND & AIMS: The aim of this study was to determine the 1-year outcome after the first course of corticosteroids in an inception cohort of patients with inflammatory bowel disease. METHODS: All patients in Olmsted County, Minnesota, diagnosed with Crohn's disease (n = 173) or ulcerative colitis (n = 185) from 1970 to 1993 who were treated with systemic corticosteroids were identified (4 denied research authorization). Immediate outcome (30 days) and 1-year outcome after the first course of corticosteroids were determined. Prednisone dose ranged from 40-60 mg/day. Taper was attempted over a variable period of 3-6 months.

9. 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.

10. 6-MP Maintenance therapy for UC 83 patients in remission induced by 6-MP Mean of 60 month follow-up 201. 6-MERCAPTOPURINE AS MAINTENANCE THERAPY FOR ULCERATIVE COLITIS The records of 83 patients with ulcerative colitis who had achieved complete remission while under treatment with 6-mercaptopurine were followed for a mean of 60 months. Of 68 patients who had continued the 6-MP, 24 (35%) had a relapse while still on the drug. The estimated median time to relapse was 32 months for those patients who had continued 6-MP. In contrast, 13 of 15 patients (87%) who had electively discontinued 6-MP at various intervals after achieving complete remission had a relapse. The median time to relapse in this group was 14 months. The rates of relapse did not appear influenced by the duration of remission on 6-MP. • George J, Present DH, Pou R et al. The long-term outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996;91:1711-14.201. 6-MERCAPTOPURINE AS MAINTENANCE THERAPY FOR ULCERATIVE COLITIS The records of 83 patients with ulcerative colitis who had achieved complete remission while under treatment with 6-mercaptopurine were followed for a mean of 60 months. Of 68 patients who had continued the 6-MP, 24 (35%) had a relapse while still on the drug. The estimated median time to relapse was 32 months for those patients who had continued 6-MP. In contrast, 13 of 15 patients (87%) who had electively discontinued 6-MP at various intervals after achieving complete remission had a relapse. The median time to relapse in this group was 14 months. The rates of relapse did not appear influenced by the duration of remission on 6-MP. • George J, Present DH, Pou R et al. The long-term outcome of ulcerative colitis treated with 6-mercaptopurine. Am J Gastroenterol 1996;91:1711-14.

11. 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.

12. Infliximab for UC: ACT I and II Remission Without Steroids Wk 30 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. 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 22 for a total of five infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 8 and Week 30. 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 clinical endpoints were consistent in both trials. 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. 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 22 for a total of five infusions. The primary endpoint was clinical response measured at Week 8. The major secondary endpoints were measured at Week 8 and Week 30. 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 clinical endpoints were consistent in both trials.

13. Case 2: Actor With Refractory Pan-colitis

15. Refractory UC and CMV: Culprit or Companion? Detection of CMV genome is higher in IBD in general 1 Current systemic steroids related to CMV infection (p = 0.03); p=NS for severity, past Rx Colectomy specimens (n=85) 20% stained positive2 27% (15/55) of steroid-refractory 9% (6/68) positive PRE-op biopsies 1 pt received pre-op anti-viral therapy Still required surgery NO post-op CMV in any of 85 (pouch bx) High false neg in pre-op bx, small n 1) Dimitroulia E et al IBD 2006. 12(9):879-84 Greek two center study 85 pts with IBD, 42 controls. 58 UC, 27 CD Controls: Immunostain: None PCR +12% in blood, 2% in tissue; UC Immunostain: + PCR associated with shorter duration of IBD 2) Maconi G et al Dig Liver Dis 2005. 37(6):418-23 Italian surgical series 77 consecutive resections for UC 55 steroid refractory 6 megacolon, 7 dysplasia/ cancer, 9 dysfunction 1) Dimitroulia E et al IBD 2006. 12(9):879-84 Greek two center study 85 pts with IBD, 42 controls. 58 UC, 27 CD Controls: Immunostain: None PCR +12% in blood, 2% in tissue; UC Immunostain: + PCR associated with shorter duration of IBD 2) Maconi G et al Dig Liver Dis 2005. 37(6):418-23 Italian surgical series 77 consecutive resections for UC 55 steroid refractory 6 megacolon, 7 dysplasia/ cancer, 9 dysfunction

16. Does Anti-Viral Therapy Help? 64 non-refractory IBD pts ( UC 23:CD 43) 1 42 (66%) had + serology: 3 recv’d DHPG 1 had CMV Ag and biopsy-proven CMV colitis only this patient benefited 40 refractory UC;40 non-refractory UC2 2/40 + H&E 10/40 + Immunostain in refractory UC 0/40 H&E, 1/40 Immunostain non-refractory 2 CMV + refractory recognized early, treated 2/2 Able to taper steroids, avoid surgery 47 inpatients with UC checked for CMV Ag in blood3 12/16 UC pts with + CMV treated 8 (66.7 %) responded Kambham N Am J Surg Pathol. 2004 Mar;28(3):365-73 Kambham N Am J Surg Pathol. 2004 Mar;28(3):365-73

17. Does Anti-Viral Therapy Help? 62 pts with severe colitis (55 UC;7 CD) 7 (5UC,2 CD) out of 19 (36%) pts with refractory disease, CMV found in rectal bx as well as buffy coat 5/6 treated patients went into remission after antiviral treatment (3 DHPG, 2 foscarnet). 1 did not->surgery Paralysis by analysis? No. Reasonable to perform rectal bx for IHC stain early, treat if positive

18. When to Infuse Dirt? CyA 2 vs 4 mg/kg/d IV (n=142): Same response/tox 1 41 (35%) of the 118 responders eventually req’d colectomy (despite scripted AZA, steroids, repeat CyA) 2 Mean # days to colectomy: 542 (42–1271 d) Same complication rate on CyA as off > 3 months Before treatment with IV CSA was initiated all patients were treated with IV glucocorticosteroids (minimum, 40 mg methylprednisolone/day). Patients were considered for CSA if their clinical condition did not improve after 5–7 days of IV steroid treatment or when there was a subjective or objective deterioration in their condition. Patients received CSA at a dose of 4 mg/kg/day or 2 mg/kg/day as a continuous IV infusion for a total of 7 days. The conditions of all patients were assessed daily by the treating physician and the consulting surgeon and when patients failed to improve after 7–10 days or when their medical condition worsened, they were scheduled for immediate colectomy. During IV treatment, CSA blood levels were kept between 250 and 450 ng/mL (4 mg/kg) or between 150 and 250 ng/mL (2 mg/kg). Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at an initial dose of 8 mg/kg/day and the dose was adjusted to blood levels between 150 and 250 ng/mL. Intravenous glucocorticosteroids were continued at stable doses during IV CSA treatment. Those patients who achieved a response to IV CSA were switched to a tapering dose of oral glucocorticosteroids. CSA was continued in responders for a total of 3 months. Patients who already were taking azathioprine or 6-mercaptopurine were continued at their current levels. Those patients not taking azathioprine or 6-mercaptopurine were started at a dose of 2.5 mg/kg and 1.5 mg/kg, respectively, at the time of response to CSA during their hospitalization, if they had no known intolerance. Before treatment with IV CSA was initiated all patients were treated with IV glucocorticosteroids (minimum, 40 mg methylprednisolone/day). Patients were considered for CSA if their clinical condition did not improve after 5–7 days of IV steroid treatment or when there was a subjective or objective deterioration in their condition. Patients received CSA at a dose of 4 mg/kg/day or 2 mg/kg/day as a continuous IV infusion for a total of 7 days. The conditions of all patients were assessed daily by the treating physician and the consulting surgeon and when patients failed to improve after 7–10 days or when their medical condition worsened, they were scheduled for immediate colectomy. During IV treatment, CSA blood levels were kept between 250 and 450 ng/mL (4 mg/kg) or between 150 and 250 ng/mL (2 mg/kg). Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at an initial dose of 8 mg/kg/day and the dose was adjusted to blood levels between 150 and 250 ng/mL. Intravenous glucocorticosteroids were continued at stable doses during IV CSA treatment. Those patients who achieved a response to IV CSA were switched to a tapering dose of oral glucocorticosteroids. CSA was continued in responders for a total of 3 months. Patients who already were taking azathioprine or 6-mercaptopurine were continued at their current levels. Those patients not taking azathioprine or 6-mercaptopurine were started at a dose of 2.5 mg/kg and 1.5 mg/kg, respectively, at the time of response to CSA during their hospitalization, if they had no known intolerance.

19. Infliximab Rescue for Sick Unto Colectomy? Jarnerot G Gastroenterology. 2005;128:1805–1811 Background & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6–8 if they fulfilled index criteria on day 5–7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.Jarnerot G Gastroenterology. 2005;128:1805–1811 Background & Aims: Despite treatment with corticosteroids, severe to moderately severe attacks of ulcerative colitis have a high colectomy rate. We intended to find a rescue therapy other than cyclosporin A, which imposes a high risk of side effects and cyclosporine-related mortality. Methods: This was a randomized double-blind trial of infliximab or placebo in severe to moderately severe ulcerative colitis not responding to conventional treatment. Patients were randomized to infliximab/placebo either on day 4 after the initiation of corticosteroid treatment if they fulfilled the index criteria for fulminant ulcerative colitis on day 3 or on day 6–8 if they fulfilled index criteria on day 5–7 for a severe or moderately severe acute attack of ulcerative colitis. Results were analyzed according to the intention-to-treat principle. The primary end point was colectomy or death 3 months after randomization. Secondary end points were clinical and endoscopic remission at that time in patients who did not undergo operation. Results: Forty-five patients were included (24 infliximab and 21 placebo). No patient died. Seven patients in the infliximab group and 14 in the placebo group had a colectomy (P = .017; odds ratio, 4.9; 95% confidence interval, 1.4–17) within 3 months after randomization. No serious side effects occurred. Three patients in the placebo group required operation for septic complications. Conclusions: Infliximab 4–5 mg/kg is an effective and safe rescue therapy in patients experiencing an acute severe or moderately severe attack of ulcerative colitis not responding to conventional treatment.

20. Current Therapeutic Choices in SuC UC CyA Infliximab Clinical Trial Colectomy Choice will depend on center expertise with drug choices and availability of expert surgical support Greatly tempered by pt preference Averaged preferences support the use of medical interventions, 1/3 of individuals may benefit most from proceeding directly to colectomy

21. Complications of UC Surgery Mortality (<0.5%)1 3-10 stools/24 hrs 1 Impotence (1.5%)2 Pouchitis (10-60%)1 SBO (20%)1 ?? fertility (56-98%)3-5 Pouch-vag fistula (4%)1 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.

22. 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.

23. Bringing Therapy to PatientsAccelerating Stages in Drug Development

24. New Targets, New Agents MAb to a4 integrin (natalizumab) MAb to IL-2Ra (daclizumab) MAb to IL-2R (basiliximab) anti-CD3 (visilizumab) EGF (enema) Apheresis (Adacolumn) IFN Opiate receptor

25. Summary Walking wounded More is better for ASA (dose, route) Expanding role for biologic agents Shrinking role for steroids Colorectal surgery consult at 1st course Sick unto colectomy Biologic therapy edging into CSA pool Bx for CMV Optimism for drug development