Ulcerative Colitis: Refining our Management and Incorporating Newer Concepts

Transcription

1 Ulcerative Colitis: Refining our Management and Incorporating Newer Concepts Asher Kornbluth, MD Clinical Professor of Medicine The Henry D. Janowitz The Mt. Sinai School of Medicine Refining our Management and Incorporating Newer Concepts in UC: Objectives Fine tuning our use of 5-ASA drugs Anti-TNF treatment in UC: Traditional Uses, Additional Uses Approaches to dysplasia diagnosis and management 1

2 Refining our Management and Incorporating Newer Concepts in UC: Objectives Fine tuning our use of 5-ASA drugs Anti-TNF treatment in UC: Traditional Uses, Additional Uses and Unknown Uses Approaches to dysplasia diagnosis and management Delayed-Release Mesalamine* in Moderate UC: Overall Improvement for 2.4 g/day vs 4.8 g/day Pa atients With Treatmen nt Success at Week 6 (%) *Asacol ASCEND II 1 ASCEND III 2 Moderate UC (n=254) P< P< g/day 4.8 g/day Delayed-Release Mesalamine Pa atients With Treatmen nt Success at Week 6 (% ) Moderate UC (n=772) 66 P=NS g/day 4.8 g/day Delayed-Release Mesalamine In the overall cohort of moderate patients, there was no difference in overall improvement rates. 1. Hanauer SB, et al. Am J Gastroenterol 2005;100: Sandborn WJ, et al. Gastroenterol 2009;137:

3 Delayed-Release Mesalamine* 2.4 g/day vs 4.8 g/day in Select Patient Subsets With Moderate UC Patients (%) Treatment success at week 6 in patients having taken previous UC therapy: ASCEND III g/day 4.8 g/day * 70% 70% 70% 60 64% 64% 61% 58% 54% n=323 n=338 Previous Oral 5-ASA P=0.07 n=188 n=192 Previous Rectal Therapies P=0.06 n=157 n=157 Previous Steroids P=0.05 n=234 n=230 Previous Use of 2 Medications *P= g/d more effective than 2.4 g/day in select patient subsets. *Asacol Included oral 5-ASAs, rectal therapies, steroids, or immunomodulators Sandborn WJ, et al. Gastroenterology 2009;137: Month Maintenance of Remission Rates With MMX-Mesalamine: QD vs. BID Dosing Kamm MA, et al. Gut 2008; 57:

4 Maintenance Efficacy with QD dosing at 6 months with Extended-Release 5-ASA Extended-release mesalamine g/day Placebo Rela apse-free Patients (%) 100 Difference (95% CI) 17% Difference (95% CI) 12% P<0.001 P= Study 1 Study 2 *Relapse counted as rectal bleeding score 1 and mucosal appearance score 2, or premature withdrawal from study. 1. Apriso (mesalamine) extended release capsules [package insert]. Morrisville, NC: Salix Pharmaceuticals, Inc.; Maintenance of Remission: QD vs. BID Dosing with Delayed Release 5-ASA Pentasa, Shire Pharmaceuticals Inc. Dignass AU, Curr Gastro Hepatol 2009;7:

5 QD is as effective as BID Dosing in Maintaining Remission With ph-release Mesalamine ng ths tients (%) Remainin Remission at 6 Mon Pa in R *95% CI for BID-QD dosing, -2.3, 4.9 Asacol 400 mg tablet 90.5% 91.8%* QD (n=473) BID (n=474) Frequency of Delayed-Release Mesalamine Dosing Sandborn WJ, et al. Gastroenterology 2010;138: ASAs in UC: Take Home Messages 4.8 gm/d of greater benefit c/w 2.4 gm/d in selected subsets of patients with moderate disease New agents for maintenance designed for once daily dosing Once daily dosing of older agents may be as effective as traditional split dosing of these agents 5

6 Refining our Management and Incorporating Newer Concepts in UC: Objectives Fine tuning our use of 5-ASA drugs Anti-TNF treatment in UC: Traditional Uses, Additional Uses Approaches to dysplasia diagnosis and management Infliximab Induction and Maintenance Therapy in Patients With UC: Clinical Remission ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg Patients (%) * Weeks 30 Weeks 54 Weeks * Weeks 30 Weeks *P vs placebo P<0.001 vs placebo Rutgeerts P, et al. N Engl J Med 2005;353:

7 Poor Correlation Between Mucosal Healing vs Clinical Remission in UC Mucosal Healing = Mayo Score 0 or 1 Week 8 Week 30 Week 54 * * * * * * *P.001 vs placebo based on a two-sided Cochran-Mantel-Haenszel chi-square test. Rutgeerts P, et al. N Engl J Med 2005;353:2462. Predictors of Colectomy in Severe Colitis: Poor Prognostic Endoscopic features Deep Ulcers Extensive Loss of Mucosal Layer* Well-like Ulcers Large Mucosal Abrasions *With or without residual mucosal areas. 7

8 Severity of Disease Correlates with Colectomy Severe Endoscopic Colitis (n = 46) Moderate Endoscopic Colitis (n = 39) 93% underwent colectomy 23% underwent colectomy Carbonnel F, et al. Dig Dis Sci 1994;39: Mucosal healing with Infliximab Reduces Colectomy Rates Colombel JF, et al. Gastro 2011, June 30, epub ahead of print 8

9 Presence of Detectable Trough Infliximab Levels Increases Remission and Reduces Colectomy Seow CH, et al. Gut 2010;59:49-54 CsA vs IFX in IV Steroid- Refractory UC: The CYSIF Study First randomized, controlled study comparing CsA to IFX in IV steroid-refractory severe acute UC n=111: 55 received CsA, 56 received IFX Co-primary endpoints Colectomy at day 7 in hospital Colectomy at day 98 Laharie D, et al. To be presented at DDW 2011; May 9, 2011;Chicago, IL. Abstract

10 CYSIF: Primary Objectives = Treatment Failure at Day 7 100% 80% Difference Cys vs. IFX: -0.3% (95%CI: to 12.8%) 85.4% 85.7% p= % 40% 20% 0% Cys (n=55) IFX (n=56) Response: Lichtiger score < 10 and decrease 3 points as compared to baseline CYSIF: Primary Objectives = Treatment Failure at Day % Difference Cys vs. IFX failure rates: -6.4% (95%CI: to 12.0%) 80% 60% 60% p= % 40% 20% 0% Cys (n=55) IFX (n=56) 10

11 CSA vs Infliximab: Time to Colectomy Co olectomy-free survi ival p=0.66 Colectomy rate Cys: 18 ± 5% IFX: 21± 5% Cys IFX Days since randomization % of patients at risk Acute Salvage With CsA After IFX Failure and Vice Versa: Mt. Sinai Experience Remission Response Patients (%) % 20% 33% 23% 0 IFX Salvage* (n=10) CSA Salvage* (n=9) *Acute salvage therapy defined as having received the alternate drug within 4 weeks of discontinuing the first agent. Maser EA, et al. Clin Gastroenterol Hepatol 2008;6:

12 Is it Safe to Use Cyclosporine After Infliximab Failure (Within 1 Month) and Vice-Versa Serious Adverse Event Total = 16% (3/19) Other Immune Suppression Drug Sequence Medication Interval Death; gram negative sepsis Azathioprine, Prednisone IFX-Salvage 1 day Pancreatitis followed by Enterococcus, and Klebsiella bacteremia None CSA-Salvage 4 weeks Herpes Esophagitis Prednisone taper (20 mg) CSA-Salvage 5 days Maser EA, et al. Clin Gastroenterol Hepatol 2008;6:1112. Acute Salvage With CsA After IFX Failure and Vice Versa: GETAID Experience 1 Proportion With hout Colectomy Months Since Second Treatment Number at risk GETAID, Groupe d Etude Therapeutique des Affections Inflammatoires du Tube Digestif Leblanc S, et al. Am J Gastroenterol 2011;106:

13 Anti-TNF treatments in UC: Take Home Messages Mucosal healing leads to reduced colectomy rates Measurement of serum infliximab trough level may guide future infliximab dosing Infliximab as effective as cyclosporine in patients with severe IV steroid-refractory UC Risk of salvage therapy with CSA after infliximab i and vice-versa, associated with significant risk and should be used very judiciously Refining our Management and Incorporating Newer Concepts in UC: Objectives Fine tuning our use of 5-ASA drugs Infliximab: Traditional Uses, Additional Uses and Unknown Uses Approaches to dysplasia diagnosis and management 13

14 5-ASA May Protect Against Dysplasia or CRC in UC Patients Any cancer or dysplasia Study type Author (Year) Number OR (95% CI) Cohort Moody (1996)* 10/0 0.1 ( ) Lashner (1997) 4/ ( ) Lindberg (2001)* 7/ ( ) Case- Control Pinczowski (1994) 102/0 Eaden (2001) 102/0 Rubin (2003) 8/18 Van Staa (2003) 76/0 Bernstein (2003) 11/0 Rutter (2004)* 14/54 Adjusted summary odds ratio P value for homogeneity *Only unadjusted odds ratio reported. Lower Risk Higher Risk 0.4 ( ) 0.5 ( ) 0.3 ( ) 0.5 ( ) 1.2 ( ) 2.1 ( ) 0.51 ( ); P= Reprinted by permission from Macmillan Publishers Ltd: Am J Gastroenterol 100(6): , copyright 2005 ( Reduced Risk of CRC with Thiopurine Use: Results of the CESAME Study Multivariate Analysis Colorectal Cancer of Thiopurine Therapy n SIR 95% CI HR 95% CI IBD, total population 19, Long-standing, extensive IBD (>10 years duration and >50% cumulative colonic extent) 2, (P=0.03) Patients with long-standing extensive colitis who received thiopurine therapy had a 3.5-fold decreased risk of colorectal advanced neoplasia CI, confidence interval; HR, hazard ratio; SIR, standardized incidence ratio Beaugerie L et al. Presented at: Digestive Disease Week, 2009; Chicago, IL; June 1, Abstract

15 Ursodeoxycholic Acid in UC and PSC Cross-sectional study: UDCA decreased prevalence of dysplasia 1 OR 0.18 ( ) P=0.005 Randomized placebo-controlled trial: UDCA vs placebo: dysplasia/cancer 2 RR= ( ) 06 0 P= Tung B, et al. Ann Intern Med 2001;134: Pardi D, et al. Gastroenterology 2003;124: Histological Inflammation Is a Risk for Neoplasia in UC Author (Year) Design Patients Inflammation Rutter (2004) Casecontrol 68 cases 136 controls Risk (OR or HR) Histologic OR 4.69* ( ) Gupta (2007) Cohort 418 patients 65 with any neoplasia 15 with advanced neoplasia Pathology reports: any neoplasia Pathology reports without polypectomy: y any neoplasia HR 1.4 HR 3.0 Rubin (2006) Casecontrol 56 cases 90 controls Average histologic OR 2.8 ( ) *P<0.001 P=0.002 OR, odds ratio; HR, hazard ratio Rutter M, et al. Gastroenterology 2004;126:451. Gupta R, et al. Gastroenterology 2007;133:1099. Rubin D, et al. Gastroenterology 2006;130:A2. Abstract

16 Chromoendoscopy in IBD Without dye spray After dye spray Kiesslich R, et al. Gastroenterology 2003;124: Prospective, Controlled Studies Comparing Chromoendoscopy to White Light: Dysplasia Yield Study # of Patients t Number of Lesions per Patient by Chromo Number of Lesions per Patient by White-Light ht Difference (x-fold) Kiesslich et al (2003) Hurlstone et al (2004) Rutter et al (2004) Kiesslich et al (2007) Marion et al (2008) Neurath M, Kiesslich R. Nature Clinical Practice Gastroenterology & Hepatology 2009;6:

17 Management of Polypoid Dysplasia Patient Population N Mean Follow-Up Outcomes (% patients) Chronic UC or Crohn s colitis % further polyps with dysplastic polyps and no dyplasia in flat mucosa 1 years 0 cancer Chronic UC with adenomalike mass (ALM) 2 months Chronic UC with sporadic adenoma outside area of colitis Non-UC with sporadic adenoma months 58% further adenoma-like DALMS 4% LGD 0 adenocarcinoma 50% further adenomas 0 LGD 0 adenocarcinoma months 39% further adenomas 1. Rubin PH, et al. Gastroenterology 1999;117: Engelsgjerd M, et al. Gastroenterology 1999;117: Management of Polypoid Dysplasia Endoscopic polypectomy (without surgical resection) is adequate treatment for adenoma-like polyps in UC patients. IF: Polypectomy complete The base of the polyp separately biopsied and found to have no dysplasia. There should be no dysplasia elsewhere in the colon. 1. Rubin PH, et al. Gastroenterology 1999;117: Engelsgjerd M, et al. Gastroenterology 1999;117:

18 Dysplasia and CRC Diagnosis and Managment: Take Home Messages Probable chemopreventive benefits of 5-ASA and thiopurines in UC, and ursodeoxycholic acid in UC/PSC Increased chronic inflammation increases dysplasia and CRC risk Chromoendoscopy increases yield of detecting dysplasia compared to white light colonoscopy Adenomas that are resected in their entirety, without adjacent or remote dysplasia, can be followed closely without colectomy 18