Which is the Safest Strategy to Treat Moderate to Severe IBD?

Which is the Safest Strategy to Treat Moderate to Severe IBD? David G. Binion, M.D. Co-Director, Inflammatory Bowel Disease Center Director, Translational Inflammatory Bowel Disease Research Visiting Professor of Medicine Division of Gastroenterology, Hepatology and Nutrition University of Pittsburgh School of Medicine UPMC Presbyterian Hospital Pittsburgh, PA, USA

Disclosure Grant Support National Institutes of Health Crohn s and Colitis Foundation of America Centocor Elan Biogen Proctor and Gamble Honoraria/consulting Centocor, Prometheus Laboratories, Abbott laboratories, UCB Pharma, Elan Biogen Off label discussion of Drugs

What is the Most Effective Strategy for Moderate to Severe IBD? Outline Heterogeneity of IBD subgroups Confounding issues infections, adverse drug reactions and strictures Personalized medicine for specific levels of disease severity

IBD 2010 More effective drugs are available for IBD at this time than ever before IBD patients are still being admitted to the hospital higher numbers than ever before Why? - 1990 2003 annual hospitalization rates for IBD (Nationwide inpatient sample) - Crohn s disease rose from 9.3 to 17.1 / 100,000 (p=0.0002) - UC rose from 8.2 to 12.4 / 100,000 (p=0.06) What is underlying severe/refractory IBD and this increase in hospitalizations? Bewtra M, et al. Clin Gastroenterol Hepatol. 2007;5:597-601.

Patients With UC (N=1161) UC: Disease Severity at Presentation 100% 80% Fulminant Disease (9%) 60% 40% Moderate-to-High Activity (71%) 20% 0% Low Activity (20%) Disease Activity Copenhagen County, Denmark, 1962 to 1987 Langholz EP et al. Scand J Gastroenterol. 1991;26:1247

Colectomy Rate (%) UC Natural History Colectomy Rate Over Time 40% 30% 31% 20% 23% 10% 10% 0% 0 5 10 15 20 Hendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163

C. difficile: Changing Spectrum of Clinical Disease Discharges per 100,000 population In the past: C. difficile linked to antibiotic use. Most cases treated successfully with metronidazole Doubling of C. difficile associated disease between 1996-2003 500,000 cases in US annually 70 60 Any diagnosis Primary 15,000 deaths in US annually 50 Diminished therapeutic response to metronidazole (50% failure rate with initial course of treatment) Increasing impact on IBD patients reported 40 30 20 10 0 1996 1997 1998 1999 2000 2001 2002 2003 McDonald LC et al. Emerg Infect Dis. 2006;12:409-415. McDonald LC et al. Emerg Infect Dis. 2006;12:409-415. Loo VG et al. N Engl J Med. 2005;353:2442. Year

Clostridium difficile and IBD C. difficile and IBD present in identical fashion ranging from mild diarrhea to fulminant colitis Early studies performed 2 decades ago indicated little overlap between C. difficile and IBD. It concluded No need for routine screening for C. difficile in IBD population Recent studies: Increasing incidence and severity of C. difficile in IBD population C. difficile recently identified to have a significant negative impact on IBD morbidity Kochlar R et al. J Clin Gastroenterol. 1993;16:26-30. Bolton RP et al. Lancet. 1980;1:383-384. Trnka Y et al. Gastroenterology. 1981;80:693-696. Issa M et al. Clin Gastroenterol Hepatol. 2007;5345-351. Rodemann JF et al. Clin Gastroenterol Hepatol. 2007; 5:339-344. Ananthakrishnan A et al. Gut. 2008;57:205-210.

Cases/1000 admissions Increasing Impact of C difficile on IBD 60 50 40 UC** IBD CD* Non-IBD* 30 20 10 0 1998 1999 2000 2001 2002 2003 2004 Year Rodemann JF et al. Clin Gastroenterol Hepatol. 2007;5: 339-44. Meyer AM et al. J Clin Gastroenterol. 2004;38(9): 772-5

Number of Patients Complications: C. difficile-infected Patients With IBD* Number of Patients Hospitalizations Colectomies 30 25 50 40 15% 20 15 10 5 0 30 20 10 0 36% 2004 2005 # of Patients With IBD With C. diff # of Colectomies *Preliminary data. Issa M et al. Clin Gastroenterol Hepatol. 2007;5:345-351

Clostridium difficile in IBD: Morbidity and Mortality Proportion of C. difficile Associated Hospitalizations IBD patients with C. difficile compared with IBD alone: Longer hospital stay Increased hospitalization costs Higher colectomy rates Increased mortality rate 118 IBD C. diff deaths in NIS 2004 (>500 IBD C. diff deaths in U.S. 2004) 40 35 30 25 20 15 10 5 0 UC IBD CD 1998 1999 2000 2001 2002 2003 2004 Year Ananthakrishnan A, et al. Gut. 2008;57:205-210.

Clostridium difficile in IBD: Increasing U.S. Hospitalizations 2004-2007 Proportion C difficile (per 1000 Hospitalizations) 60 50 40 30 20 IBD Crohn s UC All patients 10 0 1998 2004 2007 Year Ananthakrishnan AN et al. Med Clin N Am. 2009.

Number of Cases Decreasing Colectomy Rate Among Hospitalized IBD Patients with C. difficile Number of infections and rate of hospitalization remained constant, but significant decrease in colectomy rate High index of suspicion Use of oral vancomycin superiority over metronidazole Decreased corticosteroid dosing 50 40 30 20 10 0 1999 2000 2001 2002 2003 2004 2005 2006 50% 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% 45.50% 26% Colectomy rate 3.50% 2003 2004 2005 2006 2007 Issa M et al. Clin Gastroenterol Hepatol. 2007;5:345-351.

C. difficile and IBD: Summary Clostridium difficile and IBD Patients with colitis are at increased risk Maintenance immunosuppression correlated with infection (purine analogs, methotrexate) 10% of cases were new IBD presentations Contributes to flare in setting of new and longstanding disease in remission Recommend multiple stool samples for ELISA toxin A, B analysis. 54% of patients detected on first stool sample No prompt response to metronidazole, consider vancomycin p.o. Issa M et al. Clin Gastroenterol Hepatol. 2007;5:345-351.

Hypersensitivity Reactions to IBD Therapy: 5ASA Hypersensitivity 5ASA hypersensitivity - bloody diarrhea and abdominal pain in 4% of patients 5ASA hypersensitivity is partially treated with corticosteroids Diagnostic trial - 5ASA holiday Discontinuation of 5ASA in hospitalized IBD patients IBD polypharmacy is common. Mean number of daily medications for Crohn s disease = 6 Schroeder K, et al. N Engl J Med. 1987;317:1625-1628. Sninsky C, et al. Ann Internal Med. 1991;115:350-355. Hanauer, et al. Ann Internal Med. 1996;124:204-211. Cross RK, et al. Aliment Pharm Therapeutics 2005

Percent of Patients Reasons for Medication Nonadherence in UC 35 30 25 20 15 10 5 0 Forgetful Careless Felt Better Felt Worse Reason for Nonadherence Sewitch MJ, Abrahamowicz M, Barkun A, et al. Am J Gastroenterol 2003

Rates of Early Adverse Reactions in Patients with Autoimmune Hepatitis and Crohn s Disease p = 0.008 5% AUTOIMMUNE HEPATITIS 29% CROHN S DISEASE Adverse Reactions No Adverse Reaction 10% Severe adverse reaction to azathioprine/6mp: Fevers, headache, pancreatitis, respiratory failure, blistering skin lesions Within 4 weeks of initiation JS Bajaj et al. Am J Gastroenterol 2005; 100: 1121-5.

Recommendation for Colectomy Absolute indications for surgery Exsanguinating hemorrhage Frank perforation Documented or strongly suspected carcinoma Other indications for surgery Severe colitis or toxic megacolon unresponsive to maximal intravenous medical therapy Less severe, but medically intractable symptoms or intolerable medication side effects Kornbluth, A, et al. Am J Gastroenterol. 2004;99(7):1371-85.c

Can we Predict who is at Risk for Colectomy in UC? Proportion without Colectomy Risk of colectomy and history of medical hospitalization for UC (n=246; 103 hospitalized) 1.00 0.75 0.50 0.25 0.00 0 10 20 30 40 50 Duration of Disease (in years) Not hospitalized Hospitalized Ananthakrishnan AN, McGinley EM, Binion DG. Inflamm Bowel Dis 2009; 15: 176-81.

Crohn s Disease - Medical Management Algorithm: No Partial Obstruction or Abscess Detected Mild Moderate Severe 5-ASA, Budesonide or antibiotics Corticosteroid taper AZA/6MP/MTX to induce/ maintain remission No unable to taper Corticosteroids Yes Inadequate response to AZA/6MP/MTX breakthrough AZA/6MP/MTX maintenance Surgical patients infliximab adalimumab certolizumab natalizumab

CD: 20% Present with Surgical Disease Obstruction is an End-Stage Complication Probability (%) 100 100 Percent of Patients (%)* 80 60 40 20 80 60 40 20 Mean ± 2 SD 0 0 5 10 15 20 25 30 35 Mekhjian HS et al. Gastroenterology. 1979;77:907-913. *Kaplan-Meier analysis Years After Onset 0 0 D 2 5 8 11 14 17 20 Years Number of events 122 15 7 7 4 8 1 8 2 2 2 3 2 1 26 Munkholm P et al. Gastroenterology. 1993;105:1716 1723.

Cumulative Probability (%) Long-Term Course of Crohn s Disease Probability of remaining free of complications 100 90 80 70 60 50 40 30 20 10 Penetrating Surgical patients Complications of CD inflammation Stricturing 0 0 24 48 72 96 120 144 168 192 216 240 Months N = 2002 patients with Crohn s disease since diagnosis of the disease Cosnes J et al. Inflamm Bowel Dis. 2002;8:244 250

Types of Crohn s Disease Strictures Long stricture Web strictures

Ileal CD Web Stricture Intra-Operative Enteroscopy, and Retained M2A Capsule Endoscope Ileal web stricture

Search for Occult Strictures Intra-Operative Intraluminal Balloon Sizing Otterson et al, Surgery, 136:854-60, 2004.

Crohn s Disease Strictureplasty

Small Bowel Crohn s Disease: How Many Strictures? Neo-terminal Ileum stricture 4 upstream strictures detected by intraluminal balloon sizing

Accuracy of CD Barium Radiography - 118 CD pts 230 strictures by x-ray - 365 strictures by intra-op balloon - 36% of patients had x-ray/surgery discrepancy Single Stricture Correct 52% Single Stricture Incorrect 6% Mutiple Strictures Correct 12% Multiple Strictures Incorrect 30% Otterson et al, Surgery, 136:854-60, 2004.

Reduced Identification of Strictures Amenable to Strictureplasty Resection Strictureplasty* Over-estimate Accurate Under-estimate * P<0.05 Otterson et al, Surgery, 136:854-60, 2004.

Crohn s Disease - Medical Management Algorithm: No Partial Obstruction or Abscess Detected Mild Moderate Severe 5-ASA, Budesonide or antibiotics Corticosteroid taper AZA/6MP/MTX to induce/ maintain remission No unable to taper Corticosteroids Yes Inadequate response to AZA/6MP/MTX breakthrough AZA/6MP/MTX maintenance Surgical patients infliximab adalimumab certolizumab natalizumab

Crohn s Disease: 1960 s Historical Perspective Limited treatment: Sulfasalazine, prednisone. No treatment algorithm, limited options available. Irreversible complications.

Early disease Inflammation Time Late disease Tissue remodeling

Summary and Conclusions - I Acute/severe UC is common Strong suspicion for C.difficile at present time Deterioration with new 5ASA or purine analog consider hypersensitivity adverse reaction Infliximab in outpatient or early inpatient setting

Summary and Conclusions - II Occult strictures are found in 1/3 of small bowel CD patients undergoing surgery Post-operative immunodulator/biologic therapy should be considered in CD patients with severe disease (rapid abdominal reoperation cohort) Personalized medicine minimal effective therapy to control inflammation, including postoperative disease