Challenges in IBD: The Post-Op IBD Patient: Preventing Pouchitis & Recurrence

Challenges in IBD: The Post-Op IBD Patient: Preventing Pouchitis & Recurrence Sharon Dudley-Brown, PHD, FNP-BC, FAAN Assistant Professor Johns Hopkins University Baltimore, MD sdudley2@jhmi.edu

Disclosures Consultant for: AbbVie Takeda

Learning Objectives At the conclusion of this presentation, learners will: 1. Develop an approach to the pro-active assessment of post-operative recurrence of IBD, including Crohn s disease and ulcerative colitis. 2. Incorporate the emerging understanding regarding pathogenesis of post-operative recurrence into treatment algorithms, and the development of an individualized prevention strategy for their patients. 3. Critically appraise the available information about treatment of post-operative recurrence in IBD.

Case: Pete 21 y.o. presents for second opinion, after a new diagnosis of ileal Crohn s disease, 21 15 cm ileal involvement On no meds Non-smoker PMH negative You discuss biologics; surgery

2 years later.. He returns- worsening symptoms Diarrhea, wt loss, bleeding Still refusing meds? New fistula off TI Finally agrees to surgery Has an uneventful lap IC resection

Indications for Surgery Ulcerative colitis: Medically refractory disease/fulminant disease High grade dysplasia or cancer Hemorrhage/transfusion requirements Perforation Crohn s disease: Obstruction Medically refractory disease Hemorrhage/transfusion requirements High grade dysplasia or cancer Growth delay Fistula/abscess

The Significance and Rate of Post- Operative Recurrence in IBD Ulcerative colitis: Medically refractory disease: End ileostomy no recurrence IPAA risks of pouchitis, cuffitis, pre-pouch ileitis, Crohn s disease Crohn s disease: Disease of the colon and terminal ileum: End ileostomy recurrence in small bowel very low Resection and primary anastomosis recurrence at anastomosis high Disease of the proximal small bowel: Resection and primary anastomosis recurrence at anastomosis probably high (not studied well)

Assessment of Risk of Post-Operative Recurrence Should Occur Pre-operatively Know your patient Discuss the available options Manage medical therapies Communicate with the surgeons Clarify type, extent and severity of disease Discuss plans for immune suppression Be proactive! Institute prevention strategies Smoking cessation for Crohn s

Incidence of First Intestinal Surgery in IBD Crohn s Disease 1 Ulcerative Colitis 2 1-Year Surgery Incidence (95% CI) 5-Year Surgery Incidence (95% CI) 1-Year Surgery Incidence (95% CI) 1-Year Surgery Incidence (95% CI) 5-Year Surgery Incidence (95% CI) 1-Year Surgery Incidence (95% CI) Midpoint Year of Study Before 199 37.76 (3.86-46.2) 48.96 (37.14-64.53) 6.45 (5.16-72.86) 9.39% (8.37-1.53%) 15.14% (1.26-22.34%) 23.4% (18.76-28.31%) Midpoint Year of Study Between 199-2 15.13 (11.62-19.69) 28.97 (25.23-33.26) 4.7 (32.65-49.17) 5.8% (3.79-8.86%) 9.54% (5.87-15.49%) 13.42% (9.1-19.98%) Midpoint Year of Study After 2 11.63 (8.84-15.29) 2.92 (14.9-29.39) N/A 1.79% (.46-6.87%) N/A N/A Meta-regression p-value <.1 <.1.189.7.32.2 In Crohn s disease, the overall 1-year incidence of surgery is 16.7%, 5-year is 32.27%, and 1-year is 48.28%. P-value of time trend <.1 a significant reduction in 1-year surgery incidence with time. Overall, approximately 1 in 5 patients with ulcerative colitis will require surgery within 1 years of diagnosis. 1. Frolkis A, et al. Gastroenterology 213;145(5):996-16. 2. Negron et al. presented at DDW 212.

Ulcerative Colitis: Assessment & Prevention of Post-operative Complications

Ulcerative Colitis: Ileo-pouch Anal Anastomosis Colectomy Cuff/Anal Transition zone J pouch

Complications of the Ileal Pouch Surgical/ Mechanical Inflammatory/ Infectious Functional Dysplasia/ Neoplasia Systemic/ Metabolic - Afferent limb syn. - Efferent limb syn. - Strictures - Leaks - Fistulae - Sinuses - Abscess - Adhesions - Re-operation -Pouchitis -Crohn s dis. -Cuffitis -Small bowel bacterial overgrowth -CMV -C. difficile -Polyps - Irritable pouch syn. - Pelvic floor dysfunction - Poor pouch compliance - Pseudoobstruction - Dysplasia - Cancer - Anemia - Osteoporosis - Vitamin B12 deficiency - Malnutrition - Fertility - Sexuality Shen B, et al. Am J Gastroenterol. 25;1(12):2796-87.

Risk Factors for Pouchitis Extensive UC Backwash ileitis Primary sclerosing cholangitis p-anca NOD2/ IL-1 receptor antagonist polymorphisms Ex-smoker NSAIDs Arthralgias Family history of Crohn s disease Fazio VW et al. Ann Surg. 1995 August; 222(2): 12 127; Schmidt CM et al. Ann Surg. 1998 May; 227(5): 654 665; J L Lohmuller et al. Ann Surg. 199 May; 211(5): 622 629; Fleshner P et al. Clin Gastroenterol Hepatol. 27 Aug;5(8):952-8; quiz 887; Achkar JP et al.clin Gastroenterol Hepatol. 25 Jan;3(1):6-6; Shen B et al. Am J Gastroenterol. 25 Jan;1(1):93-11; Le Q et al. Inflamm Bowel Dis. 213; 19(1):3-6.

Endoscopy Is the Most Valuable Tool for the Diagnosis of Pouchitis 6 5 P <.1 4 Points 3 2 1-1 Symptom Endoscopy Histology Pouchitis No Pouchitis Shen B, Achkar JP, Lasher BA, et al. Gastroenterology 22;121(2):261-7

Management of Pouchitis (endoscopic confirmation is preferred) Modified from Shen B, Clin Gastroenterol Hepatol. 213;11(12):1538-49.

Management of Pouchitis (endoscopic confirmation is preferred) Modified from Shen B, Clin Gastroenterol Hepatol. 213;11(12):1538-49.

Management of Pouchitis (endoscopic confirmation is preferred) Modified from Shen B, Clin Gastroenterol Hepatol. 213;11(12):1538-49.

1. Gionchetti et al. Gastroenterology 2; 19: 35-39. 2. Mimura et al. Gut 24; 53: 18-14. 3. Shen et al. Aliment Pharacol Ther 25; 22:721-728. VSL#3 and Pouchitis VSL#3 is a mixture of Lactobacilli, Bifidobacteria, and Streptrococci strains Maintenance of remission of pouches with VSL#3 15% relapse vs 1% in placebo group at 9mths 1 15% relapse vs 94% in placebo group 2 Open label study: 6/31 patients remained on VSL after 8 mths, 23 quit due to relapses and 2 due to adverse effects 3

Can Pouchitis be Prevented? Frequency of Pouchitis with Probiotic Prophylaxis 1 8 % cases with flare-up 6 4 2 1% P <.5 4% VSL3 Placebo N = 2 6 grams QD x 12 months N = 2 Gionchetti P et al. Gastroenterol 23 May;124(5):122-9.

Complications of the Ileal Pouch Surgical/ Mechanical Inflammatory/ Infectious Functional Dysplasia/ Neoplasia Systemic/ Metabolic - Afferent limb syn. - Efferent limb syn. - Strictures - Leaks - Fistulae - Sinuses - Abscess - Adhesions - Re-operation -Pouchitis -Crohn s dis. -Cuffitis -Small bowel bacterial overgrowth -CMV -C. difficile -Polyps - Irritable pouch syn. - Pelvic floor dysfunction - Poor pouch compliance - Pseudoobstruction - Dysplasia - Cancer - Anemia - Osteoporosis - Vitamin B12 deficiency - Malnutrition - Fertility - Sexuality Shen B, et al. Am J Gastroenterol. 25;1(12):2796-87.

Risk Factors for Crohn s of the Pouch Long duration of pouch Shen et al Clin Gastroenterol Hepatol 26 Smoking Shen et al Clin Gastroenterol Hepatol 26; Shen et al, Am J Gastroenterol 24 Preoperative diagnosis of Indeterminate Colitis Delaney et al, Ann of Surg 22 Female gender in a pediatric population Alexander et al, J Pediatr Surg 23 Expression of ASCA IgA Melmed et al, Dis Colon Rectum 28 Family history of CD Melmed et al, Dis Colon Rectum 28

Crohn s Disease

The Challenges of Surgery in Crohn s Disease It is still required It is often done when all else has failed - but should be embraced as an effective treatment option earlier Ongoing issues and concerns Issues with peri-operative immune suppression Issues with misinterpretation of failure of medical therapy Distinction between fibrostenosis and true medically refractory disease

Cumulative Probability of Surgery in Crohn s Disease 1 8 Patients* (%) 6 4 2 5 1 15 2 25 3 35 Years After Onset Mekhjian HS et al. Gastroenterol. 1979;77(4 pt 2):97-913.

Recurrence After Surgery in Crohn s Disease 1 N=89 8 Survival without surgery Patients (%) 6 4 Survival without laboratory recurrence Survival without symptoms 2 Survival without endoscopic lesions 1 2 3 4 5 6 7 8 Years Rutgeerts P et al. Gastroenterol. 199;99(4):956-963.

Post-op Ileocecectomy is the Perfect Opportunity for Prevention! Health Subclinical Inflammation Symptomatic Inflammation Complications Disability Disease Prevention Prevention of Complications Prevention of Symptomatic Disease Prevention of Relapse

Risk Stratification for Recurrence in Post-operative Crohn s disease Smoking Perforating-type of disease Small bowel disease Ileocolonic disease Perianal fistulas Duration of disease Age? Clear margins? Length of resection?type of anastomosis Greenstein AJ et al. Gut. 1988;29(5):588-592. Bernell O et al. Ann Surg. 2;231(1):38-45. Bernell O et al. Br J Surg. 2;87(12):1697-171. D'Haens GR et al. Gut. 1995;36(5):715-717. Lautenbach E et al. Gastroenterol.1998;115(2):259-267. Moskovitz D et al. Int J Colorectal Dis. 1999;14(4-5):224-226. Kono T et al. Dis Colon Rectum 211 May;54(5):586-92.

The Neo-TI: The Rutgeerts Score Note that the neo-terminal ileum is not the anastomosis! Rutgeerts Rutgeerts 1 Rutgeerts 2 Normal ileal mucosa Ulceration without normal intervening mucosa <5 aphthous ulcers >5 aphthous ulcers, normal intervening mucosa Severe ulceration with nodules, cobblestoning, or stricture Rutgeerts 3 Rutgeerts 4

Symptoms after Crohn s Surgery are Not Always Inflammatory! Symptom/Cause Treatments Post-operative pain Post-resection diarrhesis (rapid transit due to absence of obstruction and muscular hypertrophy) Bile salts Narcotic bowel Bacterial overgrowth Limited analgesia, regional anesthesia when possible Anti-diarrheals Bile acid sequestrant NO narcotics! antibiotics

Fecal Calprotectin Can Predict Postoperative CD Endoscopic Recurrence Prospective study of 136 post-operative CD patients using 318 stool samples (POCER STUDY) Fecal Calprotectin Concentration at 6 Months Compared to Rutgeert s Score Using a cut-off of > 1ug/g, fecal calprotectin identifies which patients require colonoscopy and allows 41% of patients to avoid colonoscopy Wright EK, et al. Gastroenterology. 215 (in press).

Recurrence Rates of Crohn s Disease in Randomized Placebo Controlled Trials Vaughn BP and Moss AC. World J Gastroenterol 214; 2(5); 1147-54.

Role of Bacteria in Post-op Recurrence in Crohn s Disease Unknown Possibilities Loss of the ileocecal valve exposes the neo-terminal ileum to colonic bacteria Bacteria associated with post-op recurrence may have increased adherence and penetrance Evidence Diversion leads to durable remission Antibiotics studied to prevent recurrence Probiotics? Ahmed T et al. Gut 211;6:553-562

Post-operative Endoscopic Recurrence Infliximab vs. Placebo % patients 9 8 7 6 5 4 3 2 1 Regueiro M et al. 29 Feb;136(2):441-5.e1; quiz 716. Infliximab (n=11) Infliximab vs placebo p=.6 1/11 11/13 Endoscopic Recurrence Placebo (n=13) Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.

Two year follow-up of endoscopic recurrence in CD pts treated with Study End Trial Post Trial Post Trial 24 pts in the original 1 yr trial: 13 randomized to placebo and 11 to Group PBO PBO Score 2 4 Tx Score At completion of trial, pts had a colonoscopy and were offered open-label PBO PBO PBO 2 3 3 2 2 Repeat colonoscopy was performed 1 yr later Data available on n=12 with 1 yr of f/u and colonoscopy after trial, and 2 yrs after surgery PBO 4 No Tx No Tx 2 4 2 1 3 3 Regueiro M, et al. Clin Gastroenterol Hepatol. 214;12(9):1494-52.e1

Two year follow-up of endoscopic recurrence in CD pts treated with Study End Trial Post Trial Post Trial 24 pts in the original 1 yr trial: 13 randomized to placebo and 11 to At completion of trial, pts had a colonoscopy and were offered open-label Repeat colonoscopy was performed 1 yr later Data available on n=12 with 1 yr of f/u and colonoscopy after trial, and 2 yrs after surgery Group PBO PBO PBO PBO PBO PBO Score 2 4 2 3 3 4 Tx No Tx No Tx Score 2 2 2 4 2 1 3 3 Regueiro M, et al. Clin Gastroenterol Hepatol. 214;12(9):1494-52.e1

Infliximab vs Placebo for the prevention of active CD after ileocolonic resection (PREVENT Trial) RCT: vs Placebo 297 patients ( n=147; PBO n=15) Primary endpoint: clinical recurrence up to 76 wks.* Clin recurr wk 76 Endosc. recurr wk 14 Endosc. recurr wk 76 PBO P- Value 12.9% 2.%.97 17.7% 25.3%.98 3.6% 6% <.1 Trial stopped at wk 14, because primary endpoint not met. Clinical recurrence= CDAI 7; Point increase, CDAI 2; Rutgeerts i2) Reguiero et al. Presentation: 749. Monday 5.15-5.3pm Ballroom A - WCC

Back to Pete. Refuses post-op You tell him to return to see you 3 months post-op for colonoscopy He calls you in 2 months Fevers, weight loss, diarrhea Colonoscopy- Rutgeerts MRE- active disease in ileum Decides to start

An Updated Algorithm for Prevention of Post-Op Recurrence in Crohn s Christensen B, Rubin DT. Medical prophylaxis of recurrent Crohn s disease. Ed Fichera A, Krane M. in press 215.

Rutgeerts P. Aliment Pharmacol Ther. 26;24 Suppl 3:29-32. Calabrese E et al. J Crohns Colitis. 212 Feb 23. Jensen MD et al. Clin Gastroenterol Hepatol. 211 Feb;9(2):124-9. What to do in Follow-up after 6 Months? Clinical follow-up only? Repeat colonoscopy in 6 months or 12 months? Less invasive disease monitoring? Fecal calprotectin MR enterography Ultrasound Capsule endoscopy

Summary: The Post-Op IBD Patient: Preventing Pouchitis and Recurrence Embrace surgery as an appropriate treatment option at the right time. Understand your patient s risks for complications or recurrence. Weigh risks and benefits of long-term treatment based on risks of disease recurrence. Employ preventive strategies: Stratify follow-up based on risk- don t wait for symptoms! Perform colonoscopy/pouchoscopy when treatment options will be adjusted because of the findings. In Crohn s disease, treat to prevent- timing does matter! Post-operative prevention in UC is less well-defined, but early intervention and confirmation of inflammation is also essential.