Sharon Dudley-Brown, PHD, FNP-BC, FAANAssistant ProfessorJohns Hopkins UniversityBaltimore, MDsdudley2@jhmi.edu

Challenges in IBD: The Post-Op IBD Patient: Preventing

Pouchitis & Recurrence

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, 2010– 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 Disease1 Ulcerative Colitis2

1-Year Surgery

Incidence (95% CI)

5-Year Surgery

Incidence (95% CI)

10-Year Surgery

Incidence (95% CI)

1-Year Surgery

Incidence (95% CI)

5-Year Surgery

Incidence (95% CI)

10-Year Surgery

Incidence (95% CI)

Midpoint Year of Study Before 1990

37.76(30.86-46.20)

48.96(37.14-64.53)

60.45(50.16-72.86)

9.39% (8.37-10.53%)

15.14% (10.26-22.34%)

23.04% (18.76-28.31%)

Midpoint Year of Study Between 1990-2000

15.13(11.62-19.69)

28.97(25.23-33.26)

40.07(32.65-49.17)

5.80% (3.79-8.86%)

9.54% (5.87-15.49%)

13.42% (9.01-19.98%)

Midpoint Year of Study After 2000

11.63(8.84-15.29)

20.92(14.90-29.39) N/A 1.79%

(0.46-6.87%) N/A N/A

Meta-regression p-value <0.0001 <0.0001 0.0189 0.07 0.32 0.02

1. Frolkis A, et al. Gastroenterology 2013;145(5):996-1006. 2. Negron et al. presented at DDW 2012.

• In Crohn’s disease, the overall 1-year incidence of surgery is 16.07%, 5-year is 32.27%, and 10-year is 48.28%. P-value of time trend <0.0001 – a significant reduction in 1-year surgery incidence with time.

• Overall, approximately 1 in 5 patients with ulcerative colitis will require surgery within 10 years of diagnosis.

Ulcerative Colitis: Assessment & Prevention of Post-operative Complications

Ulcerative Colitis: Ileo-pouch Anal Anastomosis

Colectomy

J pouch

Cuff/Anal Transition zone

“Complications” of the Ileal Pouch

Shen B, et al. Am J Gastroenterol. 2005;100(12):2796-807.

Surgical/Mechanical

Inflammatory/Infectious Functional Dysplasia/

NeoplasiaSystemic/Metabolic

- Afferent limb syn.- Efferent limb syn.- Strictures- Leaks- Fistulae- Sinuses- Abscess- Adhesions- Re-operation

-Pouchitis-Crohn’s dis.-Cuffitis-Smallbowel bacterialovergrowth-CMV -C. difficile-Polyps

- Irritablepouch syn.

- Pelvic floor dysfunction

- Poor pouch compliance

- Pseudo-obstruction

- Anemia- Osteoporosis- Vitamin B12deficiency

- Malnutrition- Fertility- Sexuality

- Dysplasia- Cancer

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): 120–127; Schmidt CM et al. Ann Surg. 1998 May; 227(5): 654–665; J L Lohmuller et al. Ann Surg. 1990 May; 211(5): 622–629; Fleshner P et al. Clin Gastroenterol Hepatol. 2007 Aug;5(8):952-8; quiz 887; Achkar JP et al.Clin Gastroenterol Hepatol. 2005 Jan;3(1):60-6; Shen B et al. Am J Gastroenterol. 2005 Jan;100(1):93-101; Le Q et al. Inflamm Bowel Dis. 2013; 19(1):30-6.

Endoscopy Is the Most Valuable Tool for the Diagnosis of Pouchitis

-1

0

1

2

3

4

5

6

Poin

ts

HistologyEndoscopySymptom

Pouchitis No Pouchitis

P < 0.001

Shen B, Achkar JP, Lasher BA, et al. Gastroenterology 2002;121(2):261-7

Management of Pouchitis(endoscopic confirmation is preferred)

Modified from Shen B, Clin Gastroenterol Hepatol. 2013;11(12):1538-49.

Management of Pouchitis(endoscopic confirmation is preferred)

Modified from Shen B, Clin Gastroenterol Hepatol. 2013;11(12):1538-49.

Management of Pouchitis(endoscopic confirmation is preferred)

Modified from Shen B, Clin Gastroenterol Hepatol. 2013;11(12):1538-49.

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 100% in placebo group at

9mths1

– 15% relapse vs 94% in placebo group2

– Open label study: 6/31 patients remained on VSL after 8 mths, 23 quit due to relapses and 2 due to adverse effects3

1. Gionchetti et al. Gastroenterology 2000; 19: 305-309. 2. Mimura et al. Gut 2004; 53: 108-14. 3. Shen et al. Aliment Pharacol Ther 2005; 22:721-728.

Can Pouchitis be Prevented?Frequency of Pouchitis with Probiotic Prophylaxis

10%

40%

0

20

40

60

80

100

VSL3 Placebo

Gionchetti P et al. Gastroenterol 2003 May;124(5):1202-9.

N = 206 grams QD x 12 months

N = 20

P < 0.05

% c

ases

with

fla

re-u

p

“Complications” of the Ileal Pouch

Shen B, et al. Am J Gastroenterol. 2005;100(12):2796-807.

Surgical/Mechanical

Inflammatory/Infectious Functional Dysplasia/

NeoplasiaSystemic/Metabolic

- Afferent limb syn.- Efferent limb syn.- Strictures- Leaks- Fistulae- Sinuses- Abscess- Adhesions- Re-operation

-Pouchitis-Crohn’s dis.-Cuffitis-Smallbowel bacterialovergrowth-CMV -C. difficile-Polyps

- Irritablepouch syn.

- Pelvic floor dysfunction

- Poor pouch compliance

- Pseudo-obstruction

- Anemia- Osteoporosis- Vitamin B12deficiency

- Malnutrition- Fertility- Sexuality

- Dysplasia- Cancer

Risk Factors for “Crohn’s” of the Pouch

• Long duration of pouch – Shen et al Clin Gastroenterol Hepatol 2006

• Smoking – Shen et al Clin Gastroenterol Hepatol 2006; Shen et al, Am J

Gastroenterol 2004• Preoperative diagnosis of Indeterminate Colitis

– Delaney et al, Ann of Surg 2002• Female gender in a pediatric population

– Alexander et al, J Pediatr Surg 2003• Expression of ASCA IgA

– Melmed et al, Dis Colon Rectum 2008• Family history of CD

– Melmed et al, Dis Colon Rectum 2008

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 Surgeryin Crohn’s Disease

Mekhjian HS et al. Gastroenterol. 1979;77(4 pt 2):907-913.

Pat

ient

s* (%

)

0

20

40

60

80

100

0 5 10 15 20 25 30 35Years After Onset

Recurrence After Surgery in Crohn’s Disease

Rutgeerts P et al. Gastroenterol. 1990;99(4):956-963.

Years

Pat

ient

s (%

)

Survival without surgery

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Survival without symptoms

Survival withoutlaboratory recurrence

Survival withoutendoscopic lesions

N=89

Disability

Post-op Ileocecectomy is the Perfect Opportunity for Prevention!

DiseasePrevention

Prevention ofSymptomatic Disease

Prevention ofComplications

Prevention ofRelapse

Health SubclinicalInflammation

SymptomaticInflammation Complications

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. 2000;231(1):38-45. Bernell O et al. Br J Surg. 2000;87(12):1697-1701. 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 2011 May;54(5):586-92.

The Neo-TI: The Rutgeerts’ ScoreNote that the neo-terminal ileum is not the anastomosis!

Normal ileal mucosa

Rutgeerts 0

<5 aphthous ulcers

Rutgeerts 1

>5 aphthous ulcers, normal intervening mucosa

Rutgeerts 2

Ulceration without 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 TreatmentsPost-operative pain Limited analgesia, regional

anesthesia when possiblePost-resection “diarrhesis” (rapid transit due to absence of obstruction and muscular hypertrophy)

Anti-diarrheals

Bile salts Bile acid sequestrantNarcotic bowel NO narcotics!Bacterial overgrowth antibiotics

Fecal Calprotectin Can Predict Postoperative CD Endoscopic Recurrence

• Prospective study of 136 post-operative CD patients using 318 stool samples (POCER STUDY)

• Using a cut-off of > 100ug/g, fecal calprotectin identifies which patients require colonoscopy and allows 41% of patients to avoid colonoscopy

Fecal Calprotectin Concentration at 6 Months Compared to Rutgeert’s Score

Wright EK, et al. Gastroenterology. 2015 (in press).

Recurrence Rates of Crohn’s Disease in Randomized Placebo Controlled Trials

Vaughn BP and Moss AC. World J Gastroenterol 2014; 20(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 2011;60:553-562

0

10

20

30

40

50

60

70

80

90

Endoscopic Recurrence

% p

atie

nts

Infliximab (n=11) Placebo (n=13)

Infliximab vs placebop=0.0006

Regueiro M et al. 2009 Feb;136(2):441-50.e1; quiz 716.

1/11

11/13

Post-operative Endoscopic RecurrenceInfliximab vs. Placebo

Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4.

Two year follow-up of endoscopic recurrence in CD pts treated with IFX

• 24 pts in the original 1 yr trial: 13 randomized to placebo and 11 to IFX

• At completion of trial, pts had a colonoscopy and were offered open-label IFX

• 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

Regueiro M, et al. Clin Gastroenterol Hepatol. 2014;12(9):1494-502.e1

3IFX3IFX

0IFX0IFX

1IFX0IFX

0IFX0IFX

2No Tx0IFX

4No Tx0IFX

2IFX4PBO

2IFX3PBO

0IFX3PBO

2IFX2PBO

0IFX4PBO

0IFX2PBO

Post Trial Score

Post Trial Tx

End Trial Score

Study Group

Two year follow-up of endoscopic recurrence in CD pts treated with IFX

• 24 pts in the original 1 yr trial: 13 randomized to placebo and 11 to IFX

• At completion of trial, pts had a colonoscopy and were offered open-label IFX

• 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

3IFX3IFX

0IFX0IFX

1IFX0IFX

0IFX0IFX

2No Tx0IFX

4No Tx0IFX

2IFX4PBO

2IFX3PBO

0IFX3PBO

2IFX2PBO

0IFX4PBO

0IFX2PBO

Post Trial Score

Post Trial Tx

End Trial Score

Study Group

Regueiro M, et al. Clin Gastroenterol Hepatol. 2014;12(9):1494-502.e1

Infliximab vs Placebo for the prevention of active CD after ileocolonic resection (PREVENT Trial)

• RCT: IFX vs Placebo• 297 patients (IFX n=147; PBO n=150)• Primary endpoint: clinical recurrence up to 76 wks.*

• Trial stopped at wk 104, because primary endpoint not met.

Clinical recurrence= CDAI ≥ 70; Point increase, CDAI ≥ 200; Rutgeerts ≥ i2)

IFX PBO P- ValueClin recurr≤ wk 76

12.9% 20.0% 0.097

Endosc. recurr≤ wk 104

17.7% 25.3% 0.098

Endosc. recurr≤ wk 76

30.6% 60% <0.001

Reguiero et al. Presentation: 749. Monday 5.15-5.30pm – Ballroom A - WCC

Back to Pete….

• Refuses IFX 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 0– MRE- active disease in ileum

• Decides to start IFX

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 2015.

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

Rutgeerts P. Aliment Pharmacol Ther. 2006;24 Suppl 3:29-32. Calabrese E et al. J Crohns Colitis. 2012 Feb 23. Jensen MD et al. Clin Gastroenterol Hepatol. 2011 Feb;9(2):124-9.

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.