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Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review) Holubar SD, Cima RR, Sandborn WJ, Pardi DS This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 6 http://www.thecochranelibrary.com Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review) Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Page 1: Treatment and prevention of pouchitis after ileal pouch ...

Treatment and prevention of pouchitis after ileal pouch-anal

anastomosis for chronic ulcerative colitis (Review)

Holubar SD, Cima RR, Sandborn WJ, Pardi DS

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2010, Issue 6

http://www.thecochranelibrary.com

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Page 2: Treatment and prevention of pouchitis after ileal pouch ...

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

12DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

27DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Acute Pouchitis, Outcome 1 Ciprofloxacin vs. Metronidazole: Achieved Remission (PDAI

<7). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.2. Comparison 1 Acute Pouchitis, Outcome 2 Budesonide enema vs. Metronidazole: Achieved Remission (PDAI

<7). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Analysis 1.3. Comparison 1 Acute Pouchitis, Outcome 3 Rifaximin vs. Placebo: Achieved Remission (PDAI <7). . . 29

Analysis 1.4. Comparison 1 Acute Pouchitis, Outcome 4 Lactobacillus GG vs. Placebo: Improved (PDAI reduction ≥ 3). 29

Analysis 2.1. Comparison 2 Chronic Pouchitis, Outcome 1 Glutamine suppositories vs. Butyrate suppositories: Achieved

Remission (no recurrence of symptoms). . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 2.2. Comparison 2 Chronic Pouchitis, Outcome 2 Bismuth Carbomer Foam Enemas vs. Placebo: Improved

(PDAI reduction ≥ 3). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Analysis 2.3. Comparison 2 Chronic Pouchitis, Outcome 3 VSL#3 vs. Placebo: Relapse of Pouchitis (PDAI increase ≥

2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Analysis 3.1. Comparison 3 Prevention of Pouchitis, Outcome 1 VSL#3 vs. Placebo: No Episodes of Acute Pouchitis (PDAI

≥ 7). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Analysis 3.2. Comparison 3 Prevention of Pouchitis, Outcome 2 VSL#3 vs. No Treatment: No Episodes of Acute Pouchitis

(PDAI ≥ 7). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Analysis 3.3. Comparison 3 Prevention of Pouchitis, Outcome 3 Allopurinol vs. Placebo: No Episodes of Pouchitis (clinical

diagnosis). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

32WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

33SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iTreatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Treatment and prevention of pouchitis after ileal pouch-analanastomosis for chronic ulcerative colitis

Stefan D Holubar2, Robert R Cima2, William J Sandborn1 , Darrell S Pardi1

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA. 2 Division of Colon and Rectal Surgery, Department

of Surgery, Mayo Clinic, Rochester, MN, USA

Contact address: Darrell S Pardi, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN,

55905, USA. [email protected].

Editorial group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 6, 2010.

Review content assessed as up-to-date: 4 October 2009.

Citation: Holubar SD, Cima RR, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal

anastomosis for chronic ulcerative colitis. Cochrane Database of Systematic Reviews 2010, Issue 6. Art. No.: CD001176. DOI:

10.1002/14651858.CD001176.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

A B S T R A C T

Background

Pouchitis may occur following ileal pouch-anal anastomosis for chronic ulcerative colitis in approximately 30% of patients.

Objectives

The primary objective was to determine the efficacy of medical therapies for pouchitis (including antibiotic, probiotic, and other agents)

as substantiated by data from randomized controlled trials (RCTs).

Search strategy

A search for RCTs from 1966 to October 2009 was performed using the MEDLINE, Cochrane Library, EMBASE, Web of Science,

and Scopus databases.

Selection criteria

Randomized controlled treatment or prevention trials of adult patients who underwent ileal pouch-anal anastomosis for ulcerative

colitis who subsequently developed pouchitis or were at risk for pouchitis were considered for inclusion.

Data collection and analysis

Extracted data were converted to 2X2 tables and then synthesized in to a summary statistic using the Peto odds ratio (OR) and [95%

confidence intervals], or weighted mean difference (WMD), using RevMan-5 for Mac OS 10.6.

Main results

Eleven RCTs fulfilled the inclusion criteria and were included in the review. The efficacy of 10 different pharmacologic agents was

assessed. For the treatment of acute pouchitis (4 RCTS, 5 agents), ciprofloxacin was more effective at inducing remission than

metronidazole. Neither rifaximin nor lactobacillus GG were more effective than placebo, while budesonide enemas and metronidazole

were similarly effective, for inducing remission of acute pouchitis. For the treatment and maintenance of remission of chronic pouchitis

(4 RCTs, 4 agents), glutamine suppositories were not more effective than butyrate suppositories, and bismuth carbomer foam enemas

were not more effective than placebo, while VSL#3 was more effective than placebo in maintaining remission of chronic pouchitis in

1Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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patients with chronic pouchitis who achieved remission with antibiotics. For the prevention of pouchitis (3 RCTs, 2 agents), in one

study VSL#3 was more effective than placebo while in another study VSL#3 was not more effective than no treatment. Allopurinol

was not more effective than placebo, while inulin was more effective than placebo but the results were not clinically significant.

Authors’ conclusions

For acute pouchitis, ciprofloxacin was more effective than metronidazole, while budesonide enemas and metronidazole were similarly

effective. For chronic pouchitis, VSL#3 was more effective than placebo. For the prevention of pouchitis, VSL#3 was more effective

than placebo. Larger RCTs are needed to determine the optimal agent(s) for the treatment and prevention of pouchitis.

P L A I N L A N G U A G E S U M M A R Y

Several antibiotic agents, including metronidazole, ciprofloxacin, and rifaximin, as well as oral probiotics, may be effective

treatments for pouchitis.

Some patients with ulcerative colitis have their colon and rectum removed with construction of a reservoir or pouch (made from a loop

of small intestine) to serve in place of the rectum. This is known as an ileal pouch-anal anastomosis (IPAA) surgery. Pouchitis is acute

inflammation of the surgically constructed pouch which may cause diarrhea and other problems. The exact cause of pouchitis is not

known, but it may be caused by an imbalance in bacteria (similar to an infection) and can be treated by antibiotics, probiotics (bacteria

important for the health of the bowel), or other agents that may reduce or prevent inflammation. Metronidazole and Ciprofloxacin

(two antibiotics), budesonide enemas (a topical steroid that may decrease inflammation), and oral probiotic therapy with VSL#3 all

appear to be effective therapies for acute and/or chronic pouchitis. Current evidence does not support the use of lactobacillus GG (a

different probiotic), bismuth (a metal that may be useful in some diarrheal disorders), butyrate and glutamine (two nutrients required

by the bowel), allopurinol (a gout medication which may decrease inflammation), or inulin (a non-absorbable sugar which may decrease

inflammation). So far the research performed has generally consisted of small studies that were not reproduced, so more research is

needed to determine which of these different medications are best for treatment of pouchitis.

B A C K G R O U N D

Pouchitis is an idiopathic chronic inflammatory disease that may

occur in the ileal pouch after restorative proctocolectomy with ileal

pouch-anal anastomosis (IPAA) or Kock pouch (Sandborn 1994a).

Although pouchitis can occur after construction of pouches for

either chronic ulcerative colitis or familial adenomatous polypo-

sis, pouchitis occurs much less frequently in the latter, evidence

that pouchitis is less related to the structure of the pouch, but

is a function of the patients’ underlying immune dysregulation

interacting with the pouch. The diagnosis of pouchitis is sug-

gested by variable clinical symptoms including increased stool fre-

quency, rectal bleeding, abdominal cramping, fecal urgency and

tenesmus, incontinence, and fever. A clinical diagnosis should

ideally be confirmed by endoscopy and mucosal biopsy of the

pouch. Endoscopic examination shows inflammatory changes that

may include mucosal edema, granularity, contact bleeding, loss

of vascular pattern, hemorrhage, and ulceration (Di Febo 1990;

Moskowitz 1986). Histologic examination shows acute inflam-

mation, including neutrophil infiltration and mucosal ulceration

superimposed on a background of chronic inflammation includ-

ing villous atrophy, crypt hyperplasia, and chronic inflammatory

cell infiltration (Moskowitz 1986; Shepherd 1987). Patients with

pouchitis can be classified according to disease activity and symp-

tom duration (Sandborn 1997; Pardi 2009). Disease activity can

be classified as: remission (no active pouchitis); mild-to-moder-

ately active (increased stool frequency, urgency, infrequent incon-

tinence); or severely active (hospitalization for dehydration, fre-

quent incontinence). Symptom duration can be classified as: acute

(≤ 4 weeks); or chronic (> 4 weeks). The Pouchitis Disease Ac-

tivity Index (PDAI) is a 19 point index of pouchitis activity based

on both clinical symptoms and endoscopic and histologic findings

(Sandborn 1994b). Active pouchitis is defined as a PDAI ≥ 7 and

remission is defined as a PDAI < 7. Clinical response to treatment

can also be quantified by reduction in the PDAI.

At the time of the original Cochrane review of this topic (Sandborn

1998), pouchitis was a relatively new disease; criteria for diagno-

sis, classification, and measurement of disease activity had only

recently been proposed and adopted. At that time, the previous

lack of consensus on these issues had hampered the design and

2Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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conduct of randomized, double-blind, placebo-controlled trials,

and as a result the medical therapy for pouchitis was largely em-

piric. The medical therapies that had been reported to be of ben-

efit in uncontrolled trials include metronidazole, ciprofloxacin

and other quinolones, amoxicillin/clavulanic acid, erythromycin,

tetracycline, mesalamine enemas, sulfasalazine, oral mesalamine,

conventional corticosteroid enemas, budesonide enemas, oral cor-

ticosteroids, cyclosporine enemas, azathioprine, short chain fatty

acid (SCFA) enemas or suppositories, allopurinol, bismuth car-

bomer enemas, and bismuth subsalicylate (Sandborn 1994a). At

the time of the previous review, only four small placebo-controlled

trials have been performed, evaluating treatment with metron-

idazole [(Madden 1994) this study has been excluded from the

present review as described below), oral probiotic bacteria (VSL#3)

(Gionchetti 2000), bismuth carbomer enemas (Tremaine 1997),

and glutamine versus butyrate suppositories (Wischmeyer 1993).

Since then, an additional 9 randomized controlled trials have

been performed, including 4 studies of treatments for acute pou-

chitis: ciprofloxacin versus metronidazole (Shen 2001), budes-

onide versus metronidazole (Sambuelli 2002), rifaximin versus

placebo (Isaacs 2007), Lactobacillus GG versus placebo (Kuisma

2003); 1 new study of VSL#3 versus placebo for chronic pouchitis

(Mimura 2004); and 3 studies of pouchitis prevention: VSL#3

versus placebo and VSL#3 versus no treatment (Gionchetti 2003;

Pronio 2008), allopurinol versus placebo (Joelsson 2001); a study

of inulin versus placebo (Welters 2002) was excluded as described

below. This updated Cochrane review will examine the results

from a total of 11 randomized controlled trials to determine which

of the currently utilized empiric medical therapies for pouchitis

can be substantiated with valid data from controlled trials.

O B J E C T I V E S

The primary objective was to determine the efficacy of various oral

and topical (per rectum) medical therapies (including antibiotics,

probiotics, and modulators of inflammation) for the treatment of

acute pouchitis, chronic pouchitis, and the prevention of pouchitis

as assessed by randomized controlled clinical trials.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomized, controlled trials were considered for inclusion.

Study designs could include parallel arm placebo-controlled tri-

als, crossover placebo-controlled trials, and trials comparing two

active agents. Studies which reported duplicate results were ex-

cluded, as was a single patient “n-of-1” placebo-controlled trial.

In addition a cross-over trial of oral metronidazole 400 mg three

times daily (Madden 1994) and a cross-over trial of oral inulin

24 g daily (Welters 2002) were excluded because data were not

available before the first cross-over.

Types of participants

Adult patients (age ≥ 18 years) with pouchitis variably defined by

1) solely clinical criteria; 2) clinical criteria in combination with

endoscopic and histologic criteria; or 3) the PDAI. Pouchitis was

categorized as active (defined clinically as the presence of mild-to-

severe symptoms or by a PDAI ≥ 7) or in remission (absence of

symptoms or by a PDAI < 7). Pouchitis was further categorized

as acute (symptom duration ≤ 4 weeks) or chronic (symptom

duration > 4 weeks).

Types of interventions

The following interventions were considered for inclusion:

1. Oral metronidazole 20 mg/kg/day (Shen 2001), or 500 mg

twice daily (Sambuelli 2002);

2. Oral VSL-3 probiotic bacterial formulation containing 300 bil-

lion bacteria per gram of viable lyophilized bacteria with 4 strains

of lactobacilli (L. acidophilus, L. delbrueckii subspecies Bulgaricus,

L. plantarum, L. casei), 3 strains of Bifidobacterium (B. infantis, B.

longum, B. breve) and 1 strain of Streptococcus salivarius subspecies

Thermophilus; 6 grams per day (Gionchetti 2000), 3 grams per

day (Gionchetti 2003), 3 grams twice daily (Mimura 2004), 3

grams once per day (Pronio 2008);

3. Bismuth carbomer foam enemas containing 513 mg bismuth

citrate (270 mg metallic bismuth) complexed with carbomer (a

synthetic high-molecular weight polymer of acrylic acid cross

linked with poly alkenyl polyether) administered once nightly

(Tremaine 1997);

4. Glutamine suppositories containing 1 gram of L-glutamine in

a polyethylene glycol base administered twice daily (Wischmeyer

1993);

5. Butyrate suppositories containing 40 mmol sodium butyrate in

a polyethylene glycol base administered twice daily (Wischmeyer

1993);

6. Ciprofloxacin 1000 mg/day (Shen 2001);

7. Rifaximin 400 mg orally three times daily (Isaacs 2007);

8. Lactobacillus GG in two gelatine capsules orally twice daily

versus microcrystalline cellulose-only gelatine placebo capsules (

Kuisma 2003);

9. Budesonide enema 2 mg/100 mL at bedtime plus oral placebo

tablets (Sambuelli 2002); and

10. Allopurinol 100 mg twice daily (Joelsson 2001).

3Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Types of outcome measures

The primary outcome was the proportion of patients with clinical

improvement or remission of pouchitis. The exact definition of

improvement and remission varied from study to study limiting

the ability to make comparisons across studies. However, the def-

inition of improvement or remission used in each study was used

for extraction of data from the individual studies for the purposes

of this systematic review.

Search methods for identification of studies

Original review: A computer-assisted search of the on-line bib-

liographic database MEDLINE was carried out so as to identify

potentially relevant studies published between 1966 and Decem-

ber 1997. The Medical Subject Heading (MeSH) terms “Coli-

tis, Ulcerative/su [surgery]” or Ileitis/et [etiology]“ or ”Ileitis/th

[therapy]“ or ”Proctocolectomy, Restorative/ae [adverse events]“,

and key words: ”Antibiotics“ or ”Metronidazole“ or ”Ciproflo-

xacin“ or ”Amoxicillin“ or ”Erythromycin“ or ”Tetracycline“ or

”Sulfasalazine“ or ”Aminosalicylic acids“ or ”Glucocorticoids“ or

”Azathioprine“ or ”6-Mercaptopurine“ or ”Cyclosporine“ or ”Al-

lopurinol“ or “Fatty Acids, Volatile”, or “Butyric Acids” or “Glu-

tamine” or “Probiotic” or “Bismuth” were used to perform searches

of the database. Manual searches of the reference lists from the

potentially relevant studies were performed in order to identify

additional studies that may have been missed using the computer-

assisted search strategy. Proceedings from the American Gastroen-

terological Association, American Society of Colon and Rectal

Surgery, and the British Society of Gastroenterology were also

manually searched from 1965-1997 in order to identify unpub-

lished studies.

The updated review: A computer-assisted search for randomized

controlled trials from 1966 to October 2009 was performed using

the MEDLINE, Cochrane Library, EMBASE, Web of Science,

and Scopus databases. Search terms included “pouchitis”, “remis-

sion induction”, “proctocolectomy, restorative”, “drug therapy”,

“colitis, ulcerative” and “postoperative complication”. This search

was limited to clinical trials (phase 1, 2, 3, or 4) or comparative

studies or meta-analyses or multicenter studies or practice guide-

lines or randomized controlled trial. A text word search was also

employed.

Data collection and analysis

Study Selection:

Potentially relevant articles were reviewed in an independent un-

blinded fashion by two authors (SDH, DSP) to determine if they

met the criteria specified above. The studies were then rated as

being eligible, ineligible, or as having insufficient information to

make a judgment as to eligibility and were then excluded.

Data Collection:

Eligible articles were reviewed in triplicate (SDH, RRC, and WJS)

and the results of the primary research trials were abstracted into

specially designed data extraction forms. The proportion of pa-

tients who had clinical improvement in the active treatment and

control groups of each study was derived from life tables, survival

curves, or where possible, by calculating life tables from the data

provided.

Risk of Bias:

Three authors (SDH, RRC, WJS) independently assessed method-

ological quality, using the Cochrane risk of bias tool as described in

the Cochrane Handbook for Systematic Reviews of Interventions

(Higgins 2008). Briefly, an assessment was made of the method of

allocation generation (i.e. was the allocation sequence adequately

generated?), allocation concealment (i.e. was allocation adequately

concealed?), blinding (i.e. was knowledge of the allocated interven-

tion adequately prevented during the study?), incomplete outcome

data (i.e. were incomplete outcome data adequately addressed?);

and selective outcome reporting (i.e. are reports of the study free of

suggestion of selective outcome reporting?). A judgement of ’Yes’

indicates low risk of bias, ’No’ indicates high risk of bias, and ’Un-

clear’ indicates unclear or unknown risk of bias. Disagreements

were resolved by consensus.

Statistical Analysis:

Data extracted from the original research articles were converted

into individual 2X2 tables (response versus no response X med-

ical therapy versus placebo, or medical therapy versus medical

therapy). All results were tabulated on an intention-to-treat basis

if available; otherwise modified-intention-to-treat or per-protocol

results are reported. Where available, individual 2X2 tables for

strata within studies were also used. The 2X2 tables were synthe-

sized into a summary test statistic using an un-pooled (or pooled

where appropriate) Peto odds ratio and 95% confidence intervals

as described by Cochran and Mantel and Haenszel. A fixed effects

model was used for the pooling of data.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Two hundred and ninety-seven abstracts were reviewed and a total

of 19 RCTs were identified that were considered for inclusion. A

total of 11 trials satisfied the inclusion criteria (Wischmeyer 1993;

Tremaine 1997; Gionchetti 2000; Joelsson 2001; Shen 2001;

Sambuelli 2002; Gionchetti 2003; Kuisma 2003; Mimura 2004;

Isaacs 2007; Pronio 2008). Eight studied were excluded (see table

of excluded studies), including a single patient “n-of-1” trial for

active chronic pouchitis (metronidazole vs. placebo), two random-

ized trials of alicaforsen enema vs. mesalazine enema for ulcerative

4Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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colitis (not pouchitis), a non-randomized sub-study (VSL#3), and

two non-randomized follow-up studies of Cultura (a fermented

milk probiotic), a randomized cross-over trial of metronidazole

and a randomized cross-over trial of inulin both without outcome

data from before the first cross-over.

Risk of bias in included studies

The Cochrane risk of bias tool indicates that the risk of bias was low

for 3 of the 11 included studies (See Figure 1). The risk of bias in

the other studies was high for blinding in 2 studies (open studies)

and allocation concealment in 1 study. Some quality items were

unclear in 10 studies (due to inadequate descriptions of methods

used for sequence generation, allocation concealment and blinding

and possible selective reporting).

5Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Figure 1. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.

6Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Effects of interventions

The eleven included studies had a variety of designs (although

all were randomized controlled trials) and categories of outcomes.

For analysis, these eleven studies were categorized according to

the type of study 1) treatment of acute pouchitis, 2) treatment, or

maintenance of remission, for chronic pouchitis, and 3) prevention

of pouchitis.

1. Treatment of Acute Pouchitis - 4 Studies, 5 agents

Ciprofloxacin versus metronidazole (Figure 2)

Figure 2. Forest plot of comparison: 1 Acute Pouchitis, outcome: 1.1 Ciprofloxacin vs. Metronidazole:

Achieved Remission (PDAI < 7).

Shen 2001 was a randomized, non-blinded, parallel-arm trial of

ciprofloxacin compared to metronidazole for the induction of re-

mission of acute pouchitis. All patients had a PDAI score > 7 at

entry, and there was no statistically significant difference in mean

baseline PDAI scores between groups. A total of 16 patients were

enrolled; 7 patients received ciprofloxacin and 9 received metron-

idazole for two-weeks. After two weeks of therapy, both groups had

significantly lower PDAI scores compared to baseline. Overall 7/7

(100%) of the ciprofloxacin group achieved remission (defined as

PDAI score < 7), compared with 6/9 (67%) of the metronidazole

group (P = 0.008). The Peto odds ratio for induction of remission

by ciprofloxacin compared to metronidazole was 14.39 (95% CI

2.00 to 103.76).

Budesonide enema versus metronidazole (Figure 3)

Figure 3. Forest plot of comparison: 1 Acute Pouchitis, outcome: 1.2 Budesonide enema vs. Metronidazole:

Achieved Remission (PDAI < 7).

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Sambuelli 2002 was a randomized, double-blind, double dummy,

placebo-controlled, parallel-arm trial of budesonide enemas plus

placebo tablets compared to placebo enemas and metronidazole

tablets for the induction of remission of acute pouchitis (Sambuelli

2002). At entry patients had a PDAI score ≥ 7 and no treatment

during the previous month. A total of 26 patients were enrolled; 12

received budesonide enemas plus placebo tablets and 14 received

placebo enema plus metronidazole tablets for 6 weeks. Of note,

the randomization resulted in un-balanced groups with respect to

age (metronidazole group older, P = 0.044). Overall, 7/12 (58%)

of the budesonide group and 7/14 (50%) of the metronidazole

group had a reduction in the PDAI score ≥ 3 (58% versus 50%,

P = 0.67). In addition, 6/12 (50%) in the budesonide group and

6/14 (43%) in the metronidazole achieved remission as defined

by a PDAI < 7 (50% versus 43%, P = 0.72). The Peto odds ratio

for induction of remission of pouchitis by budesonide compared

to metronidazole was 1.32 (95% CI 0.29 to 6.01).

Rifaximin versus placebo (Figure 4)

Figure 4. Forest plot of comparison: 1 Acute Pouchitis, outcome: 1.3 Rifaximin vs. Placebo: Achieved

Remission (PDAI < 7).

Isaacs 2007 was a randomized, double-blind, placebo-controlled,

parallel-arm, multi-center trial of rifaximin tablets compared to

placebo for the induction of remission of acute pouchitis. A total

of 18 patients were enrolled; 8 patients received rifaximin and 10

patients received placebo for 4 weeks. One patient in the placebo

group did not undergo post-treatment evaluation and was there-

fore excluded from the modified intention-to-treat analysis. Clin-

ical remission (defined as a PDAI score < 7) was achieved in 2/8

(25%) patients in the rifaximin group and 0/9 (0%) in the placebo

group (25% vs 0%, P = 0.1). The modified intention-to-treat Peto

odds ratio for induction of remission of pouchitis by rifaximin

compared to placebo was 9.65 (95% CI 0.55 to 169.75); the un-

modified intention-to-treat Peto odds ratio for induction of remis-

sion by rifaximin compared to placebo was 10.92 (95% CI 0.62

to 193.55).

Lactobacillus GG versus placebo (Figure 5)

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Figure 5. Forest plot of comparison: 1 Acute Pouchitis, outcome: 1.4 Lactobacillus GG vs. Placebo:

Improved (PDAI reduction ≥ 3).

Kuisma 2003 was a randomized, double-blind, placebo-con-

trolled, parallel arm of Lactobacillus GG compared to placebo for

inducing clinical response of acute pouchitis. All patients had a pre-

vious history of pouchitis and endoscopic inflammation. Patients

who had received antibiotics within one month were excluded, as

were active chronic pouchitis (intermittent or continuous medical

treatment) or symptoms [fever, bleeding, and increased number of

stools (> 2/day within 1 week)] indicative of an acute exacerbation

of pouchitis. A total of 22 patients were enrolled; 2 patients were

excluded after enrollment for severe endoscopic pouchitis requir-

ing immediate antibiotics. The assigned group of these 2 patients

was not provided; hence only per protocol analysis results were

available. A total of 10 patients received Lactobacillus GG and 10

patients received placebo for 3 months. Clinical response (defined

as a PDAI score reduction of ≥ 3) occurred in 1/10 (10%) patients

in the Lactobacillus group and 0/10 (0%) patients in the placebo

group (10% vs. 0%, P = 0.32). The Peto odds ratio for induction

of remission by Lactobacillus GG compared to placebo was 7.39

(95% CI 0.15 to 372.38).

2. Treatment of Chronic Pouchitis - 4 studies, 4 agents

Glutamine versus Butyrate Suppositories (Figure 6)

Figure 6. Forest plot of comparison: 2 Chronic Pouchitis, outcome: 2.1 Glutamine suppositories vs.

Butyrate suppositories: Achieved Remission (no recurrence of symptoms).

Wischmeyer 1993 was a randomized, double-blind trial of glu-

tamine compared to butyrate suppositories for maintenance of

remission in patients with chronic pouchitis after withdrawal of

other suppressive medical therapy. All patients had chronic pouch-

itis (defined as at least 4 episodes of pouchitis within one year and

the need for suppressive medications for at least 6 of the prior 12

months) and all discontinued suppressive medical therapy 7 days

prior to study entry. At entry, patients could have either active or

remitted pouchitis following the recent withdrawal of suppressive

medical therapy. A total of 19 patients were enrolled into a single

study; 10 received glutamine suppositories and 9 received butyrate

suppositories. The relapse rate was 4/10 (40%) for glutamine and

6/9 (67%) for butyrate. Therefore, the remission rate was 6/10

(60%) for glutamine and 3/9 (33%) for butyrate (60% vs. 33%,

P = 0.26). The Peto odds ratio for maintenance of remission with

glutamine compared to butyrate at 3 weeks was 2.75 (95% CI

0.48 to 15.94).

Bismuth Carbomer Foam Enemas versus placebo (Figure 7)

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Figure 7. Forest plot of comparison: 2 Chronic Pouchitis, outcome: 2.3 Bismuth Carbomer Foam Enemas

vs. Placebo: Improved (PDAI reduction ≥ 3).

Tremaine 1997 was a randomized, double-blind, placebo-con-

trolled, parallel-arm trial of bismuth carbomer enemas for induc-

tion of clinical response in active chronic pouchitis. All patients

had active, chronic pouchitis (defined as a PDAI score ≥ 7 points

and failure or intolerance to treatment with antibiotics and other

medical therapies). A total 40 patients were enrolled; 20 received

bismuth carbomer foam enemas and 20 received placebo. The re-

sponse rate, as measured by a decrease in the PDAI score of ≥ 3

points, was 9/20 (45%) for bismuth carbomer foam enemas and

9/20 (45%) for placebo (P = 1.0). The Peto odds ratio for response

to bismuth carbomer enemas compared to placebo was 1.00 (95%

CI 0.29 to 3.42).

Oral Probiotic Bacteria (2 studies, Figure 8):

Figure 8. Forest plot of comparison: 2 Chronic Pouchitis, outcome: 2.4 VSL#3 vs. Placebo: Relapse of

Pouchitis (PDAI increase ≥ 2).

Gionchetti 2000 was a randomized, double-blind, placebo-con-

trolled, parallel-arm trial of probiotic bacteria (VSL#3) to main-

tain remission in chronic pouchitis. All patients were in remission

(defined as a PDAI score of 0 following open label induction with

antibiotics) and had chronic pouchitis (history of requiring con-

tinuing medical suppressive therapy and recurrence within a few

weeks of discontinuing suppression). In total, 40 patients were

enrolled; 20 received probiotic bacteria and 20 received placebo.

The relapse rate, as measured by an increase ≥ 2 points in the 6

point clinical portion of the PDAI, was 3/20 (15%) for probiotic

therapy compared to 20/20 (100%) for placebo. Therefore, the

rates of maintenance of remission was 17/20 (85%) for probiotic

therapy and 0/20 (0%) for placebo (P < 0.0001).

Mimura 2004 was a randomized, placebo-controlled, multicen-

ter, parallel-arm trial of probiotic bacteria (VSL#3) to maintain

remission in chronic pouchitis. All patients had pouchitis at least

twice in the previous year or requiring continuous antibiotics, as-

sociated with a PDAI ≥ 7, in whom remission was induced by

four weeks of combined metronidazole and ciprofloxacin. Active

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refractory or recurrent pouchitis was defined as a total PDAI score

of >7 and a history of relapsing or persistent pouchitis. A total

of 36 patients were enrolled for 1 year of treatment; 20 patients

received VSL#3 and 16 patients received placebo. Remission at

one year, as defined by a clinical PDAI score ≤ 2 and endoscopic

PDAI ≤ 1, was maintained in 17/20 (85%) in the VSL#3 group

and 1/16 (6%) in the placebo group (P < 0.0001).

The pooled Peto odds ratio for these two studies for the combined

rate of maintenance of remission with probiotic bacteria compared

to placebo (97% versus 3%, P < 0.0001) was 25.39 (95% CI 10.37

to 62.17). The number needed to treat with oral probiotic therapy

to prevent one additional relapse was 2.

3. Prevention of Pouchitis - 3 studies, 2 agents

Oral Probiotic Bacteria (2 studies, Figure 9, Figure 10):

Figure 9. Forest plot of comparison: 3 Prevention of Pouchitis, outcome: 3.1 VSL#3 vs. Placebo: No

Episodes of Acute Pouchitis (PDAI ≥ 7).

Figure 10. Forest plot of comparison: 3 Prevention of Pouchitis, outcome: 3.2 VSL#3 vs. No Treatment: No

Episodes of Acute Pouchitis (PDAI ≥ 7).

Gionchetti 2003 was a randomized, double-blind, placebo-con-

trolled, parallel-arm trial which assessed the efficacy of oral pro-

biotic therapy with VSL#3 for the prevention of pouchitis. All

patients were randomized within one week of ileostomy closure

after IPAA. A total of 40 patients were enrolled for 12 months of

treatment; 2/10 (20%) of the VSL#3 group and 8/20 (40%) of

the placebo group had an episode of pouchitis (no episodes 80%

versus 60%, P = 0.03). The Peto odds ratio for prevention of pou-

chitis by VSL#3 compared with placebo was 4.76 (95% CI 1.16

to 19.56).

Pronio 2008 was a randomized, open-label, parallel-arm trial

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which assessed the efficacy of oral probiotic therapy with VSL#3

compared with no treatment for the prevention of pouchitis. All

patients were taking no medication at entry. Exclusion criteria in-

cluded patients with active pouchitis (PDAI ≥ 7), perianal disease

(including abscess, fissure, stricture, or anal sphincter weakness),

and pregnant or lactating women. A total of 31 patients were en-

rolled for 12 months. A total of 0/16 patients (0%) in the VSL#3

group and 1/12 (8.3%) in the control group developed pouchitis

(no pouchitis 100% versus 92%, P = 0.24). The Peto odds ratio for

prevention of pouchitis by VSL#3 compared with no treatment

was 10.31 (95% CI 0.20 to 541.25).

Allopurinol versus placebo (Figure 11)

Figure 11. Forest plot of comparison: 3 Prevention of Pouchitis, outcome: 3.3 Allopurinol vs. Placebo: No

Episodes of Pouchitis (clinical diagnosis).

Joelsson 2001 was a randomized, double-blind, multi-center,

placebo-controlled, parallel-arm study assessing the efficacy of al-

lopurinol for the prevention of pouchitis. All patients were ran-

domized 1 week after IPAA surgery. A total of 184 patients were

enrolled for 24 months; 94 patients received allopurinol and 90

placebo. Of these patients, 116 (36%) completed the study. At one

year, pouchitis, as defined by a functional score, occurred in 19/

62 (31%) patients in the allopurinol group, and in 15/54 (28%)

of patients in the placebo group (no pouchitis 69% versus 72%, P

= 0.74). A per protocol analysis showed the Peto odds ratio for the

prevention of pouchitis by allopurinol compared to placebo was

0.87 (95% CI 0.39 to 1.94); on an intention-to-treat basis the Peto

odds ratio for the prevention of pouchitis by allopurinol compared

to placebo was 1.10 (95% CI 0.62 to 1.97).

D I S C U S S I O N

The results presented in this review must be interpreted with ex-

treme caution given the small numbers of trials and patients evalu-

ated for any one comparison. For each comparison, the confidence

intervals about the pooled odds ratio were wide. This indicates

a moderate amount of uncertainty in the estimate of the pooled

odds ratio. As an example, in the comparison of oral ciprofloxacin

versus metronidazole, we are 95% confident that the true pooled

odds ratio is between 2.00 and 103.76. This interval describes a

statistically significant benefit in favour of oral ciprofloxacin over

metronidazole, however, the estimate of the therapeutic advantage

of oral ciprofloxacin over metronidazole is imprecise.

Additionally for each comparison, with the exception of VSL#3

for chronic pouchitis, only one trial was eligible. Therefore, the

generalizability and external validity of these results must be ques-

tioned. The reader must exercise clinical judgement, and ensure

the patient populations (those being generalized to, and those in

the trials) are similar before these findings can be implemented

into clinical practice.

Two cross-over studies which were excluded (because of lack of data

prior to cross-over) merit further discussion. Madden 1994 was

a randomized, double-blind, placebo-controlled, crossover trial of

metronidazole for induction of clinical response in active chronic

pouchitis. All patients had active pouchitis (defined as chronic,

recurrent clinical symptoms, > 6 stools/24 hours, and endoscopic

inflammation) at entry. In total 13 patients were enrolled, and 11

patients completed both arms of the crossover trial. The overall

response, as measured by a reduction in stool frequency of at least 3

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stools/24 hours, was 8/11 (73%) for metronidazole compared to 1/

11 (9%) for placebo (P = 0.003). The Peto odds ratio for response

to metronidazole compared to placebo was 12.34 (95% CI 2.34 to

64.94). The number needed to treat with metronidazole to prevent

one additional relapse was 2. Welters 2002 was a randomized,

double-blind, placebo-controlled, cross-over study assessing the

efficacy of inulin for the prevention of pouchitis. Patients with

IPAA for CUC or FAP were included. Patients with a history of

pouchitis were not excluded, none of the included patients had

overt clinical pouchitis at the time of the study, and none were

taking pouchitis-related medications. A total of 20 patients were

enrolled to receive inulin followed by placebo, or placebo followed

by insulin, for 3 weeks each. One patient who started in the placebo

group dropped out due to lactose intolerance. Overall, there was

no difference in pouchitis prevention, as measured by the final

mean PDAI score, which was 1.42 for inulin and 1.66 for the

placebo. However, the modified intention-to-treat weighted mean

difference (MD) in PDAI for the prevention of pouchitis by inulin

compared to placebo was 1.34 (P < 0.001, 95% CI 0.85 to 1.83).

Although this was statistically significant, this difference was not

clinically significant.

Based on the results of this analysis the following conclusions may

be drawn. For the treatment of acute pouchitis ciprofloxacin ap-

pears to be more effective than metronidazole, metronidazole and

budesonide enemas were equally effective, while neither Lacto-

bacillus GG nor Rifaximin were more effective than placebo. For

the treatment of chronic pouchitis VSL#3 was more effective than

placebo in maintaining remission; glutamine suppositories were

not more effective than butyrate suppositories for maintenance of

remission, and bismuth carbomer foam enemas were not more ef-

fective than placebo for induction of remission. For the prevention

of pouchitis VSL#3 was more effective than placebo, but not more

effective than no treatment hence the efficacy of VSL#3 for pre-

vention is questionable. Allopurinol was not more effective than

placebo for prevention of pouchitis.

A U T H O R S ’ C O N C L U S I O N SImplications for practice

After IPAA, the primary function of the terminal ileum changes

from absorption to storage, and bacterial overgrowth occurs with

bacterial concentrations increasing to levels which are interme-

diate between an end ileostomy and the colon (Sandborn 1995;

Shepherd 1989). However, there is no correlation between fecal

bacterial concentrations and histologic changes of acute inflamma-

tion (Sandborn 1995; Shepherd 1989), demonstrating that pou-

chitis is not directly related to the quantity of bacterial overgrowth.

However, anaerobic bacterial overgrowth of the pouch is associ-

ated with transformation of the ileal mucosa to a “colon-like” mor-

phology (villous atrophy, chronic inflammatory cell infiltration)

(Sandborn 1995; Natori 1992). Thus, pouch bacterial overgrowth

may indirectly set the stage for pouchitis to the extent that “colon-

like” ileal mucosa may be more susceptible to a recurrence of UC-

like inflammation. Strategies directed towards reducing fecal con-

centrations of anaerobic bacteria through the use of antibiotics, or

altering the relative balance of anaerobes and other bacteria using

probiotic bacteria therapy, may be useful in treating pouchitis.

Using this rationale, clinicians have empirically treated patients

with antibiotics and have observed that most patients with pou-

chitis experience clinical improvement. In the absence of ade-

quate and well controlled trials, antibiotics have become the de

facto “standard medical therapy” for pouchitis. In the past, the

most commonly used antibiotic for pouchitis was metronidazole

(Sandborn 1994a; Moskowitz 1986; Zuccaro 1989; Lohmuller

1990; Svaninger 1993; Kelly 1983; Boerr 1995; Boerr 1996;

Kmiot 1993; Hurst 1996; Tytgat 1988; Scott 1989; Bonello 1981;

Klein 1983; Knobler 1986). More recently, ciprofloxacin has be-

come the more commonly used antibiotic (Hurst 1996). Amox-

icillin/clavulanic acid, erythromycin, and tetracycline have also

been reported to be of benefit (Scott 1989). Most patients with

pouchitis initially respond to ciprofloxacin at a dose of 500 to

1000 mg/day or metronidazole at doses of 750 to 1500 mg/day.

Symptomatic improvement usually occurs within 1 to 2 days. Pa-

tients with relapsing or continuous pouchitis may require chronic

maintenance ciprofloxacin therapy with doses ranging from 250

mg every 3rd day up to 1000 mg/day. Based on the Sambuelli

2002 study, budesonide enemas and metronidazole appear to have

similar efficacy (58% and 50%). Although the authors of that

study suggested that the enema preparation may be more tolerable

than oral metronidazole, which is known to produce a metallic

taste when it comes in contact with the tongue, many patients pre-

fer oral administration to administration per anus. Nonetheless,

the results of that study suggest that additional study of budes-

onide, whether administered orally or as a suppository, is war-

ranted. There are two uncontrolled reports supporting this con-

clusion (Gionchetti 2007; Chopra 2006).

To a limited extent, this empiric approach to the manipulation

of pouch bacterial flora has been validated by controlled trials

of metronidazole and the oral probiotic formulation VSL#3 in

patients with chronic pouchitis. Madden 1994 reported that the

odds ratio for a decrease in stool frequency following metronida-

zole therapy compared with placebo in patients with active chronic

pouchitis was 12.34 (95% CI 2.34 to 64.94). The single patient

“n-of-1” study of metronidazole for active chronic pouchitis also

suggested benefit (McLeod 1986). However, despite the signifi-

cant decrease in stool frequency, there was no difference between

metronidazole and placebo for changes of endoscopic inflamma-

tion, general well-being, stool blood, and histologic inflammation

(Madden 1994). The pooled odds ratio for maintaining remission

in patients with chronic pouchitis during administration of the

oral probiotic bacteria formulation VSL#3 was 25.39 (95% CI

10.37 - 62.17) (Gionchetti 2000; Mimura 2004). However, when

13Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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examining the efficacy of VSL#3 for prevention of pouchitis, con-

flicting results were obtained, with VSL#3 being more efficacious

than placebo (Gionchetti 2003) but not more efficacious than

no treatment (Pronio 2008). The reason for this discrepancy is

not clear. Thus, while antibiotic and probiotic bacterial therapies

appear to be efficacious, antibiotic selection, dose, and duration

of therapy remain empiric. Ingestion of other lactobacillus-based

formulations (such as Lactobacillus GG) do not appear to be as

effective as VSL#3 probiotic therapy. At the present time, based on

the limited controlled clinical trial data available, it is reasonable

to treat pouchitis with antibiotics and perhaps probiotic bacterial

therapy (at least for chronic pouchitis), but additional controlled

trials are needed to optimize therapeutic recommendations.

In the well-functioning ileal pouch, the bacterial flora produce

SCFAs including acetate, propionate, and butyrate at concentra-

tions similar to those in the colon of healthy controls, and in-

creased compared to stomal SCFA concentrations in ileostomy pa-

tients (Sandborn 1995; Nasmyth 1989). In the colon, SCFAs are

the preferred fuel for colonic epithelial cell metabolism, whereas

in the small bowel, glutamine is the preferred fuel for enterocyte

metabolism. Some (Clausen 1992; Wischmeyer 1993) but not all

(Sandborn 1995) studies have reported that patients with pouch-

itis have significantly lower fecal concentrations of SCFAs than

patients with well-functioning IPAAs, perhaps as a result of dilu-

tion (Clausen 1992). Strategies directed at replacing “nutritional

deficits” of SCFAs or glutamine in the ileal pouch by adminis-

tering SCFA or glutamine enemas or suppositories may be use-

ful in treating pouchitis. However, small uncontrolled studies of

SCFA enemas have, for the most part, shown low overall clin-

ical response rates, suggesting that SCFA enemas are not bene-

ficial for pouchitis (De Silva 1989; Tremaine 1994; den Hoed

1996). This lack of efficacy of SCFA-based therapies is supported

by the Welters 2002 study, which examined the use of inulin, a

sugar which is fermented to SCFA, which was not clinically ef-

fective for the prevention of pouchitis; although it did produce a

statistically significant reduction in the mean PDAI scores (1.34

WMD). Wischmeyer 1993 reported that the pooled odds ratio

for maintenance of remission in patients with chronic pouchitis

by glutamine suppositories compared with butyrate suppositories

was 2.75 (95% CI 0.48 to 15.94). It is not clear from this single

controlled trial whether glutamine and butyrate suppositories are

equally effective or equally ineffective, but considering the low

overall response rates observed during open therapy with SCFA

enemas, it appears that “nutritional replacement” with SCFA, bu-

tyrate, or glutamine is probably not beneficial for pouchitis and

cannot be advocated as standard therapy.

Bismuth has both anti-microbial and anti-diarrheal properties,

and has been useful for the treatment of traveller’s diarrhea and

collagenous colitis. A randomized, double-blind, controlled trial

suggested that bismuth citrate may have efficacy comparable to

mesalamine for the treatment of left-sided UC (Pullan 1993).

Given the proven benefit of bismuth in traveller’s diarrhea, and its

potential benefit in UC and collagenous colitis, therapeutic trials

of bismuth in patients with acute pouchitis seemed reasonable. An

uncontrolled study of bismuth complexed to carbomer suggested

beneficial effects for both inducing and maintaining remission in

patients with chronic pouchitis (Gionchetti 1997) while another

uncontrolled study suggested that bismuth subsalicylate may also

be of benefit in chronic pouchitis (Tremaine 1998). In contrast,

a placebo-controlled trial with the bismuth carbomer formula-

tion in patients with active chronic pouchitis showed no benefit

(Tremaine 1997). It is possible that the xanthan gum placebo in

this study was actually a positive control (Parihar 1997), and an-

other uncontrolled study suggested that bismuth subsalicylate may

be of benefit in chronic pouchitis (Tremaine 1998). Additional

controlled trials using an inactive placebo are needed to determine

with certainty whether or not bismuth is effective for pouchitis.

However, based on the currently available controlled data, bismuth

cannot be advocated as a therapy for pouchitis. Finally, allopuri-

nol (Joelsson 2001) did not appear to be clinically effective for

the prevention of pouchitis. An initial uncontrolled prospective

trial (Levin 1992) indicated that allopurinol, a oxygen-related free

radical scavenger, may be efficacious in decreasing inflammation

hypothesized to be related to chronic ischemia and subsequent free

radical damage; however the results of the Joelsson 2001 trial, the

largest randomized trial of any treatment for any form of pouchitis

(184 patients randomized) have refuted this hypothesis.

Implications for research

The medical therapy of pouchitis remains largely empiric, and

additional multicenter, randomized, double-blind, placebo-con-

trolled, dose-ranging trials of antibiotics, probiotic bacteria, and

other therapies known to be beneficial in UC such as mesalamine

and corticosteroids are needed. Trials of VSL#3 compared to ci-

profloxacin or metronidazole for the treatment and maintenance

of remission of chronic pouchitis are warranted, and perhaps ad-

ditional trials of rifaximin and inulin. In addition trials of newer

agents, such as biologic therapies, need to be performed in order

to establish the true efficacy of these agents prior to widespread

clinical application. In future trials, treatment indications such as

active acute or chronic pouchitis and maintenance of remission

for acute or chronic pouchitis should be clearly defined using the

gold standard PDAI definitions.

A C K N O W L E D G E M E N T S

Funding for the IBD/FBD Review Group (October 1, 2005 -

September 30, 2010) has been provided by the Canadian Insti-

tutes of Health Research (CIHR) Knowledge Translation Branch;

the Canadian Agency for Drugs and Technologies in Health

14Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Page 17: Treatment and prevention of pouchitis after ileal pouch ...

(CADTH); and the CIHR Institutes of Health Services and Pol-

icy Research; Musculoskeletal Health and Arthritis; Gender and

Health; Human Development, Child and Youth Health; Nutri-

tion, Metabolism and Diabetes; and Infection and Immunity.

Miss Ila Stewart has provided support for the IBD/FBD Review

Group through the Olive Stewart Fund.

Miss Patricia J. Erwin has provided technical support in creating

the electronic search pattern and is an employee of Mayo Clinic,

Rochester MN.

R E F E R E N C E S

References to studies included in this review

Gionchetti 2000 {published data only}

Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D,

Bazzocchi G, et al.Oral bacteriotherapy as maintenance treatment

in patients with chronic pouchitis: a double-blind, placebo-

controlled trial. Gastroenterology 2000;119(2):305–9.

Gionchetti 2003 {published data only}

Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM,

Brigidi P, et al.Prophylaxis of pouchitis onset with probiotic

therapy: a double-blind, placebo-controlled trial. Gastroenterology

2003;124(5):1202–9.

Isaacs 2007 {published data only}

Isaacs KL, Sandler RS, Abreu M, Picco MF, Hanauer SB, Bickston

SJ, et al.Rifaximin for the treatment of active pouchitis: a

randomized, double-blind, placebo-controlled pilot study. Inflamm

Bowel Dis 2007;13(10):1250–5. [: 1078–0998]

Joelsson 2001 {published data only}

Joelsson M, Andersson M, Bark T, Gullberg K, Hallgren T, Jiborn

H, et al.Allopurinol as prophylaxis against pouchitis following ileal

pouch-anal anastomosis for ulcerative colitis. A randomized

placebo-controlled double-blind study. Scand J Gastroenterol 2001;

36(11):1179–84.

Kuisma 2003 {published data only}

Kuisma J, Mentula S, Jarvinen H, Kahri A, Saxelin M, Farkkila M.

Effect of Lactobacillus rhamnosus GG on ileal pouch inflammation

and microbial flora. Aliment Pharmacol Ther 2003;17(4):509–15.

Mimura 2004 {published data only}

Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot

IC, et al.Once daily high dose probiotic therapy (VSL#3) for

maintaining remission in recurrent or refractory pouchitis. Gut

2004;53(1):108–14.

Pronio 2008 {published data only}

Pronio A, Montesani C, Butteroni C, Vecchione S, Mumolo G,

Vestri A, et al.Probiotic administration in patients with ileal pouch-

anal anastomosis for ulcerative colitis is associated with expansion

of mucosal regulatory cells. Inflamm Bowel Dis 2008;14(5):662–8.

Sambuelli 2002 {published data only}

Sambuelli A, Boerr L, Negreira S, Gil A, Camartino G, Huernos S,

et al.Budesonide enema in pouchitis - A double-blind, double-

dummy, controlled trial. Aliment Pharmacol Ther 2002;16(1):

27–34.

Shen 2001 {published data only}

Shen B, Achkar JP, Lashner BA, Ormsby A, Remzi F, Bevins CL, et

al.Ciprofloxacin is more effective in treating acute pouchitis than

metronidazole: A randomized clinical trial. Gastroenterology 2001;

120(5 Suppl 1):A453.

Tremaine 1997 {published data only}

Tremaine WJ, Sandborn WJ, Wolff BG, Carpenter HA,

Zinsmeister AR, Metzger PP. Bismuth carbomer foam enemas for

active chronic pouchitis: a randomized, double-blind, placebo-

controlled trial. Aliment Pharmacol Ther 1997;11:1041–6.

Wischmeyer 1993 {published data only}

Wischmeyer P, Pemberton JH, Phillips SF. Chronic pouchitis after

ileal pouch-anal anastomosis: responses to butyrate and glutamine

suppositories in a pilot study. Mayo Clin Proc 1993;68:978–81.

References to studies excluded from this review

Kuhbacher 2006 {published data only}

Kuhbacher T, Ott SJ, Helwig U, Mimura T, Rizzello F, Kleessen B,

et al.Bacterial and fungal microbiota in relation to probiotic therapy

(VSL#3) in pouchitis. Gut 2006;55(6):833–41.

Laake 2005 {published data only}

Laake KO, Bjørneklett A, Aamodt G, Aabakken L, Jacobsen M,

Bakka A, et al.Outcome of four weeks’ intervention with probiotics

on symptoms and endoscopic appearance after surgical

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Madden 1994 {published data only}

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trial of metronidazole versus placebo in chronic unremitting

pouchitis. Dig Dis Sci 1994;39:1193–6.

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randomised clinical trial. Use in determining optimum treatment

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Meijer 2000 {published data only}

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15Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Page 18: Treatment and prevention of pouchitis after ileal pouch ...

expression and cell turnover within the ileoanal pouch -

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Van 2006 {published data only}

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Soeters PB, Baeten CG. Effect of dietary inulin supplementation on

inflammation of pouch mucosa in patients with an ileal pouch-anal

anastomosis. Dis Colon Rectum 2002;45(5):621–7.

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complication of the continent ileostomy. Dis Colon Rectum 1981;

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Gionchetti 1997

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16Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Nasmyth 1989

Nasmyth DG, Godwin PG, Dixon MF, Williams NS, Johnston D.

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Pardi 2009

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HP. Effects of boswella serrata gum resin in patients with ulcerative

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al.Comparison of bismuth citrate and 5-aminosalicylic acid enemas

in distal ulcerative colitis: a controlled trial. Gut 1993;34:676–9.

Sandborn 1994a

Sandborn WJ. Pouchitis following ileal pouch-anal anastomosis:

definition, pathogenesis, and treatment. Gastroenterology 1994;107:

1856–60.

Sandborn 1994b

Sandborn WJ, Tremiane WJ, Batts KP, Pemberton JH, Phillips SF.

Pouchitis following ileal pouch-anal anastomosis: a pouchitis

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Sandborn 1995

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Hofmann AF, et al.Fecal bile acids, short chain fatty acids, and

bacteria after ileal pouch-anal anastomosis do not differ in patients

with pouchitis. Dig Dis Sci 1995;40:1474–83.

Sandborn 1997

Sandborn WJ. Pouchitis: definition, risk factors, frequency, natural

history, classification, and public health perspectives. In: Trends In

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Scott AD, Phillips RK. Ileitis and pouchitis after colectomy for

ulcerative colitis. Br J Surg 1989;76:668–9.

Shepherd 1987

Shepherd NA, Jass JR, Duval I, Moskowitz RL, Nicholls RJ,

Morson BC. Restorative proctocolectomy with ileal reservoir:

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J Clin Pathol 1987;40:601–7.

Shepherd 1989

Shepherd NA, Hulten L, Tytgat GN, Nicholls RJ, Nasmyth DG,

Hill MJ, et al.Workshop: pouchitis. Int J Colorectal Dis 1989;4:

205–29.

Svaninger 1993

Svaninger G, Nordgren S, Oresland T, Hulten L. Incidence and

characteristics of pouchitis in the Kock continent ilesotomy and the

pelvic pouch. Scand J Gastroenterol 1993;28:695–700.

Tremaine 1994

Tremaine WJ, Sandborn WJ, Phillips SF, Pemberton JH, Carpenter

HA. Short chain fatty acid (SCFA) enema therapy for treatment-

resistant pouchitis following ileal pouch-anal anastomosis (IPAA)

for ulcerative colitis (UC). Gastroenterology 1994;106:A784.

Tremaine 1998

Tremaine WJ, Sandborn WJ, Kenan ML. Bismuth subsalicylate

tablets for chronic antibiotic-resistant pouchitis. Gastroenterology

1998;114(1):A1101.

Tytgat 1988

Tytgat GN, Van Deventer SJ. Pouchitis. Int J Colorectal Dis 1988;3:

226–8.

Zuccaro 1989

Zuccaro G, Fazio VW, Church JW, Lavery IC, Ruderman WB,

Farmer RG. Pouch ileitis. Dig Dis Sci 1989;34:1505–10.∗ Indicates the major publication for the study

17Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Gionchetti 2000

Methods Randomized, double-blind, placebo-controlled. Parallel-arm design. Intention to treat.

36 weeks. N=40

Participants Patients with pouchitis in remission (defined as a PDAI = 0) and chronic (require con-

tinuing medical suppression therapy and recur within a few weeks of discontinuing sup-

pression). Prior to study entry patients were treated with open antibiotics (types not

specified) to induce remission. Antibiotic therapy discontinued at study entry

Interventions VSL#3, 6 grams per day versus placebo

Outcomes Maintenence of remission. Relapse from remission to active pouchitis (defined as an

increase by 2 points in the 6 point clinical portion of the PDAI, from a baseline score of

0)

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated

Allocation concealment? Yes Adequate

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes No drop outs

Free of selective reporting? Yes The published report includes all expected

outcomes

Gionchetti 2003

Methods Randomized, double-blind, placebo-controlled. Parallel-arm design. Intention to treat.

12 months. N=40

Participants Patients were randomized within one week of ileostomy closure after ileal pouch-anal

anastomosis for ulcerative colitis

Interventions VSL#3, 1 packet per day versus 3 g/day placebo (maize)

18Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Gionchetti 2003 (Continued)

Outcomes Prophylaxis. Primary endpoint was pouchitis, defined as PDAI score ≥ 7, with symptoms,

histologic, and endoscopic evidence of inflammation. Secondary endpoints included

IBDQ score, fecal bacterial concentrations, and stool frequency

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated

Allocation concealment? Yes Adequate

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes No drop outs

Free of selective reporting? Yes The published report includes all expected

outcomes

Isaacs 2007

Methods Randomized, double-blind, multi-center, placebo-controlled. Parallel-arm design. In-

tention-to-treat analysis. 4 weeks. N=18

Participants Patients with active pouchitis defined as a PDAI score of at least 7

Interventions Oral rifaximin 400 mg or placebo 3 times per day for 4 weeks

Outcomes Acute treatment. Clinical remission defined as a PDAI score < 7 points and a decrease

in the baseline PDAI score of 3 points

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated with permuted blocks

Allocation concealment? Unclear Not described

Blinding?

All outcomes

Yes Double blind

19Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Isaacs 2007 (Continued)

Incomplete outcome data addressed?

All outcomes

Yes Two patients withdrew from placebo group

due to lack of efficacy. These patients were

classified as treatment failures.

Free of selective reporting? Yes The published report includes all expected

outcomes

Joelsson 2001

Methods Randomized, double-blind, multi-center, placebo-controlled. Parallel-arm design. Per

protocol analysis. 24 months. N=184

Participants Patients with IPAA for UC were randomized 1 week after surgery. Excluded: age <

18 or > 75 years, breastfeeding, pregnancy or planned pregnancy during the coming

year, psychiatric disease, known alcohol abuse, other disease of relevance according to

the clinician judgement, allergy/intolerance to allopurinol, or current azathioprine, 6-

mercaptopurine, cyclophosphamide, cyclosporine or anticoagulation use

Interventions Allopurinol 100 mg twice daily or placebo

Outcomes Prophylaxis. Pouchitis defined by a functional score (similar to PDAI)

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Unclear Not described

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes Missing outcome data balanced in num-

bers across intervention groups with simi-

lar reasons for missing data across groups

Free of selective reporting? Yes The published report includes all expected

outcomes

20Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Kuisma 2003

Methods Randomized, double-blind, placebo-controlled. Parallel arm design. Per protocol analy-

sis. 3 months. N=20

Participants Patients with a previous history of pouchitis and endoscopic inflammation. Patients

who had received antibiotics within one month were excluded, as were active chronic

pouchitis (intermittent or continuous medical treatment) or symptoms [fever, bleeding,

increased number of stools (> 2/day within 1 week)] indicative of an acute exacerbation

of pouchitis

Interventions Lactobacillus GG in two gelatine capsules orally twice daily versus microcrystalline cel-

lulose-only gelatine placebo capsules

Outcomes Acute treatment. Total PDAI score and quantitative bacterial culture of fresh faecal

samples and biopsies taken from the pouch and afferent limb was performed before and

after supplementation

Notes After randomization 2 patients were excluded after the first endoscopy because of severe

endoscopic pouchitis (large ulcers, stricture) requiring immediate antibiotic therapy

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Unclear Not described

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes Two patients were excluded because of se-

vere disease before treatment began. No pa-

tients dropped out

Free of selective reporting? Yes The published report includes all expected

outcomes

Mimura 2004

Methods Randomized, placebo-controlled. Multi-center. Parallel-arm design. Intention to treat.

1-year. N=36.

Participants Patients with pouchitis at least twice in the previous year or requiring continuous an-

tibiotics, associated with a PDAI ≥ 7, in whom remission was induced by four weeks of

combined metronidazole and ciprofloxacin. Active refractory or recurrent pouchitis was

defined as a total PDAI score of > 7 and a history of relapsing or persistent pouchitis

Interventions VSL#3 3 g orally twice per day versus maize placebo

21Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Mimura 2004 (Continued)

Outcomes Maintence of remission. Remission was defined as a clinical PDAI ≤ 2 and endoscopic

PDAI ≤ 1. Relapse was defined as an increased clinical PDAI score ≥ 2 and increased

endoscopic PDAI score ≥ 3

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Yes Computer generated in blocks of four at

each institution

Allocation concealment? Yes Adequate

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes One patient dropped out from the VSL#3

group due to adverse events

Free of selective reporting? Yes The published report includes all expected

outcomes

Pronio 2008

Methods Randomized, open-label study. Parallel-arm design. Modified intention to treat. 12

months. N=28

Participants Patients had no active disease, no chronic pouchitis, and were taking no medication.

Excluded patients with acute pouchitis (PDAI ≥7), patients with perianal disease in-

cluding abscess, fissure, stricture, or anal sphincter weakness, and pregnant or lactating

women

Interventions VSL#3, 2 packets once per day versus no treatment

Outcomes Acute pouchitis defined as a PDAI score ≥ 7. Secondary endpoint included prevalence

of regulatory T-cells

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described in sufficient detail

Allocation concealment? No Open study

22Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Pronio 2008 (Continued)

Blinding?

All outcomes

No Open study

Incomplete outcome data addressed?

All outcomes

Yes Two patients in the VSL#3 group dropped

out (refusals) and one control patient de-

veloped anal carcinoma

Free of selective reporting? Yes The published report includes all expected

outcomes

Sambuelli 2002

Methods Randomized, double-blind, placebo-controlled. Parallel-arm design. Intention to treat.

6-weeks. N=26

Participants Patients with an active episode of pouchitis, defined as a PDAI score ≥ 7 and no treatment

during the previous month or during the trial. Patients were defined as having chronic

pouchitis, if they presented with recurrence of symptoms at least four times a year or if

they needed therapy for more than 6 months in the last year, and required a 1 month

treatment-free period prior to enrollment

Interventions Budesonide enema (2 mg/100 mL at bedtime) plus placebo tablets or oral metronidazole

(0.5 g twice per day.) plus placebo enema

Outcomes Acute treatment. Decrease in PDAI ≥ 3 and/or remission or non-pouchitis criteria

(PDAI < 7 points with a decrease of ≥ 3 points from baseline

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Unclear Not described

Blinding?

All outcomes

Yes Double blind, double dummy

Incomplete outcome data addressed?

All outcomes

Yes Missing outcome data balanced in num-

bers across intervention groups with simi-

lar reasons for missing data across groups

Free of selective reporting? Yes The published report includes all expected

outcomes

23Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Shen 2001

Methods Randomized, non-blinded, placebo-controlled. Parallel-arm design. Intention to treat.

2-weeks. N=16

Participants Patients with acute pouchitis, defined as a PDAI score of ≥ 7 and symptom duration of

4 weeks or less who had not received any treatment for pouchitis within 2-weeks prior

to enrollment. Excluded patients with chronic pouchitis defined as symptoms lasting 4

weeks or longer

Interventions Oral ciprofloxacin 1 g/d or metronidazole 20 mg/kg/d

Outcomes Acute treatment. Total PDAI score as well as in the symptom, endoscopy, and histology

subscores

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Unclear Not described

Blinding?

All outcomes

No Not used (pouch biopsies were blindly

scored by a GI pathologist)

Incomplete outcome data addressed?

All outcomes

Unclear Dropouts were not described

Free of selective reporting? Unclear Outcomes were not prespecified

Tremaine 1997

Methods Randomized, double-blind, placebo-controlled. Parallel-arm design. Intention to treat.

3 weeks. N=40

Participants Patients with pouchitis that was active (defined as a PDAI ≥ 7) and chronic (defined as

failure or intolerance to treatment with antibiotics and other medical therapies)

Interventions Bismuth carbomer foam enemas containing bismuth citrate 513 mg (metallic bismuth

270 mg) complexed with carbomer (a synthetic high molecular weight polymer of acrylic

acid cross linked with polyalkenyl polyether) versus placebo administered nightly

Outcomes Treatment of chronic pouchitis. Improvement or remission defined as a decrease in the

PDAI ≥ 3 or a PDAI of 0, respectively

Notes

Risk of bias

24Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Tremaine 1997 (Continued)

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Yes Adequate

Blinding?

All outcomes

Yes Double blind

Incomplete outcome data addressed?

All outcomes

Yes Two patients in the bismuth carbomer

foam group with missing data at the end of

treatment were considered to be treatment

failures

Free of selective reporting? Yes The published report includes all expected

outcomes

Wischmeyer 1993

Methods Randomized, double-blind, controlled trial comparing two active agents. Parallel-arm

design. Intention to treat. 3 weeks. N=19

Participants Patients with pouchitis that was chronic (defined as at least 4 episodes of recurrent

pouchitis within one year and the need for suppressive medications for at least 6 of the

prior 12 months). Eligible patients with chronic pouchitis discontinued all concomitant

medications for 7 days and then began investigational therapy. At the time that the

investigational therapy was begun, the patients could have either active or remitted

pouchitis following discontinuation of suppressive medical therapy

Interventions L-glutamine 1 g in a polyethylene glycol base suppository versus sodium butyrate 40

mmol in a polyethylene glycol base suppository administered twice per day

Outcomes Treatment of chronic pouchitis. Induction of symptomatic remission (resolution of in-

creased stool frequency, urgency and cramping, fever, and blood in stools), if necessary,

and subsequent maintenance of symptomatic remission (asymptomatic) after discontin-

uing other suppressive medical therapy

Notes

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear Not described

Allocation concealment? Unclear Not described

25Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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Wischmeyer 1993 (Continued)

Blinding?

All outcomes

Unclear Not described

Incomplete outcome data addressed?

All outcomes

Yes One patient withdrew from each group

Free of selective reporting? Yes The published report includes all expected

outcomes

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Kuhbacher 2006 Non-randomized sub-study

Laake 2005 Non-randomized follow-up study

Madden 1994 Data were not available before the first cross-over

McLeod 1986 Randomized, double-blind, placebo-controlled “n-of-1” trial in a single patient with chronic pouchitis in a Kock

pouch. Five 14 day treatment courses with oral metronidazole 250 mg/day and five 14 day treatment courses with

placebo, administered in random order. Overall, the study demonstrated a beneficial effect for metronidazole as

compared to placebo. The study was excluded from the analysis because the purpose of such trials is to determine

whether a given intervention is beneficial for a single patient, not to determine whether one intervention is more

effective than another in groups of patients with a given disease

Meijer 2000 Follow-up study (actually published before the main results) of the randomized trial by Welters et al in 2002

Miner 2006 Not pouchitis but mild to moderate active left-sided ulcerative colitis

Van 2006 Not pouchitis but mild to moderate left-sided ulcerative colitis

Welters 2002 Data were not available before the first cross-over

26Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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D A T A A N D A N A L Y S E S

Comparison 1. Acute Pouchitis

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Ciprofloxacin vs. Metronidazole:

Achieved Remission (PDAI <7)

1 16 Peto Odds Ratio (Peto, Fixed, 95% CI) 14.39 [2.00, 103.76]

2 Budesonide enema vs.

Metronidazole: Achieved

Remission (PDAI <7)

1 26 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.32 [0.29, 6.01]

3 Rifaximin vs. Placebo: Achieved

Remission (PDAI <7)

1 18 Peto Odds Ratio (Peto, Fixed, 95% CI) 10.92 [0.62, 193.55]

4 Lactobacillus GG vs. Placebo:

Improved (PDAI reduction ≥

3)

1 20 Peto Odds Ratio (Peto, Fixed, 95% CI) 7.39 [0.15, 372.38]

Comparison 2. Chronic Pouchitis

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Glutamine suppositories

vs. Butyrate suppositories:

Achieved Remission (no

recurrence of symptoms)

1 19 Peto Odds Ratio (Peto, Fixed, 95% CI) 2.75 [0.48, 15.94]

2 Bismuth Carbomer Foam

Enemas vs. Placebo: Improved

(PDAI reduction ≥ 3)

1 40 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.0 [0.29, 3.42]

3 VSL#3 vs. Placebo: Relapse of

Pouchitis (PDAI increase ≥ 2)

2 76 Peto Odds Ratio (Peto, Fixed, 95% CI) 25.39 [10.37, 62.17]

Comparison 3. Prevention of Pouchitis

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 VSL#3 vs. Placebo: No Episodes

of Acute Pouchitis (PDAI ≥ 7)

1 40 Peto Odds Ratio (Peto, Fixed, 95% CI) 4.76 [1.16, 19.56]

2 VSL#3 vs. No Treatment: No

Episodes of Acute Pouchitis

(PDAI ≥ 7)

1 28 Peto Odds Ratio (Peto, Fixed, 95% CI) 10.31 [0.20, 541.25]

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3 Allopurinol vs. Placebo: No

Episodes of Pouchitis (clinical

diagnosis)

1 184 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.10 [0.62, 1.97]

Analysis 1.1. Comparison 1 Acute Pouchitis, Outcome 1 Ciprofloxacin vs. Metronidazole: Achieved

Remission (PDAI <7).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 1 Acute Pouchitis

Outcome: 1 Ciprofloxacin vs. Metronidazole: Achieved Remission (PDAI <7)

Study or subgroup Cipro Metronizadole Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Shen 2001 7/7 3/9 100.0 % 14.39 [ 2.00, 103.76 ]

Total (95% CI) 7 9 100.0 % 14.39 [ 2.00, 103.76 ]

Total events: 7 (Cipro), 3 (Metronizadole)

Heterogeneity: not applicable

Test for overall effect: Z = 2.65 (P = 0.0082)

0.01 0.1 1 10 100

Favors Metronizadole Favors Cipro

Analysis 1.2. Comparison 1 Acute Pouchitis, Outcome 2 Budesonide enema vs. Metronidazole: Achieved

Remission (PDAI <7).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 1 Acute Pouchitis

Outcome: 2 Budesonide enema vs. Metronidazole: Achieved Remission (PDAI <7)

Study or subgroup Budesonide Metronizadole Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Sambuelli 2002 6/12 6/14 100.0 % 1.32 [ 0.29, 6.01 ]

Total (95% CI) 12 14 100.0 % 1.32 [ 0.29, 6.01 ]

Total events: 6 (Budesonide), 6 (Metronizadole)

Heterogeneity: not applicable

Test for overall effect: Z = 0.36 (P = 0.72)

0.05 0.2 1 5 20

Favors Metronizadole Favours Budesonide

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Analysis 1.3. Comparison 1 Acute Pouchitis, Outcome 3 Rifaximin vs. Placebo: Achieved Remission (PDAI

<7).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 1 Acute Pouchitis

Outcome: 3 Rifaximin vs. Placebo: Achieved Remission (PDAI <7)

Study or subgroup Rifaximin Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Isaacs 2007 2/8 0/10 100.0 % 10.92 [ 0.62, 193.55 ]

Total (95% CI) 8 10 100.0 % 10.92 [ 0.62, 193.55 ]

Total events: 2 (Rifaximin), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.63 (P = 0.10)

0.01 0.1 1 10 100

Favors Placebo Favors Rifaximin

Analysis 1.4. Comparison 1 Acute Pouchitis, Outcome 4 Lactobacillus GG vs. Placebo: Improved (PDAI

reduction ≥ 3).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 1 Acute Pouchitis

Outcome: 4 Lactobacillus GG vs. Placebo: Improved (PDAI reduction ≥ 3)

Study or subgroup LGG Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Kuisma 2003 1/10 0/10 100.0 % 7.39 [ 0.15, 372.38 ]

Total (95% CI) 10 10 100.0 % 7.39 [ 0.15, 372.38 ]

Total events: 1 (LGG), 0 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 1.00 (P = 0.32)

0.005 0.1 1 10 200

Favors Placebo Favors LGG

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Analysis 2.1. Comparison 2 Chronic Pouchitis, Outcome 1 Glutamine suppositories vs. Butyrate

suppositories: Achieved Remission (no recurrence of symptoms).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 2 Chronic Pouchitis

Outcome: 1 Glutamine suppositories vs. Butyrate suppositories: Achieved Remission (no recurrence of symptoms)

Study or subgroup Glutamine Butyrate Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Wischmeyer 1993 6/10 3/9 100.0 % 2.75 [ 0.48, 15.94 ]

Total (95% CI) 10 9 100.0 % 2.75 [ 0.48, 15.94 ]

Total events: 6 (Glutamine), 3 (Butyrate)

Heterogeneity: not applicable

Test for overall effect: Z = 1.13 (P = 0.26)

0.01 0.1 1 10 100

Favors Butyrate Favors Glutamine

Analysis 2.2. Comparison 2 Chronic Pouchitis, Outcome 2 Bismuth Carbomer Foam Enemas vs. Placebo:

Improved (PDAI reduction ≥ 3).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 2 Chronic Pouchitis

Outcome: 2 Bismuth Carbomer Foam Enemas vs. Placebo: Improved (PDAI reduction ≥ 3)

Study or subgroup Bismuth Enema Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Tremaine 1997 9/20 9/20 100.0 % 1.00 [ 0.29, 3.42 ]

Total (95% CI) 20 20 100.0 % 1.00 [ 0.29, 3.42 ]

Total events: 9 (Bismuth Enema), 9 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P = 1.0)

0.1 0.2 0.5 1 2 5 10

Favors Placebo Favors Bismuth

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Analysis 2.3. Comparison 2 Chronic Pouchitis, Outcome 3 VSL#3 vs. Placebo: Relapse of Pouchitis (PDAI

increase ≥ 2).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 2 Chronic Pouchitis

Outcome: 3 VSL#3 vs. Placebo: Relapse of Pouchitis (PDAI increase ≥ 2)

Study or subgroup Placebo VSL#3 Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Gionchetti 2000 20/20 3/20 52.3 % 29.70 [ 8.61, 102.44 ]

Mimura 2004 15/16 3/20 47.7 % 21.38 [ 5.85, 78.17 ]

Total (95% CI) 36 40 100.0 % 25.39 [ 10.37, 62.17 ]

Total events: 35 (Placebo), 6 (VSL#3)

Heterogeneity: Chi2 = 0.13, df = 1 (P = 0.72); I2 =0.0%

Test for overall effect: Z = 7.08 (P < 0.00001)

0.01 0.1 1 10 100

Favors Placebo Favors VSL#3

Analysis 3.1. Comparison 3 Prevention of Pouchitis, Outcome 1 VSL#3 vs. Placebo: No Episodes of Acute

Pouchitis (PDAI ≥ 7).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 3 Prevention of Pouchitis

Outcome: 1 VSL#3 vs. Placebo: No Episodes of Acute Pouchitis (PDAI ≥ 7)

Study or subgroup VSL#3 Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Gionchetti 2003 18/20 12/20 100.0 % 4.76 [ 1.16, 19.56 ]

Total (95% CI) 20 20 100.0 % 4.76 [ 1.16, 19.56 ]

Total events: 18 (VSL#3), 12 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 2.16 (P = 0.031)

0.01 0.1 1 10 100

Favors pacebo Favors VSL#3

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Analysis 3.2. Comparison 3 Prevention of Pouchitis, Outcome 2 VSL#3 vs. No Treatment: No Episodes of

Acute Pouchitis (PDAI ≥ 7).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 3 Prevention of Pouchitis

Outcome: 2 VSL#3 vs. No Treatment: No Episodes of Acute Pouchitis (PDAI ≥ 7)

Study or subgroup VSL#3 No treatment Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Pronio 2008 16/16 11/12 100.0 % 10.31 [ 0.20, 541.25 ]

Total (95% CI) 16 12 100.0 % 10.31 [ 0.20, 541.25 ]

Total events: 16 (VSL#3), 11 (No treatment)

Heterogeneity: not applicable

Test for overall effect: Z = 1.15 (P = 0.25)

0.005 0.1 1 10 200

Favors no treatment Favors VSL#3

Analysis 3.3. Comparison 3 Prevention of Pouchitis, Outcome 3 Allopurinol vs. Placebo: No Episodes of

Pouchitis (clinical diagnosis).

Review: Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis

Comparison: 3 Prevention of Pouchitis

Outcome: 3 Allopurinol vs. Placebo: No Episodes of Pouchitis (clinical diagnosis)

Study or subgroup Allopurinol Placebo Peto Odds Ratio Weight Peto Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Joelsson 2001 43/94 39/90 100.0 % 1.10 [ 0.62, 1.97 ]

Total (95% CI) 94 90 100.0 % 1.10 [ 0.62, 1.97 ]

Total events: 43 (Allopurinol), 39 (Placebo)

Heterogeneity: not applicable

Test for overall effect: Z = 0.33 (P = 0.74)

0.1 0.2 0.5 1 2 5 10

Favors Placebo Favors Allopurinol

32Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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W H A T ’ S N E W

Last assessed as up-to-date: 4 October 2009.

Date Event Description

5 October 2009 New search has been performed New search, new studies included.

5 October 2009 New citation required and conclusions have changed Change in authors, additional conclusions due to new

data.

H I S T O R Y

Protocol first published: Issue 3, 1998

Review first published: Issue 3, 1998

C O N T R I B U T I O N S O F A U T H O R S

Dr. Holubar - data analysis, drafting of review, critical revision.

Dr. Cima - data analysis, critical revision.

Dr. Sandborn - data analysis, critical revision.

Dr. Pardi - data analysis, critical revision.

D E C L A R A T I O N S O F I N T E R E S T

Disclosures: Dr. Holubar and Dr. Cima - none; Dr. Sandborn - consulting for Salix Pharmaceuticals; Dr. Pardi - research and consulting

for Salix Pharmaceuticals.

S O U R C E S O F S U P P O R T

Internal sources

• none, Not specified.

33Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

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External sources

• none, Not specified.

I N D E X T E R M S

Medical Subject Headings (MeSH)

Ciprofloxacin [therapeutic use]; Colitis, Ulcerative [∗surgery]; Enema; Gastrointestinal Agents [∗therapeutic use]; Metronidazole [ther-

apeutic use]; Postoperative Complications [∗drug therapy; prevention & control]; Pouchitis [∗drug therapy; prevention & control];

Randomized Controlled Trials as Topic; Remission Induction; Rifamycins [therapeutic use]; Suppositories

MeSH check words

Adult; Humans

34Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.