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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.
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.
[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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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).
7Treatment 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.
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)
8Treatment 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.
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)
9Treatment 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.
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
10Treatment 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.
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
11Treatment 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.
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
12Treatment 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.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.
(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
reconstruction with a J-configurated ileal-pouch-anal-anastomosis
in ulcerative colitis. Scand J Gastroenterol 2005;40(1):43–51.
Madden 1994 {published data only}
Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover
trial of metronidazole versus placebo in chronic unremitting
pouchitis. Dig Dis Sci 1994;39:1193–6.
McLeod 1986 {published data only}
McLeod RS, Taylor DW, Cohen Z, Cullen JB. Single-patient
randomised clinical trial. Use in determining optimum treatment
for patients with inflammation of Kock continent ileostomy
reservoir. Lancet 1986;1(8483):726–8.
Meijer 2000 {published data only}
Meijer HP, Welters CF, Heineman E, Salomons GS, Buller HA,
Dekker J, et al.Enteral inulin doles not affect epithelial gene
15Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis (Review)
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expression and cell turnover within the ileoanal pouch -
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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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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.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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]
27Treatment 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.
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
28Treatment 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.
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
29Treatment 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.
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
30Treatment 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.
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
31Treatment 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.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.