Systematic Review and Meta-analysis of Randomised Controlled Trials

Medical Therapies for the Treatment and Prevention of Pouchitis

Lotus Alphonsus; Theshani A. De Silva; Christopher Ma; John K. MacDonald; Jurij Hanzel; Melanie Beaton; Talat Bessissow; Maia Kayal; Rocio Sedano; Siddharth Singh; Vipul Jairath

Disclosures

Aliment Pharmacol Ther. 2023;58(3):268-282.

Abstract and Introduction

Abstract

Background and Aims: We conducted a systematic review to assess medical therapy for the treatment and prevention of pouchitis.

Methods: Randomised controlled trials (RCTs) of medical therapy in adults with or without pouchitis were searched to March 2022. Primary outcomes included clinical remission/response, maintenance of remission and prevention of pouchitis.

Results: Twenty RCTs (N = 830) were included. Acute pouchitis: One study compared ciprofloxacin with metronidazole. At 2 weeks, 100% (7/7) of ciprofloxacin participants achieved remission, compared with 67% (6/9) of metronidazole participants (RR: 1.44, 95% CI: 0.88–2.35, very low certainty evidence). One study compared budesonide enemas with oral metronidazole. Fifty percent (6/12) of budesonide participants achieved remission compared with 43% (6/14) of metronidazole participants (RR: 1.17, 95% CI: 0.51–2.67, low certainty evidence). Chronic pouchitis: Two studies (n = 76) assessed De Simone Formulation. Eighty-five percent (34/40) of De Simone Formulation participants maintained remission at 9–12 months compared with 3% (1/36) placebo participants (RR: 18.50, 95% CI: 3.86–88.56, moderate certainty evidence). One study assessed vedolizumab. Thirty-one percent (16/51) of vedolizumab participants achieved clinical remission at 14 weeks compared with 10% (5/51) of placebo participants (RR: 3.20, 95% CI: 1.27–8.08, moderate certainty evidence). Prophylaxis: Two studies assessed De Simone Formulation. Ninety percent (18/20) of De Simone Formulation participants did not develop pouchitis compared with 60% (12/20) of placebo participants (RR: 1.50, 95% CI: 1.02–2.21, moderate certainty evidence).

Conclusions: Apart from vedolizumab and the De Simone formulation, the effects of other medical interventions for pouchitis are uncertain.

Introduction

Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgery of choice in patients with ulcerative colitis (UC) who undergo colectomy due to medically refractory disease or development of dysplasia. The most common long-term complication of IPAA is idiopathic inflammation of the pouch—pouchitis, which affects approximately one-half of patients within the first 10 years following colectomy.^[1] Pouchitis is characterised by increased stool frequency, urgency, abdominal pain and impaired quality of life. The diagnosis of pouchitis is made in the presence of relevant symptoms with objective evidence of inflammation by endoscopic and/or histologic assessment. While there are no formally validated instruments for the measurement of disease activity in pouchitis, the Pouchitis Disease Activity Index (PDAI) is the most widely used and measures symptoms, endoscopy and histopathology.^[1,2] Pouchitis is a rare condition that has an orphan disease designation in the United States and Europe. The cumulative prevalence of pouchitis in the United States between 1999 and 2018 was estimated to be 1 in 10,000.^[3] This cumulative prevalence includes patients with pouches constructed for UC, familial adenomatous polyposis and Crohn's disease and those who respond to first-line therapy with antibiotics, which includes approximately 80% of patients with pouchitis. For patients with IPAA for UC and active pouchitis that does not respond to antibiotic therapy, the estimated prevalence is much lower at 2 to 3 per 100,000 patients.^[3]

Acute pouchitis is usually treated with short-term antibiotics, however, up to one-fifth of patients develop chronic pouchitis, defined by symptom duration >4 weeks.^[4] Uncontrolled studies have suggested tumour necrosis factor (TNF) antagonists and ustekinumab may be effective for the treatment of antibiotic-refractory pouchitis.^[5] Recently, vedolizumab a monoclonal antibody blocking the interaction of α₄β₇ integrin with mucosal addressin cell adhesion molecule-1, inhibiting migration of gastrointestinal-homing T lymphocytes across the gut vascular endothelium, was approved by the European Medicines Agency for treatment of chronic pouchitis based on the results of the phase 4 EARNEST trial.^[6,7]

The primary objective of this systematic review was to assess the efficacy and safety of various medical therapies including, antibiotics, probiotics, biologics, small molecules, microbiome and faecal microbiota transplantation (FMT) for the treatment and prevention of pouchitis in patients with IPAA following colectomy for UC.

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Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Characteristics of included studies.
Study ID	Study design and duration	Study eligibility	Treatment arms			Efficacy outcomes and definitions^a
Study ID	Study design and duration	Study eligibility	Interventions (N)	Female, n/N (%)	Mean age (years, SD)	Efficacy outcomes and definitions^a
Tremaine 1997	Induction 3 weeks	Chronic pouchitis (PDAI ≥ 7; symptoms for ≥4 weeks; failure or intolerance to standard therapy)	Placebo (20) Bismuth carbomer (20)	8/20 (40) 10/20 (50)	40, 37	Remission (PDAI = 0) Clinical response (decrease in PDAI by ≥3)
Tan 1999	Induction 4 weeks	Poor pouch function (functional score [range 0–12] >4; nocturnal bowel seepage)	Placebo (16)^b Ursodeoxycholic acid (16)	2/16 (13)^c	Median 50^c	12-point functional score (scores >4 indicate poor pouch function) Bowel frequency
Gionchetti 2000	Maintenance 36 weeks	Chronic relapsing pouchitis (≥3 episodes/year) In remission (clinical and endoscopic PDAI = 0)	Placebo (20) De Simone Formulation - probiotic (20)	8/20 (40) 9/20 (45)	34.2, 32.8	Relapse (increase in clinical PDAI by ≥2; confirmed by endoscopy and histology)
Joelsson 2001	Prevention 104 weeks	No history of pouchitis	Placebo (90) Allopurinol (94)	35/90 (39) 39/94 (41)	37, 39	Development of pouchitis (pouchitis scoring system [range 0–11] ≥5; endoscopy subscore ≥1)
Shen 2001	Induction 2 weeks	Acute pouchitis (PDAI ≥ 7; symptoms for ≤4 weeks)	Ciprofloxacin (7) Metronidazole (9)	3/7 (43) 4/9 (44)	43.6 (16.9) 39.7 (10.5)	Remission (PDAI < 7)
Sambuelli 2002	Induction 6 weeks	Active pouchitis (PDAI ≥ 7)	Budesonide (12) Metronidazole (14)	2/12 (17) 6/14 (43)	Median 31, 39	Remission (PDAI < 7; decrease in PDAI by ≥3) Clinical response (decrease in PDAI by ≥3)
Gionchetti 2003	Prevention 52 weeks	No history of pouchitis	Placebo (20) De Simone Formulation – probiotic (20)	8/20 (40) 9/20 (45)	34.2, 31.8	Development of acute pouchitis (PDAI ≥ 7; confirmed by endoscopy and histology)
Kuisma 2003	Induction 12 weeks	Previous history of pouchitis (treated ≥1 times; endoscopic and histological inflammation on follow-up endoscopy)	Placebo (10) Lactobacillus rhamnosus GG (10)	6/10 (60) 3/10 (30)	48.2, 46.4	Clinical response (decrease in PDAI by ≥3)
Brown 2004	Prevention 26 weeks	No active pouchitis	Placebo (5) Bifidobacterium longum BB-536 (7)	NR	NR	Development of pouchitis
Mimura 2004	Maintenance 52 weeks	Active refractory or recurrent pouchitis (PDAI ≥ 7; ≥2 episodes/year) In remission after a 4-week course of antibiotics (clinical PDAI ≤ 2; endoscopic PDAI ≤ 1)	Placebo (16) De Simone Formulation – probiotic (20)	8/16 (50) 8/20 (40)	Median 36 36	Relapse (increase in clinical PDAI by ≥2; increase in endoscopic PDAI by ≥3) Maintenance of endoscopic remission (endoscopic PDAI ≤ 1)
Isaacs 2007	Induction 4 weeks	Acute (PDAI ≥ 7; no antibiotics or other therapy in the past 30 days) or chronic pouchitis (PDAI ≥ 7; treated with antibiotics or other therapy in the past 30 days)	Placebo (9) Rifaximin (8)	1/9 (11) 2/8 (25)	39.7 (9.5) 43.6 (12.3)	Remission (PDAI < 7; decrease in PDAI by ≥3) Clinical response (decrease in clinical PDAI by ≥2) Endoscopic response (decrease in endoscopic PDAI by ≥2)
Pronio 2008	Prevention 52 weeks	No active or chronic pouchitis	Placebo (12) De Simone Formulation – probiotic (16)	8/16 (50) 4/12 (33)	35, 37	Development of pouchitis (PDAI ≥ 7)
Ha 2010	Prevention 52 weeks	No history of pouchitis	Placebo (13) Tinidazole (25)	NR	NR	Development of pouchitis
Van Assche 2012	Induction 1 week	Pouch dysfunction (≥7 loose stools/day for ≥7 consecutive days)	Placebo (6)^d Octreotide (9)	4/15 (27)^c	Median 52^c	Remission (based on mPDAI) Clinical response (reduction in SF by ≥30% and ≥3 stools/day)
Yasueda 2016	Prevention 104 weeks	No history of pouchitis	Placebo (8) Clostridium butyricum (9)	4/8 (50) 4/9 (44)	34 47	Development of pouchitis (mPDAI ≥4)
Herfarth 2019	Maintenance 16 weeks	Antibiotic-dependent pouchitis (either [1] maintenance antibiotics for >4 weeks; ≥2 episodes in the past 24 months due to antibiotic discontinuation, or [2] mPDAI ≥5; ≥4 antibiotics in the past 12 months) – In clinical remission (mPDAI < 4; SF and faecal urgency subscores ≤1)	Placebo (2) FMT (4)	2/2 (100) 4/4 (100)	33.5 (1.5) 39.3 (13.8)	Maintenance of clinical remission (mPDAI < 4; SF and faecal urgency subscores ≤1; no need for antibiotics)
Kjaer 2019	Induction 12 weeks	Chronic refractory pouchitis (PDAI ≥ 7; clinical PDAI > 2; endoscopic PDAI > 3; symptoms for ≥4 weeks despite antibiotics)	Placebo (7) Adalimumab (6)	2/7 (29) 4/6 (67)	Median 40.1, 40.9	Remission (PDAI ≤ 4; clinical PDAI ≤ 2; endoscopic PDAI ≤ 1) Clinical response (decrease in clinical PDAI by ≥2)
NCT02790138 2021	Induction 34 weeks	Chronic or recurrent pouchitis (mPDAI score ≥5; endoscopic PDAI ≥ 2; either [1] ≥3 episodes/year, or [2] maintenance antibiotics for ≥4 weeks)	Placebo (51) Vedolizumab (51)	13/51 (25) 19/51 (37)	42.9 (13.5) 40.8 (11.3)	Remission (mPDAI < 5; decrease in mPDAI by ≥2) PDAI remission (PDAI < 7; decrease in PDAI by ≥3) Change in mean IBDQ
Feagan 2021	Induction 10 weeks	Chronic pouchitis (modified MES ≥ 2; ≥6 stools/day; ≥3 stools/day above the post-IPAA baseline; confirmed by histology)	Placebo (69) Alicaforsen (69)	NR	NR	Endoscopic remission (based on modified MES)
Karjalainen 2021	Maintenance 52 weeks	Chronic pouchitis (endoscopic and histologic inflammation; symptoms for ≥4 weeks; antibiotics required >1 times in the past 12 months)	Placebo (13) FMT (13)	5/13 (38) 6/13 (46)	45.5 (11.7) 42.7 (10.2)	Remission (PDAI < 7; no need for antibiotics)

Abbreviations: FMT, faecal microbiota transplantation; IBDQ, Inflammatory Bowel Disease Questionnaire; IPAA, ileal pouch-anal anastomosis; MES, Mayo endoscopic subscore; mPDAI, modified Pouchitis Disease Activity Index; NR, not reported; PDAI, Pouchitis Disease Activity Index; SF, stool frequency; UC, ulcerative colitis.
^aIncludes efficacy outcomes of interest pre-specified in the systematic review protocol.
^bCross-over design where study participants (n = 16) received a 4-week course of ursodeoxycholic acid and a 4-week course of placebo.
^cPooled data for placebo and treatment arms.
^dNumber of participants before study cross-over.

Table 2. GRADE summary of findings: vedolizumab compared to placebo for treatment of active pouchitis.
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with vedolizumab	Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Clinical remission at 14 weeks	98 per 1000	314 per 1000 (125–792)	RR 3.20 (1.27–8.08)	102 (1 RCT)	⊕⊕⊕◯ Moderate^b
Clinical response at 14 weeks	98 per 1000	353 per 1000 (142–878)	RR 3.60 (1.45–8.96)	102 (1 RCT)	⊕⊕⊕◯ Moderate^c
Adverse events	686 per 1000	824 per 1000 (659–1000)	RR 1.20 (0.96–1.50)	102 (1 RCT)	⊕⊕⊕◯ Moderate^d
Serious adverse events	78 per 1000	59 per 1000 (14–249)	RR 0.75 (0.18–3.18)	102 (1 RCT)	⊕⊕◯◯ Low^e
Withdrawals due to adverse events	98 per 1000	39 per 1000 (8–193)	RR 0.40 (0.08–1.97)	102 (1 RCT)	⊕⊕◯◯ Low^e
Change in PDAI from baseline	The mean change in PDAI from baseline was −1.6	MD 1.3 lower (2.73 lower to 0.13 higher)	–	102 (1 RCT)	⊕⊕⊕◯ Moderate^f
Change in IBDQ from baseline	The mean change in IBDQ from baseline was 10.4	MD 14 higher (2.21 higher to 25.79 higher)	–	102 (1 RCT)	⊕⊕⊕◯ Moderate^f

Note: Patient or population: Patients with active pouchitis. Setting: Outpatient. Intervention: Vedolizumab. Comparison: Placebo. GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Abbreviations: CI, confidence interval; MD, mean difference; RR, risk ratio.
^aThe risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
^bDowngraded one level due to sparse data (27 events).
^cDowngraded one level due to sparse data (28 events).
^dDowngraded one level due to sparse data (77 events).
^eDowngraded two levels due to serious imprecision (7 events).
^fDowngraded one level due to sparse data (102 participants).

Table 3. GRADE summary of findings: De Simone Formulation compared to placebo for prevention of pouchitis or treatment of quiescent pouchitis.
Outcomes	Anticipated absolute effects^a (95% CI)		Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with De Simone formulation	Relative effect (95% CI)	No of participants (studies)	Certainty of the evidence (GRADE)	Comments
No episodes of acute pouchitis at 52 weeks	600 per 1000	900 per 1000 (612–1000)	RR 1.50 (1.02–2.21)	40 (1 RCT)	⊕⊕⊕◯ Moderate^b
Maintenance of clinical remission at 9–12 months	28 per 1000	514 per 1000 (107–1000)	RR 18.50 (3.86–88.56)	76 (2 RCTs)	⊕⊕⊕◯ Moderate^c
Maintenance of endoscopic remission at 12 months	63 per 1000	850 per 1000 (126–1000)	RR 13.60 (2.02–91.53)	36 (1 RCT)	⊕⊕◯◯ Low^d
Adverse events (maintenance studies)	0 per 1000	0 per 1000 (0–0)	RR 2.43 (0.11–55.89)	76 (2 RCTs)	⊕⊕◯◯ Low^e
Withdrawal due to adverse events (maintenance studies)	0 per 1000	0 per 1000 (0–0)	RR 2.43 (0.11–55.89)	76 (2 RCTs)	⊕⊕◯◯ Low^e

Note: Patient or population: Patients with IPAA or quiescent pouchitis. Setting: Outpatient. Intervention: De Simone formulation. Comparison: Placebo. GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Abbreviations: CI, confidence interval; IPAA, ileal pouch-anal anastomosis; RR, risk ratio.
^aThe risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
^bDowngraded one level due to sparse data (30 events).
^cDowngraded one level due to sparse data (35 events).
^dDowngraded two levels due to serious imprecision (18 events).
^eDowngraded two levels due to serious imprecision (1 event).

Authors and Disclosures

Lotus Alphonsus¹, Theshani A. De Silva¹, Christopher Ma^2–4, John K. MacDonald², Jurij Hanzel^2,5, Melanie Beaton^1,6, Talat Bessissow⁷, Maia Kayal⁸, Rocio Sedano^2,6, Siddharth Singh⁹ and Vipul Jairath^2,6,10,11

¹Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada
²Alimentiv, Inc., London, Ontario, Canada
³Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
⁴Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
⁵Department of Gastroenterology, Faculty of Medicine, University Medical Center Ljubljana, University of Ljubljana, Ljubljana, Slovenia
⁶Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada
⁷Division of Gastroenterology, Department of Medicine, McGill University Health Center, Montreal, Quebec, Canada
⁸Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
⁹Division of Gastroenterology, Department of Medicine, University of California, San Diego, California, USA
¹⁰Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
¹¹Lawson Health Research Institute, London, Ontario, Canada

Correspondence
Vipul Jairath, Department of Medicine, Division of Gastroenterology; Department of Epidemiology and Biostatistics. Western University, London, ON, Canada. Email: vjairath@uwo.ca

Lotus Alphonsus and Theshani A. De Silva are joint first authors.

Author Contributions
Lotus Alphonsus: Data curation (equal); writing – original draft (equal); writing – review and editing (equal). Theshani A De Silva: Data curation (equal); writing – original draft (equal); writing – review and editing (equal). Christopher Ma: Writing – review and editing (equal). John K MacDonald: Data curation (equal); formal analysis (equal); supervision (equal); writing – original draft (equal); writing – review and editing (equal). Jurij Hanzel: Writing – review and editing (equal). Melanie Beaton: Writing – review and editing (equal). Talat Bessissow: Writing – review and editing (equal). Maia Kayal: Writing – review and editing (equal). Rocio Sedano: Writing – review and editing (equal). Siddharth Singh: Writing – review and editing (equal). Vipul Jairath: Conceptualization (equal); data curation (equal); supervision (equal); writing – original draft (equal); writing – review and editing (equal). All authors have approved the final version of the manuscript, including the authorship list.

Conflict of Interest Statement
LA and TD have no conflict of interest to disclose. CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda and Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer and Takeda; royalties from Springer Publishing and research support from Ferring, Pfizer. JKM is an employee of Alimentiv Inc. JH has received speaker's fees from Abbvie, Janssen and Takeda and consulting fees from Alimentiv Inc. MB has received honoraria/advisory board fees from AbbVie, Takeda, Janssen, Lupin Pharma, Gilead, Pfizer, Novo Nordisk, McKesson, Shire and Allergan. TB has received consulting or speaker fees from Abbvie, Alimentiv, Amgen, Bristol Myers Squibb, Ferring, Janssen, Merck, Pfizer, Roche, Sandoz, Takeda, Gilead, Viatris and Fresenius Kabi. MK has received consulting fees from AbbVie, Pfizer, Fresenius and GoodRx. RS is an employee of Alimentiv Inc. SS has received personal fees from Pfizer for ad hoc grant review and research funding from Pfizer and AbbVie. VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, Topivert; and speaker's fees from, Abbvie, Ferring, Janssen Pfizer Shire and Takeda.