Pouchitis: What Every Gastroenterologist Needs to Know

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;xx:xxx

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Pouchitis: What Every Gastroenterologist Needs to Know AQ: au

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AQ: 1 AGAF, Department of Gastroenterology/Hepatology, Digestive Disease Institute, The Cleveland Clinic Foundation, Cleveland, Ohio

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Pouchitis is the most common complication among patients with ulcerative colitis who have undergone restorative proctocolectomy with ileal pouch–anal anastomosis. Pouchitis is actually a spectrum of diseases that vary in etiology, pathogenesis, phenotype, and clinical course. Although initial acute episodes typically respond to antibiotic therapy, patients can become dependent on antibiotics or develop refractory disease. Many factors contribute to the course of refractory pouchitis, such as the use of nonsteroidal anti-inflammatory drugs, infection with Clostridium difficile, pouch ischemia, or concurrent immune-mediated disorders. Identification of these secondary factors can help direct therapy. Keywords: Ileal Pouch; Pouchitis; Restorative Proctocolectomy; Ulcerative Colitis.

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he past decade has witnessed a rapid process in the medical treatment for ulcerative colitis (UC), particularly the availability and a wide use of anti–tumor necrosis factor (TNF) biological agents.1 Although the medical community has anticipated that the advance in medical therapy may have an impact on the disease course of UC, by reducing the need for colectomy,2 the long-term efficacy of the biological agents is still unclear. On the other hand, restorative proctocolectomy with ileal pouch–anal anastomosis (IPAA) has become the surgical treatment of choice for the majority of patients with UC or familial adenomatous polyposis (FAP) who require colectomy. Over the years, various forms of the ileal pouch configuration have been developed, ranging from Kock pouch (also known K or continent ileostomy), S pouch, to W or J pouches (Figure 1). One pouch configuration may offer technical advantages over the other. For example, UC patients with a poor anal sphincter function may be elected to have a K pouch after colectomy. Obese UC patients with a short mesentery may be chosen to have an S pouch after colectomy because this particular pouch configuration offers an additional 2 to 2.5 cm of small bowel, as an efferent limb, to reach the anal canal. The W pouch, which was designed in the 1980s, largely has been abandoned because of its frequent complications. The choice between the various forms of ileal pouches depends on the following: (1) indication for colectomy (neoplasia vs refractory UC); (2) mucosectomy vs no mucosectomy; and (3) technical feasibility (body mass index, length of mesentery, and pathology of the anal canal or rectal stump). Currently, the most commonly performed ones are J and S pouches. The pouch procedure has been shown to improve patients’ health-related quality of life significantly and to reduce the risk for colitis-associated neoplasia. On the other hand, various

complications from the pouch surgery have been reported, ranging from procedure-associated leaks, strictures, sinuses, or fistulae, to pouchitis, cuffitis, and de novo Crohn’s disease (CD)-like conditions and irritable pouch syndrome (IPS). Pouchitis is the most common complication in UC patients with IPAA, with a reported cumulative prevalence ranging from 23% to 46%,3– 6 and an annual incidence up to 40%.7 Oral antibiotic therapy has been the mainstay treatment for patients with pouchitis based on the current theory that the inflammation at the ileal pouch reservoir results from or is triggered by the alteration in the composition of microbiota. However, we have encountered an increasing number of patients with pouchitis who initially responded to antibiotic therapy and developed refractory disease later on. The management of chronic antibiotic-refractory pouchitis (CARP) has been challenging and, in fact, chronic pouchitis is one of the most common causes for pouch failure, defined as permanent diversion, pouch excision, or complete pouch revision.8

Etiology and Pathogenesis Mounting evidence suggests that gut microbiota play a key role in the initiation and disease progression of pouchitis. The contribution of gut microbiota to the pathogenesis of pouchitis may be 2-fold: the alteration in commensal bacteria (ie, dysbiosis)9 –12 and the emergence of pathogenic bacteria, fungi, or viruses (such as Clostridium difficile13). The exact role of bacterial diversity or dysbiosis in the pathogenesis of pouchitis is not entirely clear, as it is in the field of inflammatory bowel disease (IBD).14 The construction of the ileal reservoir leads to an altered bowel anatomy that can promote fecal stasis and colonic metaplasia in the pouch body from the original ileal mucosa, creating an environment favorable to the development of inflammation. It is intriguing that certain bacterial species, such as Bacteriodaceae species and Clostridiaceae species, were shown to be associated with inflammation of the pouch mucosa, whereas others, such as Enterococcaceae species, may have an active role in maintaining immunologic homeostasis in the pouch mucosa.15 Unfortunately, even with the state-of-the-art molecular microbiology technology, no individual species or phylotypes have been shown consistently to be related specifiAbbreviations used in this paper: CARP, chronic antibiotic-dependent pouchitis; CD, Crohn’s disease; CDI, Clostridium difficile infection; CMV, cytomegalovirus; FAP, familial adenomatous polyposis; IBD, inflammatory bowel disease; IPAA, ileal pouch-anal anastomosis; IPS, irritable pouch syndrome; NSAID, nonsteroidal anti-inflammatory drugs; PSC, primary sclerosing cholangitis; TNF, tumor necrosis factor; UC, ulcerative colitis. © 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.03.033

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C O L O R Figure 1. Configurations and anatomy of various ileal pouches.

cally to pouchitis.12,16 Potential candidate bacterial species related to pouchitis may include Lachnospiraceae, Incertae Sedis XIV, and Clostridial cluster IV.17 Pathogen-associated pouchitis can occur in a subset of patients. C difficile infection (CDI) is common in symptomatic patients with IPAA, with either enzyme immunoassay (EIA)13 or polymerase chain reaction (PCR)18-based assays. Patients who were positive for C difficile after IPAA had a wide range of clinical presentations, ranging from being asymptomatic carriers (with colonization) to fatal outcomes.19 Other pathogens have been reported to be associated with episodes of active pouchitis, including C perfringens,9 Campylobacter species,20 group D streptococci (Enterococcus species),21 hemolytic strains of E coli,22 and cytomegalovirus (CMV)23,24 infection. These pathogenic microbes detected in pouchitis patients with systemic symptoms may contribute to disease episodes or be responsible for a refractory course to conventional antibiotic therapy. The alteration in both innate and adaptive mucosal immunity in the noninflamed pouch and pouchitis has been studied extensively.25–30 Different bacterial species may exert different impacts on innate and adaptive mucosal immune function.15,31 Fecal stasis, the increased microbial load, and constant exposure to lumen contents might collectively cause adaptive morphologic alterations in the pouch mucosa that mimic colonic metaplasia.32 Colonic metaplasia seems to be associated with dysbiosis, particularly the presence of sulfate-reducing bacteria.33 Alterations in mucin glycoproteins, similar to that seen in UC, also occur in pouchitis.34 Altered glycoproteins are more susceptible than the native molecules to enzymatic degradation by microbiota with the breach of mucosal barrier function.35 An increased permeability of the gastrointestinal mucosa to microbiota was observed in the ileal pouch.25 Aberrant expression of Toll-like receptors have been found in the ileal pouches of patients with and without pouchitis.31,36,37 Antimicrobial peptides produced by intestinal Paneth cells and other gut epithelial cells are important components of innate immunity in the gastrointestinal tract.38 – 40 The expression of Paneth-cell–specific human defensin-5 is increased in both inflamed and noninflamed pouches compared with that in the normal terminal ileum.41,42 The findings suggest that innate mucosal immunity

actively is involved in both normal adaptation to fecal stasis/ bacterial overload and the development of pouchitis. Adaptive mucosal immunity also has been studied in pouchitis for the past 2 decades. There was an increased proliferation of immature plasma cells in pouchitis.29,30,43 There was also an increased production of proinflammatory mediators/cytokines, such as TNF,44 – 47 cell adhesion molecules,48 platelet-activating factor,49 lipoxygenase products of arachidonic acids,50,51 vascular endothelial growth factor,51 and proinflammatory neuropeptides.45,52–54 UC pouches were shown to have higher levels of proinflammatory cytokines than that of FAP pouches.55 Imbalance between proinflammatory (such as interleukin [IL]-8) and immunoregulatory (such as IL-10) cytokines may contribute to the inflammatory process of pouchitis.47 However, the abnormalities in adaptive mucosal immunity probably reflect activation of a nonspecific inflammatory cascade or pathway.45 Nonetheless, the up-regulation of the proinflammatory mediators may provide therapeutic targets, particularly in CARP.

Risk Factors In addition to gut microbiota and mucosal immunity, genetic, vascular, and luminal factors (such as nonsteroidal anti-inflammatory drugs [NSAIDs]) are likely to contribute to the initiation, exacerbation, and progression of pouchitis. Pouchitis almost exclusively occurs in patients with restorative proctocolectomy with underlying IBD and rarely in those with FAP, suggesting the contribution of genetic and/systemic factors to its pathogenesis. Immunogenetic studies showed that genetic polymorphisms such as those of IL-1–receptor antagonist,56 NOD2/CARD15,57,58 or a combined carriership of Tolllike receptor 9-1237C and CD14-260T alleles,59 were associated with the risk for chronic pouchitis. Mutations of NOD2/ CARD15 and TNFSF15 also were shown to be related to severe pouchitis.60 Systemic or environmental risk factors reported to be associated with pouchitis include extensive UC,61,62 the presence of backwash ileitis,61,63 precolectomy thrombocytosis,64 the presence of concurrent primary sclerosing cholangitis (PSC)63,65,66 or other immune-mediated disorders,67 being a nonsmoker,62,68

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the regular use of NSAIDs,62,66 and ischemia.69 Systemic immune reactions to bacterial antigens as well as host’s self-tissue also have been studied in pouchitis. Reported pouchitis-related serology markers include perinuclear antineutrophil cytoplasmic antibodies,6,63,70,71 anti-CBir1 flagellin,6 IgG4,72 and microsomal antibodies.73 It should be pointed out that pouchitis represents a disease spectrum from an acute antibiotic-responsive form to a chronic antibiotic-refractory phenotype. Different phenotypes of pouchitis may reflect the same disease process at different stages or different disease processes with various etiopathogenetic pathways. As such, acute and chronic pouchitis may be associated with different risk factors.62 For example, smoking was associated with acute pouchitis,6 whereas extraintestinal manifestations, 6 preoperative thrombocytosis, a long duration of IPAA,6 and postoperative surgery-related complications,74 were reported to be associated with chronic pouchitis. Smoking appears to be a protective factor against the development of chronic pouchitis.75 Patients with CARP, not acute pouchitis, were reported to be associated with concurrent autoimmune disorders.67

Diagnosis and Differential Diagnosis

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The diagnosis of pouchitis is not always straightforward because of the lack of specific symptoms and signs. Patients with healthy pouches are expected to have 4 to 7 soft bowel movements a day, with continence. Patients with pouchitis can have a wide range of clinical presentations, ranging from increased stool frequency, urgency, abdominal cramps, night time seepage, to incontinence. These symptoms, however, are not specific and they can be present in other inflammatory and noninflammatory disorders of the pouch. Furthermore, the severity of subjective symptoms does not correlate with the objective degree of objective inflammation on endoscopy or on histology.76,77 Therefore, the diagnosis of pouchitis should not be dependent solely on the symptom assessment. To complicate the matter further, the diagnosis of pouchitis may resemble hitting a moving target because the disease process of pouchitis and other pouch disorders may not be static. For example, a patient who has typical acute antibiotic-responsive pouchitis as an initial presentation may later develop CD of the pouch. Therefore, a combined assessment of symptoms, endoscopic features, and histologic features is advocated for the diagnosis and differential diagnosis of pouchitis.76,78 Several diagnostic instruments have been proposed for the diagnosis of pouchitis and grading of severity. Among them is the 18-point Pouchitis Disease Activity Index consisting of symptom, endoscopy, and histology subscores,78 which has been the most commonly used, mainly as a research tool. The endoscopy is the most accurate to grade the degree of inflammation. Differential diagnosis of pouchitis. Various inflammatory and functional disorders of the pouch share similar clinical presentations with pouchitis. Among them are IPS, cuffitis, CD of the pouch, and fecal incontinence from anal sphincter damage. IPS, by definition, is featured with clinical symptoms of diarrhea, cramps, and urgency, in the absence of endoscopic or histologic inflammation of the pouch. Currently, IPS is a diagnosis of exclusion, although evaluation with a barostat examination often yields visceral hypersensitivity in patients.79 Cuffitis, which is considered a variant of ulcerative proctitis, typically causes urgency and blood in stools. De novo

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CD of the pouch can occur in patients with a preoperative diagnosis of UC. It has 3 phenotypes: inflammatory, fibrostenotic, and fistulizing. Pouch inflammation can be a part of CD. Endoscopic evaluation. It is important to correctly identify the landmarks of J, S, and K pouches during endoscopic and radiographic evaluation. The characteristic landmarks include the afferent limb, pouch inlet, the tip of J (in J pouch), efferent limb (which are different between J and S pouches), and the pouch outlet (the anal transitional zone or rectal cuff for J and S pouches or the nipple valve for a K pouch) (Figure 1). Pouchoscopy is the most valuable tool for the diagnosis and differential diagnosis of pouchitis. A careful pouchoscopy should include the evaluation of the earlier-described landmarks, including the afferent limb, pouch inlet, the tip of the J, pouch body, anastomosis, and anal transitional zone or cuff (Figure 2A). Sedated or nonsedated pouchoscopy provides the most valuable information on the configuration and distensibility of the pouch body, severity, extent, or distribution of mucosal inflammation (Figures 2 and 3), and the presence of concurrent backwash ileitis, cuffitis, or inflammatory polyps. The presence of a mucosal ridge, inflammatory polyps (Figure 2D), poorly distensible or pouch body (Figure 2B), or the loss of the “owls’ eye” configuration of a J pouch (Figure 2A),80 suggests chronic inflammation. Immune-mediated pouchitis, such as those caused by PSC, autoimmune disorders, and IgG4associated pouchitis, often has concurrent long segment inflammation at the afferent limb in addition to diffuse pouchitis (Figure 3B and C). Asymmetric distribution of inflammation in the pouch body may be a sign of ischemic pouchitis. Typically, inflammation in ischemic pouchitis is present only at the distal half to quarter of the pouch body or at one limb of the pouch body, sparing the rest of the pouch, with a sharp demarcation of inflamed and inflamed parts (Figure 2C).69 Pouchoscopy is also a major modality for the diagnosis of CD of the pouch and surgery-related complications (such as stricture, fistula, sinus [Figure 3D], and prolapse).81 Patients with CD of the pouch typically have segmental inflammation of the pouch body and/or afferent limb, strictures at the pouch inlet or afferent limb, the presence of complex perianal fistulas or pouch-vaginal fistulas with an internal fistular orifice at the anal canal (rather than at the dentate line for cryptoglandular fistula or at the anastomosis for surgical leak). Abdominal/pelvic imaging. Abdominal imaging is an important part of the evaluation for the diagnosis and differential diagnosis of ileal pouch disorders. Pouchitis can be present alone or with other concurrent inflammatory or mechanical/structural complications (such as stricture, sinus, or fistula). In fact, pouch inflammation can be a part of CD. A water-soluble contrast pouchogram often is used to delineate the pouch shape and anatomy and the presence of luminal angulation, stricture, sinus, or fistula. Computed tomography enterography or magnetic resonance imaging enterography is useful for the evaluation of the location, number, and degree of strictures, the presence of an abscess, or the presence of inflammation of the pouch as well as the proximal small bowel. Contrast pelvic magnetic resonance imaging with fistula protocol is valuable for the evaluation of the anatomy and abnormalities around the pouch and anal transitional zone, such as sinus, fistula, sinus, abscess, and presacral sinus-associated osteomyelitis. Anorectal ultrasound often is useful in the detec-

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C O L O R Figure 2. Normal pouch and pouchitis of various etiologies on endoscopy. (A) Normal pouch with an owls’ eye configuration, reflecting a widely opened pouch inlet and the tip of a J. (B) Chronic pouchitis with ulcers and a stiff pouch. (C) Pouchitis with an ischemic pattern, with inflammation at the afferent limb side, and normal mucosa at the efferent limb side of the J pouch, with sharp demarcation of inflammation and noninflamed parts along the suture line. (D) A large pouch inflammatory polyp resulting from chronic mucosal inflammation.

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tion of anal sphincter injury, sinus, or fistula. In addition, examination under anesthesia in the operating room may be needed in complex pouch disorders (Figure 4).81 Histologic evaluation. Histology may have a limited role in grading acute or chronic inflammation of the pouch because it does not correlate with the more robust endoscopy scoring system. However, histologic evaluation provides valuable information on special features, such as granulomas, viral inclusion bodies (for CMV infection), pyloric gland metaplasia (a sign of chronic mucosal inflammation),82 and dysplasia, and the presence of crypt apoptosis (a sign of autoimmune enteritis)83 or IgG4-expressing plasma cells in the lamina propria.84 Laboratory evaluation. Laboratory testing is often necessary as a part of the evaluation for patients with pouch disorders, particularly in those with chronic pouchitis. Patients with healthy or diseased pouches often have iron-deficiency anemia85 and/or a low vitamin D level.86,87 Pouch patients with a cholestatic picture on the liver function panel, such as an increase of alkaline phosphatase, should be investigated for the presence of PSC. In patients with persistent symptoms, a stool test for CDI should be performed.88 For the majority of patients with a repeated or chronic exposure to antibiotics, CDI has been a growing problem.13 For patients with systemic symptoms, such as chills, fever, and night sweats, a fecal assay for other intestinal pathogens (such as Campylobacter species) and a blood or tissue assay for CMV or Epstein–Barr virus infection may be needed.

In patients with chronic pouchitis, fecal coliform culture and sensitivity testing could help to identify effective antibiotic agents.89 For patients with CARP, other etiologies need to be evaluated, in particular, one must look for the components of autoimmunity. The serology panel may include celiac tests, antinuclear antigens, serum IgG4 level,72 and antimicrosomal antibodies.73 Fecal assays of lactoferrin90 –92 and calprotectin93 have been investigated for the diagnosis and differential diagnosis of pouchitis. They may have some value in the assessment of treatment outcome (eg, mucosal healing). Genetic testing and IBD serology have been shown to provide useful information on the pathogenesis and prognosis of pouch disorders and IBD. However, the role of current available genetic and serologic profiles in the diagnosis and differential diagnosis of pouchitis is limited.

Classification and Disease Course Pouchitis represents a disease spectrum, with ranging pathogenetic pathways, clinical presentations, and disease courses. Clinically, the treatment for different phenotypes of pouchitis is not the same. Initial episodes of pouchitis in the majority of patients respond favorably to therapy with oral broad-spectrum antibiotics such as metronidazole, ciprofloxacin,94 and tinidazole. According to the duration of pouch-related symptoms, pouchitis can be classified into acute (⬍4 wk) and chronic (ⱖ4 wk) forms. Based on the response to and frequency of antibiotic therapy, pouchitis

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C O L O R Figure 3. Pouchitis of various etiologies on endoscopy. (A) Chronic pouch with concurrent distal pouch sinus (arrow). (B and C) Diffuse pouchitis and enteritis with a similar mucosa pattern in a patient with PSC. (D) Chronic pouchitis with C difficile infection.

can be categorized into antibiotic-responsive, antibiotic-dependent, and antibiotic-refractory phenotypes. Based on the etiology, pouchitis also can be divided into idiopathic and secondary (such as NSAID-induced, ischemia-related, and

CMV-associated) entities. Sometimes, the terminology combining the earlier-described features is used to characterize certain types of pouchitis, such as chronic antibiotic-refractory pouchitis (CARP).

Figure 4. Diagnostic algorithm for recurrent pouchitis. ANA, antinuclear antibody; LFT, liver function test.

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Table 1. Controlled Trials in Pouchitis Study

Study design

N

Indication

Agent

Duration

Madden et al,105 1994

RCT

13

Treatment of chronic pouchitis

Metronidazole 1.4 g/d vs placebo

1 wk

Gionchetti et al,114 2000

RCT, placebocontrolled

40

Secondary prophylaxis of relapsing pouchitis

Probioticsa 6 g/d vs placebo

9 mo

Shen, 2001

RCT

16

Treatment of acute antibiotic responsive pouchitis

2 wk

Gionchetti et al,7 2003

RCT, placebocontrolled

40

Primary prophylaxis of pouchitis

Ciprofloxacin 1 g/d vs metronidazole 20 mg/kg/d Probioticsa 3 g/d vs placebo

Mimura et al,115 2004

RCT, placebocontrolled

36

Secondary prophylaxis of relapsing pouchitis

Probioticsa 6 g/d vs placebo

Up to 1 y

Isaacs et al,104 2007

RCT, placebocontrolled

18

Treatment of active pouchitis

Rifaximin 1.2 g/d vs placebo

4 wk

12 mo

Outcome 2 in stool frequency, more in study group than in placebo Relapse in 15% of study group; 100% in placebo (P ⬍ .001). 2 in PDAI score: ciprofloxacin ⫺6.7; metronidazole ⫺5.9 Pouchitis in 10% of the study group; 40% in placebo (P ⬍ .05). Relapse in 15% of the study group; 94% in placebo (P ⬍ .0001) Remission in 25% of the study group; 0% in control (P ⫽ .206)

PDAI, Pouchitis Disease Activity Index (range, 0 –18 points); RCT, randomized, controlled trial. aVSL#3 contains 4 strains of Lactobacillus (L casei, L plantarum, L acidophilus, and L delbrueckii subspecies bulgaricus), 3 strains of Bifidobacterium (B longum, B breve, and B infantis), and 1 strain of Streptococcus salivarius subspecies thermophilus.

The timing of the initial onset of pouchitis may suggest its etiology. In our anecdotal experience, pouchitis, which occurs immediately after ileostomy closure, may result from procedure-associated complications, such as ischemia or anastomotic leaks. On the other hand, the late initial onset of pouchitis (ie, onset occurring years after pouch construction), can be related to systemic or local factors, such as excessive weight gain.95 The natural history of pouchitis may follow the disease course of IBD, progressing from an acute disease of bacterial etiology to a chronic disease with persistent inflammation from dysregulated immunity. For example, acute, antibiotic-responsive pouchitis may evolve into CARP. The disease course varies between affected individuals. Approximately 39% of patients with acute pouchitis who have a single episode responding to antibiotic therapy may never have recurrence.96 However, relapse of pouchitis or recurrent pouchitis is common; however, in this study, the remaining 61% had at least one subsequent relapse. It is estimated that 5% to 19% of patients with acute pouchitis develop refractory pouchitis or a frequently relapsing form of the disease.97–99 CARP is one of the common causes for pouch failure, resulting in permanent diversion or pouch excision.

Management Pouchitis patients often benefit from low-carbohydrate and/or low-fiber diets. Its rationale is the presence of smallbowel bacterial overgrowth from the lack of valve function at the junction between the afferent limb and pouch body. An elemental diet has been shown to help relieve symptoms of chronic pouchitis.100 Antidiarrheal agents can be used for the treatment of frequent and/or loose/watery bowel movements. Primary prophylaxis of initial episodes of pouchitis. Primary prophylaxis of the initial episodes of pouchitis after ileostomy closure, using probiotic or antibiotic agents, has been investigated. In a randomized trial of a probiotic agent,

called VSL#3 (containing Lactobacillus species, Bifidobacterium species, Streptococcus salivarius species, and Thermophilus species), 2 of 20 patients (10%) in the study group and 8 of 20 (40%) in the placebo group developed pouchitis within 12 months of ileostomy closure.7 The administration of Lactobacillus rhamnosus GG also was shown to be effective in the primary prophylaxis.101,102 A small, randomized, placebo-controlled trial of oral tinidazole also showed some efficacy in preventing initial episodes of pouchitis.103 Treatment of acute pouchitis. Patients with initial episodes of acute pouchitis typically respond to antibiotic therapy. In patients who experience pouchitis symptoms immediately after pouch construction and ileostomy closure and do not respond to the antibiotic therapy, surgery-associated complications, such as pouch anastomotic leaks or sinus, should be suspected. There are few published randomized placebo-controlled trials on the treatment of or on the secondary prevention of pouchitis (Table 1). Metronidazole, ciprofloxacin, tinidazole, and rifaximin104 commonly have been used in the treatment of acute pouchitis in clinical practice. The first-line therapy includes a 14-day course of metronidazole (15–20 mg/ kg/d) or ciprofloxacin (1 g/d).94,105,106 Open-label combination therapy using ciprofloxacin and metronidazole for 4 weeks was effective in treating pouchitis and backwash ileitis in patients with or without concomitant PSC.107 Other antibiotic or nonantibiotic agents also have been investigated and shown to be effective in some patients in small case studies, including amoxicillin-clavulanic acid and a carbon microsphere agent.108 Diffuse pouchitis can be associated with backwash ileitis, particularly in patients with concurrent PSC, which can be treated with oral budesonide.109 High-dose VSL#3 was reported to be effective for treating mild pouchitis.110 Secondary prophylaxis of subsequent episodes of pouchitis. Relapse of pouchitis or recurrent pouchitis is common after the treatment and resolution of the initial treatment.111 An estimated 5% to 19% of patients with acute pouchi-

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tis develop treatment-refractory or a frequently relapsing form of the disease.99,112,113 Randomized placebo-controlled trials hae shown that VSL#3 was effective for maintaining antibioticinduced remission in patients with relapsing pouchitis.114,115 In the first randomized controlled trial from Bologna, Italy, VSL#3 was given at a dose of 6 g/d as maintenance therapy after remission had been induced by oral ciprofloxacin (1 g/d) and rifaximin (2 g/d). During this 9-month trial conducted in 40 patients, 15% of patients in the probiotic group relapsed, compared with 100% of patients in the placebo group.114 Similar results were reported in another randomized controlled trial of VSL#3 from St Mark’s Hospital in London, in which 29 of 36 participants also were from Bologna, Italy.115 In postmarketing, open-label studies, the response rate to VSL#3 was not as high as in the randomized controlled trials. In a study of 31 patients with antibiotic-dependent pouchitis, who received VSL#3 as maintenance therapy after induction of remission using 2 weeks of treatment with ciprofloxacin, 25 patients (81%) had stopped taking the probiotic at 8 months because of the lack of efficacy or the development of adverse effects.116 Similar results with 13% efficacy were reported in a separate open-label trial of this agent.117 The discrepancy in the reported efficacy among the published or presented studies may be owing to the dietary structure of the study populations, inclusion criteria, and dosage of the probiotic agents. Other options for maintenance therapy for antibiotic-dependent pouchitis could be rifaximin,118 and oral or topical mesalamine.119 Treatment of chronic antibiotic-refractory pouchitis. Patients with CARP, by definition, do not respond to conventional antibiotic therapy. The treatment of CARP has been challenging. The commonly used broad-spectrum antibiotics, such as ciprofloxacin and metronidazole, do not target any specific bacterial agents. Therefore, fecal bacterial culture and sensitive assay have been recommended to identify suitable antibiotics.89 Secondary factors that are associated with an antibiotic-refractory course should be identified and managed. These factors include NSAID use, concurrent pouch surgery–related mechanical complications (such as ischemia,69 stricture, fistula, and sinus), CDI, CMV infection, and the presence of immunemediated disorders (eg, PSC and celiac disease).67 Treatment options for CARP include a prolonged course of combined antibiotic therapy, such as 4 weeks of a combination of ciprofloxacin (1 g/d) with rifaximin (2 g/d),120,121 metronidazole (1 g/d),122 or tinidazole (1–1.5 g/d).119 In small case series, corticosteroids (including topical or oral budesonide109,123), immunosuppressive agents, or even infliximab124 or adalimumab125 have been studied for the treatment of CARP with some efficacy. The efficacy of those agents suggests the role of immune-mediated processes in the disease initiation, relapse, and progression of CARP. Newly described autoimmune pouchitis83 and IgG4-associated pouchitis84 also may be evaluated. The treatment for immune-medicated pouchitis is empiric at this point and treatment options include corticosteroids, immunomodulators, or anti-TNF biologics. It should be pointed out that there is a great overlap in pharmaceutical therapy between the treatment of CARP and CD of the pouch. For example, a long-term single or dual antibiotic therapy or topically active corticosteroid (budesonide) has been used for both CARP and CD of the pouch. Although immunomodulator or anti-TNF biological therapy commonly is used in treating the fistulizing form of CD of the pouch,126,127 those agents are

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not applied routinely in CARP. For fibrostenotic CD of the pouch, medical therapy often is combined with endoscopic treatment.128 Chronic pouchitis may be associated with concurrent mechanical or structural disorders of the pouch, such as strictures and anastomotic sinus. For example, pouch outlet obstruction (such as anastomotic stricture), can be associated with pouchitis, presumably owing to bacteria overload from prolonged fecal stasis. The release of the obstruction, often along with concurrent antibiotic therapy, may promote the resolution of pouchitis.128 Treatment of C difficile pouchitis. CDI poses a unique problem for patients with ileal pouches. Fecal C difficile toxins should be tested routinely in patients with antibioticdependent or antibiotic-refractory pouchitis. Pouch patients with a positive stool test for C difficile toxins may have a different clinical presentation, ranging from being an asymptomatic carrier to having fulminant pouchitis/enteritis.19 With an emerging prevalence and severity of CDI in patients with or without IBD (including those with ileal pouches), it has been recommended that oral vancomycin be considered as the firstline therapy in severe infection requiring hospitalization.129 Oral or intravenous metronidazole traditionally has been considered the first-line therapy for CDI. However, its efficacy specifically in the IBD or pouch population with CDI is unknown. Failure rates of metronidazole before the emergence of the epidemic C difficile BI/NAP1/027 strain were 16%, but more recently reported failure rates have been alarmingly high at 35%.130,131 In pouch patients with or without CDI, a vast majority were exposed to, and were on, oral metronidazole therapy.13,18 Therefore, I recommend that for patients with CARP or severe pouchitis and CDI, which can be fulminant and lethal,19 oral vancomycin may be considered as the first-line therapy. The recommended dose of oral vancomycin is 125 to 250 mg qid twice daily for 4 weeks. For patients with mild acute pouchitis, without prior or concurrent exposure to metronidazole, oral metronidazole may be used as the first-line therapy. Oral fidoxamicin 200 mg twice a day for 10 to 14 days or fecal microbiota transplantation (personal unpublished data) can be valid alternatives for refractory or recurrent CDI.

Prospective View and Recommendations It is obvious that microbiota play a critical role in the pathogenesis of pouchitis. In fact, all currently published randomized controlled trials in pouchitis are regarding the efficacy of antibiotics or probiotics (Table 1). On the other hand, the investigation of the role of gut microbiota in the etiopathogenesis of pouchitis has been difficult because 90% of gut bacteria are not culturable.132 Molecular microbiology techniques for the qualitative and quantitative measurement of microbiota are expensive and labor-intensive, particularly for the identification of the individual responsible bacteria. There are great variations in the composition of gut microbiota among healthy individuals, not mentioning the difference among healthy and diseased individuals. Therefore, the interpretation of the microbiota profile in cross-sectional studies comparing healthy and diseased pouches can be difficult. Furthermore, the commonly used broad-spectrum antibiotic agents are not targeted for any specific bacteria species. We hope that those agents can help restore the normal balance between good and bad bacteria in the pouch. It is common that patients with antibiotic-responsive pouchitis later develop antibiotic dependency or resistance.

369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 AQ: 21 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429

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Figure 5. Treatment algorithm for pouchitis.

We speculate that the persistent alteration of gut microbiota or dysbiosis, despite intermittent or chronic antibiotic therapy or probiotic therapy, consistently induces an abnormal mucosal immune response, leading to chronic pouchitis or CARP. Patients with genetic susceptibility (such as those with a NOD2 mutation) and/or systemic immune-mediated disorders (such as PSC, IgG4-associated systemic disorders) may be particularly vulnerable to the development of CARP. A molecular classification of pouchitis, with a combined assay of immunogenetic, serologic, and clinical markers, would be invaluable for the identification of etiopathogenesis, diagnosis, treatment stratification, and prognosis prediction. It has become clear that we should take a 3-dimensional view of pouchitis. Pouchitis represents a disease spectrum with various pathogenetic pathways, clinical presentations, and disease courses ranging from acute antibiotic-response type to chronic antibiotic-refractory phenotypes. For each individual patient, on the other hand, the diagnosis of pouchitis or other pouch disorders can be a moving target. Therefore, patients with IPAA should be monitored closely. Pouchoscopy is the best way to monitor the disease status of the pouch, to grade the degree of inflammation, and to identify structural abnormalities. Patients with minimal symptoms but with endoscopic inflammation still should be treated to minimize smoldering inflammation causing chronic “stiff” pouch with transmural inflammation, which can result in pouch failure.133 More importantly, different treatment strategies should be applied to treat different phenotypes of pouchitis at different stages. Diagnosis (Figure 4) and treatment (Figure 5) algorithms are proposed based on published studies as well as my own experience in the subspecialty Pouch Center at the Cleveland Clinic.134 If a patient has symptoms of increased bowel frequency, watery stools, or urgency, antidiarrheal agents can be used first. If the symptoms do not get better in 1 to 2 days, the patient should be evaluated and in some cases treated empirically with antibiotics. Pouchoscopy, the diagnostic test of choice, needs to be performed, along with laboratory evalua-

tion. In most cases, the combined evaluation of endoscopy, histology, and laboratory testing often provides clues for triggering, or etiologic factors for, the flare-up. For patients with diffuse pouchitis and diffuse enteritis of the afferent limb, immune-mediated pouchitis/enteritis may be considered. For patients with pouch inflammation that is distributed asymmetrically and has a sharp demarcation of inflamed and noninflamed parts, ischemic pouchitis is a possibility (Figure 4). Often, pouchoscopy may show clues of structural abnormalities, such as strictures, fistulas, and sinuses. If CD of the pouch is suspected, abdominal and pelvic imaging or examination under anesthesia often is needed. The treatment of antibiotic-responsive pouchitis is straightforward. The prognosis of pouchitis is determined by the frequency of the need for antibiotic therapy (antibiotic-dependent pouchitis) and the development of the refractory disease course (CARP). A prolonged course of dual antibiotic therapy may help induce remission in patients with CARP. Oral or topical mesalamine agents and a topically active corticosteroid agent (budesonide) are the preferred first-line drugs for immune-mediated pouchitis/enteritis. Back-up agents may include 6-mercaptopurine/azathioprine, methotrexate, tacrolimus, or anti-TNF agents (Figure 5). In summary, the diagnosis and management of pouchitis and the identification of its etiologic or triggering factors can be challenging. Pouchitis represents a disease spectrum, ranging from an acute antibiotic-responsive form to a chronic antibiotic-refractory phenotype, with different disease mechanisms and prognoses. A combined evaluation of pouchoscopy, histology, and laboratory testing may help classify disease phenotypes and stratify their management. References 1. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–2476.

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2. Targownik LE, Singh H, Nugent Z, et al. The epidemiology of colectomy in ulcerative colitis: results from a population-based cohort. Am J Gastroenterol 2012;107:1228 –1235. 3. Penna C, Dozois R, Tremaine W, et al. Pouchitis after ileal pouch–anal anastomosis for ulcerative colitis occurs with increased frequency in patients with associated primary sclerosing cholangitis. Gut 1996;38:234 –239. 4. Fazio VW, Ziv Y, Church JM, et al. Ileal pouch–anal anastomosis complications and function in 1005 patients. Ann Surg 1995; 222:120 –127. 5. Ferrante M, Declerck S, De Hertogh G, et al. Outcome after proctocolectomy with ileal pouch–anal anastomosis for ulcerative colitis. Inflamm Bowel Dis 2008;14:20 –28. 6. Fleshner P, Ippoliti A, Dubinsky M, et al. Both preoperative perinuclear antineutrophil cytoplasmic antibody and anti-CBir1 expression in ulcerative colitis patients influence pouchitis development after ileal pouch–anal anastomosis. Clin Gastroenterol Hepatol 2008;6:561–568. 7. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202–1209. 8. Tulchinsky H, Hawley PR, Nicholls J. Long-term failure after restorative proctocolectomy for ulcerative colitis. Ann Surg 2003;238:229 –234. 9. Duffy M, O’Mahony L, Coffey JC, et al. Sulfate-reducing bacteria colonize pouches formed for ulcerative colitis but not for familial adenomatous polyposis. Dis Colon Rectum 2002;45:384 –388. 10. Nasmyth DG, Godwin PG, Dixon MF, et al. Ileal ecology after pouch-anal anastomosis or ileostomy. A study of mucosal morphology, fecal bacteriology, fecal volatile fatty acids, and their interrelationship. Gastroenterology 1989;96:817– 824. 11. Komanduri S, Gillevet PM, Sikaroodi M, et al. Dysbiosis in pouchitis: evidence of unique microfloral patterns in pouch inflammation. Clin Gastroenterol Hepatol 2007;5:352–360. 12. Sokol H, Lay C, Seksik P, et al. Analysis of bacterial bowel communities of IBD patients: what has it revealed? Inflamm Bowel Dis 2008;14:858 – 867. 13. Shen BO, Jiang ZD, Fazio VW, et al. Clostridium difficile infection in patients with ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol 2008;6:782–788. 14. Lim M, Sagar P, Finan P, et al. Dysbiosis and pouchitis. Br J Surg 2006;93:1325–1334. 15. Scarpa M, Grillo A, Faggian D, et al. Relationship between mucosa-associated microbiota and inflammatory parameters in the ileal pouch after restorative proctocolectomy for ulcerative colitis. Surgery 2011;150:56 – 67. 16. McLaughlin SD, Walker AW, Churcher C, et al. The bacteriology of pouchitis: a molecular phylogenetic analysis using 16S rRNA gene cloning and sequencing. Ann Surg 2010;252:90 –98. 17. Tannock GW, Lawley B, Munro K, et al. Comprehensive analysis of the bacterial content of stool from patients with chronic pouchitis, normal pouches, or familial adenomatous polyposis pouches. Inflamm Bowel Dis 2012;18:925–934. 18. Li Y, Qian J, Queener E, et al. Risk factors and outcome of PCR-detected Clostridium difficile infection in ileal pouch patients. Inflamm Bowel Dis 2013;19:397– 403. 19. Shen B, Remzi FH, Fazio VW. Fulminant Clostridium difficileassociated pouchitis with a fatal outcome. Nat Rev Gastroenterol Hepatol 2009;6:492– 495. 20. Shen B. Campylobacter infection in patients with ileal pouches. Am J Gastroenterol 2010;105:472– 473. 21. Ingram S, McKinley JM, Vasey F, et al. Are inflammatory bowel disease (IBD) and pouchitis a reactive enteropathy to group D streptococci (enterococci)? Inflamm Bowel Dis 2009;15:1609 – 1610.

POUCHITIS

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22. Gosselink MP, Schouten WR, van Lieshout LM, et al. Eradication of pathogenic bacteria and restoration of normal pouch flora: comparison of metronidazole and ciprofloxacin in the treatment of pouchitis. Dis Colon Rectum 2004;47:1519 –1525. 23. Muñoz-Juarez M, Pemberton JH, Sandborn WJ, et al. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as a refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum 1999;42:117–120. 24. Moonka D, Furth EE, MacDermott RP, et al. Pouchitis associated with primary cytomegalovirus infection. Am J Gastroenterol 1998;93:264 –266. 25. Kroesen AJ, Leistenschneider P, Lehmann K, et al. Increased bacterial permeation in long-lasting ileoanal pouches. Inflamm Bowel Dis 2006;12:736 –744. 26. de Silva HJ, Jones M, Prince C, et al. Lymphocyte and macrophage subpopulations in pelvic ileal pouches. Gut 1991;32: 1160 –1165. 27. Hirata I, Berrebi G, Austin LL, et al. Immunohistological characterization of intraepithelial and lamina propria lymphocytes in control ileum and colon and in inflammatory bowel disease. Dig Dis Sci 1986;31:593– 603. 28. Stallmach A, Schäfer F, Hoffmann S, et al. Increased state of activation of CD4 positive T cells and elevated interferon gamma production in pouchitis. Gut 1998;43:499 –505. 29. Thomas PD, Forbes A, Nicholls RJ, et al. Altered expression of the lymphocyte activation markers CD30 and CD27 in patients with pouchitis. Scand J Gastroenterol 2001;36:258 –264. 30. Goldberg PA, Herbst F, Beckett CG, et al. Leukocyte typing, cytokine expression and epithelial turn over in the ileal pouch in patients with ulcerative colitis and familial adenomatous polyposis. Gut 1996;38:549 –553. 31. Scarpa M, Grillo A, Pozza A, et al. TLR2 and TLR4 up-regulation and colonization of the ileal mucosa by Clostridiaceae spp. in chronic/relapsing pouchitis. J Surg Res 2011;169:e145– e154. 32. Shepherd NA, Healey CJ, Warren BF, et al. Distribution of mucosal pathology and an assessment of colonic phenotype change in the pelvic ileal reservoir. Gut 1993;34:101–105. 33. Coffey JC, Rowan F, Burke J, et al. Pathogenesis of and unifying hypothesis for idiopathic pouchitis. Am J Gastroenterol 2009; 104:1013–1023. 34. Tysk C, Riedesel H, Lindberg E, et al. Colonic glycoproteins in monozygote twins with inflammatory bowel disease. Gastroenterology 1991;100:419 – 423. 35. Merrett MN, Soper N, Mortensen N, et al. Intestinal permeability in the ileal pouch. Gut 1996;39:226 –230. 36. Toiyama Y, Araki T, Yoshiyama S, et al. The expression patterns of Toll-like receptors in the ileal pouch mucosa of postoperative ulcerative colitis patients. Surg Today 2006;36:287–290. 37. Heuschen G, Leowardi C, Hinz U, et al. Differential expression of Toll-like receptor 3 and 5 in ileal pouch mucosa of ulcerative colitis patients. Int J Colorectal Dis 2007;22:293–301. 38. Porter EM, van Dam E, Valore EV, et al. Broad-spectrum antimicrobial activity of human intestinal defensin 5. Infect Immun 1997;65:2396 –2401. 39. Ayabe T, Satchell DP, Wilson CL, et al. Secretion of microbicidal ␣-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000;1:113–118. 40. Salzman NH, Ghosh D, Huttner KM, et al. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003;422:522–526. 41. Wehkamp J, Salzman NH, Porter E, et al. Decreased Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci U S A 2005;102:18129 –18134. 42. Scarpa M, Grillo A, Scarpa M, et al. Innate immune environment in ileal pouch mucosa: ␣5 defensin up-regulation as predictor of chronic/relapsing pouchitis. J Gastrointest Surg 2012;16:188 – 201.

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43. Hirata N, Oshitani N, Kamata N, et al. Proliferation of immature plasma cells in pouchitis mucosa in patients with ulcerative colitis. Inflamm Bowel Dis 2008;14:1084 –1090. 44. Patel RT, Bain I, Youngs D, et al. Cytokine production in pouchitis is similar to that in ulcerative colitis. Dis Colon Rectum 1995;38:831– 837. 45. Schmidt C, Giese T, Ludwig B, et al. Increased cytokine transcripts in pouchitis reflect the degree of inflammation but not the underlying entity. Int J Colorectal Dis 2006;21:419 – 426. 46. Gionchetti P, Campieri M, Belluzzi A, et al. Mucosal concentrations of interleukin-1 beta, interleukin-6, interleukin-8, and tumor necrosis factor-␣ in pelvic ileal pouches. Dig Dis Sci 1994; 39:1525–1531. 47. Bulois P, Tremaine WJ, Maunoury V, et al. Pouchitis is associated with mucosal imbalance between interleukin-8 and interleukin-10. Inflamm Bowel Dis 2000;6:157–164. 48. Patel RT, Pall AA, Adu D, et al. Circulating soluble adhesion molecules in inflammatory bowel disease. Eur J Gastroenterol Hepatol 1995;7:1037–1041. 49. Chaussade S, Denizot Y, Valleur P, et al. Presence of PAFacether in stool of patients with pouch ileoanal anastomosis and pouchitis. Gastroenterology 1991;100:1509 –1514. 50. Gertner DJ, Rampton DS, Madden MV, et al. Increased leukotriene B4 release from ileal pouch mucosa in ulcerative colitis compared with familial adenomatous polyposis. Gut 1994;35: 1429 –1432. 51. Romano M, Cuomo A, Tuccillo C, et al. Vascular endothelial growth factor and cyclooxygenase-2 are overexpressed in ileal pouch–anal anastomosis. Dis Colon Rectum 2007;50:650 – 659. 52. Stucchi AF, Shebani KO, Leeman SE, et al. A neurokinin 1 receptor antagonist reduces an ongoing ileal pouch inflammation and the response to a subsequent inflammatory stimulus. Am J Physiol Gastrointest Liver Physiol 2003;285:G1259 – G1267. 53. Stallmach A, Chan CC, Ecker KW, et al. Comparable expression of matrix metalloproteinases 1 and 2 in pouchitis and ulcerative colitis. Gut 2000;47:415– 422. 54. Ulisse S, Gionchetti P, D’Alò S, et al. Expression of cytokines, inducible nitric oxide synthase, matrix metalloproteinases in pouchitis: effects of probiotic treatment. Am J Gastroenterol 2001;96:2691–2699. 55. Leal RF, Coy CS, Ayrizono ML, et al. Differential expression of pro-inflammatory cytokines and a pro-apoptotic protein in pelvic ileal pouches for ulcerative colitis and familial adenomatous polyposis. Tech Coloproctol 2008;12:33–38. 56. Carter MJ, Di Giovine FS, Cox A, et al. The interleukin 1 receptor antagonist gene allele 2 as a predictor of pouchitis following colectomy and IPAA in ulcerative colitis. Gastroenterology 2001; 121:805– 811. 57. Meier CB, Hegazi RA, Aisenberg J, et al. Innate immune receptor genetic polymorphisms in pouchitis: is CARD15 a susceptibility factor? Inflamm Bowel Dis 2005;11:965–971. 58. Tyler AD, Milgrom R, Stempak JM, et al. The NOD2insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis. Gut 2012. Epub ahead of print. 59. Lammers KM, Ouburg S, Morré SA, et al. Combined carriership of TLR9-1237C and CD14-260T alleles enhances the risk of developing chronic relapsing pouchitis. World J Gastroenterol 2005;11:7323–7329. 60. Sehgal R, Berg A, Polinski JI, et al. Genetic risk profiling and gene signature modeling to predict risk of complications after IPAA. Dis Colon Rectum 2012;55:239 –248. 61. Schmidt CM, Lazenby AJ, Hendrickson RJ, et al. Preoperative terminal ileal and colonic resection histopathology predicts risk

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. xx, No. x

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

of pouchitis in patients after ileoanal pull-through procedure. Ann Surg 1998;227:654 – 662. Achkar JP, Al-Haddad M, Lashner B, et al. Differentiating risk factors for acute and chronic pouchitis. Clin Gastroenterol Hepatol 2005;3:60 – 66. White E, Melmed GY, Vasiliauskas EA, et al. A prospective analysis of clinical variables, serologic factors, and outcome of ileal pouch-anal anastomosis in patients with backwash ileitis. Dis Colon Rectum 2010;53:987–994. Okon A, Dubinsky M, Vasiliauskas EA, et al. Elevated platelet count before ileal pouch–anal anastomosis for ulcerative colitis is associated with the development of chronic pouchitis. Am Surg 2005;71:821– 826. Hata K, Watanabe T, Shinozaki M, et al. Patients with extraintestinal manifestations have a higher risk of developing pouchitis in ulcerative colitis: multivariate analysis. Scand J Gastroenterol 2003;38:1055–1058. Lepistö A, Kärkkäinen P, Järvinen HJ. Prevalence of primary sclerosing cholangitis in ulcerative colitis patients undergoing proctocolectomy and ileal pouch-anal anastomosis. Inflamm Bowel Dis 2008;14:775–779. Shen B, Remzi FH, Nutter B, et al. Association between immuneassociated disorders and adverse outcomes of ileal pouch-anal anastomosis. Am J Gastroenterol 2009;104:655– 664. Shen B, Fazio VW, Remzi FH, et al. Risk factors for diseases of ileal pouch-anal anastomosis after restorative proctocolectomy for ulcerative colitis. Clin Gastroenterol Hepatol 2006;4:81– 89. Shen B, Plesec TP, Remer E, et al. Asymmetric endoscopic inflammation of the ileal pouch: a sign of ischemic pouchitis? Inflamm Bowel Dis 2010;16:836 – 846. Fleshner PR, Vasiliauskas EA, Kam LY, et al. High level perinuclear antineutrophil cytoplasmic antibody (pANCA) in ulcerative colitis patients before colectomy predicts the development of chronic pouchitis after ileal pouch-anal anastomosis. Gut 2001; 49:671– 677. Kuisma J, Järvinen H, Kahri A, et al. Factors associated with disease activity of pouchitis after surgery for ulcerative colitis. Scand J Gastroenterol 2004;39:544 –548. Navaneethan U, Venkatesh PG, Kapoor S, et al. Elevated serum IgG4 is associated with chronic antibiotic-refractory pouchitis. J Gastrointest Surg 2011;15:1556 –1561. Navaneethan U, Venkatesh PG, Manilich E, et al. Prevalence and clinical implications of positive serum anti-microsomal antibodies in symptomatic patients with ileal pouches. J Gastrointest Surg 2011;15:1577–1582. Hoda KM, Collins JF, Knigge KL, et al. Predictors of pouchitis after ileal pouch-anal anastomosis: a retrospective review. Dis Colon Rectum 2008;51:554 –560. Fleshner P, Ippoliti A, Dubinsky M, et al. A prospective multivariate analysis of clinical factors associated with pouchitis after ileal pouch-anal anastomosis. Clin Gastroenterol Hepatol 2007; 5:952–958. Shen B, Achkar JP, Lashner BA, et al. Endoscopic and histologic evaluation together with symptom assessment are required to diagnose pouchitis. Gastroenterology 2001;121: 261–267. Moskowitz RL, Shepherd NA, Nicholls RJ. An assessment of inflammation in the reservoir after restorative proctocolectomy with ileoanal ileal reservoir. Int J Colorectal Dis 1986;1:167– 174. Sandborn WJ, Tremaine WJ, Batts KP, et al. Pouchitis after ileal pouch-anal anastomosis: a Pouchitis Disease Activity Index. Mayo Clin Proc 1994;69:409 – 415. Shen B, Sanmiguel C, Bennett AE, et al. Irritable pouch syndrome is characterized by visceral hypersensitivity. Inflamm Bowel Dis 2011;17:994 –1002.

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80. Elder K, Lopez R, Kiran RP, et al. Endoscopic features associated with ileal pouch failure. Inflamm Bowel Dis 2013;19: 1202–1209. 81. Tang L, Cai H, Moore L, et al. Evaluation of endoscopic and imaging modalities in the diagnosis of structural disorders of the ileal pouch. Inflamm Bowel Dis 2010;16:1526 –1531. 82. Kariv R, Plesec TP, Gaffney K, et al. Pyloric gland metaplasia and pouchitis in patients with ileal pouch-anal anastomoses. Aliment Pharmacol Ther 2010;31:862– 873. 83. Jiang W, Goldblum JR, Lopez R, et al. Increased crypt apoptosis is a feature of autoimmune-associated chronic antibiotic refractory pouchitis. Dis Colon Rectum 2012;55:549 –557. 84. Navaneethan U, Bennett AE, Venkatesh PG, et al. Tissue infiltration of IgG4⫹ plasma cells in symptomatic patients with ileal pouch-anal anastomosis. J Crohns Colitis 2011;5:570 –576. 85. M’Koma AE, Wise PE, Schwartz DA, et al. Prevalence and outcome of anemia after restorative proctocolectomy: a clinical literature review. Dis Colon Rectum 2009;52:726 –739. 86. Miller HL, Farraye FA, Coukos J, et al. Vitamin D deficiency and insufficiency are common in ulcerative colitis patients after ileal pouch-anal anastomosis. Inflamm Bowel Dis 2013. Epub ahead of print. 87. Khanna R, Wu X, Shen B. Low levels of vitamin D are common in patients with ileal pouches irrespective of pouch inflammation. J Crohns Colitis 2012. Epub ahead of print. 88. Shen B, Fazio VW, Remzi FH, et al. Effect of withdrawal of nonsteroidal anti-inflammatory drug use on ileal pouch disorders. Dig Dis Sci 2007;52:3321–3328. 89. McLaughlin SD, Clark SK, Shafi S, et al. Fecal coliform testing to identify effective antibiotic therapies for patients with antibioticresistant pouchitis. Clin Gastroenterol Hepatol 2009;7:545– 548. 90. Parsi MA, Shen B, Achkar JP, et al. Fecal lactoferrin for diagnosis of symptomatic patients with ileal pouch-anal anastomosis. Gastroenterology 2004;126:1280 –1286. 91. Lim M, Gonsalves S, Thekkinkattil D, et al. The assessment of a rapid noninvasive immunochromatographic assay test for fecal lactoferrin in patients with suspected inflammation of the ileal pouch. Dis Colon Rectum 2008;51:96 –99. 92. Parsi MA, Ellis JJ, Lashner BA. Cost-effectiveness of quantitative fecal lactoferrin assay for diagnosis of symptomatic patients with ileal pouch-anal anastomosis. J Clin Gastroenterol 2008; 42:799 – 805. 93. Johnson MW, Maestranzi S, Duffy AM, et al. Faecal calprotectin: a noninvasive diagnostic tool and marker of severity in pouchitis. Eur J Gastroenterol Hepatol 2008;20:174 –179. 94. Shen B, Achkar JP, Lashner BA, et al. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7:301–305. 95. Wu X, Zhu H, Kiran RP, et al. Excessive weight gain is associated with an increased risk for pouch failure in patents with restorative proctocolectomy. Inflamm Bowel Dis 2013. AQ: 23 96. Lohmuller JL, Pemberton JH, Dozois RR, et al. Pouchitis and extraintestinal manifestations of inflammatory bowel disease after ileal pouch–anal anastomosis. Ann Surg 1990;211:622– 629. 97. Mowschenson PM, Critchlow JF, Peppercorn MA. Ileoanal pouch operation: long-term outcome with or without diverting ileostomy. Arch Surg 2000;135:463– 465. 98. Hurst RD, Chung TP, Rubin M, et al. The implications of acute pouchitis on the long-term functional results after restorative proctocolectomy. Inflamm Bowel Dis 1998;4:280 –284. 99. Madiba TE, Bartolo DC. Pouchitis following restorative proctocolectomy for ulcerative colitis: incidence and therapeutic outcome. J R Coll Surg Edinb 2001;46:334 –337. 100. McLaughlin SD, Culkin A, Cole J, et al. Exclusive elemental diet impacts on the gastrointestinal microbiota and improves symp-

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101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

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toms in patients with chronic pouchitis. J Crohns Colitis 2012. 613 Epub ahead of print. 614 Gosselink MP, Schouten WR, van Lieshout LM, et al. Delay of 615 the first onset of pouchitis by oral intake of the probiotic strain 616 Lactobacillus rhamnosus GG. Dis Colon Rectum 2004;47:876 – 617 884. 618 Nicholls RJ. Review article: ulcerative colitis—surgical indica619 tions and treatment. Aliment Pharmacol Ther 2002;16(Suppl 620 4):25–28. 621 Ha CY, Bauer JJ, Lazarev M, et al. Early institution of tinidazole 622 may prevent pouchitis following ileal pouch anal anastomosis 623 (IPAA) surgery in ulcerative colitis (UC) patients. Gastroenterology 2010;138(Suppl):S-69. 624 Isaacs KL, Sandler RS, Abreu M, et al. Rifaximin for the treat625 ment of active pouchitis: a randomized, double-blind, placebo626 controlled pilot study. Inflamm Bowel Dis 2007;13:1250 – 627 1255. 628 Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover 629 trial of metronidazole versus placebo in chronic unremitting 630 pouchitis. Dig Dis Sci 1994;39:1193–1196. 631 Holubar SD, Cima RR, Sandborn WJ, et al. Treatment and 632 prevention of pouchitis after ileal pouch-anal anastomosis for 633 chronic ulcerative colitis. Cochrane Database Syst Rev 2010; 634 6:CD001176. McLaughlin SD, Clark SK, Bell AJ, et al. An open study of 635 antibiotics for the treatment of pre-pouch ileitis following restor636 ative proctocolectomy with ileal pouch–anal anastomosis. Ali637 ment Pharmacol Ther 2009;29:69 –74. 638 Shen B, Pardi DS, Bennett AE, et al. The efficacy and tolerability 639 of AST-120 (spherical carbon adsorbent) in active pouchitis. 640 Am J Gastroenterol 2009;104:1468 –1474. 641 Navaneethan U, Venkatesh PGK, Bennett AE, et al. Impact of 642 budesonide on liver function tests and gut inflammation in 643 patients with primary sclerosing cholangitis and ileal pouch-anal 644 anastomosis. J Crohns Colitis 2012;6:536 –542. 645 Gionchetti P, Rizzello F, Morselli C, et al. High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum 2007; 646 50:2075–2084. 647 Lohmuller JL, Pemberton JH, Dozois RR, et al. Pouchitis and 648 extraintestinal manifestations of inflammatory bowel disease 649 after ileal pouch–anal anastomosis. Ann Surg 1990;211:622– 650 629. AQ: 24 651 Mowschenson PM, Critchlow JF, Peppercorn MA. Ileoanal pouch 652 operation: long-term outcome with or without diverting ileostomy. Arch Surg 2000;135:463– 465. AQ: 25 653 654 Hurst RD, Chung TP, Rubin M, et al. The implications of acute 655 pouchitis on the long-term functional results after restorative proctocolectomy. Inflamm Bowel Dis 1998;4:280 –284. AQ: 26 656 Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as 657 maintenance treatment in patients with chronic pouchitis: a 658 double-blind, placebo-controlled trial. Gastroenterology 2000; 659 119:305–309. 660 Mimura T, Rizzello F, Helwig U, et al. Once daily high dose 661 probiotic therapy (VSL#3) for maintaining remission in recurrent 662 or refractory pouchitis. Gut 2004;53:108 –114. 663 Shen B, Brzezinski A, Fazio VW, et al. Maintenance therapy with 664 a probiotic in antibiotic-dependent pouchitis: experience in clin665 ical practice. Aliment Pharmacol Ther 2005;22:721–728. 666 McLaughlin SD, Johnson MW, Clark SK, et al. VSL#3 for chronic 667 pouchitis: experience in UK clinical practice. Gastroenterology 2008;134(Suppl 1):A711. 668 Shen B, Remzi FH, Lopez AR, et al. Rifaximin for maintenance 669 therapy in antibiotic-dependent pouchitis. BMC Gastroenterol 670 2008;8:26. 671 Shen B, Fazio VW, Remzi FH, et al. Combined ciprofloxacin and 672 tinidazole therapy in the treatment of chronic refractory pouchi673 tis. Dis Colon Rectum 2007;50:498 –508.

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120. Gionchetti P, Rizzello F, Venturi A, et al. Antibiotic combination therapy in patients with chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther 1999;13:713–718. 121. Abdelrazeq AS, Kelly SM, Lund JN, et al. Rifaximin– ciprofloxacin combination therapy is effective in chronic active refractory pouchitis. Colorectal Dis 2005;7:182–186. 122. Mimura T, Rizzello F, Helwig U, et al. Four-week open-label trial of metronidazole and ciprofloxacin for the treatment of recurrent or refractory pouchitis. Aliment Pharmacol Ther 2002;16: 909 –917. 123. Gionchetti P, Rizzello F, Poggioli G, et al. Oral budesonide in the treatment of chronic refractory pouchitis. Aliment Pharmacol Ther 2007;25:1231–1236. 124. Barreiro-de Acosta M, García-Bosch O, Souto R, et al. Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a multicenter study. Inflamm Bowel Dis 2012;18: 812– 817. 125. Barreiro-de Acosta M, García-Bosch O, Gordillo J, et al. Efficacy of adalimumab rescue therapy in patients with chronic refractory pouchitis previously treated with infliximab: a case series. Eur J Gastroenterol Hepatol 2012;24:756 –758. 126. Colombel JF, Ricart E, Loftus EV Jr, et al. Management of Crohn’s disease of the ileoanal pouch with infliximab. Am J Gastroenterol 2003;98:2239 –2244. 127. Li Y, Lopez R, Queener E, et al. Adalimumab therapy in Crohn’s disease of the ileal pouch. Inflamm Bowel Dis 2012;18:2232– 2239. 128. Shen B, Lian L, Kiran RP, et al. Efficacy and safety of endoscopic treatment of ileal pouch strictures. Inflamm Bowel Dis 2011;17:2527–2535.

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129. Ananthakrishnan AN, Issa M, Binion DG. Clostridium difficile and inflammatory bowel disease. Med Clin North Am 2010;94: 135–153. 130. Gerding DN, Muto CA, Owens RC Jr. Treatment of Clostridium difficile infection. Clin Infect Dis 2008;46(Suppl 1):S32–S42. 131. Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005;40:1591–1597. 132. Zoetendal EG, Rajilic-Stojanovic M, De Vos WM. High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut 2008;57:1605–1615. 133. Liu ZX, Deroche T, Remzi FH, et al. Transmural inflammation is not pathognomonic for Crohn’s disease of the pouch. Surg Endosc 2011;25:3509 –3517. 134. Shen B, Remzi FH, Lavery IC, et al. A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy. Clin Gastroenterol Hepatol 2008;6: 145–148.

Reprint requests AQ:2 Address requests for reprints to: Bo Shen, MD, AGAF, Department of Gastroenterology/Hepatology Desk A31, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. e-mail: shenb@ ccf.org; fax: (216) 444-6305. AQ: 3 Conflicts of interest The author discloses the following: Bo Shen has received honoraria from Aptalis, Abbott, and Prometheus Lab.

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