Pouchitis is defined as a total PDAI score > 7 points. Adapted with permission from Sandborn WJ et al. Mayo Clin Proc 1994; 69: 409–415.
Patients with pouchitis can be classified according to disease activity (mild, moderate, or severe), symptom duration, disease pattern or response to antibiotics [1]. Duration can be classified as acute (<4 weeks) or chronic (≥4 weeks). Disease pattern can be classified as infrequent (1–2 episodes per year), relapsing (≥3 episodes per year), or continuous. Relapsing pouchitis is also considered a form of chronic pouchitis, even if the symptoms during a single episode do not last for four weeks on therapy. Finally, pouchitis can be classified as antibiotic-responsive, dependent or refractory.
Treatment with antibiotics
Rationale
The fact that pouchitis typically does not occur until the diverting ileostomy is closed and luminal contents flow through the pouch suggests that bacterial antigens are important in driving the inflammatory process. However, it is not clear whether pouchitis occurs due to overgrowth of commensal bacteria or the presence of abnormal bacteria [13–17]. After IPAA, the primary function of the terminal ileum changes from absorption to storage, and bacterial overgrowth occurs by design, with bacterial concentrations increasing to levels that are intermediate between those seen with an end ileostomy and in the colon [18, 19]. There is no correlation between fecal bacterial concentrations and histologic changes of acute inflammation [18,19], suggesting that pouchitis and bacterial overgrowth are not directly related. However, anaerobic bacterial overgrowth of the pouch is associated with transformation of the ileal mucosa to a “colon-like” morphology (with villous atrophy, and chronic inflammatory cell infiltration) [18, 20]. Furthermore, the flora in pouch effluent has a higher ratio of anaerobes to aerobes and more Bacteroides and Bifidobacteria than effluent from subjects with an end ileostomy [19, 21]. However, in other studies, total aerobes and some pathogenic bacteria (Clostridium perfringens and hemolytic strains of Escherichia coli) may be increased, while total anaerobes are decreased [22]. Thus, pouch anaerobic 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. Strategies directed towards reducing fecal concentrations of anaerobic bacteria through the use of antibiotics may be useful in treating pouchitis.
Clinical results
Antibiotics are the standard medical therapy for pouchitis, based on a small number of controlled trials as well as overwhelming clinical evidence that antibiotics are effective. Previously, the most commonly used antibiotic for pouchitis was metronidazole [19,23–26], with most patients responding to doses of 750–1500mg/day within 1–2 days. The first controlled trial of metronidazole was a small, placebo-controlled crossover trial [27]. Each patient had a seven-day washout period before crossing over to the second therapy. Metronidazole was better than placebo at improving the daily stool frequency, although the overall change was small, and there was no significant difference in endoscopic or histologic improvement. A second small controlled trial compared two weeks of treatment with metronidazole 20mg/kg/day with ciprofloxacin 1000mg/ day in patients with acute pouchitis [28]. Both drugs significantly reduced the PDAI score, but ciprofloxacin had a greater reduction with fewer side effects. Based on this study, other reports of the effectiveness of ciprofloxacin [25], and the high risk of adverse effects seen during metronidazole treatment (33–55%, including nausea, vomiting, abdominal discomfort, headache and skin rash [27–29]), ciprofloxacin has become the antibiotic of choice for most patients with active pouchitis. A1d Amoxicillin/clavulanic acid, erythromycin, tetracycline and topical metronidazole have also been reported to be of benefit [1]. Rifaximin, a non-absorbed oral antibiotic, was not superior to placebo in a small randomized clinical trial [30]. A1d
In patients who do not respond to a single antibiotic, treatment with combination antibiotics, such as ciprofloxacin and rifaximin [31], ciprofloxacin and metronidazole [32], or ciprofloxacin and tinidazole [33] have been reported beneficial in open-label studies.
Patients with relapsing pouchitis may require chronic maintenance antibiotic therapy. Given the risk of adverse effects with prolonged metronidazole therapy, these patients are usually treated with ciprofloxacin at doses ranging from 250mg every third day up to 1000mg/day, although many can be controlled with 250 mg every 1–2 days.
Treatment with probiotics
Rationale
As mentioned above, there is extensive evidence implicating changes in the pouch bacterial milieu in the pathogen-esis of pouchitis. Thus, strategies directed at altering the relative balance of bacteria using probiotic therapy may be useful in treating or preventing pouchitis.
Clinical results
Three controlled trials have been performed [34–36]. The first two studies randomized patients with chronic pouchitis in remission after induction therapy with antibiotics to treatment with either an oral probiotic preparation (VSL-3, which contains strains of lactobacilli, bifidobacteria and streptococci) or placebo for 9–12 months [34, 35]. The relapse rates in the VSL-3 groups were 10-15% compared with 94–100% with placebo. In a third study, patients undergoing colectomy and IPAA were randomized to prophylactic therapy with VSL-3 or placebo for one year [36]. The rate of developing pouchitis during the first year was 10% in the VSL-3 group and 40% in the placebo group. A1d In this study, VSL-3 also reduced the stool frequency of patients without clinical pouchitis. Finally, an open-label study of VSL-3 suggested efficacy for the treatment of mildly active acute pouchitis [37], and a case report of two patients suggested that another probiotic, E. coli Nissle 1917, may be of benefit for the treatment of active pouchitis and for maintenance therapy [38].
In contrast, an open-label study of VSL-3 in clinical practice was less encouraging [39]. In this uncontrolled report of 31 patients with antibiotic-dependent chronic pouchitis treated at a referral center, <20% were able to maintain remission on VSL-3 during eight months of follow-up..
Treatment with anti-inflammatory and immune modifier agents
Rationale
Pouchitis may represent a recurrence of IBD in the ileal pouch. Data to support this view include: an increased frequency of pouchitis in patients with UC compared to those with familial polyposis; an increased frequency of pouchitis in patients who have extra-intestinal manifestations of UC, primary sclerosing cholangitis (PSC) or antineutrophil cytoplasmic antibodies (pANCA); and a decreased frequency of pouchitis in current smokers. Strategies directed towards empirical medical therapy with agents known to be efficacious in IBD may be useful in treating pouchitis. Unfortunately, few controlled trials have been reported to provide evidence for the efficacy of these approaches.
Clinical results
Uncontrolled studies suggest that topical mesalamine (enemas or suppositories), sulfasalazine and oral mesalamine may be beneficial for active pouchitis [19, 26, 40–42]. Uncontrolled reports also have suggested that oral and topical corticosteroids may be of benefit in pouchitis [19, 26, 42, 43]. Budesonide suppositories resulted in clinical and endoscopic improvement, and decreased pouch concentrations of inflammatory mediators, in a small study in acute pouchitis [44]. A randomized controlled trial of budesonide enemas versus oral metronidazole showed equivalent efficacy, but fewer side effects from budesonide [29]. A1d Oral controlled release budesonide has also been reported to be effective for the treatment of pouchitis in uncontrolled reports. In one study, budesonide (9mg/day for eight weeks) induced remission in 72% of patients not responding to one month of ciprofloxacin or metronidazole [45]. In another small open-label series [46], budesonide therapy induced a 60% response rate in patients refractory to antibiotics. B4
Cyclosporin enemas were reported to be beneficial in one patient with active chronic pouchitis [47]. Two studies involving 11 patients with IPAA who underwent liver transplantation for PSC have reported on the clinical course of pouchitis [48, 49]. Five of 11 patients had chronic pouchitis following transplantation, despite immunosuppression with cyclosporin or tacrolimus, pred-nisone, and azathioprine, suggesting that immunosuppression may not be efficacious for pouchitis, at least in this population. B4 Two small reports have suggested a beneficial effect of azathioprine in patients with Crohn’s disease and an IPAA [50, 51]. Recently, infliximab has been reported to be of benefit in patients with pouchitis [51, 52] and patients with Crohn’s disease of the ileoanal pouch [53, 54,55]
Treatment with nutritional agents
Rationale
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