The Bacterial Pathogenesis and Treatment of Pouchitis
S. D. McLaughlin, MBBS, MRCP; S. K. Clark, MD, FRCS; P. P. Tekkis, MD, FRCS; R. J. Nicholls, MChir, FRCS; P. J. Ciclitira, PhD, MD, FRCP
Ther Adv Gastroenterol. 2010;3(6):335-348. © 2010 Sage Publications, Inc.
Abstract
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis. Pouchitis is the most common cause of pouch dysfunction. Although the pathogenesis of this disease is not well understood, bacteria have been implicated in the disease process. Numerous bacterial studies have been reported over the last 25 years with few unifying findings. In addition, many different treatments for pouchitis have been reported with varying results. Antibiotic treatment remains the most studied and is the mainstay of treatment. In this article we review the aetiology of pouchitis and the evidenced-based treatment options.
Background
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis (UC) who require surgery and is also performed in selected patients with familial adenomatous polyposis (FAP). After surgery most patients experience a satisfactory functional outcome. Inflammation of the ileoanal reservoir (pouchitis) is the most common long-term complication. Pouchitis is diagnosed when histologically proven acute inflammation is associated with symptoms of frequency, urgency and liquid stool in the presence of endoscopic evidence of inflammation [McLaughlin et al. 2008b]. The incidence of pouchitis is markedly different between patients with UC and FAP. In UC the quoted incidence varies from 20% to 50% between studies [Hahnloser et al. 2007; Romanos et al. 1997; Stahlberg et al. 1996]. In FAP the incidence of pouchitis is much lower than in UC and varies from 0% to 11% [Barton et al. 2001; Nyam et al. 1997; Kartheuser et al. 1996; Fazio et al. 1995; Dozois et al. 1989]. This large interdisease variation in incidence is explained by the differences in definition and length of follow up. Some studies have based the diagnosis on symptoms alone whereas others correctly have required a triad of symptoms, endoscopic findings and compatible histology. Since the risk of pouchitis increases over time, studies of a longer duration are more likely to demonstrate a higher incidence of pouchitis.
About 39% of patients who develop pouchitis will have a single episode which is easily treated and does not recur. The remaining 61% will suffer at least one further episode [Lohmuller et al. 1990] and about 5–19% of patients will develop chronic relapsing pouchitis [Madiba and Bartolo, 2001; Mowschenson et al. 2000; Hurst et al. 1998]. In this article we review the aetiology of pouchitis and the evidenced-based treatment options.
The Aetiology of Pouchitis
Pathological Similarities to Ulcerative Colitis and Crohn's Disease
Similarly to UC and Crohn's disease (CD) the mucosal inflammation that occurs in pouchitis is localized to the areas with the highest concentration of bacteria. There is a tenfold increased risk of pouchitis in patients who undergo RPC for UC compared with FAP. Therefore, it has been suggested that pouchitis represents reactivation of UC in the colonized small bowel of the pouch.
Prepouch ileitis (PPI; small intestinal inflammation proximal to the pouch inlet) is known to occur in some RPC patients with UC [Slatter et al. 2008; Calabrese et al. 2007; Iwata et al. 2007; Kuisma et al. 2004]. The pathogenesis of PPI has not been studied. Ischaemia [Bell et al. 2006], CD and nonsteroidal anti-inflammatory drugs (NSAIDs) [Shen et al. 2006; Wolf et al. 2004] have been implicated in some cases, but where these factors have been excluded the pathogenesis is likely to be similar to that of pouchitis where bacteria are considered fundamental to the disease process. It is possible that reflux of pouch contents into the prepouch ileum analogous to backwash ileitis in UC, a higher bacterial load or more pathogenic bacteria may be responsible for the disease process. Evidence for this comes from knowledge that the antibiotic therapy is an effective treatment [McLaughlin et al. 2008a] and that PPI appears to be a risk factor for developing antibiotic resistance in patients treated with maintenance antibiotic therapy [McLaughlin et al. 2009b]. One group has suggested that inflammation proximal to the pouch is indicative of CD or associated with the use of NSAIDs [Shen et al. 2006;Wolf et al. 2004]. This study included 87 patients with available colectomy histology including 28 with UC, 32 with indeterminate colitis and 27 with CD. Only 5 UC patients had signs of PPI, all of whom were taking NSAIDs. Therefore, the study did not assess UC patients with PPI who were not taking NSAIDs. Recent work by our group has demonstrated that histologically PPI is a distinct entity which can be differentiated from CD [Bell et al. 2006] and it is therefore possible that PPI is similar to backwash ileitis seen in UC, providing evidence of similarity to UC
Despite this there are several similarities between pouchitis and CD. Both are inflammatory conditions which can affect the small bowel, both respond to treatment with antibiotics and both improve with diversion of the faecal stream (importantly these treatments are not effective in UC). There is also evidence at an immunological level that pouchitis has a similar pathogenesis to CD. In UC inflammation is predominately Th2-cytokine driven, whereas in CD a Th1-mediated immune response dominates [Fiocchi, 1998; Gately et al. 1998; Sartor, 1991; Wolf et al. 1991; Kobayashi et al. 1989]. It might therefore be expected that pouchitis would be associated with a Th2-cytokine activation, but an increase in the Th1 cytokine interferon gamma (IFN-γ) has been described in acute and chronic pouchitis [Stallmach et al. 1998]. Our group has previously investigated the association between CD30 and pouchitis. CD30 was shown to be upregulated in UC but not in CD [Elewaut et al. 1998; Giacomelli et al. 1998]. In this study CD30 was elevated in acute pouchitis but not in those with chronic pouchitis [Thomas et al. 2001] and therefore it was postulated that this may be due to a more CD-type disease occurring in these individuals.
Evidence for Pouchitis Being a Novel Third Form of Inflammatory Bowel Disease
It has been suggested that pouchitis may represent a novel third form of inflammatory bowel disease (IBD) [Sandborn and Pardi, 2004]. The differences in treatment response seen in pouchitis patients compared with UC and CD could be considered to fit with this. Although antibiotics are of some clinical benefit in CD, they are much less so than in pouchitis where they are more effective than any other therapy. Interestingly there is no evidence that immunomodulators are effective in pouchitis (we return to this later) suggesting that the pathogenesis of the disease may differ from that of UC and CD where these agents are very effective.
S. D. McLaughlin, MBBS, MRCP; S. K. Clark, MD, FRCS; P. P. Tekkis, MD, FRCS; R. J. Nicholls, MChir, FRCS; P. J. Ciclitira, PhD, MD, FRCP
Ther Adv Gastroenterol. 2010;3(6):335-348. © 2010 Sage Publications, Inc.
Abstract
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis. Pouchitis is the most common cause of pouch dysfunction. Although the pathogenesis of this disease is not well understood, bacteria have been implicated in the disease process. Numerous bacterial studies have been reported over the last 25 years with few unifying findings. In addition, many different treatments for pouchitis have been reported with varying results. Antibiotic treatment remains the most studied and is the mainstay of treatment. In this article we review the aetiology of pouchitis and the evidenced-based treatment options.
Background
Restorative proctocolectomy (RPC) with ileal pouch-anal anastomosis is the operation of choice for patients with ulcerative colitis (UC) who require surgery and is also performed in selected patients with familial adenomatous polyposis (FAP). After surgery most patients experience a satisfactory functional outcome. Inflammation of the ileoanal reservoir (pouchitis) is the most common long-term complication. Pouchitis is diagnosed when histologically proven acute inflammation is associated with symptoms of frequency, urgency and liquid stool in the presence of endoscopic evidence of inflammation [McLaughlin et al. 2008b]. The incidence of pouchitis is markedly different between patients with UC and FAP. In UC the quoted incidence varies from 20% to 50% between studies [Hahnloser et al. 2007; Romanos et al. 1997; Stahlberg et al. 1996]. In FAP the incidence of pouchitis is much lower than in UC and varies from 0% to 11% [Barton et al. 2001; Nyam et al. 1997; Kartheuser et al. 1996; Fazio et al. 1995; Dozois et al. 1989]. This large interdisease variation in incidence is explained by the differences in definition and length of follow up. Some studies have based the diagnosis on symptoms alone whereas others correctly have required a triad of symptoms, endoscopic findings and compatible histology. Since the risk of pouchitis increases over time, studies of a longer duration are more likely to demonstrate a higher incidence of pouchitis.
About 39% of patients who develop pouchitis will have a single episode which is easily treated and does not recur. The remaining 61% will suffer at least one further episode [Lohmuller et al. 1990] and about 5–19% of patients will develop chronic relapsing pouchitis [Madiba and Bartolo, 2001; Mowschenson et al. 2000; Hurst et al. 1998]. In this article we review the aetiology of pouchitis and the evidenced-based treatment options.
The Aetiology of Pouchitis
Pathological Similarities to Ulcerative Colitis and Crohn's Disease
Similarly to UC and Crohn's disease (CD) the mucosal inflammation that occurs in pouchitis is localized to the areas with the highest concentration of bacteria. There is a tenfold increased risk of pouchitis in patients who undergo RPC for UC compared with FAP. Therefore, it has been suggested that pouchitis represents reactivation of UC in the colonized small bowel of the pouch.
Prepouch ileitis (PPI; small intestinal inflammation proximal to the pouch inlet) is known to occur in some RPC patients with UC [Slatter et al. 2008; Calabrese et al. 2007; Iwata et al. 2007; Kuisma et al. 2004]. The pathogenesis of PPI has not been studied. Ischaemia [Bell et al. 2006], CD and nonsteroidal anti-inflammatory drugs (NSAIDs) [Shen et al. 2006; Wolf et al. 2004] have been implicated in some cases, but where these factors have been excluded the pathogenesis is likely to be similar to that of pouchitis where bacteria are considered fundamental to the disease process. It is possible that reflux of pouch contents into the prepouch ileum analogous to backwash ileitis in UC, a higher bacterial load or more pathogenic bacteria may be responsible for the disease process. Evidence for this comes from knowledge that the antibiotic therapy is an effective treatment [McLaughlin et al. 2008a] and that PPI appears to be a risk factor for developing antibiotic resistance in patients treated with maintenance antibiotic therapy [McLaughlin et al. 2009b]. One group has suggested that inflammation proximal to the pouch is indicative of CD or associated with the use of NSAIDs [Shen et al. 2006;Wolf et al. 2004]. This study included 87 patients with available colectomy histology including 28 with UC, 32 with indeterminate colitis and 27 with CD. Only 5 UC patients had signs of PPI, all of whom were taking NSAIDs. Therefore, the study did not assess UC patients with PPI who were not taking NSAIDs. Recent work by our group has demonstrated that histologically PPI is a distinct entity which can be differentiated from CD [Bell et al. 2006] and it is therefore possible that PPI is similar to backwash ileitis seen in UC, providing evidence of similarity to UC
Despite this there are several similarities between pouchitis and CD. Both are inflammatory conditions which can affect the small bowel, both respond to treatment with antibiotics and both improve with diversion of the faecal stream (importantly these treatments are not effective in UC). There is also evidence at an immunological level that pouchitis has a similar pathogenesis to CD. In UC inflammation is predominately Th2-cytokine driven, whereas in CD a Th1-mediated immune response dominates [Fiocchi, 1998; Gately et al. 1998; Sartor, 1991; Wolf et al. 1991; Kobayashi et al. 1989]. It might therefore be expected that pouchitis would be associated with a Th2-cytokine activation, but an increase in the Th1 cytokine interferon gamma (IFN-γ) has been described in acute and chronic pouchitis [Stallmach et al. 1998]. Our group has previously investigated the association between CD30 and pouchitis. CD30 was shown to be upregulated in UC but not in CD [Elewaut et al. 1998; Giacomelli et al. 1998]. In this study CD30 was elevated in acute pouchitis but not in those with chronic pouchitis [Thomas et al. 2001] and therefore it was postulated that this may be due to a more CD-type disease occurring in these individuals.
Evidence for Pouchitis Being a Novel Third Form of Inflammatory Bowel Disease
It has been suggested that pouchitis may represent a novel third form of inflammatory bowel disease (IBD) [Sandborn and Pardi, 2004]. The differences in treatment response seen in pouchitis patients compared with UC and CD could be considered to fit with this. Although antibiotics are of some clinical benefit in CD, they are much less so than in pouchitis where they are more effective than any other therapy. Interestingly there is no evidence that immunomodulators are effective in pouchitis (we return to this later) suggesting that the pathogenesis of the disease may differ from that of UC and CD where these agents are very effective.