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Clinical management of pouchitis
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CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California
Clinical Management of Pouchitis WILLIAM J. SANDBORN and DARRELL S. PARDI Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Clinical Case A 31-year-old man who had an ileoanal J pouch with a hand sewn anastomosis 6 months ago for ulcerative colitis presents with a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort.
Background Ileoanal Pouch Epidemiology Up to 25% of patients with ulcerative colitis eventually require colectomy, and the majority of these patients have an ileoanal pouch created. Pouchitis is an idiopathic chronic inflammatory disease, which may occur in the ileal pouch.1 It is expected that the total number of patients with pouchitis in the United States will eventually reach 30,000 – 45,000 persons (prevalence of 12–18/100,000 persons).2 Pouchitis is therefore emerging as an important third form of inflammatory bowel disease. Differential Diagnosis of Symptoms of Pouch Dysfunction The differential diagnosis for conditions leading to symptoms of pouch dysfunction is shown in Table 1.3 The most common cause of pouch dysfunction is pouchitis. The diagnosis of pouchitis is suggested by variable clinical symptoms of increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency and tenesmus, incontinence, and fever. A clinical diagnosis of pouchitis should be confirmed by endoscopy and mucosal biopsy of the pouch.1 Endoscopic examination shows inflammatory changes, which may include mucosal edema, granularity, contact bleeding, loss of vascular pattern, hemorrhage, and ulceration.4,5 Histologic examination shows acute inflammation, including neutrophil infiltration and mucosal ulceration, superimposed on a background of chronic inflammation, including villous
atrophy, crypt hyperplasia, and chronic inflammatory cell infiltration.5,6 Endoscopic examination of the neoterminal ileum above the ileal pouch should be normal. Patients with pouchitis can be classified according to disease activity, symptom duration, and disease pattern.2 Disease activity can be classified as the following: remission (no active pouchitis), mildly to moderately active (increased stool frequency, urgency, infrequent incontinence), or severely active (hospitalization for dehydration, frequent incontinence). Symptom duration can be classified as the following: acute (⬍4 weeks) or chronic (ⱖ4 weeks). Finally, the disease pattern can be classified as the following: infrequent (1–2 acute episodes), relapsing (ⱖ3 acute episodes), or continuous. The cumulative risk of having 1 or more episodes of pouchitis reaches nearly 50% by 5 years.7,8 The majority of these episodes of pouchitis are acute pouchitis (either infrequent or relapsing pattern), with approximately 5% of patients developing chronic pouchitis.7 Other causes of pouch dysfunction include Crohn’s disease, specific infection of the pouch, decreased pouch compliance, irritable pouch syndrome, cuffitis, strictured anastomosis, long efferent limb, decreased pouch emptying, pelvic floor dysfunction, pouch stricture, and adhesions. Approximately 5% of patients with ulcerative colitis who undergo colectomy with ileoanal pouch will eventually have a change in diagnosis to Crohn’s disease.9,10 This diagnosis is suspected when the pouch endoscopy shows prepouch ileitis or the patient develops perianal or pouch vaginal fistulas (pouch fistulas should be further evaluated with pelvic MRI and or examination under anesthesia). Infection of the ileoanal pouch with cytomegalovirus (CMV) or Clostridium difficile (C difficile) occur rarely and should be suspected when patients who Abbreviation used in this paper: CMV, cytomegalovirus. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.10.011
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Table 1. Etiology, Primary Symptoms, Diagnosis, and Treatment of Ileoanal Pouch Dysfunction Etiology
Primary symptoms
Diagnosis
Pouchitis Crohn’s disease
Increased stool frequency Increased stool frequency Abdominal pain and bloating Perianal or pouch vaginal fistulas
Pouch endoscopy with biopsy Pouch endoscopy with biopsy Small bowel x-ray Pouchogram Pelvic MRI
Specific infection CMV C difficile Primary decreased pouch compliance
Increased stool frequency
Biopsy for CMV Stool for C difficile
Increased stool frequency
Decreased pouch compliance secondary to pelvic sepsis
Increased stool frequency
Irritable pouch syndrome
Increased stool frequency Abdominal pain and bloating
Cuffitis
Fecal bleeding Fecal urgency Difficulty evacuating
Pouchogram Exam under anesthesis Pelvic MRI Pouchogram Exam under anesthesis Diagnosis of exclusion (negative endoscopy, pouchogram, small bowel x-ray) Pouch/cuff endoscopy with biopsy Physical examination
Strictured anastomosis Long efferent limb (S pouch, lateral pouch) Decreased pouch emptying
Difficulty evacuating
Pelvic floor dysfunction Pouch stricture Ischemic Crohn’s disease Torsion
Difficulty evacuating Difficulty evacuating
Adhesions
Abdominal pain and bloating
Difficulty evacuating
have endoscopic findings consistent with pouchitis fail to respond to antibiotic therapy.11,12 The diagnoses of CMV pouchitis or C difficile pouchitis are made by pouch biopsy and stool studies. Decreased pouch compliance typically occurs in patients with previous or ongoing pelvic sepsis and can be diagnosed by digital examination and pelvic MRI.3 Irritable pouch syndrome is diagnosed in patients with symptoms of pouchitis who have a negative pouch endoscopy.13 Cuffitis is inflammation of the rectal cuff in patients with a stapled ileoanal pouch; it is diagnosed with endoscopy.14 Ileoanal anastomotic stricture is diagnosed by digital examination.15 A functionally obstructed, long efferent limb should be suspected in patients with S pouches or lateral pouches who have obstructive symptoms and is diagnosed by pouchogram. Decreased pouch emptying, pelvic floor dysfunction, and pouch stricture should be considered in patients with bloating symptoms and difficulty evacuating. These conditions are diagnosed by pouchogram, nuclear
History Pouchogram Pouchogram Nuclear scintographic emptying study Anorectal manometry Pouch endoscopy Pouchogram Small bowel x-ray Mesenteric angiogram (rarely indicated) Small bowel x-ray
Treatment Antibiotics Antibiotics Corticosteroids Budesonide Azathioprine 6-mercaptopurine Methotrexate Infliximab Gancyclovir Metronidazole Vancomycin Diet Anti-diarrheal therapy Antibiotics Drainage Diversion Antispasmodics Anti-diarrheal therapy Fiber Topical mesalamine Exam under anesthesia with dilation Surgical shortening of spout or pouch revision Catheterization Tap water enemas Biofeedback Exam under anesthesia with dilation Endoscopic balloon dilation Stricturoplasty Pouch excision Exploratory laparotomy with lysis of adhesions
scintigraphic emptying study, and anorectal manometry.3
Potential Management Strategies Stool for Enteric Pathogens There are few cases in the literature of C difficile enteritis of the ileoanal pouch and no reported cases of bacterial enteric pathogens (bacterial or parasitic). For this reason, there is no utility in ordering these tests in patients presenting for the first time with symptoms of ileoanal pouch dysfunction. Flexible Sigmoidoscopy Flexible sigmoidoscopy is a useful test in identifying inflammation of the prepouch ileum (which would suggest Crohn’s disease), inflammation of the ileoanal pouch (which would suggest the possibilities of Crohn’s disease, pouchitis, and rarely ischemia and specific infec-
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tion of the pouch with CMV), and inflammation of the rectal cuff in a patient with a stapled J pouch (which means that 1–2 cm of rectum remains distal to the pouch-anal anastomosis). At a patient’s first endoscopic evaluation for ileoanal pouch dysfunction, biopsies of the pouch for histology should be performed to help establish a diagnosis (see below). Once a diagnosis of pouchitis is established, then repeated biopsies of the ileoanal pouch at the time of future endoscopies are not routinely required. In patients with a stapled J pouch, the rectal cuff should be examined for endoscopic findings of inflammation, which would indicate cuffitis. It should be noted that patients can have both pouchitis and cuffitis simultaneously. Flexible Sigmoidoscopy Plus Biopsy The prepouch ileum should be biopsied only if there are apthous ulcers or other endoscopic findings of inflammation to confirm a diagnosis of Crohn’s disease. The finding of inflammation of the pouch seen at endoscopy is nonspecific. Thus, we recommend that biopsy of the pouch be performed at the time of the initial endoscopy to help establish a diagnosis because histology can be helpful in distinguishing among Crohn’s disease, pouchitis, CMV pouchitis, and ischemia. We typically biopsy the pouch, even if the mucosa appears normal at endoscopy because some patients with mildly symptomatic pouchitis may have clear evidence of active acute pouchitis on biopsy with minimal endoscopic findings. Finally, for patients with a stapled ileoanal J pouch, the rectal cuff should be biopsied yearly for dysplasia. For patients with ileoanal pouch dysfunction and evidence of cuffitis at endoscopy, the endoscopic diagnosis of cuffitis can be confirmed with cuff biopsies. Pelvic MRI Pelvic MRI should be performed if the patient has perianal fistulas or vaginal drainage or pain in the pelvic or perianal region to delineate fistula anatomy and to identify absesses and pelvic sepsis. Perianal and vaginal fistulas may arise from the pouch, which is more consistent with Crohn’s disease, or from the anastomosis itself, which is more compatible with a technical complication from the surgery. Perianal Crohn’s disease may have associated perianal or pelvic abscesses, and an anastomotic fistula may be associated with peripouch pelvic sepsis. A pelvic MRI is not necessary if a patient does not have fistulas or prominent symptoms of pelvic or perianal pain. Pouchogram Contrast X-ray Pouchogram contrast x-ray is useful in evaluating for Crohn’s disease, a pouch stricture, decreased pouch com-
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pliance, a strictured anastomosis, a long efferent limb, and decreased pouch emptying. Crohn’s disease will manifest as fistulas arising from the pouch or stricturing of the pouch seen on pouchogram. Other causes of pouch structuring that can be seen with pouchogram include ischemic damage to the pouch and torsion or kinking of the pouch because of adhesions or surgical misadventure. Decreased pouch compliance (which usually occurs as a result of scarring from prior or ongoing pelvic sepsis) will show a small contracted pouch on pouchgram. Patients with an S pouch or lateral pouch have an efferent limb referred to as a spout. The spout can become elongated and intermittently kink, leading to functional obstruction of the outlet of the pouch. Pouchogram x-ray can be useful in delineating the pouch anatomy and identifying an elongated spout. Nuclear Medicine Pouch-Emptying Study Some patients will develop decreased pouch emptying, either because the pouch is too large or because possibly because of damage to enteric nerves during pouch construction. A nuclear medicine scintigraphic pouch-emptying study can be used to measure quantitatively the pouch emptying. The typical clinical presentation is difficulty with pouch evacuation. Patients with reduced pouch emptying may benefit from pouch irrigation and possibly pouch reconstruction. A scintigraphic pouch-emptying study is not necessary in a patient who does not complain of difficulty evacuating the pouch. Anorectal Manometry Anorectal manometry can be useful in diagnosing pelvic floor dysfunction. The typical clinical presentation is pelvic pain and difficulty with pouch evacuation. Such patients may benefit from biofeedback therapy. Anorectal manometry is not necessary in a patient who does not complain of significant pelvic pain or difficulty evacuating the pouch. Empiric Therapy for Pouchitis In the past, it was common to make an empiric diagnosis of pouchits in patients with an ileoanal pouch and increased stool frequency. The empiric diagnosis was followed by empiric therapy with antibiotics. This strategy often leads to an incorrect diagnosis of pouchitis in patients who actually have Crohn’s disease, anastomotic stricture, cuffitis, irritable pouch syndrome, and other causes of pouch dysfunction. Because pouchitis tends to reoccur in many patients, it is important to make an accurate diagnosis initially. Thus, empiric therapy is not appropriate in a patient with new onset pouch dysfunction. Once a diagnosis of pouchitis has been established
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by endoscopy and confirmed by biopsy, it may be reasonable to treat symptomatic relapse with empiric antibiotics, reserving repeat endoscopy for patients who fail to respond to antibiotic therapy.
Recommended Management Strategy The patient in the case outlined above has a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort. The most likely cause of these symptoms is pouchitis, which is diagnosed by pouch endoscopy with biopsy. Therefore, the recommended management strategy to evaluate this patient with pouch dysfunction is pouch endoscopy with biopsy. Biopsy of the pouch should be performed not only to establish a diagnosis of pouchitis but to exclude other causes of pouch dysfunction. If this management strategy does not lead to a diagnosis, then pouchogram x-ray would be a reasonable next diagnostic step.
Evolution of the Case The patient underwent endoscopy of the ileoanal pouch. An adult gastroscope was used rather than a flexible sigmoidoscope because of its smaller diameter (which allows easier passage across the ileoanal anastomosis) and greater flexibility (which allows easier passage into the prepouch ileum to evaluate for Crohn’s disease). The prepouch ileum had a normal endoscopic appearance. The pouch itself showed patchy friability with multiple apthous ulcers. Biopsies showed acute and chronic inflammation, mucosal ulceration, and villous atrophy. Based on the clinical history and these endoscopic and histologic findings, the patient was diagnosed with acute pouchitis.
Subsequent Management Treatment Options for Pouchitis Specific treatments for pouchitis are outlined in Table 2. Clinical experience has demonstrated that most patients with pouchitis who are empirically treated with metronidazole or ciprofloxacin experience clinical improvement.16 A few small clinical trials have confirmed these observations.17–20 Madden et al treated 13 patients with active chronic pouchitis in a crossover trial of oral metronidazole 400 mg, 3 times daily or placebo for 14 days.18 Metronidazole reduced the (mean ⫾ SD) daily stool frequency from 10.0 ⫾ 2.8 to 9.0 ⫾ 5.2, whereas placebo-treated patients had an increase in mean daily stool frequency from 8.9 ⫾ 2.5 up to 10.7 ⫾ 4.1 (P ⬍ .05). A second randomized controlled trial by Shen et al compared 2 weeks of treatment with metronidazole 20
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Table 2. Treatments Reported to be Beneficial for Pouchitis Class example Antibiotics Metronidazole Ciprofloxacin Amoxicillin/clavulanic acid Erythromycin Tetracycline Rifaximin ⫹ tetracycline Metronidazole ⫹ ciprofloxacin Probiotic bacteria Lactobacilli, Bifidobacteria, S thermophilus E coli Nissle 1917 5-Aminosalicylates Mesalamine enemas Sulfasalazine Oral mesalamine Corticosteroids Conventional corticosteroid enemas Budesonide suppositories Budesonide enemas Oral corticosteroids Immune modifier agents Cyclosporin enemas Azathioprine, 6-mercaptopurine Infliximab Nutritional agents SCFA enemas or suppositories Glutamine suppositories Dietary fiber (pectin, methylcellulose, inulin) Oxygen radical inhibitors Allopurinol Antidiarrheal/antimicrobial Bismuth carbomer enemas Bismuth subsalicylate NOTE. Modified with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003; 124:1636 –1650. SCFA, short chain fatty acid.
mg/kg per day to ciprofloxacin 1000 mg/day in patients with acute pouchitis.19 Both drugs significantly reduced the pouchitis disease activity index score (0 –18 point score), but ciprofloxacin had a greater reduction in overall pouchitis disease activity index score (6.9 ⫾ 1.2 vs. 3.8 ⫾ 1.7, respectively, P ⫽ .002), symptom score (2.4 ⫾ 0.9 vs. 1.3 ⫾ 0.9, respectively, P ⫽ .03), and endoscopic score (3.6 ⫾ 1.3 vs. 1.9 ⫾ 1.5, respectively, P ⫽ .03) vs. metronidazole. A third randomized controlled trial comparing metronidazole 1000 mg/day and budesonide enemas 2 mg/day is described below.20 The most commonly used antibiotic for pouchitis is metronidazole.16 –20 The main alternative to metronidazole is ciprofloxacin.16,19 Most patients with pouchitis will have symptomatic improvement after 1 or 2 days of therapy with metronidazole at doses of 750 –1500 mg/day. Patients with a clinical course of relapsing or chronic pouchitis may need continuous maintenance treatment with metronidazole at doses ranging from 250 mg every
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➝ Endoscopy with Biopsy ➝
➝
Pouchitis
No Pouchitis ➝
➝ Metronidazole or Ciprofloxacin
Irritable Pouch Syndrome
➝
➝
Response
No Response
Metamucil, Imodium, Lomotil
➝
➝
Prompt Recurrence Therapies
Other Antibioticsa
Irritable Bowel Syndrome
➝
➝
➝
Repeat Antibiotics dysfunction
Anti-Inflammatory Drugsb
Evaluation for pelvic floor
➝
➝
➝
Prompt Recurrence
Immunosuppressive Drugsc
Surgical Consultation
➝
Repeat Antibiotics OR Add Probiotics
Surgical Consultation
➝
➝
An algorithm of the approach to treatment of pouchitis is shown in Figure 1. Patients with acute pouchitis are treated with metronidazole or ciprofloxacin. Patients who experience frequent relapses of pouchitis
Symptoms of Pouchitis
➝
Treatment Algorithm for Pouchitis
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➝
third day up to 750 mg/day. Adverse effects occurred in 33%–55% of patients during metronidazole treatment, including nausea, vomiting, abdominal discomfort, headache, and skin rash.18 –20 Recent studies have demonstrated that altering pouch bacterial contents by administering probiotic bacteria can be an effective therapeutic strategy. Three controlled trials have been performed.21–23 Gionchetti et al randomized 40 patients with chronic pouchitis in remission (after induction therapy with antibiotics) to treatment with either an oral probiotic preparation (2, 3-gram bags of VSL-3, each containing 300 billion viable lyophilized bacteria per gram) or placebo for 9 months.21 The VSL-3 preparation contained viable lyophilized bacteria including the following: 4 strains of lactobacilli (L acidophilus, L delbrueckii subsp. bulgaricus, L plantarum, L casei), 3 strains of bifidobacteria (B infantis, B longum, B breve), and 1 strain of Streptococcus salivarius subsp. thermophilus. At 9 months, the relapse rate was 15% in the VSL-3 group and 100% in the placebo group (P ⬍ .01). In a second controlled trial, 36 patients with recurrent or refractory pouchitis were treated with antibiotics and then randomized to maintenance therapy with VSL-3 or placebo for 1 year. The relapse rates were 10% in the VSL-3 group and 94% in the placebo group, P ⬍ .0001.22 In a controlled trial, patients undergoing colectomy and ileoanal pouch were randomized to prophylactic therapy with VSL-3 or placebo for 1 year.23 The rate of developing pouchitis during the first year was 10% in the VSL-3 group and 40% in the placebo group, P ⬍ .05. Of interest, the VSL-3 appeared to reduce the mean stool frequency of asymptomatic patients as well. Uncontrolled studies have reported that oral and rectal corticosteroids may be clinically beneficial in patients with active pouchitis.24 –26 A randomized, placebo controlled trial of 2 mg budesonide enemas vs. metronidazole showed similar efficacy for budesonide and metronidazole.20 Twenty-six patients with acute pouchitis were randomized to either budesonide enemas or oral metronidazole 500 mg twice daily for 6 weeks. Fiftyeight percent of budesonide patients and 50% of metronidazole patients improved. Fifty-seven percent of metronidazole patients had adverse events vs. only 25% of budesonide patients. Unpublished clinical experience suggests that oral, controlled-release budesonide 9 mg/day is also of clinical benefit for pouchitis.
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➝
? Pouch Reconstruction OR ? Pouch Excision
Figure 1. Treatment algorithm for pouchitis. Other Antibioticsa indicates rifaximin, amoxicillin/clavulanate, erythromycin, tetracycline, and cycling of multiple antibiotics. Anti-inflammatory Drugsb indicates bismuth subsalicylate, mesalamine enemas, sulfasalazine, and oral mesalamine. Immunosuppressive Drugsc indicates budesonide, steroid enemas, oral steroids, azathioprine. Reprinted with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636 –1650.
and patients with chronic pouchitis will require longterm maintenance therapy with antibiotics or probiotics. In practice, we would institute maintenance therapy for patients who relapse at least 3 times within 1 year or within 1 month of discontinuation of antibiotics. Among patients receiving maintenance antibiotics who develop loss of clinical benefit after prolonged treatment, rotation of 3 or 4 antibiotics in 1-week intervals may be beneficial. Those patients who do not respond to metronidazole or other antibiotics can be treated with rectal or oral budesonide. Other treatment options may include rectal therapy with mesalamine enemas or suppositories and oral therapy with sulfasalazine or mesalamine, rectal or oral steroids, and possibly azathioprine or 6-mercaptopurine, or infliximab. Some patients may require combination therapy with multiple agents. There is little evidence to support therapy with short-chain fatty acid enemas, glutamine suppositories, inulin, or allopurinol. A minority of patients will be unresponsive to all medical therapy. These patients should be referred to a colorectal surgeon for consideration of permanent ileostomy with pouch exclusion or excision. Recommended Treatment The evidence-based treatment options for this patient include metronidazole, ciprofloxacin, and budes-
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onide. Although there is more overall experience with metronidazole, we prefer ciprofloxacin because it has a more favorable toxicity profile. In this patient, we would use ciprofloxacin 500 mg orally twice daily for 14 days and then discontinue therapy.
Conclusions Patients with pouch dysfunction should be evaluated with ileoanal pouch endoscopy and biopsy before a diagnosis of pouchitis is made. Small controlled trials have reported superior efficacy of metronidazole compared with placebo and similar efficacy for metronidazole compared with both ciprofloxacin and budesonide enemas for active chronic pouchitis. Three somewhat larger placebo-controlled trials reported that probiotic bacteria are effective for maintaining remission in patients with chronic pouchitis and for preventing the onset of pouchitis after colectomy with ileoanal pouch. Some patients with chronic pouchitis require maintenance therapy with antibiotics or probiotics, and some will require permanent ileostomy with pouch exclusion or excision.
References 1. Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636 –1650. 2. Sandborn WJ. Pouchitis: risk factors; frequency; natural history; classification; and public health perspective. Lancaster, UK: Kluwer Academic Publishers, 1997. 3. Sagar PM, Pemberton JH. Ileo-anal pouch function and dysfunction. Dig Dis 1997;15:172–188. 4. Di Febo G, Miglioli M, Lauri A, Biasco G, Paganelli GM, Poggioli G, Gozzetti G, Barbara L. Endoscopic assessment of acute inflammation of the ileal reservoir after restorative ileo-anal anastomosis. Gastrointest Endosc 1990;36:6 –9. 5. 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. 6. Shepherd NA, Jass JR, Duval I, Moskowitz RL, Nicholls RJ, Morson BC. Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens. J Clin Pathol 1987;40:601– 607. 7. Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, Ilstrup D. 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. 8. Svaninger G, Nordgren S, Oresland T, Hulten L. Incidence and characteristics of pouchitis in the Kock continent ileostomy and the pelvic pouch. Scand J Gastroenterol 1993;28:695–700. 9. Hyman NH, Fazio VW, Tuckson WB, Lavery IC. Consequences of ileal pouch-anal anastomosis for Crohn’s colitis. Dis Colon Rectum 1991;34:653– 657. 10. Sagar PM, Dozois RR, Wolff BG. Long-term results of ileal pouchanal anastomosis in patients with Crohn’s disease. Dis Colon Rectum 1996;39:893– 898.
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11. Munoz-Juarez M, Pemberton JH, Sandborn WJ, Tremaine WJ, Dozois RR. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum 1999;42:117–120. 12. Mann SD, Pitt J, Springall RG, Thillainayagam AV. Clostridium difficile infection—an unusual cause of refractory pouchitis: report of a case. Dis Colon Rectum 2003;46:267–270. 13. Shen B, Achkar JP, Lashner BA, Ormsby AH, Brzezinski A, Soffer EE, Remzi FH, Bevins CL, Fazio VW. Irritable pouch syndrome: a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol 2002;97:877–972. 14. Shen B, Lashner BA, Bennett AE, Remzi FH, Brzezinski A, Achkar JP, Bast J, Bambrick ML, Fazio VW. Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis. Am J Gastroenterol 2004;99:1527–1531. 15. Prudhomme M, Dozois RR, Godlewski G, Mathison S, FabbroPeray P. Anal canal strictures after ileal pouch-anal anastomosis. Dis Colon Rectum 2003;46:20 –23. 16. Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg 1996;131:497–502. 17. McLeod RS, Taylor DW, Cohen Z, Cullen JB. Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir. Lancet 1986;1:726 –728. 18. Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci 1994;39:1193–1196. 19. Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Brzezinski A, Bevins CL, Bambrick ML, Seidner DL, Fazio VW. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7:301–305. 20. Sambuelli A, Boerr L, Negreira S, Gil A, Camartino G, Huernos S, Kogan Z, Cabanne A, Graziano A, Peredo H, Doldan I, Gonzalez O, Sugai E, Lumi M, Bai JC. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial. Aliment Pharmacol Ther 2002;16:27–34. 21. Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggioli G, Miglioli M, Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119: 305–309. 22. Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53:108 –114. 23. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202–1209. 24. Shepherd NA, Hulten L, Tytgat GN, Nicholls RJ, Nasmyth DG, Hill MJ, Fernandez F, Gertner DJ, Rampton DS, Owen RW, Kmist WA, Keighley MRB, O’Connell PR, Kumar D, Williams NS. Pouchitis. Int J Colorectal Dis 1989;4:205–229. 25. Tytgat GN, van Deventer SJ. Pouchitis. Int J Colorectal Dis 1988; 3:226 –228. 26. Scott AD, Phillips RK. Ileitis and pouchitis after colectomy for ulcerative colitis. Br J Surg 1989;76:668 – 669.
Address requests for reprints to: William J. Sandborn, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0335.
CLINICAL MANAGEMENT Loren Laine, M.D. Clinical Management Editor University of Southern California Los Angeles, California
Clinical Management of Pouchitis WILLIAM J. SANDBORN and DARRELL S. PARDI Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
Clinical Case A 31-year-old man who had an ileoanal J pouch with a hand sewn anastomosis 6 months ago for ulcerative colitis presents with a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort.
Background Ileoanal Pouch Epidemiology Up to 25% of patients with ulcerative colitis eventually require colectomy, and the majority of these patients have an ileoanal pouch created. Pouchitis is an idiopathic chronic inflammatory disease, which may occur in the ileal pouch.1 It is expected that the total number of patients with pouchitis in the United States will eventually reach 30,000 – 45,000 persons (prevalence of 12–18/100,000 persons).2 Pouchitis is therefore emerging as an important third form of inflammatory bowel disease. Differential Diagnosis of Symptoms of Pouch Dysfunction The differential diagnosis for conditions leading to symptoms of pouch dysfunction is shown in Table 1.3 The most common cause of pouch dysfunction is pouchitis. The diagnosis of pouchitis is suggested by variable clinical symptoms of increased stool frequency, rectal bleeding, abdominal cramping, rectal urgency and tenesmus, incontinence, and fever. A clinical diagnosis of pouchitis should be confirmed by endoscopy and mucosal biopsy of the pouch.1 Endoscopic examination shows inflammatory changes, which may include mucosal edema, granularity, contact bleeding, loss of vascular pattern, hemorrhage, and ulceration.4,5 Histologic examination shows acute inflammation, including neutrophil infiltration and mucosal ulceration, superimposed on a background of chronic inflammation, including villous
atrophy, crypt hyperplasia, and chronic inflammatory cell infiltration.5,6 Endoscopic examination of the neoterminal ileum above the ileal pouch should be normal. Patients with pouchitis can be classified according to disease activity, symptom duration, and disease pattern.2 Disease activity can be classified as the following: remission (no active pouchitis), mildly to moderately active (increased stool frequency, urgency, infrequent incontinence), or severely active (hospitalization for dehydration, frequent incontinence). Symptom duration can be classified as the following: acute (⬍4 weeks) or chronic (ⱖ4 weeks). Finally, the disease pattern can be classified as the following: infrequent (1–2 acute episodes), relapsing (ⱖ3 acute episodes), or continuous. The cumulative risk of having 1 or more episodes of pouchitis reaches nearly 50% by 5 years.7,8 The majority of these episodes of pouchitis are acute pouchitis (either infrequent or relapsing pattern), with approximately 5% of patients developing chronic pouchitis.7 Other causes of pouch dysfunction include Crohn’s disease, specific infection of the pouch, decreased pouch compliance, irritable pouch syndrome, cuffitis, strictured anastomosis, long efferent limb, decreased pouch emptying, pelvic floor dysfunction, pouch stricture, and adhesions. Approximately 5% of patients with ulcerative colitis who undergo colectomy with ileoanal pouch will eventually have a change in diagnosis to Crohn’s disease.9,10 This diagnosis is suspected when the pouch endoscopy shows prepouch ileitis or the patient develops perianal or pouch vaginal fistulas (pouch fistulas should be further evaluated with pelvic MRI and or examination under anesthesia). Infection of the ileoanal pouch with cytomegalovirus (CMV) or Clostridium difficile (C difficile) occur rarely and should be suspected when patients who Abbreviation used in this paper: CMV, cytomegalovirus. © 2004 by the American Gastroenterological Association 0016-5085/04/$30.00 doi:10.1053/j.gastro.2004.10.011
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Table 1. Etiology, Primary Symptoms, Diagnosis, and Treatment of Ileoanal Pouch Dysfunction Etiology
Primary symptoms
Diagnosis
Pouchitis Crohn’s disease
Increased stool frequency Increased stool frequency Abdominal pain and bloating Perianal or pouch vaginal fistulas
Pouch endoscopy with biopsy Pouch endoscopy with biopsy Small bowel x-ray Pouchogram Pelvic MRI
Specific infection CMV C difficile Primary decreased pouch compliance
Increased stool frequency
Biopsy for CMV Stool for C difficile
Increased stool frequency
Decreased pouch compliance secondary to pelvic sepsis
Increased stool frequency
Irritable pouch syndrome
Increased stool frequency Abdominal pain and bloating
Cuffitis
Fecal bleeding Fecal urgency Difficulty evacuating
Pouchogram Exam under anesthesis Pelvic MRI Pouchogram Exam under anesthesis Diagnosis of exclusion (negative endoscopy, pouchogram, small bowel x-ray) Pouch/cuff endoscopy with biopsy Physical examination
Strictured anastomosis Long efferent limb (S pouch, lateral pouch) Decreased pouch emptying
Difficulty evacuating
Pelvic floor dysfunction Pouch stricture Ischemic Crohn’s disease Torsion
Difficulty evacuating Difficulty evacuating
Adhesions
Abdominal pain and bloating
Difficulty evacuating
have endoscopic findings consistent with pouchitis fail to respond to antibiotic therapy.11,12 The diagnoses of CMV pouchitis or C difficile pouchitis are made by pouch biopsy and stool studies. Decreased pouch compliance typically occurs in patients with previous or ongoing pelvic sepsis and can be diagnosed by digital examination and pelvic MRI.3 Irritable pouch syndrome is diagnosed in patients with symptoms of pouchitis who have a negative pouch endoscopy.13 Cuffitis is inflammation of the rectal cuff in patients with a stapled ileoanal pouch; it is diagnosed with endoscopy.14 Ileoanal anastomotic stricture is diagnosed by digital examination.15 A functionally obstructed, long efferent limb should be suspected in patients with S pouches or lateral pouches who have obstructive symptoms and is diagnosed by pouchogram. Decreased pouch emptying, pelvic floor dysfunction, and pouch stricture should be considered in patients with bloating symptoms and difficulty evacuating. These conditions are diagnosed by pouchogram, nuclear
History Pouchogram Pouchogram Nuclear scintographic emptying study Anorectal manometry Pouch endoscopy Pouchogram Small bowel x-ray Mesenteric angiogram (rarely indicated) Small bowel x-ray
Treatment Antibiotics Antibiotics Corticosteroids Budesonide Azathioprine 6-mercaptopurine Methotrexate Infliximab Gancyclovir Metronidazole Vancomycin Diet Anti-diarrheal therapy Antibiotics Drainage Diversion Antispasmodics Anti-diarrheal therapy Fiber Topical mesalamine Exam under anesthesia with dilation Surgical shortening of spout or pouch revision Catheterization Tap water enemas Biofeedback Exam under anesthesia with dilation Endoscopic balloon dilation Stricturoplasty Pouch excision Exploratory laparotomy with lysis of adhesions
scintigraphic emptying study, and anorectal manometry.3
Potential Management Strategies Stool for Enteric Pathogens There are few cases in the literature of C difficile enteritis of the ileoanal pouch and no reported cases of bacterial enteric pathogens (bacterial or parasitic). For this reason, there is no utility in ordering these tests in patients presenting for the first time with symptoms of ileoanal pouch dysfunction. Flexible Sigmoidoscopy Flexible sigmoidoscopy is a useful test in identifying inflammation of the prepouch ileum (which would suggest Crohn’s disease), inflammation of the ileoanal pouch (which would suggest the possibilities of Crohn’s disease, pouchitis, and rarely ischemia and specific infec-
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tion of the pouch with CMV), and inflammation of the rectal cuff in a patient with a stapled J pouch (which means that 1–2 cm of rectum remains distal to the pouch-anal anastomosis). At a patient’s first endoscopic evaluation for ileoanal pouch dysfunction, biopsies of the pouch for histology should be performed to help establish a diagnosis (see below). Once a diagnosis of pouchitis is established, then repeated biopsies of the ileoanal pouch at the time of future endoscopies are not routinely required. In patients with a stapled J pouch, the rectal cuff should be examined for endoscopic findings of inflammation, which would indicate cuffitis. It should be noted that patients can have both pouchitis and cuffitis simultaneously. Flexible Sigmoidoscopy Plus Biopsy The prepouch ileum should be biopsied only if there are apthous ulcers or other endoscopic findings of inflammation to confirm a diagnosis of Crohn’s disease. The finding of inflammation of the pouch seen at endoscopy is nonspecific. Thus, we recommend that biopsy of the pouch be performed at the time of the initial endoscopy to help establish a diagnosis because histology can be helpful in distinguishing among Crohn’s disease, pouchitis, CMV pouchitis, and ischemia. We typically biopsy the pouch, even if the mucosa appears normal at endoscopy because some patients with mildly symptomatic pouchitis may have clear evidence of active acute pouchitis on biopsy with minimal endoscopic findings. Finally, for patients with a stapled ileoanal J pouch, the rectal cuff should be biopsied yearly for dysplasia. For patients with ileoanal pouch dysfunction and evidence of cuffitis at endoscopy, the endoscopic diagnosis of cuffitis can be confirmed with cuff biopsies. Pelvic MRI Pelvic MRI should be performed if the patient has perianal fistulas or vaginal drainage or pain in the pelvic or perianal region to delineate fistula anatomy and to identify absesses and pelvic sepsis. Perianal and vaginal fistulas may arise from the pouch, which is more consistent with Crohn’s disease, or from the anastomosis itself, which is more compatible with a technical complication from the surgery. Perianal Crohn’s disease may have associated perianal or pelvic abscesses, and an anastomotic fistula may be associated with peripouch pelvic sepsis. A pelvic MRI is not necessary if a patient does not have fistulas or prominent symptoms of pelvic or perianal pain. Pouchogram Contrast X-ray Pouchogram contrast x-ray is useful in evaluating for Crohn’s disease, a pouch stricture, decreased pouch com-
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pliance, a strictured anastomosis, a long efferent limb, and decreased pouch emptying. Crohn’s disease will manifest as fistulas arising from the pouch or stricturing of the pouch seen on pouchogram. Other causes of pouch structuring that can be seen with pouchogram include ischemic damage to the pouch and torsion or kinking of the pouch because of adhesions or surgical misadventure. Decreased pouch compliance (which usually occurs as a result of scarring from prior or ongoing pelvic sepsis) will show a small contracted pouch on pouchgram. Patients with an S pouch or lateral pouch have an efferent limb referred to as a spout. The spout can become elongated and intermittently kink, leading to functional obstruction of the outlet of the pouch. Pouchogram x-ray can be useful in delineating the pouch anatomy and identifying an elongated spout. Nuclear Medicine Pouch-Emptying Study Some patients will develop decreased pouch emptying, either because the pouch is too large or because possibly because of damage to enteric nerves during pouch construction. A nuclear medicine scintigraphic pouch-emptying study can be used to measure quantitatively the pouch emptying. The typical clinical presentation is difficulty with pouch evacuation. Patients with reduced pouch emptying may benefit from pouch irrigation and possibly pouch reconstruction. A scintigraphic pouch-emptying study is not necessary in a patient who does not complain of difficulty evacuating the pouch. Anorectal Manometry Anorectal manometry can be useful in diagnosing pelvic floor dysfunction. The typical clinical presentation is pelvic pain and difficulty with pouch evacuation. Such patients may benefit from biofeedback therapy. Anorectal manometry is not necessary in a patient who does not complain of significant pelvic pain or difficulty evacuating the pouch. Empiric Therapy for Pouchitis In the past, it was common to make an empiric diagnosis of pouchits in patients with an ileoanal pouch and increased stool frequency. The empiric diagnosis was followed by empiric therapy with antibiotics. This strategy often leads to an incorrect diagnosis of pouchitis in patients who actually have Crohn’s disease, anastomotic stricture, cuffitis, irritable pouch syndrome, and other causes of pouch dysfunction. Because pouchitis tends to reoccur in many patients, it is important to make an accurate diagnosis initially. Thus, empiric therapy is not appropriate in a patient with new onset pouch dysfunction. Once a diagnosis of pouchitis has been established
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by endoscopy and confirmed by biopsy, it may be reasonable to treat symptomatic relapse with empiric antibiotics, reserving repeat endoscopy for patients who fail to respond to antibiotic therapy.
Recommended Management Strategy The patient in the case outlined above has a 6-week history of fecal urgency, increased frequency of stools (sometimes with blood), and pelvic discomfort. The most likely cause of these symptoms is pouchitis, which is diagnosed by pouch endoscopy with biopsy. Therefore, the recommended management strategy to evaluate this patient with pouch dysfunction is pouch endoscopy with biopsy. Biopsy of the pouch should be performed not only to establish a diagnosis of pouchitis but to exclude other causes of pouch dysfunction. If this management strategy does not lead to a diagnosis, then pouchogram x-ray would be a reasonable next diagnostic step.
Evolution of the Case The patient underwent endoscopy of the ileoanal pouch. An adult gastroscope was used rather than a flexible sigmoidoscope because of its smaller diameter (which allows easier passage across the ileoanal anastomosis) and greater flexibility (which allows easier passage into the prepouch ileum to evaluate for Crohn’s disease). The prepouch ileum had a normal endoscopic appearance. The pouch itself showed patchy friability with multiple apthous ulcers. Biopsies showed acute and chronic inflammation, mucosal ulceration, and villous atrophy. Based on the clinical history and these endoscopic and histologic findings, the patient was diagnosed with acute pouchitis.
Subsequent Management Treatment Options for Pouchitis Specific treatments for pouchitis are outlined in Table 2. Clinical experience has demonstrated that most patients with pouchitis who are empirically treated with metronidazole or ciprofloxacin experience clinical improvement.16 A few small clinical trials have confirmed these observations.17–20 Madden et al treated 13 patients with active chronic pouchitis in a crossover trial of oral metronidazole 400 mg, 3 times daily or placebo for 14 days.18 Metronidazole reduced the (mean ⫾ SD) daily stool frequency from 10.0 ⫾ 2.8 to 9.0 ⫾ 5.2, whereas placebo-treated patients had an increase in mean daily stool frequency from 8.9 ⫾ 2.5 up to 10.7 ⫾ 4.1 (P ⬍ .05). A second randomized controlled trial by Shen et al compared 2 weeks of treatment with metronidazole 20
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Table 2. Treatments Reported to be Beneficial for Pouchitis Class example Antibiotics Metronidazole Ciprofloxacin Amoxicillin/clavulanic acid Erythromycin Tetracycline Rifaximin ⫹ tetracycline Metronidazole ⫹ ciprofloxacin Probiotic bacteria Lactobacilli, Bifidobacteria, S thermophilus E coli Nissle 1917 5-Aminosalicylates Mesalamine enemas Sulfasalazine Oral mesalamine Corticosteroids Conventional corticosteroid enemas Budesonide suppositories Budesonide enemas Oral corticosteroids Immune modifier agents Cyclosporin enemas Azathioprine, 6-mercaptopurine Infliximab Nutritional agents SCFA enemas or suppositories Glutamine suppositories Dietary fiber (pectin, methylcellulose, inulin) Oxygen radical inhibitors Allopurinol Antidiarrheal/antimicrobial Bismuth carbomer enemas Bismuth subsalicylate NOTE. Modified with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003; 124:1636 –1650. SCFA, short chain fatty acid.
mg/kg per day to ciprofloxacin 1000 mg/day in patients with acute pouchitis.19 Both drugs significantly reduced the pouchitis disease activity index score (0 –18 point score), but ciprofloxacin had a greater reduction in overall pouchitis disease activity index score (6.9 ⫾ 1.2 vs. 3.8 ⫾ 1.7, respectively, P ⫽ .002), symptom score (2.4 ⫾ 0.9 vs. 1.3 ⫾ 0.9, respectively, P ⫽ .03), and endoscopic score (3.6 ⫾ 1.3 vs. 1.9 ⫾ 1.5, respectively, P ⫽ .03) vs. metronidazole. A third randomized controlled trial comparing metronidazole 1000 mg/day and budesonide enemas 2 mg/day is described below.20 The most commonly used antibiotic for pouchitis is metronidazole.16 –20 The main alternative to metronidazole is ciprofloxacin.16,19 Most patients with pouchitis will have symptomatic improvement after 1 or 2 days of therapy with metronidazole at doses of 750 –1500 mg/day. Patients with a clinical course of relapsing or chronic pouchitis may need continuous maintenance treatment with metronidazole at doses ranging from 250 mg every
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➝ Endoscopy with Biopsy ➝
➝
Pouchitis
No Pouchitis ➝
➝ Metronidazole or Ciprofloxacin
Irritable Pouch Syndrome
➝
➝
Response
No Response
Metamucil, Imodium, Lomotil
➝
➝
Prompt Recurrence Therapies
Other Antibioticsa
Irritable Bowel Syndrome
➝
➝
➝
Repeat Antibiotics dysfunction
Anti-Inflammatory Drugsb
Evaluation for pelvic floor
➝
➝
➝
Prompt Recurrence
Immunosuppressive Drugsc
Surgical Consultation
➝
Repeat Antibiotics OR Add Probiotics
Surgical Consultation
➝
➝
An algorithm of the approach to treatment of pouchitis is shown in Figure 1. Patients with acute pouchitis are treated with metronidazole or ciprofloxacin. Patients who experience frequent relapses of pouchitis
Symptoms of Pouchitis
➝
Treatment Algorithm for Pouchitis
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➝
third day up to 750 mg/day. Adverse effects occurred in 33%–55% of patients during metronidazole treatment, including nausea, vomiting, abdominal discomfort, headache, and skin rash.18 –20 Recent studies have demonstrated that altering pouch bacterial contents by administering probiotic bacteria can be an effective therapeutic strategy. Three controlled trials have been performed.21–23 Gionchetti et al randomized 40 patients with chronic pouchitis in remission (after induction therapy with antibiotics) to treatment with either an oral probiotic preparation (2, 3-gram bags of VSL-3, each containing 300 billion viable lyophilized bacteria per gram) or placebo for 9 months.21 The VSL-3 preparation contained viable lyophilized bacteria including the following: 4 strains of lactobacilli (L acidophilus, L delbrueckii subsp. bulgaricus, L plantarum, L casei), 3 strains of bifidobacteria (B infantis, B longum, B breve), and 1 strain of Streptococcus salivarius subsp. thermophilus. At 9 months, the relapse rate was 15% in the VSL-3 group and 100% in the placebo group (P ⬍ .01). In a second controlled trial, 36 patients with recurrent or refractory pouchitis were treated with antibiotics and then randomized to maintenance therapy with VSL-3 or placebo for 1 year. The relapse rates were 10% in the VSL-3 group and 94% in the placebo group, P ⬍ .0001.22 In a controlled trial, patients undergoing colectomy and ileoanal pouch were randomized to prophylactic therapy with VSL-3 or placebo for 1 year.23 The rate of developing pouchitis during the first year was 10% in the VSL-3 group and 40% in the placebo group, P ⬍ .05. Of interest, the VSL-3 appeared to reduce the mean stool frequency of asymptomatic patients as well. Uncontrolled studies have reported that oral and rectal corticosteroids may be clinically beneficial in patients with active pouchitis.24 –26 A randomized, placebo controlled trial of 2 mg budesonide enemas vs. metronidazole showed similar efficacy for budesonide and metronidazole.20 Twenty-six patients with acute pouchitis were randomized to either budesonide enemas or oral metronidazole 500 mg twice daily for 6 weeks. Fiftyeight percent of budesonide patients and 50% of metronidazole patients improved. Fifty-seven percent of metronidazole patients had adverse events vs. only 25% of budesonide patients. Unpublished clinical experience suggests that oral, controlled-release budesonide 9 mg/day is also of clinical benefit for pouchitis.
CLINICAL MANAGEMENT OF POUCHITIS
➝
? Pouch Reconstruction OR ? Pouch Excision
Figure 1. Treatment algorithm for pouchitis. Other Antibioticsa indicates rifaximin, amoxicillin/clavulanate, erythromycin, tetracycline, and cycling of multiple antibiotics. Anti-inflammatory Drugsb indicates bismuth subsalicylate, mesalamine enemas, sulfasalazine, and oral mesalamine. Immunosuppressive Drugsc indicates budesonide, steroid enemas, oral steroids, azathioprine. Reprinted with permission from Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636 –1650.
and patients with chronic pouchitis will require longterm maintenance therapy with antibiotics or probiotics. In practice, we would institute maintenance therapy for patients who relapse at least 3 times within 1 year or within 1 month of discontinuation of antibiotics. Among patients receiving maintenance antibiotics who develop loss of clinical benefit after prolonged treatment, rotation of 3 or 4 antibiotics in 1-week intervals may be beneficial. Those patients who do not respond to metronidazole or other antibiotics can be treated with rectal or oral budesonide. Other treatment options may include rectal therapy with mesalamine enemas or suppositories and oral therapy with sulfasalazine or mesalamine, rectal or oral steroids, and possibly azathioprine or 6-mercaptopurine, or infliximab. Some patients may require combination therapy with multiple agents. There is little evidence to support therapy with short-chain fatty acid enemas, glutamine suppositories, inulin, or allopurinol. A minority of patients will be unresponsive to all medical therapy. These patients should be referred to a colorectal surgeon for consideration of permanent ileostomy with pouch exclusion or excision. Recommended Treatment The evidence-based treatment options for this patient include metronidazole, ciprofloxacin, and budes-
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onide. Although there is more overall experience with metronidazole, we prefer ciprofloxacin because it has a more favorable toxicity profile. In this patient, we would use ciprofloxacin 500 mg orally twice daily for 14 days and then discontinue therapy.
Conclusions Patients with pouch dysfunction should be evaluated with ileoanal pouch endoscopy and biopsy before a diagnosis of pouchitis is made. Small controlled trials have reported superior efficacy of metronidazole compared with placebo and similar efficacy for metronidazole compared with both ciprofloxacin and budesonide enemas for active chronic pouchitis. Three somewhat larger placebo-controlled trials reported that probiotic bacteria are effective for maintaining remission in patients with chronic pouchitis and for preventing the onset of pouchitis after colectomy with ileoanal pouch. Some patients with chronic pouchitis require maintenance therapy with antibiotics or probiotics, and some will require permanent ileostomy with pouch exclusion or excision.
References 1. Mahadevan U, Sandborn WJ. Diagnosis and management of pouchitis. Gastroenterology 2003;124:1636 –1650. 2. Sandborn WJ. Pouchitis: risk factors; frequency; natural history; classification; and public health perspective. Lancaster, UK: Kluwer Academic Publishers, 1997. 3. Sagar PM, Pemberton JH. Ileo-anal pouch function and dysfunction. Dig Dis 1997;15:172–188. 4. Di Febo G, Miglioli M, Lauri A, Biasco G, Paganelli GM, Poggioli G, Gozzetti G, Barbara L. Endoscopic assessment of acute inflammation of the ileal reservoir after restorative ileo-anal anastomosis. Gastrointest Endosc 1990;36:6 –9. 5. 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. 6. Shepherd NA, Jass JR, Duval I, Moskowitz RL, Nicholls RJ, Morson BC. Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens. J Clin Pathol 1987;40:601– 607. 7. Penna C, Dozois R, Tremaine W, Sandborn W, LaRusso N, Schleck C, Ilstrup D. 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. 8. Svaninger G, Nordgren S, Oresland T, Hulten L. Incidence and characteristics of pouchitis in the Kock continent ileostomy and the pelvic pouch. Scand J Gastroenterol 1993;28:695–700. 9. Hyman NH, Fazio VW, Tuckson WB, Lavery IC. Consequences of ileal pouch-anal anastomosis for Crohn’s colitis. Dis Colon Rectum 1991;34:653– 657. 10. Sagar PM, Dozois RR, Wolff BG. Long-term results of ileal pouchanal anastomosis in patients with Crohn’s disease. Dis Colon Rectum 1996;39:893– 898.
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11. Munoz-Juarez M, Pemberton JH, Sandborn WJ, Tremaine WJ, Dozois RR. Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis: report of two cases. Dis Colon Rectum 1999;42:117–120. 12. Mann SD, Pitt J, Springall RG, Thillainayagam AV. Clostridium difficile infection—an unusual cause of refractory pouchitis: report of a case. Dis Colon Rectum 2003;46:267–270. 13. Shen B, Achkar JP, Lashner BA, Ormsby AH, Brzezinski A, Soffer EE, Remzi FH, Bevins CL, Fazio VW. Irritable pouch syndrome: a new category of diagnosis for symptomatic patients with ileal pouch-anal anastomosis. Am J Gastroenterol 2002;97:877–972. 14. Shen B, Lashner BA, Bennett AE, Remzi FH, Brzezinski A, Achkar JP, Bast J, Bambrick ML, Fazio VW. Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis. Am J Gastroenterol 2004;99:1527–1531. 15. Prudhomme M, Dozois RR, Godlewski G, Mathison S, FabbroPeray P. Anal canal strictures after ileal pouch-anal anastomosis. Dis Colon Rectum 2003;46:20 –23. 16. Hurst RD, Molinari M, Chung TP, Rubin M, Michelassi F. Prospective study of the incidence, timing and treatment of pouchitis in 104 consecutive patients after restorative proctocolectomy. Arch Surg 1996;131:497–502. 17. McLeod RS, Taylor DW, Cohen Z, Cullen JB. Single-patient randomised clinical trial. Use in determining optimum treatment for patient with inflammation of Kock continent ileostomy reservoir. Lancet 1986;1:726 –728. 18. Madden MV, McIntyre AS, Nicholls RJ. Double-blind crossover trial of metronidazole versus placebo in chronic unremitting pouchitis. Dig Dis Sci 1994;39:1193–1196. 19. Shen B, Achkar JP, Lashner BA, Ormsby AH, Remzi FH, Brzezinski A, Bevins CL, Bambrick ML, Seidner DL, Fazio VW. A randomized clinical trial of ciprofloxacin and metronidazole to treat acute pouchitis. Inflamm Bowel Dis 2001;7:301–305. 20. Sambuelli A, Boerr L, Negreira S, Gil A, Camartino G, Huernos S, Kogan Z, Cabanne A, Graziano A, Peredo H, Doldan I, Gonzalez O, Sugai E, Lumi M, Bai JC. Budesonide enema in pouchitis—a double-blind, double-dummy, controlled trial. Aliment Pharmacol Ther 2002;16:27–34. 21. Gionchetti P, Rizzello F, Venturi A, Brigidi P, Matteuzzi D, Bazzocchi G, Poggioli G, Miglioli M, Campieri M. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology 2000;119: 305–309. 22. Mimura T, Rizzello F, Helwig U, Poggioli G, Schreiber S, Talbot IC, Nicholls RJ, Gionchetti P, Campieri M, Kamm MA. Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis. Gut 2004;53:108 –114. 23. Gionchetti P, Rizzello F, Helwig U, Venturi A, Lammers KM, Brigidi P, Vitali B, Poggioli G, Miglioli M, Campieri M. Prophylaxis of pouchitis onset with probiotic therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202–1209. 24. Shepherd NA, Hulten L, Tytgat GN, Nicholls RJ, Nasmyth DG, Hill MJ, Fernandez F, Gertner DJ, Rampton DS, Owen RW, Kmist WA, Keighley MRB, O’Connell PR, Kumar D, Williams NS. Pouchitis. Int J Colorectal Dis 1989;4:205–229. 25. Tytgat GN, van Deventer SJ. Pouchitis. Int J Colorectal Dis 1988; 3:226 –228. 26. Scott AD, Phillips RK. Ileitis and pouchitis after colectomy for ulcerative colitis. Br J Surg 1989;76:668 – 669.
Address requests for reprints to: William J. Sandborn, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected]; fax: (507) 266-0335.