Management of Pouchitis

Paolo Gionchetti, Claudia Morselli, Fernando Rizzello, Rosy Tambasco, Gilberto Poggioli, Silvio Laureti, Federica Ugolini, Filippo Pierangeli, Massimo Campieri

Introduction Risk Factors

Total proctocolectomy with ileal pouch-anal anasto- The risk of developing pouchitis is much higher in mosis (IPAA) proposed for the first time by Parks in patients with pre-operative extra-intestinal manifes- 1978 [1], represents nowadays the surgical treatment tations [8] and primary sclerosing cholangitis [9]. of choice for the management of patients with famil- More controversial is the predictive role of anti-neu- ial adenomatous polyposis (FAP) and ulcerative coli- trophil cytoplasmic antibody with a perinuclear pat- tis (UC) [2, 3]. This procedure allows the removal of tern (p-ANCA) [10-15] and of the pre-operative the whole diseased colorectal mucosal and has the extent of UC [16-17]. Similarly to UC, smoking may great advantage of preserving the anal sphincter be protective against the development of pouchitis function. Most patients undergoing IPAA for severe (Table 1) [18]. The surgical technique (different type colitis or for chronic continuous disease will achieve of reservoir) does not influence the frequency of pou- excellent functional results and physical well-being. chitis [19-20]. In a prospective evaluation of health related quality of life (HRLQ) after IPAA, a significant improvement of HRQL has been shown, assessed with both generic Etiology and disease-specific measures, with many patients experiencing improvements as early as 1 month post- The etiology is still unknown and is likely to be mul- operatively [4]. However pouchitis, a non-specific tifactorial; a variety of hypotheses have been suggest- (idiopathic) inflammation of the ileal reservoir, is the ed, including bacterial overgrowth due to faecal sta- most common long-term complication after pouch sis, mucosal ischemia of the pouch, missed diagnosis surgery for UC [5]. of Crohn’s disease, recurrence of UC and a novel form of IBD. Most likely pouchitis is the results of the interaction of a genetical and immunological suscep- Epidemiology, Risks Factors and Etiology tibility and an ileal mucosa that has adapted from its absorptive function to a new role of that of a reser- Frequency voir with a colon-like morphology in response to fae- cal stasis [21]. The true incidence is still difficult to determine, depending on the diagnostic criteria used to define the syndrome, the accuracy of the evaluation and, particularly, on the duration of the follow-up. Reported incidence rates vary between 10 and 59%; Table 1. Pouchitis: predictive factors most patients experience their first episode of acute Positive Association pouchitis within 12 months after surgery, but some Extra-intestinal manifestations may suffer their first attack some years later [6]. Primary sclerosing cholangitis Recently, Simchuk et al. performed a retrospective Antineutrophil cytoplasmic antibody with a perinuclear review of patients who underwent IPAA with a mean staining pattern (p-ANCA) follow-up of 3 years: the incidence of pouchitis was Extent of preoperative UC 59%, but it increased with the duration of follow-up Negative Association [7]. Smoking 302 P. Gionchetti, C. Morselli, F. Rizzello, R. Tambasco, G. Poggioli, S. Laureti, F. Ugolini, F. Pierangeli, M. Campieri

Diagnosis ical symptoms, endoscopic appearance and histologic findings, represents an objective and reproducible 26 The diagnosis of pouchitis should be based on clini- scoring system for pouchitis [ ]. Active pouchitis is Ն7 cal, endoscopic and histologic criteria; the key point defined by a total PDAI score and remission is 7 is that endoscopic and histopathologic evaluation is defined as a score < . Once diagnosis is made, pouch- required to make the diagnosis of pouchitis. itis can be further classified. The disease activity can be defined as remission, mild-moderate (increased stool frequency, urgency, infrequent incontinence) or Clinical Diagnosis severe (dehydration, frequent incontinence). Pouchi- tis can also be defined on the basis of the duration of Յ4 4 The most frequent symptoms which characterise this disease: acute ( weeks) or chronic (> weeks). syndrome include increased stool frequency and flu- Another way to classify this syndrome considers the idity, rectal bleeding, abdominal cramping, urgency, following patterns: infrequent (a single or two acute malaise and tenesmus, and in most severe cases, episodes), relapsing (more than three acute episodes) incontinence and fever [21]. Patients with pouchitis in about two thirds of cases, continuous or chronic may also have extra-intestinal manifestations such as disease (a treatment responsive form requiring a arthritis, ankylosing spondylitis, pyoderma gan- maintenance therapy or a treatment-resistant form). 15 grenosum, erythema nodosum and uveitis [8]. These About % of patients have a chronic disease and extra-intestinal manifestations may develop for the some of them require surgical excision or exclusion of first time with pouchitis, but frequently patients have the pouch because of impairment of reservoir function previously experienced these extra-intestinal mani- and poor quality of life. festations before surgery. The PDAI, nowadays, is the most frequently used scoring system in clinical studies to determine pou- chitis disease activity. The validity of PDAI and the Endoscopic Findings necessity of its application in epidemiological, patho- physiological or clinical studies, as well as in clinical A clinical diagnosis should be confirmed by practice in order to make a correct diagnosis of pou- 27 endoscopy and histology. With endoscopy the chitis, have been shown by Shen et al. [ ] in a study mucosa of the neo-terminal ileum above the pouch evaluating the correlation between symptoms, should be normal. Inflammation of the pouch endoscopy and histologic findings in patients with mucosa, with mucosal erythema, edema, friability, IPAA for UC. They found that symptoms alone do petechiae, granularity, loss of vascular pattern, not reliably diagnose pouchitis, whereas an evalua- mucosal haemorrhages, contact bleeding, mucus tion including symptoms, endoscopy and histology is 25 exudates, erosions and small superficial mucosal the best way to make the diagnosis. In fact, % of ulcerations can be present with varying degrees of patients with a high symptom score did not, in any of 36 severity [22-23]. Inflammation may be uniform or the cases, reach the PDAI diagnostic criteria and % more severe to the distal part of the pouch. of patients with minimal symptoms achieved a PDAI score ജ7 because of significant endoscopic and his- tologic inflammation [27]. Histologic Findings Differential Diagnosis Histologic examination shows acute inflammatory cell infiltrate with crypt abscesses and ulcerations on a background of chronic inflammatory changes with Before treatment is started, it is important to exclude villous atrophy and crypt hyperplasia [24-25]. other less frequent causes of pouch dysfunction or pouch inflammation, and this is particularly neces- sary in the case of a refractory patient. An anasto- Disease Activity Score and Classification motic stricture, with consequent outlet obstruction and faecal stasis, is a common complication of IPAA; Because of the great variability in the results of reports this increases stool frequency, makes the defecation on the incidence of pouchitis and in the assessment of painful with an incomplete evacuation predisposing therapy due to the lack of standardised diagnostic cri- to pouchitis. Diagnosis could be made by evacuation teria, Sandborn and colleagues developed a pouchitis pouchography, while the stricture can usually be disease activity index (PDAI). This 18-point index, cal- dilated with a finger or a rubber dilator. culated via three separate 6-point scales based on clin- Infectious etiology, caused by intestinal pathogens such as Shigella, Escherichia coli, Salmonella, Clostridi- Management of Pouchitis 303 um difficile, should be ruled out by microbiology ana- pathogenesis of acute pouchitis has led clinicians to lysis and pouch biopsy. Multiple cases of treat patients with antibiotics, which have become cytomegalovirus infection have been reported showing the mainstay of treatment, in absence of controlled the need for using monoclonal immunofluorescent trials. Usually metronidazole represents the most staining for CMV for the examination of pouch biopsies common first therapeutic approach, and most when treatment with antibiotics has proven unsuccess- patients with acute pouchitis respond quickly to ful. In these patients the CMV infection must be exclud- administration of 1–1.5 g/day [33-34]. A double- ed before starting immune modifier therapy [28-29]. blind, randomised, placebo-controlled, crossover Cuffitis is the inflammation of the retained rectal trial was carried out in 1993 by Madden et al. [22] to mucosa (columnar cuff) above the anal transitional assess the efficacy of 400 mg three times a day of zone (ATZ) after stapled anastomosis between the metronidazole per os in 13 patients (11 completed pouch and the top of the anal canal; this kind of both arms of the study) with chronic, unremitting inflammation, usually mild and not related to inflam- pouchitis, defined by the presence of recurrent or mation of the pouch, can cause anal discomfort, peri- persistent symptoms with almost six bowel move- anal irritation and pouch dysfunction. Clinically sig- ments a day and typical endoscopic findings. Patients nificant cuffitis should be defined using a triad of were treated for 2 weeks, with a 7-day wash-out peri- diagnostic criteria including clinical symptoms, endo- od before the crossover to the second treatment. scopic inflammation and acute histologic inflamma- Metronidazole was significantly more effective than tion [30]. This syndrome rarely reaches dramatic pro- placebo in reducing the stool frequency (73 vs. 9%), portions and clinical improvement can be obtained even without improvement of endoscopic appear- with topical corticosteroid, mesalazine suppositories ance and histologic grade of activity. Some patients and lidocaine gel applications. Scintigraphic pelvic (55%) experienced side effects from metronidazole pouch emptying scans can be used to evaluate including nausea, vomiting, abdominal discomfort, patients who have inadequate pouch evacuation. headache, skin rash and metallic taste [35]. Dysgeu- Fistulae and perianal abscesses should be suspect- sia and peripheral neuropathy may limit long-term ed as being the expression of misdiagnosed Crohn’s administration of metronidazole, while patients disease. Review of the proctocolectomy specimen drinking alcohol may have a disulfiram-like reaction. and new biopsy samples are needed to make a correct Recently Shen and colleagues have compared the diagnosis. If Crohn’s disease is suspected, a small- effectiveness and side effects of ciprofloxacin and bowel follow-through x-ray will rule out disease metronidazole in a randomised clinical trial regard- above the pouch. Approximately 5% of IPAA surgery ing the treatment of acute pouchitis. Seven patients is performed in patients whose primary diagnosis of received ciprofloxacin 1 g/day and nine patients UC is revised at some point after surgery to a defini- metronidazole 20 mg/kg/day for a period of 2 weeks. tive diagnosis of Crohn’s disease. Other disorders The results of this study have shown that both that are able to mimic pouchitis symptoms are bile ciprofloxacin and metronidazole are efficacious in acid malabsorption, irritable pouch syndrome [31], the treatment of acute pouchitis; they reduced the and chronic pelvic sepsis. total PDAI scores and led to a significant improve- ment of symptoms and endoscopic and histologic scores. However, ciprofloxacin led to a greater degree Medical Treatment of reduction in the total PDAI score and to a greater improvement in symptoms and endoscopic scores; Until now, few small placebo-controlled trials and furthermore ciprofloxacin was better tolerated than small controlled comparisons of two active agents metronidazole (33% of metronidazole-treated patients have been carried out and, as a consequence, the reported adverse effects; none were reported in the medical treatment of pouchitis is still widely empiric. ciprofloxacin-treated group). The authors have sug- The reason for this small amount of randomised gested that ciprofloxacin should be considered the double-blind controlled clinical trials may be found first-line therapy for acute pouchitis [36]. in the lack of a general agreement about the criteria for definition, diagnosis, classification and disease activity [32]. Other Agents

Anedoctal reports have suggested that oral or topical Antibiotics conventional corticosteroids may be of benefit to patients with pouchitis. Recently a double-blind, The awareness of the crucial importance that faecal double-dummy, 6-week-controlled trial investigated stasis and bacterial overgrowth may have in the the efficacy and tolerability of budesonide enema in 304 P. Gionchetti, C. Morselli, F. Rizzello, R. Tambasco, G. Poggioli, S. Laureti, F. Ugolini, F. Pierangeli, M. Campieri

the treatment of pouchitis compared with oral Allopurinol, a scavenger of oxygen-derived free metronidazole. This study showed that budesonide radicals through inhibition of xanthine oxidase, was enemas (2 mg/100 ml at bedtime) have a similar effi- evaluated as post-operative prophylactic treatment cacy as oral metronidazole (0.5 g bid) in terms of dis- (100 mg twice daily) against pouchitis in a ran- ease activity, clinical and endoscopic findings (58 domised placebo-controlled double-blind study con- and 50% of patients, respectively, improved with a ducted at 12 centres in Sweden; however, it was not decrease in PDAI score ജ3), but less side-effects (25 proven to be able to reduce the risk of a first attack of vs. 57%) and better tolerability, representing conse- pouchitis [48]. quently a valid therapeutic alternative for active pou- chitis [37]. While no data have been published on the efficacy Treatment of Chronic Pouchitis of oral 5-ASA, uncontrolled studies have suggested the efficacy of topical 5-ASA either as suppositories or ene- Medical treatment of patients with chronic refracto- mas in treatment of acute pouchitis [38]. As concerns ry pouchitis is particularly difficult and disappoint- immunosuppressive agents, cyclosporine enemas have ing. The usual therapeutic strategy for these patients, been reported to be successful in chronic pouchitis in a who fail to respond to antibiotics or relapse once pilot study [39] and other small studies have suggested antibiotic therapy is stopped, includes: (1) a pro- that oral azathioprine may also be useful. longed course of an antimicrobial agent, (2) a main- The observation reported in some studies [40], but tenance therapy with the most effective antibiotic at not all [41], that the faecal concentration of SCFAs is the lowest clinically effective dose, (3) cycles of mul- lower in patients with pouchitis, led to the hypothe- tiple antibiotics at 1-week intervals. A possible thera- sis that the topical administration of nutrients, such peutic alternative for chronic refractory pouchitis is as SCFAs or butyrate or glutamine, may produce the use of a combined antibiotic treatment. We car- clinical benefit. Poor clinical results were obtained in ried out a pilot trial to evaluate the efficacy of the uncontrolled trials using SCFAs enemas [42-43]. In a association of two antibiotics in chronic active treat- 3-week double-blind trial, glutamine and butyrate ment-resistant pouchitis. Eighteen patients who were suppositories were compared in a group of 19 not responders to the standard therapy (metronida- patients with chronic pouchitis with recurrent symp- zole or ciprofloxacin or amoxycillin/clavulanic acid) toms; the end-point was clinical remission. As the for 4 weeks, were treated orally with rifaximin relapse rate was 40% for the glutamine group and 2 g/day (non-absorbable, wide spectrum antibiotic) 67% for the butyrate group and no placebo group plus ciprofloxacin 1 g/day for 15 days; symptoms was included, it was almost impossible to state if the assessment, endoscopic and histologic evaluations two treatments were both ineffective and similarly were performed at screening and after 15 days using effective [44]. In consideration of all these studies, the PDAI. Sixteen out of 18 patients (88.8%) either nutritional therapy thus far should not be considered improved (n=10) or went into remission (n=6); the beneficial for pouchitis. median PDAI scores before and after therapy were 11 Bismuth, effective in UC and traveller’s diarrhoea and 4 respectively (p<0.002) [49]. Unfortunately all because of its anti-microbial and anti-diarrhoeal patients relapsed within 2 months. effects, was also investigated. One open-label long- More recently, 44 patients with refractory pouchi- term study evaluated the efficacy and safety of bis- tis received metronidazole 800 mg – 1 g/day and muth-citrate carbomer enemas in achieving and ciprofloxacin 1 g/day for 28 days. Symptomatic, maintaining remission in a group of patients with endoscopic and histological evaluations were under- chronic treatment-resistant pouchitis. After 45 days taken before and after the antibiotic therapy, accord- of nightly treatment, 83% of patients went into ing to the PDAI score, and the related quality of life remission with a significant decrease of the mean was assessed with the inflammatory bowel disease total PDAI score from 12 to 6. Moreover, these questionnaire (IBDQ). Thirty-six patients (82%) patients entered a maintenance phase with enemas went into remission; the median PDAI scores before administered every third night for 12 months (60%) and after therapy were 12 and 3 respectively were able to maintain remission for 12 months [45]. (p<0.0001). Patients’ quality of life significantly On the other hand, a double-blind randomised trial improved with the treatment and median IBDQ in patients with active chronic pouchitis did not find strongly correlated with the disease activity and gen- a difference between bismuth enemas and placebo eral satisfaction (from 96.5 to 175). Even in the eight [46]. More recently, a 4-week treatment open trial patients who did not go into remission, the median showed patients benefited from bismuth subsalicy- PDAI score significantly improved from 14.5 to 9.5 as late tablets administered for chronic antibiotic- well as the median IBDQ score from 96 to 127 [50]. resistant pouchitis [47]. Oral-controlled release budesonide can be useful Management of Pouchitis 305 for certain patients. In a small open trial, 16 patients and their metabolic activities in the ileal pouch [55]. with chronic pouchitis refractory to a 1-month These results have been recently confirmed by a antibiotic therapy (ciprofloxacin 1 g/day and study evaluating the efficacy of a single, daily dose of metronidazole 1 g/day) were treated with budesonide VSL#3 in maintaining antibiotic-induced remission CIR 9 mg/day for 8 weeks; the dose was gradually (obtained after a 1 month treatment with metronida- tapered (3 mg every month) and remission was zole 800 mg/day plus ciprofloxacin 1 g/day) for 1 year defined as a clinical PDAI score ഛ2 and an endo- in patients with refractory or recurrent pouchitis: 20 scopic PDAI ഛ1. Twelve patients (72%) went into patients received VSL#3 at 1 800 billion bacteria once remission and the total PDAI score significantly a day for 1 year and 16 patients received a placebo decreased from 13 (range 8–16) to 3 (range 2-9) during the same period. Clinical, endoscopic and his- (p<0.001). Budesonide treatment increased the IBDQ tological evaluations were made before 2 and score from 102 (range 77–176) to 182 (range 84–225) 12 months after the randomisation. A parallel assess- (p<0.001) [51]. ment of quality of life (QoL) was obtained with IBDQ. In a subsequent study, 12 patients with active pou- This study has substantially confirmed the observa- chitis refractory to ciprofloxacin and metronidazole tions made previously, with a maintenance remission for 1 month and oral budesonide for 8 weeks, were rate of 85% at 1 year in the VSL#3 group and 6% in treated with three infusions of infliximab at a dosage the placebo group. A high rating in the QoL score was of 5 mg/kg at week 0, 2 and 6. Ten patients (83.3%) obtained by the group treated with VSL#3 [56]. achieved remission; the total PDAI score decreased The same probiotic preparation was also more from 13 (range 8–18) to 2 (range 0–9) (p<0.001). The recently shown to be significantly superior to place- IBDQ score strongly increased from 96 (range bo in the prevention of pouchitis onset within the 74–184) to 196 (range 92–230; p<0.001) [52]. first year after surgery in a randomised double-blind placebo-controlled study. Forty consecutive patients who underwent IPAA for UC were randomised with- Probiotics in a week after ileostomy closure, and received VSL#3 at a dosage of 3 g per day or an identical placebo for The term “probiotic” refers to “living organisms, 12 months. They were assessed clinically, endoscopi- which upon ingestion in certain numbers, exert cally, histologically at 1, 3, 6, 9 and 12 months, health benefits beyond inherent basic nutrition” [53]. according to PDAI; QoL was also assessed at baseline Recent observations have suggested a potential ther- at the end of the study. Patients treated with VSL#3 apeutic role for probiotics in inflammatory bowel had a significantly lower incidence of acute pouchitis diseases (IBD), based on convincing evidence impli- (10%) compared with those treated with placebo cating intestinal bacteria in their pathogenesis [54]. (40%) (p<0.05), and they experienced a significant On the basis of this information, we carried out a improvement in quality of life, whereas this did not double-blind study comparing the efficacy of a high- happen in the placebo group, indicating the effective- ly concentrated probiotic preparation, VSL#3 (450 ness of a highly concentrated probiotic preparation billion bacteria of eight different strains; VHS Phar- in preventing pouchitis onset during the first year ma, USA) vs. placebo in maintenance treatment of after surgery [57]. chronic relapsing pouchitis. In our study, 40 patients Preliminary data of a pilot study to evaluate the who obtained clinical and endoscopic remission after efficacy of high dosage of VSL#3 (6 g b.i.d. equivalent one month of combined antibiotic treatment (rifax- to 3 600 billion bacteria per day) administered for imin 2 g/day plus ciprofloxacin 1 g/day), were ran- 1 month as treatment for mildly active pouchitis domised to receive either VSL#3, 6 g/day (1 800 bil- (PDAI score 7–12), have shown its potential useful- lion bacteria per day), or an identical-appearing ness in improving active pouch inflammation and placebo for 9 months. Relapse was defined as an health related quality of life [58]. increase of at least 2 points in the clinical portion of PDAI, which should be confirmed by endoscopy and histology. All the 20 patients who received the place- Management bo relapsed; in contrast 17 of the 20 patients (85%) treated with VSL#3 were still in remission at the end In a proposed algorithm for treatment of pouchitis, of the study. All the 17 patients had a relapse within once diagnosis is confirmed by endoscopy and his- 4 months after suspension of the treatment. The tology, and other causes of inflammation or pouch results of this study suggested that oral administra- dysfunction have been excluded, the main treatment tion of this highly concentrated probiotic preparation consists of metronidazole 250 mg three times/day or is effective in preventing relapse of chronic pouchitis, ciprofloxacin 500 mg b.i.d. for at least 2 weeks. In enhancing the concentration of protective bacteria case of a subsequent prompt relapse, the patients can 306 P. Gionchetti, C. Morselli, F. Rizzello, R. Tambasco, G. Poggioli, S. Laureti, F. Ugolini, F. Pierangeli, M. Campieri

Pouchitis

Metronidazole/Ciprofloxacin

Response No response

Exclude CD prompt relapse no relapse stenosis, cuffitis Prompt relapse No relapse CMV infection

Oother antibiotics or MTZ or Cipro combined antibiotic or combined antibiotic treatment

Response No response No response Response

Probiotics maintenance 5-ASA, AZA/6MP Probiotics maintenance treatment GCS,Budesonide, Infliximab treatment

Pouch excision or reconstruction Fig. 1. Proposal for a treat- ment algorithm

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