A Systematic Review and Meta-analysis of Randomized Clinical Trials on the Prevention and Treatment of Pouchitis after Ileoanal Pouch Anastomosis.

BACKGROUND: This systematic review explored different medications and methods for prevention and treatment of pouchitis after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: PubMed, Scopus, and Web of Science were searched for randomized clinical trials that assessed prevention or treatment of pouchitis. The systematic review was reported in line with updated 2020 PRISMA guidelines. Risk of bias in the trials included was assessed using the ROB-2 tool and certainty of evidence was assessed using GRADE. The main outcomes were the incidence of new pouchitis episodes in the preventative studies and resolution or improvement of active pouchitis in the treatment studies. RESULTS: Fifteen randomized trials were included. A meta-analysis of 7 trials on probiotics revealed significantly lower odds of pouchitis with the use of probiotics (RR: 0.26, 95% CI: 0.16-0.42, I2 = 20%, p < 0.001) and similar odds of adverse effects to placebo (RR: 2.43, 95% CI: 0.11-55.9, I2 = 0, p = 0.579). One trial investigated the prophylactic role of allopurinol in preventing pouchitis and found a comparable incidence of pouchitis in the two groups (31% vs 28%; p = 0.73). Seven trials assessed different treatments for active pouchitis. One recorded the resolution of pouchitis in all patients treated with ciprofloxacin versus 67% treated with metronidazole. Both budesonide enema and oral metronidazole were associated with similar significant improvement in pouchitis (58.3% vs 50%, p = 0.67). Rifaximin, adalimumab, fecal microbiota transplantation, and bismuth carbomer foam enema were not effective in treating pouchitis. CONCLUSIONS: Probiotics are effective in preventing pouchitis after IPAA. Antibiotics, including ciprofloxacin and metronidazole, are likely effective in treating active pouchitis.

Vedolizumab for the Treatment of Chronic Pouchitis.

BACKGROUND: Approximately half the patients with ulcerative colitis who undergo restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) will subsequently have pouchitis, and among those patients, one fifth will have chronic pouchitis. METHODS: We conducted a phase 4, double-blind, randomized trial to evaluate vedolizumab in adult patients in whom chronic pouchitis had developed after undergoing IPAA for ulcerative colitis. Patients were assigned (in a 1:1 ratio) to receive vedolizumab intravenously at a dose of 300 mg or placebo on day 1 and at weeks 2, 6, 14, 22, and 30. All the patients received concomitant ciprofloxacin from weeks 1 to 4. The primary end point was modified Pouchitis Disease Activity Index (mPDAI)-defined remission (an mPDAI score of ≤4 and a reduction from baseline of ≥2 points in the mPDAI total score; scores range from 0 to 12, with higher scores indicating more severe pouchitis) at week 14. The mPDAI is based on clinical symptoms and endoscopic findings. Other efficacy end points included mPDAI-defined remission at week 34, mPDAI-defined response (a reduction from baseline of ≥2 points in the mPDAI score) at weeks 14 and 34, and PDAI-defined remission (a PDAI score of ≤6 and a reduction from baseline of ≥3 points; scores range from 0 to 18, with higher scores indicating more severe pouchitis) at weeks 14 and 34. The PDAI is based on clinical symptoms, endoscopic findings, and histologic findings. RESULTS: Among the 102 patients who underwent randomization, the incidence of mPDAI-defined remission at week 14 was 31% (16 of 51 patients) with vedolizumab and 10% (5 of 51 patients) with placebo (difference, 21 percentage points; 95% confidence interval [CI], 5 to 38; P = 0.01). Differences in favor of vedolizumab over placebo were also seen with respect to mPDAI-defined remission at week 34 (difference, 17 percentage points; 95% CI, 0 to 35), mPDAI-defined response at week 14 (difference, 30 percentage points; 95% CI, 8 to 48) and at week 34 (difference, 22 percentage points; 95% CI, 2 to 40), and PDAI-defined remission at week 14 (difference, 25 percentage points; 95% CI, 8 to 41) and at week 34 (difference, 19 percentage points; 95% CI, 2 to 37). Serious adverse events occurred in 3 of 51 patients (6%) in the vedolizumab group and in 4 of 51 patients (8%) in the placebo group. CONCLUSIONS: Treatment with vedolizumab was more effective than placebo in inducing remission in patients who had chronic pouchitis after undergoing IPAA for ulcerative colitis. (Funded by Takeda; EARNEST ClinicalTrials.gov number, NCT02790138; EudraCT number, 2015-003472-78.).

Long-term Antibiotic Treatment in Pouchitis-Patterns of Use and Safety.

INTRODUCTION: Pouchitis, often developing after colectomy and ileal pouch-anal anastomosis for ulcerative colitis, is highly responsive to antibiotics. Ciprofloxacin and/or metronidazole are commonly used, often for prolonged periods. We report patterns of antibiotic use, adverse events, and resistant infections in patients with pouchitis with long-term antibiotic treatment. METHODS: In a cohort of patients following pouch surgery, a retrospective nested case-control analysis was performed between 2010 and 2017. Ultra-long-term use, defined as the top 10% of users, was compared with the remaining users. Patterns of antibiotic use, adverse events, and resistant infections were analyzed. RESULTS: The cohort included 205 patients with UC, of whom 167 (81.5%) used antibiotics for pouchitis, predominantly ciprofloxacin. The long-term antibiotic use rate was 18% and 42% at 5 and 20 years postsurgery, respectively. Mean antibiotic use of at least 1, 3, and 6 months/year was noted in 54 (26.3%), 31 (15.1%), and 14 (6.8%) patients, respectively. Twenty-two (13.2%) and 4 (2.4%) patients reported mild and severe (transient) adverse events, respectively, without mortalities, tendinopathies or arrhythmias. Adverse event rates for ciprofloxacin and metronidazole were 1per 10,000 and 6 per 10,000 use-days, respectively. Longer, but not ultra-long antibiotic use, was associated with mild adverse events. There was no association between antibiotic use and resistant infections. Thirteen (6.3%) patients required ileostomy procedures-more commonly in the ultra-long-term antibiotic users. CONCLUSIONS: Patients with pouchitis may require prolonged antibiotic treatment, reflecting clinical benefit and favorable safety profile. Few adverse events and resistant infections were observed with long-term antibiotics use. However, resistant microbial strains selection, which are potentially transmittable, warrants consideration of different therapeutic alternatives.

Safety and Efficacy of Biological Therapy in Chronic Antibiotic Refractory Pouchitis: A Systematic Review With Meta-analysis.

BACKGROUND: Pouchitis is the most common long-term complication after ileal pouch-anal anastomosis in patients with ulcerative colitis. Those with ≥3 episodes of pouchitis/year and symptoms despite antibiotics are considered to have chronic antibiotic refractory pouchitis (CARP). While several agents including probiotics, steroids and immunomodulators have been used, treatment of CARP remains challenging. We conducted a systematic review and meta-analysis evaluating the safety and efficacy of various biological agents in treatment of CARP. METHODS: Multiple databases were searched through June 2020 for studies that reported the efficacy and safety of biological therapy including antitumor necrosis factor-alpha agents [infliximab (IFX) and adalimumab (ADA)], vedolizumab (VDZ), and ustekinumab in CARP. We excluded studies on Crohn's like and/or other inflammatory complications of the pouch. Meta-analysis was performed to calculate pooled rates of clinical as well as endoscopic improvement and remission. RESULTS: We included 15 studies with 311 patients in our final analysis. Ninety-two patients were treated with IFX, 42 with ADA, 144 with VDZ and 33 with ustekinumab. Pooled rate of clinical improvement was 71.4%, 58.2%, 47.9% and clinical remission was 65.7%, 31%, 47.4% with IFX, ADA, and VDZ, respectively. Pooled rate of endoscopic improvement was achieved in 61.2% patients treated with VDZ while endoscopic remission was achieved in 70.3% patients treated with IFX. Adverse events were reported in 3.9% patients. CONCLUSION: Biologic therapy is safe and effective in the treatment of CARP.

Hyperbaric Oxygen Therapy in Chronic Inflammatory Conditions of the Pouch.

BACKGROUND: Pouchitis can be a chronic complication of ileal pouch-anal anastomosis. We aimed to determine the efficacy and safety of hyperbaric oxygen therapy (HBOT) for chronic antibiotic-refractory pouchitis (CARP) and other inflammatory conditions of the pouch. METHODS: This was a retrospective case series of adults with inflammatory bowel disease (IBD) who underwent ileal pouch-anal anastomosis and then developed CARP and received HBOT between January 2015 and October 2019. A modified Pouchitis Disease Activity Index (mPDAI) score was used to quantify subjective symptoms (0-6) and endoscopic findings (0-6) before and after HBOT. RESULTS: A total of 46 patients were included, with 23 (50.0%) being males with a mean age of 43.6 ± 12.9 years. The median number of HBOT sessions was 30 (range 10-60). There was a significant reduction in the mean mPDAI symptom subscore from 3.19 to 1.91 after HBOT (P < 0.05). The pre- and post-HBOT mean mPDAI endoscopy subscores for the afferent limb were 2.31 ± 1.84 and 0.85 ± 1.28 (P = 0.006); for the pouch body, 2.34 ± 1.37 and 1.29 ± 1.38 (P < 0.001); and for the cuff, 1.93 ± 1.11 and 0.63 ± 1.12 (P < 0.001), respectively. Transient side effects included ear barotrauma in 5 patients (10.9%) and hyperbaric myopic vision changes in 5 patients (10.9%). CONCLUSIONS: Despite minor adverse events, HBOT was well tolerated in patients with CARP and significantly improved symptoms and endoscopic parameters.

A New Rat Model of Pouchitis After Proctocolectomy and Ileal Pouch-Anal Anastomosis Using 2,4,6-Trinitrobenzene Sulfonic Acid.

BACKGROUND: Pouchitis is a common complication after ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. However, an ideal model remains lacking. Therefore, we aimed to establish an appropriate model resembling human pouchitis. METHODS: Sprague-Dawley rats were randomly assigned to five groups: TNBS group, DSS group, NS group (following IPAA procedure, administrated with TNBS enema, DSS orally, normal saline enema, respectively), NI group (underwent IPAA), and sham group (underwent switch abdominal surgery). General status, weight change, hematochezia, and fecal scores were recorded. Fecal microbiota were counted under a microscope and analyzed by 16S rRNA gene high-throughput sequencing. Specimens of ileal pouch and small intestine (proximal, mid, distal) were collected to evaluate myeloperoxidase and occludin expression by immunohistochemistry and mRNA expression of pro-inflammatory markers by PCR. RESULTS: General status, hematochezia, fecal score, and increased mRNA expression of interleukin-6 and TNF-α in the TNBS group were similar to those in the DSS group, whereas the TNBS-induced model displayed a more stable weight change and more serious dysbacteriosis, not only was fecal bacterial diversity reduced, the dominant microbiota was altered. Histopathology scores of the distal small intestine in the TNBS group were lower compared with those in the DSS group (P < 0.05). A significant difference in myeloperoxidase and occludin expression in the small intestine was also detected between the TNBS and DSS groups. CONCLUSIONS: Our model mimicked the characteristics of human pouchitis and avoided potential side effects in the small intestine, and thus could be employed for further research.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear. Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence). Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation (a probiotic formulation) participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

ANTECEDENTES: La reservoritis ocurre en aproximadamente el 50% de los pacientes después de la anastomosis entre la bolsa ileal y el ano (IPAA, por sus siglas en inglés) para la colitis ulcerosa crónica (CU). OBJETIVOS: El objetivo primario fue determinar la eficacia y la seguridad de los tratamientos médicos para la prevención o el tratamiento de la reservoritis aguda o crónica. MÉTODOS DE BÚSQUEDA: Se hicieron búsquedas en MEDLINE, Embase y en CENTRAL, desde su inicio hasta el 25 julio 2018. También se buscó en las listas de referencias, registros de ensayos en curso y actas de congresos. CRITERIOS DE SELECCIÓN: Se consideraron para inclusión los ensayos controlados aleatorios de prevención o tratamiento de la reservoritis aguda o crónica en adultos a los que se les realiza IPAA para la CU. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los estudios, extrajeron los datos y analizaron el riesgo de sesgo. La calidad de la evidencia se evaluó mediante los criterios GRADE. El resultado primario la mejoría clínica o remisión en los pacientes con reservoritis aguda o crónica, o la proporción de pacientes sin episodios de reservoritis después de IPAA. Se incluyeron los eventos adversos como resultado secundario. Se calculó el cociente de riesgos (CR) y el intervalo de confianza (IC) del 95% correspondiente para los resultados dicotómicos. RESULTADOS PRINCIPALES: Se incluyeron 15 estudios (547 participantes). Cuatro estudios evaluaron el tratamiento de la reservoritis aguda. Cinco estudios evaluaron el tratamiento de la reservoritis crónica. Seis estudios evaluaron la prevención de la reservoritis. Tres estudios presentaban bajo de riesgo de sesgo. En tres estudios el riesgo fue alto y en los otros estudios fue poco claro. reservoritis aguda: Todos los pacientes que recibieron ciprofloxacina (7/7) lograron la remisión a las dos semanas en comparación con el 33% (3/9) de los pacientes que recibieron metronidazol (CR 2,68; IC del 95%: 1,13 a 6,35) (evidencia de certeza muy baja). Ninguno de los participantes que recibieron ciprofloxacina (0/7) presentó eventos adversos en comparación con el 33% (3/9) de los participantes que recibieron metronidazol (CR0,18; IC del 95%: 0,01 a 2,98; evidencia de certeza muy baja). Los eventos adversos incluyeron vómitos, disgeusia o neuropatía periférica transitoria. El 40% (6/14) de los participantes que recibieron metronidazol lograron la remisión a las 6 semanas en comparación con el 50% (6/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,37 a 1,96; evidencia de certeza muy baja). El 50% (7/14) de los participantes del grupo de metronidazol mejoraron clínicamente a las 6 semanas en comparación con el 58% (7/12) de los participantes que recibieron enema de budesonida (CR 0,86; IC del 95%: 0,42 a 1,74; evidencia de certeza muy baja). El 57% (8/14) de los participantes del grupo de metronidazol presentaron eventos adversos en comparación con el 25% (3/12) de los participantes que recibieron enema de budesonida (CR 2,29; IC del 95%: 0,78 a 6,73; evidencia de certeza muy baja). Los eventos adversos incluyeron anorexia, náuseas, cefalea, astenia, sabor metálico, vómitos, parestesia y depresión. El 25% (2/8) de los participantes que recibieron rifaximina lograron la remisión a las 4semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 6,11; IC del 95%: 0,33 a 111,71; evidencia de certeza muy baja). El 38% (3/8) de los participantes del grupo de rifaximina mejoraron clínicamente a las 4 semanas en comparación con el 30% (3/10) de los participantes que recibieron placebo (CR 1,25; IC del 95%: 0,34 a 4,60; evidencia de certeza muy baja). El 75% (6/8) de los participantes del grupo de rifaximina presentaron un evento adverso en comparación con el 50% (5/10) de los participantes que recibieron placebo (CR 1,50; IC del 95%: 0,72 a 3,14; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, flatulencias, náuseas, proctalgia, vómitos, sed, cándida, infección de las vías respiratorias superiores, aumento de las enzimas hepáticas y cefalea en racimos. El 10% (1/10) de los participantes del grupo de Lactobacillus GGmejoraron clínicamente a las 12 semanas en comparación con el 0% (0/10) de los participantes que recibieron placebo (CR 3,00; IC del 95%: 0,14 a 65,90; evidencia de certeza muy baja). Reservoritis crónica: El 85% (34/40) de los pacientes que recibieron la formulación De Simone mantuvieron la remisión de nueve a 12 meses en comparación con el 3% (1/36) de los participantes que recibieron placebo (CR 20,24; IC del 95%: 4,28 a 95,81; dos estudios; evidencia de certeza baja). El 2% (1/40) de los participantes que recibieron la fórmula De Simone presentaron un evento adverso, en comparación con el 0% (0/36) de los participantes que recibieron placebo (CR 2,43; IC del 95%: 0,11 a 55,89; evidencia de certeza baja). Los efectos secundarios incluyeron cólicos abdominales, vómitos y diarrea. Cuarenta y tres por ciento (3/6) de los pacientes en el grupo de adalimumab lograron una mejoría clínica a las 4 semanas en comparación con un 43 (3/7) de los pacientes del grupo de placebo (CR 1,17, IC del 95%: 0,36 a 3,76; evidencia de certeza baja). El 60% (6/10) de los participantes del grupo de glutamina mantuvieron la remisión a las 3 semanas en comparación con el 33% (3/9) de los participantes que recibieron placebo (CR 1,80; IC del 95%: 0,63 a 5,16; evidencia de certeza muy baja). El 45% (9/20) de los participantes del grupo de enema de espuma de carbómero de bismuto mejoraron clínicamente a las 3 semanas en comparación con el 45% (9/20) de los participantes que recibieron placebo (CR 1,00; IC del 95%: 0,50 a 1,98; evidencia de certeza muy baja). El 25% (5/20) de los participantes del grupo de aceite de cannabis presentaron un evento adverso en comparación con el 35% (7/20) de los participantes que recibieron placebo (CR 0,71; IC del 95%: 0,27 a 1,88; evidencia de certeza muy baja). Los eventos adversos incluyeron diarrea, síntomas de empeoramiento, cólicos, sinusitis y dolor abdominal. Prevención: A los 12 meses, el 90% (18/20) de los pacientes que recibieron la formulación De Simone no presentaron episodios de reservoritis aguda en comparación con el 60% (12/20) de los pacientes que recibieron placebo (CR 1,50: IC del 95%: 1,02 a 2,21; evidencia de certeza baja). Otro estudio halló que el 100% (16/16) de los participantes que recibieron la fórmula De Simone no presentaron episodios de reservoritis aguda a los 12 meses en comparación con el 92% (11/12) de los pacientes del grupo control sin tratamiento (CR 1,10: IC del 95%: 0,89 a 1,36; evidencia de certeza muy baja). El 86% (6/7) de los participantes del grupo de Bifidobacterium longum no presentaron episodios de reservoritis aguda a los 6 meses en comparación con el 60% (3/5) de los participantes que recibieron placebo (CR 1,43; IC del 95%: 0,66 a 3,11; evidencia de certeza muy baja). El 11% (1/9) de los participantes del grupo de Clostridium butyricum MIYAIRI no presentaron episodios de reservoritis aguda a los 24 meses en comparación con el 50% (4/8) de los participantes que recibieron placebo (CR 0,22; IC del 95%: 0,03 a 1,60; evidencia de certeza muy baja). El 46% (43/94) de los participantes del grupo de alopurinol no presentaron episodios de reservoritis a los 24 meses en comparación con el 43% (39/90) de los participantes que recibieron placebo (CR1,06; IC del 95%: 0,76 a 1,46; evidencia de certeza baja). El 81% (21/26) de los participantes del grupo de tinidazol no presentaron episodios de reservoritis a los 12 meses en comparación con el 58% (7/12) de los participantes que recibieron placebo (CR 1,38; IC del 95%: 0,83 a 2,31; evidencia de certeza muy baja). CONCLUSIONES DE LOS AUTORES: No se conocen los efectos de los antibióticos, probióticos y otras intervenciones para el tratamiento y la prevención de la reservoritis. Se necesitan estudios bien diseñados con poder estadístico suficiente para determinar la forma óptima de tratamiento y prevención de la reservoritis.

Prevention and Medical Treatment of Pouchitis In Ulcerative Colitis.

Approximately 50% of patients who have undergone IPAA surgery for Ulcerative Colitis (UC) develop at least 1 episode of pouchitis. Patients with pouchitis have a wide range of symptoms, endoscopic and histologic features, disease course, and prognosis. To date, there are no universally accepted diagnostic criteria in terms of endoscopy and histology; though, semi-objective assessments to diagnose pouchitis in patients with ileal pouch- anal anastomosis (IPAA) have been proposed using composite scores such as the Pouchitis Triad, Heidelberg Pouchitis Activity Score and Pouchitis Disease Activity Index (PDAI). In a systematic review that included four randomized trials evaluating five agents for the treatment of acute pouchitis, ciprofloxacin was more effective at inducing remission as compared with metronidazole. Rifaximin was not more effective than placebo, while budesonide enemas and metronidazole were similarly effective for inducing remission of acute pouchitis. Patients with pouchitis relapsing more than three times per year are advised maintenance therapy, and guidelines recommend ciprofloxacin or the probiotic VSL#3. In patients with antibiotic-refractory pouchitis, secondary factors associated with an antibiotic-refractory course should be sought and treated. In this review, we will discuss the prevention and management of pouchitis in Ulcerative Colitis patients.

Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis.

BACKGROUND: Pouchitis occurs in approximately 50% of patients following ileal pouch-anal anastomosis (IPAA) for chronic ulcerative colitis (UC). OBJECTIVES: The primary objective was to determine the efficacy and safety of medical therapies for prevention or treatment of acute or chronic pouchitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 25 July 2018. We also searched references, trials registers, and conference proceedings. SELECTION CRITERIA: Randomized controlled trials of prevention or treatment of acute or chronic pouchitis in adults who underwent IPAA for UC were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was evaluated using GRADE. The primary outcome was clinical improvement or remission in participants with acute or chronic pouchitis, or the proportion of participants with no episodes of pouchitis after IPAA. Adverse events (AEs) was a secondary outcome. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome. MAIN RESULTS: Fifteen studies (547 participants) were included. Four studies assessed treatment of acute pouchitis. Five studies assessed treatment of chronic pouchitis. Six studies assessed prevention of pouchitis. Three studies were low risk of bias. Three studies were high risk of bias and the other studies were unclear.Acute pouchitis: All ciprofloxacin participants (7/7) achieved remission at two weeks compared to 33% (3/9) of metronidazole participants (RR 2.68, 95% CI 1.13 to 6.35, very low certainty evidence). No ciprofloxacin participants (0/7) had an AE compared to 33% (3/9) of metronidazole participants (RR 0.18, 95% CI 0.01 to 2.98; very low certainty evidence). AEs included vomiting, dysgeusia or transient peripheral neuropathy. Forty-three per cent (6/14) of metronidazole participants achieved remission at 6 weeks compared to 50% (6/12) of budesonide enema participants (RR 0.86, 95% CI 0.37 to 1.96, very low certainty evidence). Fifty per cent (7/14) of metronidazole participants improved clinically at 6 weeks compared to 58% (7/12) of budesonide enema participants (RR 0.86, 95% CI 0.42 to 1.74, very low certainty evidence). Fifty-seven per cent (8/14) of metronidazole participants had an AE compared to 25% (3/12) of budesonide enema participants (RR 2.29, 95% CI 0.78 to 6.73, very low certainty evidence). AEs included anorexia, nausea, headache, asthenia, metallic taste, vomiting, paraesthesia, and depression. Twenty-five per cent (2/8) of rifaximin participants achieved remission at 4 weeks compared to 0% (0/10) of placebo participants (RR 6.11, 95% CI 0.33 to 111.71, very low certainty evidence). Thirty-eight per cent (3/8) of rifaximin participants improved clinically at 4 weeks compared to 30% (3/10) of placebo participants (RR 1.25, 95% CI 0.34 to 4.60, very low certainty evidence). Seventy-five per cent (6/8) of rifaximin participants had an AE compared to 50% (5/10) of placebo participants (RR 1.50, 95% CI 0.72 to 3.14, very low certainty evidence). AEs included diarrhea, flatulence, nausea, proctalgia, vomiting, thirst, candida, upper respiratory tract infection, increased hepatic enzyme, and cluster headache. Ten per cent (1/10) of Lactobacillus GG participants improved clinically at 12 weeks compared to 0% (0/10) of placebo participants (RR 3.00, 95% CI 0.14 to 65.90, very low certainty evidence).Chronic pouchitis: Eighty-five per cent (34/40) of De Simone Formulation participants maintained remission at 9 to 12 months compared to 3% (1/36) of placebo participants (RR 20.24, 95% CI 4.28 to 95.81, 2 studies; low certainty evidence). Two per cent (1/40) of De Simone Formulation participants had an AE compared to 0% (0/36) of placebo participants (RR 2.43, 95% CI 0.11 to 55.89; low certainty evidence). AEs included abdominal cramps, vomiting and diarrhea. Fifty per cent (3/6) of adalimumab patients achieved clinical improvement at 4 weeks compared to 43% (3/7) of placebo participants (RR, 1.17, 95% CI 0.36 to 3.76, low certainty evidence). Sixty per cent (6/10) of glutamine participants maintained remission at 3 weeks compared to 33% (3/9) of butyrate participants (RR 1.80, 95% CI 0.63 to 5.16, very low certainty evidence). Forty-five per cent (9/20) of patients treated with bismuth carbomer foam enema improved clinically at 3 weeks compared to 45% (9/20) of placebo participants (RR 1.00, 95% CI 0.50 to 1.98, very low certainty evidence). Twenty-five per cent (5/20) of participants in the bismuth carbomer foam enema group had an AE compared to 35% (7/20) of placebo participants (RR 0.71, 95% CI 0.27 to 1.88, very low certainty evidence). Adverse events included diarrhea, worsening symptoms, cramping, sinusitis, and abdominal pain. PREVENTION: At 12 months, 90% (18/20) of De Simone Formulation participants had no episodes of acute pouchitis compared to 60% (12/20) of placebo participants (RR 1.50, 95% CI 1.02 to 2.21, low certainty evidence). Another study found 100% (16/16) of De Simone Formulation participants had no episodes of acute pouchitis at 12 months compared to 92% (11/12) of the no treatment control group (RR 1.10, 95% 0.89 to 1.36, very low certainty evidence). Eighty-six per cent (6/7) of Bifidobacterium longum participants had no episodes of acute pouchitis at 6 months compared to 60% (3/5) of placebo participants (RR 1.43, 95% CI 0.66 to 3.11, very low certainty evidence). Eleven per cent (1/9) of Clostridium butyricum MIYAIRI participants had no episodes of acute pouchitis at 24 months compared to 50% (4/8) of placebo participants (RR 0.22, 95% CI 0.03 to 1.60, very low certainty evidence). Forty-six per cent (43/94) of allopurinol participants had no episodes of pouchitis at 24 months compared to 43% (39/90) of placebo participants (RR 1.06, 95% CI 0.76 to 1.46; low certainty evidence). Eighty-one per cent (21/26) of tinidazole participants had no episodes of pouchitis over 12 months compared to 58% (7/12) of placebo participants (RR 1.38, 95% CI 0.83 to 2.31, very low certainty evidence). AUTHORS' CONCLUSIONS: The effects of antibiotics, probiotics and other interventions for treating and preventing pouchitis are uncertain. Well designed, adequately powered studies are needed to determine the optimal therapy for the treatment and prevention of pouchitis.

Role of probiotics in the management of pouchitis.

The concept that the gut microbiota plays a major role in the development of pouchitis in ulcerative colitis patients after restorative proctocolectomy with ileal pouch-anal anastomosis, is widely accepted and supported by a widespread use of some antibiotics (metronidazole and/or ciprofloxacin, rifaximin) to treat this condition. A possible, safer therapeutic alternative is represented by probiotics. To date the controlled studies addressing the possible efficacy of probiotic agents in the treatment of active pouchitis are few and inconclusive. By contrast the prophylactic use of a probiotic mixture (VSL #3) appears to be able to prevent development of pouchitis. The most convincing results have been observed in the maintenance of remission, where the probiotic mixture has been found, in most of the performed controlled trials, significantly effective in preventing pouchitis recurrence.

Diet of patients after pouch surgery may affect pouch inflammation.

AIM: To investigate the diet of pouch patients compared to healthy controls, and to correlate pouch patients' diet with disease behavior. METHODS: Pouch patients were recruited and prospectively followed-up at the Comprehensive Pouch Clinic at the Tel Aviv Sourasky Medical Center. Pouch behavior was determined based on clinical, endoscopic and histological criteria. Healthy age- and sex-matched volunteers were selected from the "MABAT" Israeli Nutrition and Public Health Governmental Study and served as the control group. All the participants completed a 106-item food frequency questionnaire categorized into food groups and nutritional values based on those used in the United States Department of Agriculture food pyramid and the Israeli food pyramid. Data on Dietary behavior, food avoidance, the use of nutritional supplements, physical activity, smoking habits, and body-mass index (BMI) were also obtained. Pouch patients who had familial adenomatous polyposis (n = 3), irritable pouch syndrome (n = 4), or patients whose pouch surgery took place less than one year previously (n = 5) were excluded from analysis. RESULTS: The pouch patients (n = 80) consumed significantly more from the bakery products food group (1.2 ± 1.4 servings/d vs 0.6 ± 1.1 servings/d, P < 0.05) and as twice as many servings from the oils and fats (4.8 ± 3.4 servings/d vs 2.4 ± 2 servings/d, P < 0.05), and the nuts and seeds food group (0.3 ± 0.6 servings/d vs 0.1 ± 0.4 servings/d, P < 0.05) compared to the controls (n = 80). The pouch patients consumed significantly more total fat (97.6 ± 40.5 g/d vs 84.4 ± 39 g/d, P < 0.05) and fat components [monounsaturated fatty acids (38.4 ± 16.4 g/d vs 30 ± 14 g/d, P < 0.001), and saturated fatty acids (30 ± 15.5 g/d vs 28 ± 14.1 g/d, P < 0.00)] than the controls. In contrast, the pouch patients consumed significantly fewer carbohydrates (305.5 ± 141.4 g/d vs 369 ± 215.2 g/d, P = 0.03), sugars (124 ± 76.2 g/d vs 157.5 ± 90.4 g/d, P = 0.01), theobromine (77.8 ± 100 mg/d vs 236.6 ± 244.5 mg/d, P < 0.00), retinol (474.4 ± 337.1 µg/d vs 832.4 ± 609.6 µg/d, P < 0.001) and dietary fibers (26.2 ± 15.4 g/d vs 30.7 ± 14 g/d, P = 0.05) than the controls. Comparisons of the food consumption of the patients without (n = 23) and with pouchitis (n = 45) showed that the former consumed twice as many fruit servings as the latter (3.6 ± 4.1 servings/d vs 1.8 ± 1.7 servings/d, respectively, P < 0.05). In addition, the pouchitis patients consumed significantly fewer liposoluble antioxidants, such as cryptoxanthin (399 ± 485 µg/d vs 890.1 ± 1296.8 µg/d, P < 0.05) and lycopene (6533.1 ± 6065.7 µg/d vs 10725.7 ± 10065.9 µg/d, P < 0.05), and less vitamin A (893.3 ± 516 µg/d vs 1237.5 ± 728 µg/d, P < 0.05) and vitamin C (153.3 ± 130 mg/d vs 285.3 ± 326.3 mg/d, P < 0.05) than the patients without pouchitis. The mean BMI of the pouchitis patients was significantly lower than the BMI of the patients with a normal pouch: 22.6 ± 3.2 vs 27 ± 4.9 (P < 0.001). CONCLUSION: Decreased consumption of antioxidants by patients with pouchitis may expose them to the effects of inflammatory and oxidative stress and contribute to the development of pouchitis.

Nutrition considerations surrounding restorative proctocolectomy.

Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for patients with ulcerative colitis and familial polyposis coli syndromes. Pouch construction uses the distal 30-40 cm of ileum, and there exists a potential for postoperative nutrition consequences. These include vitamin B(12) deficiency, iron deficiency, bile acid malabsorption, and abnormalities of trace elements, fluids, and electrolytes. Patients who have undergone an ileal pouch-anal anastomosis procedure often describe specific food sensitivities that may require diet alteration, even more so than do patients with permanent ileostomy. There may be roles for postoperative probiotic supplementation in an attempt to decrease the rate of "pouchitis" and appropriate preoperative nutrition support to minimize the risk of perioperative complications.

Ileal pouch rectal anastomosis: a viable alternative to permanent ileostomy in Crohn's proctocolitis patients.

BACKGROUND: Ileal pouch rectal anastomosis (IPRA) is a possible alternative to permanent ileostomy when a short, normal-appearing rectal stump remains after total colectomy. Its outcomes in Crohn colitis (CC) patients have not been reported. STUDY DESIGN: CC patients who underwent IPRA from 1992 to 2004 were identified. Operative and morbidity data were collected. Functional outcomes and quality-of-life (QOL) data were obtained using a mailed questionnaire and compared with matched patients who underwent straight ileorectal anastomosis (SIRA). RESULTS: Twenty-three CC patients underwent IPRA. Perioperative complications included three pelvic septic fluid collections and five small bowel obstructions or ileus, and were treated nonoperatively. Twenty-two patients were available for longterm followup (median 98 months). Fourteen patients (64%) had disease recurrence. Two (9%) have lost a functioning anastomosis. Nine (41%) required additional operations. Matched SIRA patients had higher level of anastomosis (23.4 +/- 5.5 versus 9.0 +/- 4.1 cm above the dentate line; p < 0.0001). Bowel movement frequency (median 6.5/24 hours in both groups), incontinence, and urgency rates were similar. Nighttime seepage and pad usage were more frequent in IPRA. No differences were found in QOL parameters (Cleveland Global QOL score: 0.78 versus 0.73 [0 = worst, 1 = best], IPRA versus SIRA, respectively; p = 0.31). All patients with a functioning IPRA stated they would have their operation again if needed, and 94% would recommend it to others. CONCLUSIONS: IPRA offers durable preservation of bowel continuity and good function and QOL in selected CC patients who might otherwise require a permanent ileostomy.

[Diagnosis and medical treatment of pouchitis in ileal pouch-anal anastomosis in patients with ulcerative colitis].

Pouchitis is a common and long-term complication of ileal pouch-anal anastomosis in patients with underlying ulcerative colitis. Combination with clinical symptoms, endoscopic and histopathological findings are required to make accurate diagnosis. Ciprofloxacin and metronidazole are effective in patients with acute pouchitis. Probiotics may be useful in maintaining regression and preventing from remission. Immunomodulating agents are also useful in chronic pouchitis.

Diagnóstico y tratamiento de pouchitis: presentación de un caso y revisión de la literatura / Diagnostic and treatment of pouchitis: presentation of a case and review of the literature

Introducción: la proctocolectomía total con anastomosis ileo-anal en J es el procedimiento de elección para el tratamiento de la colitis ulcerosa. La inflamación inespecífica del pouch (pouchitis) es la complicación más frecuente del postoperatorio alejado. Se presenta un caso clínico de pouchitis, analizando el manejo diagnóstico y terapéutico de la entidad con revisión de la literatura al respecto. Lugar de Aplicación: Hospital de alta complejidad "Pte. Juan Domingo Perón", Formosa, Argentina. Diseño: presentación de caso clínico y revisión de la literatura. Pacientes y Métodos: mujer de 25 años, intervenida quirúrgicamente en 1995 por colitis ulcerosa, realizándose proctocolectomía total + anastomosis ileo-anal con pouch en J. En marzo de 2005 consulta por dolor abdominal, diarrea, hemoproctorragia, pujo y tenesmo rectal. Se realiza videocolonoscopía, observándose mucosa edematosa, friable y ulceraciones.Se toman muestras de biopsia. Anatomopatológicamente se informa: "mucosa intestinal con foco de ulceración, lámina propia con intenso edema, congestión vascular e infiltrado inflamatorio lifoplasmocitario y polimorfonuclear. Diagnóstico: pouchitis crónica con marcada actividad". Se indica tratamiento con Ciprofloxacina 500 mg. vía oral durante 15 días, evidenciándose mejoría clínica. Se repite videocolonoscopía, observándose remisión del cuadro. Resultados: La incidencia de pouchitis varía entre 10 y 50 por ciento. Los síntomas son inespecíficos: cólicos abdominales, artralgias, incontinencia, diarrea, hemoproctorragia, pujo y tenesmo rectal. La sospecha debe ser confirmada con endoscopía y toma de biopsias del pouch. Se comparó ciprofloxacina oral con metronidazol. La ciprofloxacina resultó más efectiva, con menores efectos colaterales. Conclusiones: La pouchitis es la complicación tardía más común asociada al procedimiento de reservorio pélvico. De etiología poco entendida, el sobrecrecimiento bacteriano puede contribuir al desarrollo de este proceso. La...

The diagnosis and treatment of pouchitis in inflammatory bowel disease.

The ileal pouch anal anastomosis (IPAA) procedure has become the preferred surgical option for most patients with ulcerative colitis who require surgical removal of the colorectum. The vast majority of patients with this new anatomy will either not develop pouchitis or develop a few discrete episodes of acute pouchitis. However approximately one fourth of patients will develop recurrent pouchitis, with 5% being categorized as chronic pouchitis requiring maintenance therapy or, on rare occasion, pouch excision. Factors that are associated with an increased risk of pouchitis include primary sclerosing cholangitis, extraintestinal manifestations, and nonsmokers. Controversy surrounds other risk factors such as extent of colitis, backwash ileitis, preoperative pANCA levels, and carrying a specific allele for IL-1 receptor antagonist. The etiology of pouchitis is unknown, but theories range from genetic susceptibility, bacterial overgrowth, ischemia, and fecal stasis, to a recurrence of ulcerative colitis in the pouch, a missed diagnosis of Crohn's disease, or possibly a novel third form of inflammatory bowel disease. Some patients with symptoms of pouchitis will not have inflammation of the pouch, but rather, irritable pouch syndrome. Thus, endoscopic investigation with biopsy is important for declaring whether a patient has pouchitis. Indeed, the more commonly used scores, such as the pouch disease activity index, incorporate both endoscopic and histologic criteria. Not surprisingly, treatment options for patients with pouchitis resemble that of regular inflammatory bowel disease, although there have only been a few controlled trials. Antibiotics are the mainstay of therapy, with metronidazole and ciprofloxacin demonstrating benefit in controlled trials. Probiotics are effective for maintaining remission of pouchitis. Mesalamine, corticosteroids, and immunomodulators have been used with some success. Occasionally, patients with well-documented ulcerative colitis as the indication for IPAA will develop what appears to be Crohn's disease of the pouch, on the basis of granulomatous inflammation, pre-pouch ileitis, or fistulae. The treatment is similar to Crohn's disease, including the use of infliximab. Dysplasia within the pouch mucosa itself is quite rare. Reports of dysplasia occurring in patients with IPAA are usually due to neoplastic change within the residual cuff of rectal or transition zone mucosa just below the pouch, rather than in the ileal mucosa of the pouch. With further elucidation of the genetic basis for inflammatory bowel disease, we should be able to more accurately classify patients with ulcerative colitis and Crohn's disease genotypically. Hopefully, this will also bring more clarity to the heterogeneous population of patients with pouchitis and allow for more focused therapeutic strategies.

An enema formulation of alicaforsen, an antisense inhibitor of intercellular adhesion molecule-1, in the treatment of chronic, unremitting pouchitis.

BACKGROUND: Pouchitis is the major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The incidence of pouchitis is as high as 50% several years after surgery. Two-thirds of pouchitis patients suffer recurrence. Of those who recur, one-quarter suffer from chronic, unremitting pouchitis. Current treatments for this disorder are disappointing. AIM: To determine whether a topically administered enema formulation of ISIS 2302 (alicaforsen), an antisense inhibitor of intercellular adhesion molecule-1, can improve the clinical symptoms, endoscopic mucosal appearance and mucosal histology in patients with chronic, unremitting pouchitis, a disorder in which this molecule is over-expressed. METHODS: In an open-label, uncontrolled study, 12 patients with chronic, unremitting pouchitis were treated with 240 mg alicaforsen antisense enema nightly for 6 weeks. Clinical evaluation and endoscopy were performed at baseline and at weeks 3, 6 and 10. Pouchoscopy with biopsy was carried out at baseline and at weeks 6 and 10. The primary end-point was the reduction from baseline of the Pouchitis Disease Activity Index (PDAI) at week 6. Secondary end-points included the PDAI at week 10. Safety was evaluated by analysing the adverse events, vital signs and laboratory parameters. RESULTS: After 6 weeks of nightly alicaforsen enema, a statistically significant (n = 12, P = 0.001) reduction in the PDAI from baseline (11.42) to week 6 (6.83) was observed. Mean reductions in the endoscopy sub-score from baseline (5.25) to week 3 (3.08) and week 6 (2.58) were statistically significant (P = 0.0039 and P = 0.0005, respectively). The mean reductions in clinical symptom sub-score from baseline (3.75) to week 3 (2.33) and week 6 (2.25) were also statistically significant (P = 0.0156 and P = 0.0117, respectively). Ten of the 12 patients achieved a mucosal appearance score of 0 or 1 at endoscopy. Five of the 12 patients (42%) had a non-statistically significant decrease in the histology component of their PDAI from baseline to week 6. By week 6, seven of the 12 patients (58%) were in remission, as defined by PDAI < 7, with a mean decrease from baseline in PDAI score of six points. The alicaforsen enemas were well tolerated and no serious side-effects were noted. CONCLUSIONS: Antisense enema to intercellular adhesion molecule-1 is safe and well tolerated. In an open-label trial, it appeared to improve the PDAI score, clinical symptoms and endoscopic mucosal appearance. It may also improve the histology. In the light of the responses observed in this trial, a randomized, placebo-controlled trial is warranted.

Functional results and visceral perception after ileo neo-rectal anastomosis in patients: a pilot study.

INTRODUCTION: To reduce pouch related complications after restorative proctocolectomy, an alternative procedure was developed, the ileo neo-rectal anastomosis (INRA). This technique consists of rectal mucosa replacement by ileal mucosa and straight ileorectal anastomosis. Our study provides a detailed description of the functional results after INRA. PATIENTS AND METHODS: Eleven patients underwent an INRA procedure with a temporary ileostomy. Anorectal function tests were performed two months prior to and six and 12 months after closure of the ileostomy and comprised: anal manometry, ultrasound examination, rectal balloon distension, and transmucosal electrical nerve stimulation (TENS). Function was subsequently related to the histopathology of rectal biopsy samples. RESULTS: Median stool frequency decreased from 15/24 hours (10-25) to 6/24 hours (4-11) at one year. All patients reported full continence. Anal sensibility, and resting and squeeze pressures did not change after INRA. Rectal compliance decreased (2.1 (0.7-2.8) v 1.5 (0.4-2.2) and 1.4 (0.8-3.7) ml/mm Hg (p=0.03)) but the maximum tolerated volume increased (70 (50-118) v 96 (39-176) (NS) and 122 (56-185) ml (p=0.03)). Decreasing rectal sensitivity was found: the maximum tolerated pressure increased (14 (8-24) v 22 (8-34) (NS) and 26 (14-40) (p=0.02)) and the rectal threshold for TENS displayed a similar tendency. All patients displayed a low grade chronic inflammatory infiltrate in neorectal biopsy samples before closure of the ileostomy, with no change during follow up. CONCLUSIONS: The technique of INRA provides a safe alternative for restorative surgery. Stool frequency after INRA improves with time and seems to be related to decreasing sensitivity and not to histopathological changes in the neorectum. Furthermore, after the INRA procedure, all patients reported full continence.