Chronic Antibiotic-refractory Pouchitis Research Articles

Pouchitis: pathophysiology and management.

Pouchitis is an acute or chronic inflammatory disease of the ileal reservoir. It is common after restorative proctocolectomy with ileal pouch-anal anastomosis, and treatment of chronic antibiotic-refractory pouchitis has proven challenging. Most cases of acute pouchitis evolve into chronic pouchitis. The aetiology of acute pouchitis is likely to be partly related to the gut microbiota, whereas the pathophysiology of chronic pouchitis involves abnormal interactions between genetic disposition, faecal stasis, the gut microbiota, dysregulated host immunity, surgical techniques, ischaemia and mesentery-related factors. Pouchoscopy with biopsy is the most valuable modality for diagnosis, disease monitoring, assessment of treatment response, dysplasia surveillance and delivery of endoscopic therapy. Triggering or risk factors, such as Clostridioides difficile infection and use of non-steroidal anti-inflammatory drugs, should be modified or eradicated. In terms of treatment, acute pouchitis usually responds to oral antibiotics, whereas chronic antibiotic-refractory pouchitis often requires induction and maintenance therapy with integrin, interleukin or tumour necrosis factor inhibitors. Chronic pouchitis with ischaemic features, fistulae or abscesses can be treated with hyperbaric oxygen therapy.

Ustekinumab in the Treatment of Inflammatory Bowel Diseases: Evolving Paradigms.

Inflammatory bowel diseases, comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, and remitting immune-mediated inflammatory diseases affecting the gastrointestinal tract. Ustekinumab (UST) is a monoclonal antibody that blocks the p40 subunit of the anti-interleukin (IL) 12/23. Pivotal trials (CERTIFI and UNITI-IM for CD, UNIFI for UC) established the efficacy of UST for the induction and maintenance of remission in both CD and UC, with the most favorable results in naïve patients to biologics. In recent years, a wealth of 'real-world' data has emerged supporting positive clinical, endoscopic, and histological outcomes in patients treated with UST, as well as reassuring safety data. More recently, the results of the first head-to-head trials of UST and tumor necrosis factor (TNF) antagonists were reported. Moreover, a number of studies exploring the role of UST in specific clinical settings, such as perianal CD, postoperative complications and recurrence, extraintestinal manifestations, chronic antibiotic-refractory pouchitis, and pregnancy, were reported. This review explores the results reported to date on UST, including those from pivotal trials, real-world data, and emerging studies regarding therapeutic drug monitoring and immunogenicity. The safety profile of UST was also reviewed.

Evidence-Based Approach to Chronic Antibiotic Refractory Pouchitis: A Review.

Chronic antibiotic refractory pouchitis after restorative proctocolectomy with IPAA, characterized by at least 4 weeks of pouchitis symptoms that have not responded to standard antibiotic therapy, presents a therapeutic challenge for patients and health care providers. The aim of this narrative review was to summarize the current evidence regarding the management of chronic antibiotic refractory pouchitis. Studies were identified through a search of the PubMed database from the National Library of Medicine. We included case series, cohort studies, randomized controlled trials, and systematic reviews with meta-analyses that addressed chronic antibiotic refractory pouchitis management, with prioritization of data published within the past 3 to 5 years. Studies examining pharmacologic and select nonpharmacologic interventions were included. Outcomes measures included clinical, endoscopic, and histologic end points. Mesalamine has demonstrated efficacy in symptom improvement but no improvement in quality of life. Budesonide has demonstrated high rates of clinical remission that have mostly been sustained in a small number of patients. Anti-tumor necrosis factor therapies have demonstrated efficacy in reaching clinical and even endoscopic end points, although rates of treatment discontinuation were not insignificant. Limited evidence is encouraging for the use of ustekinumab in achieving clinical response. Data for vedolizumab are favorable across clinical, endoscopic, and histologic end points, including one of the only randomized, placebo-controlled trials. Nonmedication therapies, including hyperbaric oxygen therapy and fecal microbiota transplant, have undergone limited evaluation, and concerns about the ultimate accessibility of these therapies remain. Overall, studies assessing therapeutic options for chronic antibiotic refractory pouchitis are mostly limited to case series and retrospective studies with small sample sizes. Biologic therapies have demonstrated efficacy in the management of chronic antibiotic refractory pouchitis and offer a steroid-sparing option for refractory disease. Nonpharmacologic therapies, including hyperbaric oxygen and fecal microbiota transplant, require further exploration. See video from symposium .

Use of Biologics for the Treatment of Inflammatory Conditions of the Pouch: A Systematic Review.

Patients with medically-refractory ulcerative colitis or advanced neoplasia are often offered an ileal-pouch-anal anastomosis to restore bowel continuity. However, up to 50% of patients can suffer from inflammatory conditions of the pouch, some of which require biological therapy to treat. The aim of this study was to determine the efficacy of each biological agent for the treatment of inflammatory conditions of the pouch. A comprehensive literature search was performed in the major databases from inception through February 11, 2020, for studies assessing the efficacy of biologics in chronic antibiotic-refractory pouchitis (CARP) and Crohn's disease (CD) of the pouch. Both prospective and retrospective studies were included. The primary outcomes of interest were complete and partial responses were defined within each study. χ 2 test was used to compare variables. Thirty-four studies were included in the systematic review and meta-analysis. Sixteen studies (N=247) evaluated the use of infliximab (IFX), showing complete response in 50.7% and partial response in 28.1% for CARP, and complete response in 66.7% and partial response in 20% for CD of the pouch. Seven studies (n=107) assessed the efficacy of adalimumab. For CARP, 33.3% of patients had a complete response, and 38.1% had a partial response, whereas for CD of the pouch, 47.7% experienced a complete response, and 24.6% had a partial response. Three studies (n=78) reported outcomes with the use of ustekinumab, showing 50% complete response and 3.8% partial response for CARP. For the CD of the pouch, 5.8% had a complete response and 78.8% had a partial response. Seven studies (n=151) reported the efficacy of vedolizumab, showing 28.4% complete response and 43.2% partial response in patients with CARP, whereas 63% of patients experienced partial response in CD of the pouch. IFX had higher rates of complete response in CARP compared with adalimumab ( P =0.04) and compared with vedolizumab ( P =0.005), but not compared with ustekinumab ( P =0.95). There were no new safety signals reported in any of the studies. Biologics are safe and efficacious in the treatment of chronic, refractory inflammatory conditions of the pouch. IFX seems to be more efficacious than adalimumab and vedolizumab for CARP. Further prospective, head-to-head evaluations are needed to compare biological therapies in the treatment of CARP and CD of the pouch.

P366 Risk factors and outcomes of chronic antibiotic-refractory pouchitis in Korean ulcerative colitis patients: a single center retrospective study

Abstract Background Chronic inflammation of the pouch after total proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains a morbid complication in ulcerative colitis (UC). The goal of this study was to investigate risk factors and clinical outcomes of chronic antibiotic-refractory pouchitis (CARP) in Korean patients with UC. Methods This was a single center retrospective study on patients with UC who underwent total proctocolectomy with IPAA at Asan Medical Center in Korea between January 1987 and December 2022. CARP was defined as failure to respond to a 4-week course of a single antibiotic, needing more than 4 weeks of therapy with 5-aminosalicylates, steroids, immunomodulators or biologics/small molecules, while chronic antibiotic-dependent pouchitis (CADP) was defined as more than 3 episodes of pouchitis per year or persistent symptoms requiring long-term antibiotics to maintain disease remission. Primary outcomes were endoscopic remission defined as complete mucosal healing of chronic pouchitis and pouch failure defined as the requirement of diverting loop ileostomy or pouch excision. Univariable and multivariable logistic regression analysis were used to identify risk factors of CARP. Results A total of 251 patients were included and 232 were analyzed (Male, 57.3%; Current smoker, 13.4%; Median age at surgery, 44 years; Disease duration at surgery, 4 years; Previous exposure to biologics/small molecules, 23.7%; Extra-intestinal manifestations, 8.2%; Preoperative cytomegalovirus infection, 19.4%). The most common cause of surgery was steroid refractoriness (50.9%), followed by dysplasia/colorectal cancer (26.7%). The median time from surgery to chronic pouchitis was 48 months (interquartile range 23.5–100.0). Among 74 patients (31.9%) with chronic pouchitis, 31 patients (13.4%) were CARP and 43 patients (18.5%) were CADP. The most frequent endoscopic phenotype according to Chicago classification was focal inflammation of the pouch in all groups (chronic pouchitis, 47.3%; CARP, 35.5%; CADP, 55.8%). Patients with CARP were less likely to have concomitant probiotics compared with CADP (29.0% vs 72.1%; p<0.01). Endoscopic remission rate in chronic pouchitis, CARP, and CADP were 14.9% (11/74), 9.7% (3/31), and 18.6% (8/43), respectively (Table 1). Pouch failure rate in chronic pouchitis, CARP, and CADP were 13.5% (10/74), 16.1% (5/31), and 11.6% (5/43), respectively (Table 1). In a multivariable analysis, current smoking status was positively associated with CARP development (OR: 3.56; 95% confidence interval 1.33–9.52; p=0.01). Conclusion Current smoker with UC who underwent IPAA had a higher risk of CARP. Concomitant use of probiotics was less likely to be associated with developing CARP.

P710 Prevalence, Characteristics and Management of Patients with Difficult-To-Treat Inflammatory Bowel Disease: A Cross-Sectional Study From a Tertiary Referral Center

Abstract Background Difficult-to-treat (D2T) inflammatory bowel disease (IBD) is defined by lack or loss of response to advanced treatments with 2 or more mechanisms of action (MoA), Crohn’s (CD) recurrence after 2 resections, chronic antibiotic refractory pouchitis, complex perianal CD or by the presence of psychiatric comorbidities impairing IBD management.1 We aimed to assess the prevalence, characteristics, management, and outcomes of D2T-IBD. Methods We retrospectively searched the electronic medical records of patients with IBD followed at San Raffaele Hospital (Milan, Italy) as of October 1st, 2023. Patients enrolled in clinical trials altering disease management were excluded. Results In total 679 patients with moderate-to-severe IBD were included (350 CD, 326 UC, 3 IBD-U). 163 patients (24%) met at least one criterion of D2T (25% CD, 23% UC). Of these, 75% did not respond or lost response to 2 or more biologics/small molecules with different MoA, 18% had complex perianal CD, 17% had CD recurrence after 2 or more resections for active CD, the remaining had antibiotic refractory pouchitis or psychiatric comorbidities impairing IBD management. Multiple criteria can coexist. Figure 1. Drug-wise, 54% of patients with D2T-IBD failed 2 MoA, 26% 3 MoA, and 3% 4 MoA, the remaining had other causes of D2T-IBD. Prevalence of D2T varied across phenotypes of CD. The presence of perianal disease doubled the probability of D2T-CD (48 vs 24%); stricturing (B2), fistulizing (B3), and upper gastrointestinal involvement (L4) also increased risk. In UC, 22% of left-sided colitis (E2) and 27% of pancolitis (E3) were D2T, no proctitis was D2T. Patients with D2T-CD had a longer mean disease duration (14 vs 8.7 years; p<0.05) and time on advanced treatments (78 vs 63 months; p<0.05). The same two analyses showed no significant difference for UC (11.6 vs 11.2 years; and 41 vs 50 months; both p>0.05). Differently from bio-naive patients (Figure 2A), patients with D2T-IBD were mostly on ustekinumab, followed by infliximab and adalimumab in CD, and by upadacitinib, infliximab and tofacitinib in UC. Notably, 11 patients with D2T-CD received a combination of advanced therapies. Figure 2B Overall, 61% of patients with D2T-IBD were in clinical remission, 43% in biochemical remission (calprotectin <150 μg/g), and 13% in endoscopic remission (Mayo≤1; or SES-CD≤3 or Rutgeerts i0-i1). Conclusion D2T-IBD is heterogeneous but most commonly due to multidrug failure and associated with certain phenotypes of IBD. Ustekinumab was the most common treatment choice for D2T-IBD. The majority of patients with D2T-IBD achieved clinical remission but failed to achieve biochemical or endoscopic remission. 1. Parigi et al. Lancet Gastroenterol. & Hep. 2023

The aetiology of pouchitis in patients with inflammatory bowel disease.

Restorative proctocolectomy with ileal pouch-anal anastomosis is a treatment option for patients with refractory ulcerative colitis. Pouchitis is the most common complication, representing a spectrum of diseases ranging from acute antibiotic-responsive type to chronic antibiotic-refractory. Early accurate diagnosis using a combined assessment of symptoms, endoscopy and histology is important for both treatment and prognostication. Most patients respond well to antibiotic therapy; however, management of chronic antibiotic-refractory pouchitis remains a challenge, and treatment options are based on small studies. Pouchitis is thought to be driven by the interaction between genetics, the immune system and the environment but as yet a causal relationship has yet to be identified. Further longitudinal assessment of the pouch integrating new technologies may help us understand the factors driving pouchitis. This review outlines the currently understood risk factors and aetiology of pouchitis.

Effectiveness of Oral Tofacitinib in Chronic Pouchitis: A Prospective, Open-Label Pilot Study.

Oral tofacitinib can be effective in inducing response and remission in patients with chronic antibiotic refractory pouchitis. In addition to improving symptoms and quality of life, it can lead to improvement in endoscopic inflammation score and fecal calprotectin.

Ileal Pouch-anal Anastomosis in Primary Sclerosing Cholangitis-inflammatory Bowel Disease (PSC-IBD): Long-term Pouch and Liver Transplant Outcomes.

To compare the effect of liver transplantation (LT) on ileal pouch-anal anastomosis (IPAA) outcomes in patients with primary sclerosing cholangitis and inflammatory bowel disease (PSC-IBD). Patients with PSC-IBD may require both IPAA for colitis and LT for PSC. Patients with PSC-IBD from out institutional pouch registry (1985-2022) were divided according to LT status and timing of LT (before and after IPAA) and their outcomes analyzed. A total of 160 patients were included: 112 (70%) nontransplanted at last follow-up; 48 (30%) transplanted, of which 23 (14%) before IPAA and 25 (16%) after. Nontransplanted patients at IPAA had more laparoscopic procedures [37 (46%) vs 8 (18%), P =0.002] and less blood loss (median 250 vs 400mL, P =0.006). Morbidity and mortality at 90 days were similar. Chronic pouchitis was higher in transplanted compared with nontransplanted patients [32 (67%) vs 51 (45.5%), P =0.03], but nontransplanted patients had a higher rate of chronic antibiotic refractory pouchitis. Overall survival was similar, but nontransplanted patients had more PSC-related deaths (12.5% vs 2%, P =0.002). Pouch survival at 10 years was 90% for nontransplanted patients and 100% for transplanted patients (log-rank P =0.052). Timing of LT had no impact on chronic pouchitis, pouch failure, or overall survival. PSC recurrence was 6% at 10 years. For transplanted patients, graft survival was similar regardless of IPAA timing. In patients with PSC-IBD and IPAA, LT is linked to an increased pouchitis rate but does not affect overall and pouch survival. Timing of LT does not influence short-term and long-term pouch outcomes.

Dietary Patterns Are Not Associated With Disease Activity Among Patients With Inflammatory Conditions of the Pouch in a Prospective Cohort.

Evidence-based recommendations regarding the influence of diet on inflammatory conditions of the pouch after restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) are limited. We analyzed dietary patterns at enrollment in a prospective registry of patients with 1 of 4 inflammatory conditions of the pouch (acute pouchitis, chronic antibiotic-dependent pouchitis, chronic antibiotic refractory pouchitis, and Crohn's disease of the pouch). We analyzed dietary intake by disease activity at enrollment and then compared dietary patterns among patients who remained in remission throughout the 12-month follow-up to those patients who experienced a disease relapse. We also compared dietary patterns among patients with inflammatory conditions of the pouch to the United States Department of Agriculture (USDA) recommended daily goals. Among 308 patients, there were no differences in dietary patterns among patients with 1 of the 4 disease states at enrollment. Additionally, among the 102 patients in remission at baseline, there were no significant differences noted among patients who went on to experience a disease flare in the 12 months after enrollment compared to those patients who remained in remission. However, patients with inflammatory conditions of the pouch demonstrated decreased intake of several food groups and macronutrients including dairy, fruits, vegetables, whole grains, and fiber when compared to USDA recommendations. In a prospective cohort, we demonstrated no impact of dietary patterns on disease activity. The relative deficiencies in several food groups and macronutrients among patients after IPAA indicate the potential role of targeted nutritional counseling in this population.

P521 Effectiveness of ustekinumab as therapy for chronic antibiotic refractory pouchitis

Abstract Background Up to 10% of patients with ulcerative colitis who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction and maintenance therapy with ustekinumab (UST). Methods We performed a prospective, multicentre, open-label study of patients with CARP (mPDAI ≥5 with an endoscopic subscore ≥2) . Patients received a weight-range-based infusion of UST at baseline (~6mg/kg) and subcutaneous injections of 90mg UST every 8 weeks thereafter until week 48. Patients underwent a pouchoscopy at baseline, week 16 and week 48, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points from baseline) at week 16. For this abstract we focus on the secondary endpoints at week 48 including the proportion of patients achieving steroid-free remission and response (reduction of mPDAI by ≥2 points from baseline) using a non-responder imputation. For patients still continuing UST at week 48, we evaluated the change in symptomatic and endoscopic mPDAI subscore, C-reactive protein (CRP) and faecal calprotectin levels compared to baseline. Descriptive statistics and paired nonparametric tests (Wilcoxon signed-rank) of changes from baseline were performed. Results We enrolled 22 patients (59% male, median age 42.2 years, median time after surgery 8.2 years). Twelve (54.5%) patients had previously been treated with biologics for CARP (table 1). At week 16, steroid-free remission was achieved in 27.3% of patients. At week 48, steroid-free remission was achieved in 36.4% and response in 54.5% of patients. In the 14 patients continuing UST at week 48, a significant decrease in total mPDAI (4 (1.8-7.3) vs. 8 (8-10), p<0.001), clinical subscore (1 (0-2.3) vs. 3 (2-4), p=0.001), and endoscopic subscore (3 (1.8-4.3) vs. 6 (4.8-6), p=0.001) was observed compared to baseline (figure 1). Faecal calprotectin (129 (80-344) vs. 229 (139-541) mg/kg, p=0.17) and CRP (2.5 (1.3-4.4) vs. 3.8 (1.6-9.3) mg/L, p=0.09) levels did however not decrease significantly (figure 2 and 3). Three serious adverse events (hospitalization for subobstruction, worsening pouchitis and choledocholithiasis) were recorded, but were not considered related to UST. Conclusion In this open-label pilot study in patients with CARP, maintenance therapy with UST showed a clinical and endoscopic effect in half of the patients, but was not associated with changes in inflammatory biomarkers. These promising results warrant confirmation in a placebo-controlled study with UST for the treatment of CARP.

P268 Development and validation of a novel composite index for the assessment of endoscopic and histologic disease activity in pouchitis: The Atlantic pouchitis index.

Abstract Background Several instruments have been used in clinical trials of pouchitis to define eligibility criteria and outcome measures but have not been formally validated. A need remains for a validated pouchitis instrument that is suitable for use in novel drug development. We developed and internally validated the novel composite Atlantic pouchitis index (API) for the assessment of endoscopic and histologic disease activity in patients with pouchitis. Methods Paired baseline and week 10 endoscopic videos and histologic images were obtained from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomised placebo-controlled trial of alicaforsen enema (ClinicalTrials.gov identifier: NCT02525523). For each pair, 4 endoscopists and 3 pathologists scored 59 items. These items included 51 component items from 11 indices (4 endoscopic, 4 histologic, 3 composite) identified in a prior systematic review and 8 additional items identified in a prior Research and Development/University of California Los Angeles appropriateness methodology exercise. The reliability of all measures was assessed using intraclass correlation coefficients (ICCs) and interpreted according to Landis and Koch benchmarks (slight, 0.00-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; almost perfect, 0.81-1.00). Responsiveness was evaluated using the area under the receiver operating characteristic curve (AUC). The API was developed using linear regression with a 100-mm visual analogue scale (VAS) of pouchitis activity as an anchor. Results Among all measures assessed for reliability and responsiveness, the simple endoscopic score for Crohn’s disease (SES-CD) and the Robarts histopathology index (RHI) were selected for inclusion in the API. The total API score ranges from 0 to 69, with higher scores indicating more severe disease activity, and can be calculated as API = (3 × SES-CD [0 to 12]) + (1 × RHI [0 to 33]). The API demonstrated almost perfect intra-rater reliability (ICC, 0.88 [95% CI: 0.81, 0.92]), substantial inter-rater reliability (ICC, 0.72 [95% CI: 0.60, 0.79]), and a high correlation with the VAS (r = 0.84 [95% CI: 0.76, 0.89]). Index responsiveness in detecting meaningful improvements in disease activity was higher for the API (AUC, 0.95 [95% CI: 0.89, 0.98]) than for existing endoscopic indices (∆AUC, 0.09-0.24; P≤0.005) (Table). Conclusion The novel API is a composite index of endoscopic (SES-CD) and histologic disease activity (RHI) that is reliable and significantly more responsive than existing endoscopic pouchitis scoring systems. The API is a promising tool for use in clinical trials of novel therapies for pouchitis. Further validation is needed in independent datasets.

S763 Twenty Percent of Patients With Inflammatory Conditions of the Pouch Demonstrate a More Refractory Disease State Within Twelve Months of Enrollment in a Multicenter Prospective Registry

Introduction: Up to 80% of patients will develop pouchitis after proctocolectomy with ileal pouch-anal anastomosis (IPAA) for ulcerative colitis, and approximately 10% will develop Crohn’s disease (CD) of the pouch. We designed a geographically diverse, eight-center, prospective registry to study the disease course among patients with one of four inflammatory conditions of the pouch. The aim of this study was to evaluate patterns of changes in diagnosis during the first 12 months after enrollment. Methods: We enrolled patients with a confirmed diagnosis of acute pouchitis, chronic antibiotic dependent pouchitis (CADP), chronic antibiotic refractory pouchitis (CARP), or CD of the pouch. Diagnoses were based on standardized criteria and we obtained detailed clinical and demographic data at the time of enrollment. Patients completed follow-up assessments at 3, 6, and 12 months after enrollment, with treating physicians confirming their respective diagnoses at each time point. Associations between clinical and demographic data at baseline and a switch in diagnosis to a more refractory disease state were analyzed using chi-square testing. Results: We enrolled 318 patients (10% acute pouchitis, 27% CADP, 12% CARP, and 51% CD of the pouch). During the first 12 months after enrollment, 31 of the 157 patients (20%) without CD of the pouch at enrollment switched diagnosis to a more refractory disease state, with 20 of 31 (65%) patients ultimately being diagnosed with CD of the pouch. Among 7 patients with acute pouchitis who switched diagnoses, 5 were diagnosed with CADP, 1 with CARP, and 1 with CD of the pouch. Among 19 patients with CADP who switched diagnoses, 4 were diagnosed with CARP and 15 were diagnosed with CD of the pouch. Four patients with CARP had a change in diagnosis to CD of the pouch during the study period. Patients who experienced a change in diagnosis were significantly more likely to be current smokers when compared to patients with no change in diagnosis during the study period (23% vs. 5%, p=0.001, Table). Conclusion: In a prospective registry of 318 patients from eight centers in the United States, 20% of patients without CD of the pouch at enrollment experienced a change in diagnosis to a more refractory inflammatory condition of the pouch during the first 12 months after enrollment. Patients who were current smokers were more likely to change diagnoses, and may represent a high risk group for earlier intervention and targeted smoking cessation efforts after IPAA. Table 1. - Comparison of Baseline Demographics and Clinical Characteristics of Patients with an Inflammatory Condition of the Pouch and a Change in Diagnosis to those with No Change in Diagnosis Change in Diagnosis within 12 Months of Enrollment n=31 No Change in Diagnosis within 12 Months of Enrollment n=287 p-value Median IQR Median IQR Current Age 50 44-59 52 38-62 0.873 n % n % Female Sex 12 39 129 45 0.636 Race >0.999 White 29 94 263 92 Black 1 3 16 6 Other 1 3 8 3 Hispanic ethnicity 3 10 7 2 0.063 BMI 0.271 Normal 17 55 114 40 Overweight 7 23 99 34 Obese 7 23 71 25 Disease extent prior to surgery 0.447 Proctitis 2 6 19 7 Left-sided colitis 5 16 22 8 Extensive colitis 19 31 151 61 Unknown 4 13 52 18 Indication for surgery >0.999 Medically-refractory colitis 29 94 256 89 Dysplasia/colorectal cancer 1 3 13 5 Medically refractory + dysplasia/colorectal cancer 0 0 8 3 Other 1 3 9 3 Number of stages in surgery 0.590 1 2 6 35 12 2 10 32 114 40 Modified 2 3 10 19 7 3 15 48 103 36 IPAA surgery performed at current medical center 20 65 181 63 >0.999 Primary Sclerosing Cholangitis 2 6 23 8 >0.999 Clostridiodes difficile infection prior to IPAA 4 13 42 15 >0.999 Smoker at the time of colectomy 2 6 15 5 0.678 Current smoker 7 23 13 5 0.001 NSAIDs in the prior two weeks 12 39 104 36 0.846

Management of Acute and Chronic Pouchitis.

Restorative proctocolectomy with IPAA is the procedure of choice when colectomy is needed for medically refractory ulcerative colitis. Pouchitis is one of the most common complications among patients who have undergone IPAA and represents a spectrum of disease varying in both phenotype and clinical course. This study aimed to assist clinicians and surgeons in the treatment of both acute and chronic pouchitis, including newer therapies and future directions. Diagnosis is made by endoscopy of the pouch with biopsy because other conditions may produce similar symptoms such as increased stool frequency, abdominal cramps, and urgency. Pouchitis is classified by duration (acute versus chronic), disease pattern (infrequent, relapsing, and continuous), and response to antibiotics (responsive, dependent, and refractory). The Pouchitis Disease Activity Index may be used to measure disease activity. The management of pouchitis is guided by the disease phenotype. Acute episodes are treated with an initial 2-week course of antibiotics (typically ciprofloxacin or metronidazole), although patients with relapsing or chronic pouchitis may require long-term antibiotic treatment or the cycling of different antibiotics. Certain probiotics may also be used for maintenance therapy in those with chronic symptoms. For patients with chronic antibiotic refractory pouchitis, oral budesonide, immunosuppressive agents (azathioprine), or biologic therapy (infliximab, adalimumab, vedolizumab, and ustekinumab) may be required for both induction and maintenance with close monitoring for potential side effects. In rare cases, diverting ileostomy or pouch excision may be required. Pouchitis represents a spectrum of disease phenotypes, ranging from acute antibiotic responsive pouchitis to chronic antibiotic refractory pouchitis. The management of pouchitis is primarily directed by the disease phenotype.

Treatment Patterns and Standardized Outcome Assessments Among Patients With Inflammatory Conditions of the Pouch in a Prospective Multicenter Registry.

BackgroundMuch of our understanding about the natural history of pouch-related disorders has been generated from selected populations. We designed a geographically diverse, prospective registry to study the disease course among patients with 1 of 4 inflammatory conditions of the pouch. The primary objectives in this study were to demonstrate the feasibility of a prospective pouch registry and to evaluate the predominant treatment patterns for pouch-related disorders.MethodsWe used standardized diagnostic criteria to prospectively enroll patients with acute pouchitis, chronic antibiotic-dependent pouchitis (CADP), chronic antibiotic refractory pouchitis (CARP), or Crohn’s disease (CD) of the pouch. We obtained detailed clinical and demographic data at the time of enrollment, along with patient-reported outcome (PRO) measures.ResultsWe enrolled 318 patients (10% acute pouchitis, 27% CADP, 12% CARP, and 51% CD of the pouch). Among all patients, 55% were on a biologic or small molecule therapy. Patients with CD of the pouch were more likely to use several classes of therapy (P < .001). Among patients with active disease at the time of enrollment, 23% with CARP and 40% with CD of the pouch were in clinical remission at 6 months after enrollment.ConclusionsIn a population where most patients had refractory inflammatory conditions of the pouch, we established a framework to evaluate PROs and clinical effectiveness. This infrastructure will be valuable for long-term studies of real-world effectiveness for pouch-related disorders.

OUTCOMES OF TOTAL PROCTOCOLECTOMY (TPC) WITH ILEAL POUCH ANAL ANASTOMOSIS (IPAA)

Abstract BACKGROUND Total proctocolectomy (TPC) followed by ileal pouch anal anastomosis (IPAA) is the surgery of choice for eligible ulcerative colitis patients who are refractory to medical therapy or develop complications such as adenocarcinoma or dysplasia. Although associated with excellent quality of life, IPAA can lead to complications including chronic antibiotic-refractory pouchitis, anatomical complications, and development of Crohn’s disease. These outcomes remain a clinical challenge. The aim of this study was to evaluate the rate of complications and their treatment following TPC with IPAA to assess for predictors of adverse postoperative outcomes. METHODS This was a single center, retrospective study from January 1,2010 to December 31, 2020. We included patients who underwent TPC with IPAA and reported at least one episode of pouchitis, some of whom also had additional complications. Chronic pouchitis was defined as recurrent episodes of biopsy-proven inflammation or as reported in the patient record based on clinical presentation and responsiveness to treatment. Crohn’s disease of the pouch was defined as pre-pouch ileitis or development of a fistula more than 6 months post-operatively. Data is presented as number of cases and proportions. RESULTS A total of 44 subjects who underwent IPAA (52% female, mean age 46.4 ± 11.3 years) were included. The rate of acute pouchitis was 9%, the rate of chronic pouchitis was 75%. In the chronic pouchitis group, 45% were antibiotic-dependent and 7% were antibiotic-refractory. We found that 70% of subjects required the initiation of medical therapy to treat symptoms of pouchitis, with the majority requiring chronic antibiotics (73%) (Table). A total of 10 subjects (23%) required biologics and 10 subjects (23%) required chronic steroid therapy. Anatomic complications were noted in 23 subjects (52%), the most common being abscess/fistula formation (30%), followed by stricture formation (27%). Anatomic complications appeared more likely to occur when more time had elapsed since the original surgery. 10 subjects (23%) needed repeat surgery and 9 subjects (20%) developed Crohn’s disease of the pouch. CONCLUSIONS In our cohort, we found that nearly two thirds of subjects required medical therapy to treat pouchitis following IPAA including 25% requiring treatment biologic/immunosuppressant therapy. In addition, one quarter required repeat surgery for treatment of complications. Limitations of this study include a tertiary patient population and small sample size. We found a lack of standardized characterization of pouchitis with respect to symptoms and lab abnormalities. In future work, we plan to use this data to develop a prospective, multi-center study to establish a standardized database of patients who underwent IPAA. This will help better understand factors that influence outcomes and guide management.

P496 Efficacy and safety of ustekinumab for chronic antibiotic refractory pouchitis: A Belgian open-label multicentre pilot study

Abstract Background Up to 10% of ulcerative colitis patients who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction therapy with ustekinumab (UST) for this indication. Methods We performed a prospective, Belgian, multicentre, open-label study of patients with CARP. Patients received a weight-range-based infusion of UST at baseline (6mg/kg) and one subcutaneous injection of 90mg UST at week 8. The first 4 weeks, ciprofloxacin 500mg BID was added as bridging therapy, but need of antibiotics thereafter was regarded as treatment failure. Patients underwent pouchoscopy at baseline and week 16, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving clinically relevant steroid-free remission (mPDAI &amp;lt;5 and reduction by ≥2 points from baseline) at week 16. Secondary endpoints at week 16 were the proportion of patients achieving response (reduction of mPDAI by ≥2 points from baseline), change in symptomatic and endoscopic mPDAI subscore, and change in C-reactive protein (CRP) and faecal calprotectin levels compared to baseline. Descriptive statistics and paired nonparametric tests (Wilcoxon signed-rank) of changes from baseline were performed. Results We report the first 18 patients (56% male, median age 41.5 years, median time after surgery 11.2 years) who reached the primary endpoint assessment. Eleven (61.1%) patients had previously been treated with biologics (anti-TNF, n=8; vedolizumab, n=6; tofacitinib, n=1) for CARP (table 1). At week 16, clinically relevant steroid-free remission was reached in 27.8% and response in 50.0% of patients. A significant decrease in total mPDAI (8.0 (7.0–8.3) vs. 6.5 (3.8–9.0), p=0.04) and clinical subscore (3.0 (2.0–4.0) vs. 2.0 (1.0–3.3), p=0.04) but not endoscopic subscore (5.0 (4.0–6.0) vs. 4.0 (3.0–6.0), p=0.1) was observed at week 16 (figure 1). Faecal calprotectin (288.0 (154.8–634.8) vs. 145 (88.3–749.3) mg/kg, p=0.47) and CRP (4.8 (1.9–7.2) vs. 3.9 (1.9–8.9) mg/L, p=0.63) levels did however not decrease significantly (figure 2). Three serious adverse events (hospitalization for subobstruction, worsening pouchitis and choledocholithiasis) were recorded, but were not considered related to UST. Conclusion In this open-label pilot study in patients with CARP, induction therapy with UST showed a clinical effect in half of the patients, but was not associated with endoscopic improvement or changes in inflammatory biomarkers. Placebo-controlled studies are needed for further positioning UST in the treatment algorithm of CARP.

OUTCOMES OF TOTAL PROCTOCOLECTOMY (TPC) WITH ILEAL POUCH ANAL ANASTOMOSIS (IPAA)

Total proctocolectomy (TPC) followed by ileal pouch anal anastomosis (IPAA) is the surgery of choice for eligible ulcerative colitis patients who are refractory to medical therapy or develop complications such as adenocarcinoma or dysplasia. Although associated with excellent quality of life, IPAA can lead to complications including chronic antibiotic-refractory pouchitis, anatomical complications, and development of Crohn’s disease. These outcomes remain a clinical challenge. The aim of this study was to evaluate the rate of complications and their treatment following TPC with IPAA to assess for predictors of adverse postoperative outcomes.

Outcomes of Standard and Intensified Dosing of Ustekinumab for Chronic Pouch Disorders.

Up to 10% of patients with ulcerative colitis (UC) require total proctocolectomy (TPC) within 10 years after diagnosis.1 Ileal pouch-anal anastomosis (IPAA) is the preferred operation in this population. However, chronic pouch disorders (CPDs), including chronic antibiotic-refractory pouchitis (CARP) and Crohn’s disease of the pouch (CDoP), may occur in up to 30% and 10% of patients after IPAA, respectively.2 Patients with refractory CPDs often require biologic therapy or pouch excision.3 Ustekinumab (UST) is an anti-interleukin therapy approved for UC and CD. Limited data from small cohorts suggest that every 8 week (q8w) dosing of UST effectively treats CPDs.4,5 However, patients with CPDs may lose response to q8w dosing. Dose intensification to every 4 weeks (q4w) or every 6 weeks (q6w) appears to be effective among CD patients who lose response to UST, however similar data does not exist for CPDs.6 We therefore sought...

Chronic Antibiotic-Refractory Pouchitis: Management Challenges.

BackgroundPouchitis is the most common long-term complication in patients with ulcerative colitis who underwent restorative proctocolectomy with ileal pouch-anal anastomosis. The incidence of acute pouchitis is 20% after 1 year and up to 40% after 5 years. Chronic antibiotic-refractory pouchitis develops in approximately 10% of patients.AimTo present a narrative review of published literature regarding the management of chronic antibiotic-refractory pouchitis.MethodsCurrent relevant literature was summarized and critically evaluated.ResultsClear definitions should be used to classify pouchitis into acute versus chronic, and responsive versus dependent versus refractory to antibiotics. Before treatment is started for chronic antibiotic-refractory pouchitis, secondary causes should be ruled out. There is a need for validated scoring systems to measure the severity of the disease. Because chronic antibiotic-refractory pouchitis is a rare condition, only small studies with often a poor study design have been performed. Treatments with antibiotics, aminosalicylates, steroids, immunomodulators and biologics have shown to be effective and safe for chronic antibiotic-refractory pouchitis. Also, treatments with AST-120, hyperbaric oxygen therapy, tacrolimus enemas, and granulocyte and monocyte apheresis suggested some efficacy.ConclusionThe available data are weak but suggest that therapeutic options for chronic antibiotic-refractory pouchitis are similar to the treatment strategies for inflammatory bowel diseases. However, randomized controlled trials are warranted to further identify the best treatment options in this patient population.