Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial.

BACKGROUND: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients. This article presents the statistical analysis plan to evaluate the outcomes of the ACCURE trial. DESIGN AND METHODS: The ACCURE trial was designed as a multicentre, randomised controlled trial. UC patients with a new diagnosis or a disease relapse within the past 12 months, treated with 5-ASA, corticosteroids, or immunomodulators until complete clinical and endoscopic remission (defined as total Mayo score < 3 with endoscopic subscore of 0 or 1), were counselled for inclusion. Also, patients previously treated with biologicals who had a washout period of at least 3 months were considered for inclusion. Patients were randomised (1:1) to laparoscopic appendectomy plus maintenance treatment or a control group (maintenance therapy only). The primary outcome is the 1-year UC relapse rate (defined as a total Mayo-score ≥ 5 with endoscopic subscore of 2 or 3, or clinically as an exacerbation of symptoms and rectal bleeding or FCP > 150 or intensified medical therapy other than 5-ASA therapy). Secondary outcomes include number of relapses per patient, time to first relapse, disease activity, number of colectomies, medication usage, and health-related quality of life. DISCUSSION: The ACCURE trial will provide comprehensive evidence whether adding an appendectomy to maintenance treatment is superior to maintenance treatment only in maintaining remission in UC patients. TRIAL REGISTRATION: Dutch Trial Register (NTR) NTR2883 . Registered May 3, 2011. ISRCTN, ISRCTN60945764 . Registered August 12, 2019.

Increased Proportion of Colorectal Cancer in Patients With Ulcerative Colitis Undergoing Surgery in the Netherlands.

INTRODUCTION: The aim of the current study was to assess whether there is an indication shift for surgery in patients with ulcerative colitis (UC) from refractory disease to malignant degeneration over the past 3 decades. METHODS: All patients with histologically confirmed UC who underwent a colorectal resection between 1991 and 2020 were extracted from the nationwide Dutch Pathology Registry. The primary outcome was the proportion of colorectal cancer (CRC) in the colon specimens. Outcomes were compared between 3 periods (P1: 1991-2000, P2: 2001-2010, and P3: 2011-2020). RESULTS: Overall, 6,094 patients with UC were included of which 4,854 underwent a (procto)colectomy and 1,240 a segmental resection. In 1,031 (16.9%) patients, CRC was demonstrated in the pathological resection specimen after a median disease duration of 11 years (IQR 3.0-19.0). The proportion of CRC increased from 11.3% in P1, to 16.1% in P2, and 22.8% in P3 ( P < 0.001). Median disease duration at the time of resection increased from 4 years in P1, to 10 years in P2, and 17 years in P3 ( P < 0.001). The proportion of patients diagnosed with advanced malignancy (pT3/T4) (P1: 61.2% vs P2: 65.2% vs P3: 62.4%, respectively, P = 0.633) and lymph node metastasis (N+) (P1: 33.0% vs P2: 41.9% vs P3: 38.2%, respectively, P = 0.113) did not change over time. DISCUSSION: This nationwide pathology study demonstrated an increased proportion of surgery for CRC over the past 3 decades. We hypothesize that the expanding therapeutic armamentarium for UC leads to exhausting medical options and hence postponed colectomy. This, however, might be at the expense of an increased risk of CRC in the long term.

Clinical relevance of endoscopic peri-appendiceal red patch in ulcerative colitis patients.

Background: Increasing evidence is suggesting appendectomy as an alternative treatment for ulcerative colitis (UC), especially in case of histological appendiceal inflammation. Therefore, preoperative identification of appendiceal inflammation could be beneficial. This study aimed to assess the prevalence of peri-appendiceal red patch (PARP) on colonoscopy. In addition, prognostic relevance of PARP for disease course and its predictive value for histological appendiceal inflammation in patients undergoing appendectomy was assessed. Methods: UC patients undergoing colonoscopy in 2014/2015 were included to determine PARP-prevalence in a cross-sectional study. Findings were correlated to patient and disease characteristics, upscaling of treatment and colectomy rates after cross-sectional colonoscopy. In patients undergoing appendiceal resection, histopathological inflammation was assessed using the Robarts Histopathology Index (RHI). Results: In total, 249 patients were included of which 17.7% (44/249) had a PARP. Patients with PARP were significantly younger with a shorter disease course. The majority of patients with PARP (61.4%) was in endoscopic remission. Patients with PARP required more upscaling of medical therapy (81.8% vs. 58.0%, p < 0.01), and more PARP patients underwent colectomy (13.6% vs. 4.9%, p = 0.04). Patients with PARP had a higher median RHI in resection specimens (14 vs. 7, p < 0.01). Conclusion: PARP was present during colonoscopy regardless disease activity and was predominantly found in UC patients with younger age and shorter disease duration. PARP patients had a more severe course of UC, and in case of appendectomy, more severe histopathological appendiceal inflammation. Appendectomy as an experimental therapy for UC has been suggested to be predominantly effective in UC patients with appendiceal inflammation. This study demonstrates that presence of a PARP on colonoscopy predicts appendiceal inflammation. After consensus has been reached on the therapeutic effect of appendectomy, assessing PARP presence during colonoscopy could therefore contribute to identifying patients most likely to respond.

New insights on the surgical management of ulcerative colitis in the 21st century.

Despite substantial advances in medical therapy since 2005 that have led to the approval and increased use of novel biological agents and small molecules, colectomy is still a therapeutic option for some patients with ulcerative colitis. In the biological era (ie, after the approval of biological agents for ulcerative colitis), improved control of disease activity has led to a trend of decreasing colectomy rates for refractory disease. Consequently, indications for colectomy for dysplasia and colorectal cancer seem to be increasing. Advances have not only been made in surgical techniques, but also in multidisciplinary approaches, the timing of surgery, and in medical management before and after surgery. This Review discusses surgical indications in patients with ulcerative colitis in relation to current medical therapy, management in the acute setting, indications for staged procedures, new techniques such as transanal surgery and robotics, and surgical alternatives to ileal pouch-anal anastomosis. A multidisciplinary approach including surgeons, gastroenterologists, pathologists, radiologists, and clinical nutritionists is essential to improving patient outcomes in different clinical scenarios of ulcerative colitis management in the 21st century.

High prevalence of ulcerative appendicitis in patients with ulcerative colitis.

BACKGROUND: Previous studies have indicated that the appendix may be a priming site of ulcerative colitis (UC). Appendectomy is inversely associated with the development of UC, and is suggested to have a beneficial effect on the disease course in patients with refractory disease. OBJECTIVE: The aim of the current study was to assess histological features of appendices from patients with UC and their clinical relevance. METHODS: Patients with UC in remission and active UC (therapy refractory) that underwent appendectomy between 2012 and 2019 were included. Histological features of UC appendices were compared to those of patients with acute appendicitis and colon carcinoma. The Robarts Histopathology Index (RHI) was used to assess appendiceal inflammation. In patients with active UC, histological and clinical characteristics were compared between patients with and without endoscopic response following appendectomy. RESULTS: In total, 140 appendix specimens were assessed (n = 35 UC remission, n = 35 active UC, n = 35 acute appendicitis, n = 35 colon carcinoma). Histological features of appendices from UC patients looked like UC rather than acute appendicitis. The presence of active appendiceal inflammation was comparable between patients in remission versus active disease (53.7% vs. 46.3%, p = 0.45) and limited versus extensive disease (58.5% vs. 41.5%, p = 0.50). Endoscopic response (Mayo 0-1) following appendectomy, assessed in 28 therapy refractory patients, was more frequently seen in patients with higher RHI scores (RHI > 6: 81.8% vs. RHI ≤ 6: 9.1%, p = 0.03) and limited disease (proctitis/left sided 63.6% vs. pancolitis 36.4%, p = 0.02). CONCLUSION: The presence of active appendiceal inflammation is common in UC and does not correlate with colonic disease activity. More than 50% of UC patients in remission showed active histological disease in the appendix. Favorable response to appendectomy for refractory UC was seen in cases with ulcerative appendicitis. These findings might support the role of the appendix as a pivotal organ in UC.

Ileal Pouch-anal Anastomosis Complications and Pouch Failure: A systematic review and meta-analysis.

Objective: This systematic review aims to assess the incidence of pouch failure and the correlation between ileal pouch-anal anastomosis (IPAA)-related complications and pouch failure. Background: Previous studies demonstrated wide variation in postoperative complication rates following IPAA. Methods: A systematic review was performed by searching the MEDLINE, EMBASE, and Cochrane Library databases for studies reporting on pouch failure published from January 1, 2010, to May 6, 2020. A meta-analysis was performed using a random-effects model, and the relationship between pouch-related complications and pouch failure was assessed using Spearman's correlations. Results: Thirty studies comprising 22,978 patients were included. Included studies contained heterogenic patient populations, different procedural stages, varying definitions for IPAA-related complications, and different follow-up periods. The pooled pouch failure rate was 7.7% (95% confidence intervals: 5.56-10.59) and 10.3% (95% confidence intervals: 7.24-14.30) for studies with a median follow-up of ≥5 and ≥10 years, respectively. Observed IPAA-related complications were anastomotic leakage (1-17%), pelvic sepsis (2-18%), fistula (1-30%), stricture (1-34%), pouchitis (11-61%), and Crohn's disease of the pouch (0-18%). Pelvic sepsis (r = 0.51, P < 0.05) and fistula (r = 0.63, P < 0.01) were correlated with pouch failure. A sensitivity analysis including studies with a median follow-up of ≥5 years indicated that only fistula was significantly correlated with pouch failure (r = 0.77, P < 0.01). Conclusions: The single long-term determinant of pouch failure was pouch fistula, which is a manifestation of a chronic leak. Therefore, all effort should be taken to prevent an acute leak from becoming a chronic leak by early diagnosis and proactive management of the leak. Mini abstract: This systematic review aims to assess the incidence of pouch failure and the correlation between IPAA-related complications and pouch failure. Long-term pouch failure was correlated with fistula, suggesting that early septic complications may result in fistula formation during long-term follow-up, leading to an increased risk of pouch failure.