Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility.

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.

Development of a New Index to Assess Small Bowel Inflammation Severity in Crohn's Disease Using Magnetic Resonance Enterography.

Background: The severity of small bowel (SB) inflammation in Crohn's disease (CD) patients is a key component of the therapeutic choice. We aimed to develop a SB-CD Magnetic Resonance Enterography (MRE) index of Inflammation Severity (CDMRIS). Methods: Each gastroenterologist/radiologist pair in 13 centers selected MREs from 6 patients with SB-CD stratified on their perceived MRE inflammation severity. The 78 blinded MREs were allocated through balanced incomplete block design per severity stratum to these 13 pairs for rating the presence/severity of 13 preselected items for each SB 20-cm diseased segment. Global inflammation severity was evaluated using a 100-cm visual analog scale. Reproducibility of recorded items was evaluated. The CDMRIS was determined through linear mixed modeling as a combination of the numbers of segments with lesions highly correlated to global inflammation severity. Results: Four hundred and forty-two readings were available. Global inflammation severity mean ± SD was 21.0 ± 16.2. The independent predictors explaining 54% of the global inflammation severity variance were the numbers of segments with T1 mild-moderate and severe intensity of enhancement, deep ulceration without fistula, comb sign, fistula, and abscess. Unbiased correlation between CDMRIS and global inflammation severity was 0.76. Conclusions: The CDMRIS is now available to evaluate the severity of SB-CD inflammation. External validation and sensitivity-to-change are mandatory next steps.

Increased incidence of systemic serious viral infections in patients with inflammatory bowel disease associates with active disease and use of thiopurines.

Background: The magnitude and drivers of the risk of serious viral infections in Inflammatory Bowel diseases (IBD) are unclear. Objective: The objective of this study was to assess the incidence and risk factors for systemic serious viral infections in IBD patients. Methods: Using MICISTA, a database detailing prospective characteristics and complications of IBD, we identified patients that were followed for IBD in 2005-2014 outside the context of organ transplantation, HIV infection or chronic viral hepatitis. We estimated incidences of systemic serious viral infections, defined by the need for hospitalization or permanent organ damage. Standardized incidence ratios (SIRs) were calculated using the French hospital database. We performed a case-control study nested in MICISTA for assessing the role of exposure to IBD drugs and IBD clinical activity in the risk of developing infection. Results: We identified 31 patients with serious viral infections among 2645 patients followed for 15,383 person-years. We observed 13 cases of cytomegalovirus, 10 Epstein-Barr virus, 5 varicella zoster virus and 3 herpes simplex virus infections. No deaths occurred. The incidence rate of infections in patients with IBD was 2.02/1000 person-years, and the SIR was 3.09 (95% confidence interval (CI), 1.98-4.20; p = 0.0002) in the study population. By multivariate analysis, increased risk of infection was associated with exposure to thiopurines (odds ratio (OR), 3.48; 95% CI, 1.36-8.90; p = 0.009), and clinically active IBD at onset of infection (OR, 3.35; 95% CI, 1.23-9.23; p = 0.02). Conclusions: The incidence of systemic serious viral infections in patients with IBD is tripled compared to general population. Clinically active IBD and exposure to thiopurines are the main drivers of the risk.

Increased risk of permanent stoma in Crohn's disease associated with hidradenitis suppurativa: a case-control study.

BACKGROUND: Crohn's disease (CD) and hidradenitis suppurativa (HS), a chronic inflammatory skin disease, induce similar inflammatory lesions of the groin and gluteal area. Both diseases are characterised by an inadequate immune response to commensal bacteria in genetically predisposed subjects and can be associated. AIM: To assess whether HS was associated with clinical and prognostic factors in CD. METHODS: A retrospective case-control study included 4645 patients with CD referred to Saint-Antoine Hospital gastroenterology tertiary care centre between 2003 and 2016. Matching variables were sex, age, age and the presence of perianal lesions at CD diagnosis, follow-up quality. HS was confirmed by dermatological examination; location, phenotype and severity (Hurley staging) were recorded. RESULTS: Hidradenitis suppurativa prevalence was 0.95% (44 cases); 80% of patients displayed Hurley stage II or III disease. CD preceded HS in 70% of cases with a median interval of 9 years (IQR 5.25-12.75). CD with HS was more active (56% vs 40% years with active disease, P < 0.001) and required more anti-TNF agents (39% vs 23% years spent with anti-TNF treatment, P < 0.001) than CD without HS. HS was associated with a higher risk of permanent stoma, 16.8% (IQR 7.5-33.3) vs 2.5% (IQR 0.8-7.4) in the control group (P = 0.002). Multivariate analysis confirmed HS as independent risk factor for permanent stoma (odds ratio 6.19; 95% CI, 2.30-38.33; P < 0.001). CONCLUSIONS: Hidradenitis suppurativa is associated with worse CD prognosis, more active disease and increased risk of permanent stoma, despite a higher use of anti-TNF agents.

Nancy Index Scores of Chronic Inflammatory Bowel Disease Activity Associate With Development of Colorectal Neoplasia.

BACKGROUND & AIMS: The degree of histologic and endoscopic disease activity has been associated with an increased risk of colorectal neoplasia (CRN) in patients with inflammatory bowel diseases (IBDs), but no histologic scoring systems have been validated for determining risk of CRN. We investigated the association between histologic and endoscopic disease activity and risk of first CRN in patients with IBD who had negative findings from a surveillance colonoscopy. METHODS: We performed a retrospective analysis of consecutive patients who underwent at least 2 colonoscopies at Saint Antoine Hospital in France from January 1, 1996, through March 1, 2015, and whose first procedure was a surveillance colonoscopy. Histologic IBD activity was assessed by the Nancy histologic index. Patients were followed up for a mean 5.7 ± 3.3 years. Logistic regression and generalized estimating equations were used to identify clinical, endoscopic, and histologic factors associated with detection of neoplasia in the inflamed colon mucosa. RESULTS: Among 398 patients who underwent 1277 colonoscopies, we identified 45 patients with CRN. Factors associated with CRN were primary sclerosing cholangitis (odds ratio [OR], 2.65; 95% CI, 1.06-6.61; P = .04), age (OR per 1-year increase, 1.04; 95% CI, 1.01-1.07; P = .003), and mean Nancy histologic index during follow-up evaluation (per 1-unit increase, OR, 1.69; 95% CI, 1.29-2.21; P < .001). After adjustment for established factors, chronic disease activity defined as detection of ulcerations at more than 50% of colonoscopies was not associated with an increased risk of CRN (OR, 1.24; 95% CI, 0.53-2.91; P = .62). CONCLUSIONS: In addition to established risk factors, we associated Nancy histologic index scores with development of CRN. Histologic findings based on the Nancy histologic index therefore should be included in determining the risk of colonic neoplasia in patients with IBD.

Correction: Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

[This corrects the article DOI: 10.1371/journal.pgen.1007329.].

Genetic effects on the commensal microbiota in inflammatory bowel disease patients.

Several bacteria in the gut microbiota have been shown to be associated with inflammatory bowel disease (IBD), and dozens of IBD genetic variants have been identified in genome-wide association studies. However, the role of the microbiota in the etiology of IBD in terms of host genetic susceptibility remains unclear. Here, we studied the association between four major genetic variants associated with an increased risk of IBD and bacterial taxa in up to 633 IBD cases. We performed systematic screening for associations, identifying and replicating associations between NOD2 variants and two taxa: the Roseburia genus and the Faecalibacterium prausnitzii species. By exploring the overall association patterns between genes and bacteria, we found that IBD risk alleles were significantly enriched for associations concordant with bacteria-IBD associations. To understand the significance of this pattern in terms of the study design and known effects from the literature, we used counterfactual principles to assess the fitness of a few parsimonious gene-bacteria-IBD causal models. Our analyses showed evidence that the disease risk of these genetic variants were likely to be partially mediated by the microbiome. We confirmed these results in extensive simulation studies and sensitivity analyses using the association between NOD2 and F. prausnitzii as a case study.

Risk of serious infection in healthcare workers with inflammatory bowel disease: a case-control study of the Groupe d'Etude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID).

BACKGROUND: Whether healthcare workers with inflammatory bowel disease (IBD) are at increased risk of severe infection due to daily pathogen exposure is controversial. AIM: To assess the risk of severe infection in healthcare workers with IBD in a large multicentre case-control study. METHODS: The study population comprised 482 healthcare workers with IBD from 17 centres who were matched for gender, age, disease subtype and year of diagnosis to 482 controls (non-healthcare workers with IBD). The study period was between the date of diagnosis of IBD and June 2016. Severe infection was defined as any community-acquired infection that required hospitalisation. RESULTS: With a median follow-up of 9.3 years, 139 severe infections were recorded among cases and controls, including 30 Clostridium difficile infections, 33 severe viral infections, nine tuberculosis infections, 21 community-acquired pneumonia and 46 others. No difference was observed between healthcare workers and controls regarding the overall incidence rates of severe infection. An increased risk of tuberculosis was noted in healthcare workers. In multivariate analysis in the entire study population, severe infection was associated with current exposure to corticosteroids (OR = 3.05, 95% CI [2.06-4.52], P < 0.001), immunosuppressants (OR = 1.98, 95% CI [1.38-2.84], P < 0.001) and anti-TNF agents (OR = 2.93, 95% CI [2.02-4.27], P < 0.001) and reduced with Crohn's disease (OR = 0.63, 95% CI [0.43-0.91], P = 0.01). CONCLUSIONS: Healthcare workers with IBD do not have an increased risk of severe infection compared with other patients with IBD, except for tuberculosis. Screening for tuberculosis exposure should be assessed in this high-risk population when treated with anti-TNF agents.

Insights into the genetic epidemiology of Crohn's and rare diseases in the Ashkenazi Jewish population.

As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at https://ibd.broadinstitute.org, also available in gnomAD at http://gnomad.broadinstitute.org). We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations. As validation we document 148 AJ enriched protein-altering alleles that overlap with "pathogenic" ClinVar alleles (table available at https://github.com/macarthur-lab/clinvar/blob/master/output/clinvar.tsv), including those that account for 10-100 fold differences in prevalence between AJ and non-AJ populations of some rare diseases, especially recessive conditions, including Gaucher disease (GBA, p.Asn409Ser, 8-fold enrichment); Canavan disease (ASPA, p.Glu285Ala, 12-fold enrichment); and Tay-Sachs disease (HEXA, c.1421+1G>C, 27-fold enrichment; p.Tyr427IlefsTer5, 12-fold enrichment). We next sought to use this catalog, of well-established relevance to Mendelian disease, to explore Crohn's disease, a common disease with an estimated two to four-fold excess prevalence in AJ. We specifically attempt to evaluate whether strong acting rare alleles, particularly protein-truncating or otherwise large effect-size alleles, enriched by the same founder-effect, contribute excess genetic risk to Crohn's disease in AJ, and find that ten rare genetic risk factors in NOD2 and LRRK2 are enriched in AJ (p < 0.005), including several novel contributing alleles, show evidence of association to CD. Independently, we find that genomewide common variant risk defined by GWAS shows a strong difference between AJ and non-AJ European control population samples (0.97 s.d. higher, p<10-16). Taken together, the results suggest coordinated selection in AJ population for higher CD risk alleles in general. The results and approach illustrate the value of exome sequencing data in case-control studies along with reference data sets like ExAC (sites VCF available via FTP at ftp.broadinstitute.org/pub/ExAC_release/release0.3/) to pinpoint genetic variation that contributes to variable disease predisposition across populations.

Specificities of the intestinal microbiota in patients with inflammatory bowel disease and Clostridium difficile infection.

Clostridium difficile infection (CDI) is a common complication in inflammatory bowel disease (IBD) and has been associated with poor IBD outcome. Intestinal microbiota composition in IBD patients with CDI has not been specifically evaluated to date. The fecal microbiota of 56 IBD patients, including 8 in flare with concomitant CDI, 24 in flare without CDI, and 24 in remission, as well as 24 healthy subjects, was studied using 16S sequencing. Analysis was performed using the Qiime pipeline. Compared to IBD patients without CDI, IBD patients with CDI had more pronounced dysbiosis with higher levels of Ruminococcus gnavus and Enterococcus operational taxonomic units (OTUs) and lower levels of Blautia and Dorea OTUs. Correlation network analysis suggested a disrupted ecosystem in IBD patients in flare, particularly in those with CDI. In patients with IBD, CDI is associated with a more pronounced intestinal dysbiosis with specific alterations in intestinal microorganisms.

Comparing Inpatient Satisfaction Collected via a Web-Based Questionnaire Self-Completion and Through a Telephone Interview: An Ancillary Study of the SENTIPAT Randomized Controlled Trial.

BACKGROUND: Assessing the satisfaction of patients about the health care they have received is relatively common nowadays. In France, the satisfaction questionnaire, I-Satis, is deployed in each institution admitting inpatients. Internet self-completion and telephone interview are the two modes of administration for collecting inpatient satisfaction that have never been compared in a multicenter randomized experiment involving a substantial number of patients. OBJECTIVE: The objective of this study was to compare two modes of survey administration for collecting inpatient satisfaction: Internet self-completion and telephone interview. METHODS: In the multicenter SENTIPAT (acronym for the concept of sentinel patients, ie, patients who would voluntarily report their health evolution on a dedicated website) randomized controlled trial, patients who were discharged from the hospital to home and had an Internet connection at home were enrolled between February 2013 and September 2014. They were randomized to either self-complete a set of questionnaires using a dedicated website or to provide answers to the same questionnaires administered during a telephone interview. As recommended by French authorities, the analysis of I-Satis satisfaction questionnaire involved all inpatients with a length of stay (LOS), including at least two nights. Participation rates, questionnaire consistency (measured using Cronbach alpha coefficient), and satisfaction scores were compared in the two groups. RESULTS: A total of 1680 eligible patients were randomized to the Internet group (n=840) or the telephone group (n=840). The analysis of I-Satis concerned 392 and 389 patients fulfilling the minimum LOS required in the Internet and telephone group, respectively. There were 39.3% (154/392) and 88.4% (344/389) responders in the Internet and telephone group, respectively (P<.001), with similar baseline variables. Internal consistency of the global satisfaction score was higher (P=.03) in the Internet group (Cronbach alpha estimate=.89; 95% CI 0.86-0.91) than in the telephone group (Cronbach alpha estimate=.84; 95% CI 0.79-0.87). The mean global satisfaction score was lower (P=.03) in the Internet group (68.9; 95% CI 66.4-71.4) than in the telephone group (72.1; 95% CI 70.4-74.6), with a corresponding effect size of the difference at -0.253. CONCLUSIONS: The lower response rate issued from Internet administration should be balanced with a likely improved quality in satisfaction estimates, when compared with telephone administration, for which an interviewer effect cannot be excluded. TRIAL REGISTRATION: Clinicaltrials.gov NCT01769261 ; http://clinicaltrials.gov/ct2/show/NCT01769261 (Archived by WebCite at http://www.webcitation.org/6ZDF5lA41).

Risk of Rectal Neoplasia after Colectomy and Ileorectal Anastomosis for Ulcerative Colitis.

BACKGROUND AND AIMS: Colectomy can be required in the management of ulcerative colitis [UC]. While ileal-pouch anal anastomosis [IPAA] is the recommended reconstruction technique, ileorectal anastomosis [IRA] is still performed and might present some advantages. However, the risk of rectal neoplasia might limit its indication. The aims of our study were to determine the incidence of rectal neoplasias following IRA for UC and to identify risk factors associated with rectal carcinomas. METHODS: We performed a multicenter retrospective study including patients who underwent IRA for UC from 1960 to 2014 in 13 centers. Cox-proportional hazard models were used to determine carcinoma-associated risk factors. RESULTS: A total of 343 patients were included, with a median follow-up of 10.4 years after IRA. At the end of follow-up, 38 rectal neoplasias (including 19 carcinomas) were diagnosed, and 7 patients [2%] had either died from rectal carcinoma or had a metastatic disease. Incidences of rectal carcinoma after IRA for UC were estimated at 3.2% at 10 years and at 7.3% at 20 years, whereas incidences of neoplasia were estimated at 7.1% and 14% at 10 and 20 years, respectively. In multivariate analysis, age at IRA, IBD duration, primary sclerosing cholangitis [PSC] and history of prior colonic carcinoma were independently associated with the risk of rectal carcinoma following IRA. CONCLUSION: The risk of rectal carcinoma in patients with IRA for UC remains, and this justifies long-term endoscopic surveillance. Either IPAA or end ileostomy should be considered in 'high-risk' patients i.e. those with PSC and/or with prior colonic neoplasia.

Clostridium difficile infection in acute flares of inflammatory bowel disease: A prospective study.

OBJECTIVES: Clostridium difficile infection (CDI) is a common complication in inflammatory bowel disease (IBD) and has been associated with poor IBD outcome. The aims of our study were to look for predictive factors of CDI in patients hospitalized for IBD flare and to evaluate a rapid testing strategy in this population. METHODS: Consecutive patients hospitalized for IBD flare in Saint-Antoine Hospital (Paris, France) were prospectively tested for CDI with a defined strategy involving rapid testing and reference methods. Risk factors for CDI were investigated and performances of diagnostic tests were evaluated. RESULTS: C. difficile testing was performed at admission in 461 hospitalizations for IBD flare. CDI was diagnosed in 35 cases (7.6%) and non-toxigenic C. difficile was identified in 10 cases (2.2%). In multivariate analysis, UC phenotype was associated with CDI (OR 2.2, 95% CI 1.03-4.6, p=0.047). Glutamate dehydrogenase (GDH) test had a 97.1% sensitivity and a 100% negative predictive value for CDI diagnosis but a positive predictive value of 79.1%. Enzyme immunoassay (EIA)-based toxin detection (C. Diff Quik Chek complete®, Alere) had a poor sensitivity and diagnosis was rescued by toxin PCR in 100% of cases. CONCLUSION: CDI is frequent in patients hospitalized for IBD flare. Clinical parameters do not help for the diagnosis and rapid testing should be performed in all patients. Currently, a negative result of an EIA-based toxin search associated with a positive GDH test cannot rule out a CDI and should not delay initiation of specific treatment in case of severe symptoms or high presumption.

What Should Be Done in Inflammatory Bowel Disease Patients with Prior Malignancy?

BACKGROUND: Treatment of inflammatory bowel disease (IBD) in patients with prior malignancy is challenging because therapeutic immunosuppression required for controlling IBD activity may increase the risk of cancer recurrence. Key Messages: Contrary to the observations in the post-transplant population, retrospective observational studies of IBD patients with prior malignancy have not demonstrated that immunosuppressive drugs increased significantly the risk of new or recurrent cancer. However, these studies are highly biased and do not permit the use of these drugs. Factors like the time since treatment completion, severity, and subtype of prior cancer should be weighed along with the current IBD activity before choosing the best therapeutic strategy. In practice, most cases of prior cancer require a delay of at least 2 years before starting or resuming immunosuppressants, including anti-TNF agents. This delay should be extended to 5 years in cancer with a high risk of recurrence including cancer of the urinary tract, gastrointestinal cancer, leukemias, and multiple myeloma. A special attention should be paid to cancers with a high risk of late metastasis (breast, melanoma, renal cell carcinoma). Enteral nutrition, Budesonide, mesalamine, and limited intestinal resection should be considered following the completion of cancer treatment and prior to the safe initiation of immunosuppressive treatment for IBD. Thiopurines should be avoided in case of prior Epstein-Barr virus-related lymphoma, HPV-related carcinomas, and cancer of the urinary tract. Methotrexate and anti-TNF agents seem to be safe except for the risk of recurrent melanoma for the latter. CONCLUSION: IBD patients with prior malignancy should benefit from individual decisions made on a case-by-case basis.

Autoimmune cytopenias associated with inflammatory bowel diseases: Insights from a multicenter retrospective cohort.

INTRODUCTION: Autoimmune cytopenias (AIC) including autoimmune hemolytic anemia (AIHA) and immunologic thrombocytopenia (ITP) are rare immunologic disorders, scarcely reported in inflammatory bowel diseases (IBD). We conducted a multicentric retrospective study, including a case-control analysis, that aimed to describe the characteristics and outcomes of patients affected by AIC and IBD. METHOD: Forty cases were recruited from 4 IBD centers and 2 AIC tertiary centers. Controls were recruited from the MICISTA registry. RESULTS: From the MICISTA registry, incidences were estimated at 4.1/100,000 patient-years and 12.5/100,000 patient-years after IBD diagnosis for AIHA and ITP, respectively. All AIHA patients (n=14) had colonic involvement (13/14 with UC), whereas CD (52%) and UC (48%) diagnoses were evenly distributed among ITP patients. Compared to control IBD patients, cases were characterized by a higher frequency of extra-intestinal manifestations (37.5% vs 17%, p<0.001) and by the presence of IBD severity's hallmark. AIHA and IBD ran mainly in parallel, and 12 out of 14 AIHA were warm AIHA. In isolated cases, rituximab and infliximab were efficient to treat IBD and AIC, respectively. IBD surgery may induce AIC remission in some cases. CONCLUSION: Although low, incidence of AIC appears higher in IBD patients compared to the general population. The association seems to be mainly non-fortuitous, especially for colitis-associated AIHA.

Fungal microbiota dysbiosis in IBD.

OBJECTIVE: The bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD. DESIGN: Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearman's test and distance correlation. RESULTS: We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohn's disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations. CONCLUSIONS: Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis.

Long-term Follow-up After Ileorectal Anastomosis for Ulcerative Colitis: A GETAID/GETAID Chirurgie Multicenter Retrospective Cohort of 343 Patients.

OBJECTIVES: To determine the cumulative incidence and the prognostic factors of ileorectal anastomosis (IRA) failure after colectomy for ulcerative colitis (UC). BACKGROUND: Although ileal pouch-anal anastomosis is recommended after colectomy for UC, IRA is still performed. METHODS: This was a multicenter retrospective cohort study, which included patients with IRA for UC performed between 1960 and 2014. IRA failure was defined as secondary proctectomy and/or rectal cancer occurrence. Uni- and multivariate survival analyses were performed using Cox-proportional hazards models. RESULTS: A total of 343 patients from 13 French centers were included. Median follow up after IRA was 10.6 years. IRA failure rates were estimated at 27.0% (95% confidence interval, CI, 22-32) and 40.0% (95% CI 33-47) at 10 and 20 years, respectively. Median survival time without IRA failure was estimated at 26.8 years. Two thirds of secondary proctectomies were performed for refractory proctitis, and 20% for rectal neoplasia. Univariate analysis identified factors associated with IRA failure: IRA performed after 2005, a longer duration of disease at the time of IRA, indication for colectomy and having received immunomodulative agents before IRA. In multivariate analysis, treatment with both immunosuppressant (IS) and anti-TNF before colectomy was independently associated with IRA failure (HR=2.9, 95% CI 1.2-7.1). Conversely, colectomy for severe acute colitis was associated with decreased risk of IRA failure (HR=0.6, 95% CI 0.4-0.97). DISCUSSION: Patients with UC have a high risk of IRA failure, particularly when colectomy is performed for refractory disease. However, IRA could be discussed after colectomy for severe acute colitis, or in patients naive to IS and anti-TNF.