A global consensus on the definitions, diagnosis and management of fibrostenosing small bowel Crohn's disease in clinical practice.

Fibrostenosis of the small bowel is common in patients with Crohn's disease. No consensus recommendations on definition, diagnosis and management in clinical practice are currently available. In this Consensus Statement, we present a clinical practice RAND/UCLA appropriateness study on the definition, diagnosis and clinical management of fibrostenosing Crohn's disease. It was conducted by a panel of 28 global experts and one patient representative. Following a systematic literature review, 526 candidate items grouped into 136 questions were generated and subsequently evaluated for appropriateness. Strictures are best defined as wall thickening, luminal narrowing and prestenotic dilation. Cross-sectional imaging is required for accurate diagnosis of fibrostenosing Crohn's disease, and it is recommended before making treatment decisions. It should also assess the degree of inflammation in the bowel wall. Multiple options for medical anti-inflammatory, endoscopic and surgical therapies were suggested, including follow-up strategies following therapy. This Consensus Statement supports clinical practice through providing guidance on definitions, diagnosis and therapeutic management of patients with fibrostenosing small bowel Crohn's disease.

Systematic review: Patient-related, microbial, surgical, and histopathological risk factors for endoscopic post-operative recurrence in patients with Crohn's disease.

BACKGROUND: Risk stratification for endoscopic post-operative recurrence (ePOR) in Crohn's disease (CD) is required to identify patients who would benefit most from initiation of prophylactic medication and intensive monitoring of recurrence. AIMS: To assess the current evidence on patient-related, microbial, surgical and histopathological risk factors for ePOR in patients with CD after ileocolic (re-)resection. METHODS: Multiple online databases (Embase, MEDLINE, Web of Science and Cochrane Library) were searched up to March 2024. Studies with reported associations of patient-related, microbial, surgical and/or histopathological factors for ePOR (i.e., Rutgeerts' score ≥i2 or modified Rutgeerts' score ≥i2a) were included. The risk of bias was assessed with the Newcastle-Ottawa Scale for observational cohort studies and case-control studies. RESULTS: In total, 47 studies were included (four RCTs, 29 cohort studies, 12 case-control studies, one cross-sectional study and one individual participant data meta-analysis) including 6006 patients (median sample size 87 patients [interquartile range 46-170]). Risk of bias assessment revealed a poor quality in 41% of the studies. An association was reported in multiple studies of ePOR with active smoking at and post-surgery, male sex and prior bowel resection. A heterogeneous association with ePOR was reported for other risk factors included in the current guidelines (penetrating disease, perianal disease, younger age, extensive small bowel disease and presence of granulomas in the resection specimen or myenteric plexitis in the resection margin), and other patient-related, microbial, surgical and histopathological factors. CONCLUSION: Risk factors for ePOR in international guidelines are not consistently reported as risk factors in current literature except for active smoking and prior bowel resection. To develop evidence-based, personalised strategies, large prospective studies are warranted to identify risk factors for ePOR. Validation studies of promising (bio)markers are also required.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS: Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS: Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS: We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.

Re-Evaluating Cross-Contamination: Additional Trials on Co-Ventilation.

BACKGROUND: Medical equipment can become scarce in disaster scenarios. Prior work has reported that four sheep could be ventilated together on a single ventilator. Others found that this maneuver is possible when needed, but no one has yet investigated whether cross-contamination occurs in co-ventilated individuals. OBJECTIVE: Our goal was to investigate whether an infection could spread between co-ventilated individuals. METHODS: Four 2-L anesthesia bags were connected to a sterilized ventilator circuit that used heat and moisture exchange filters and bacterial and viral filters, as would be expected in this dire scenario. Serratia marcescens was inoculated into "lung" no. 1. After running for 24 h, each lung and three additional points in the circuit were cultured to see whether S. marcescens had spread. These cultures were examined at 24 and 48 h to assess for cross-contamination. This entire procedure was performed three times. RESULTS: S. marcescens was not found in lung no. 2, 3, or 4 or the three additional sites on the expiratory limb at 24 and 48 h in all three trials. CONCLUSIONS: Cross-contamination does not occur within 24 h using the described ventilator circuit configuration.

Interobserver agreement of current and new proposed endoscopic scores for postoperative recurrence in Crohn's disease.

BACKGROUND AND AIMS: The modified Rutgeerts' score (mRS) is widely used for the assessment of endoscopic postoperative recurrence (ePOR) in Crohn's disease (CD) after ileocolic resection to guide therapeutic decisions. To improve the validity and prognostic value of this endoscopic assessment, two new scores have been proposed. This study assessed the interobserver agreement of the current (mRS) and new endoscopic scores for ePOR in CD. METHODS: Sixteen Dutch academic and non-academic IBD specialists assessed endoscopic videos (n=71) of postoperative CD patients (n=66) retrieved from nine Dutch centers. Each video was assessed for the degree of inflammation by four gastroenterologists using the mRS and the new proposed endoscopic score: REMIND score (separate score of anastomosis and neoterminal ileum) and updated Rutgeerts score (assessment of lesions at the anastomotic line, ileal inlet, ileal body and neoterminal ileum). In addition, lesions at the ileal body, ileal inlet, neoterminal ileum, colonic and/or ileal blind loop were separately assessed. Interobserver agreement was assessed using Fleiss' weighted kappa. RESULTS: Fleiss' weighted kappa for the mRS was 0.67 (95% confidence interval [CI] 0.59-0.74). The weighted kappa for the REMIND score was 0.73 (95% CI 0.65-0.80) for lesions in the neoterminal ileum and 0.46 (95% CI 0.35-0.58) for anastomotic lesions. The weighted kappa for the updated Rutgeerts' score was 0.69 (95% CI 0.62-0.77). The weighted kappa for lesions in the ileal body, ileal inlet, neoterminal ileum, colonic and ileal blind loop was 0.61 (95% CI 0.49-0.73), 0.63 (95% CI 0.54-0.72), 0.61 (95% CI 0.49-0.74), 0.83 (95% CI 0.62-1.00) and 0.68 (95% CI 0.46-0.89). CONCLUSION: The interobserver agreement of the mRS is substantial. Similarly, the interobserver agreement is substantial for the updated Rutgeerts' score. According to the REMIND score, the interobserver agreement was substantial for lesions in the neoterminal ileum, whereas only moderate for anastomotic lesions. Since therapeutic decisions in clinical practice are based on these assessments and these scores are used as outcome measure in clinical studies, further improvement of the interobserver agreement is essential.

Biomarkers That Predict Crohn's Disease Outcomes.

Crohn's disease (CD), a chronic inflammatory condition of the digestive tract, poses significant challenges in terms of disease prognosis and treatment selection. Biomarkers have the potential to predict CD outcomes and guide clinical decision-making. This review aims to summarize the current literature on promising biomarkers associated with CD outcomes and their potential clinical implications. The identification of reliable biomarkers for CD outcomes is of paramount importance in tailoring treatment strategies, monitoring disease activity, and predicting the risk of complications. Clinical prognostic factors traditionally used to assess disease severity, and the likelihood of complications have limitations in accuracy and predictive value. Thus, there is a need for more precise biomarkers, particularly in newly diagnosed and treatment-naive patients. Pharmacogenomic markers, such as TPMT and NUDT15 polymorphisms, have been utilized to identify patients at risk of adverse events with thiopurine therapy. Several biomarkers, including HLA haplotypes, oncostatin M expression, and transcriptomic profiles, have shown associations with response to anti-TNF therapy. Confocal laser endomicroscopy and single-cell analyses hold promise in predicting treatment response to specific therapies. The identification of biomarkers associated with post-operative recurrence in CD is crucial, as it could lead to changes in management algorithms. Several promising microbiome signatures and proteomic profiles have been identified. In conclusion, biomarkers have the potential to revolutionize the management of CD by providing valuable prognostic information and guiding treatment decisions. However, further research and validation are necessary to establish their clinical utility and integration into routine practice.

Determining the optimal treatment target in patients with ulcerative colitis: rationale, design, protocol and interim analysis for the randomised controlled VERDICT trial.

INTRODUCTION: Symptoms, endoscopy and histology have been proposed as therapeutic targets in ulcerative colitis (UC). Observational studies suggest that the achievement of histologic remission may be associated with a lower risk of complications, compared with the achievement of endoscopic remission alone. The actiVE ulcerative colitis, a RanDomIsed Controlled Trial (VERDICT) aims to determine the optimal treatment target in patients with UC. METHODS AND ANALYSIS: In this multicentre, prospective randomised study, 660 patients with moderate to severe UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2) are randomly assigned to three treatment targets: corticosteroid-free symptomatic remission (Mayo RBS=0) (group 1); corticosteroid-free endoscopic remission (MES ≤1) and symptomatic remission (group 2); or corticosteroid-free histologic remission (Geboes score <2B.0), endoscopic remission and symptomatic remission (group 3). Treatment is escalated using vedolizumab according to a treatment algorithm that is dependent on the patient's baseline UC therapy until the target is achieved at weeks 16, 32 or 48. The primary outcome, the time from target achievement to a UC-related complication, will be compared between groups 1 and 3 using a Cox proportional hazards model. ETHICS AND DISSEMINATION: The study was approved by ethics committees at the country level or at individual sites as per individual country requirements. A full list of ethics committees is available on request. Study results will be disseminated in peer-reviewed journals and at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT: 2019-002485-12; NCT04259138.

Clinical predictors of early and late endoscopic recurrence following ileocolonic resection in Crohn's disease.

BACKGROUND AND AIM: Multiple factors are suggested to place Crohn's disease patients at risk of recurrence after ileocolic resection with conflicting associations. We aimed to identify clinical predictors of recurrence at first (early) and further (late) postoperative colonoscopy. METHODS: Crohn's disease patients undergoing ileocolic resection were prospectively recruited at six North American centers. Clinical data was collected and endoscopic recurrence was defined as Rutgeerts score ≥i2. A multivariable model was fitted to analyze variables independently associated with recurrence. RESULTS: A total of 365 patients undergoing 674 postoperative colonoscopies were included with a median age of 32 years, 189 (51.8%) were male and 37 (10.1%) non-Whites. Postoperatively, 133 (36.4%) used anti-TNF and 30 (8.2%) were smokers. At first colonoscopy, 109 (29.9%) had recurrence. Male gender (OR = 1.95, 95% CI 1.12 - 3.40), non-White ethnicity (OR = 2.48, 95% CI 1.09 - 5.63), longer interval between surgery and colonoscopy (OR = 1.09, 95% CI 1.002 - 1.18), and postoperative smoking (OR = 2.78, 95% CI 1.16 - 6.67) were associated with recurrence, while prophylactic anti-TNF reduced the risk (OR = 0.28, 95% CI 0.14 - 0.55). Postoperative anti-TNF prophylaxis had a protective effect on anti-TNF experienced patients but not on anti-TNF naïve patients. Among patients without recurrence at first colonoscopy, Rutgeerts score i1 was associated with subsequent recurrence (OR = 4.43, 95% CI 1.73 - 11.35). CONCLUSIONS: We identified independent clinical predictors of early and late Crohn's disease postoperative endoscopic recurrence. Clinical factors traditionally used for risk stratification failed to predict recurrence and need to be revised.

Analysis of Clinical Trial Screen Failures in Inflammatory Bowel Diseases (IBD): Real World Results from the International Organization for the study of IBD.

BACKGROUND: Recruitment for randomized controlled trials (RCTs) in IBD have substantially dropped over time. This study aimed to assess reasons why IBD patients are not included in sponsored multicenter phase IIb-III RCTs. METHODS: All IOIBD members (n=58) were invited to participate. We divided barriers to participation as follow: 1) reasons patients with active IBD were not deemed appropriate for a RCT; 2) reasons qualified patients did not wish to participate; 3) reasons for screen failure (SF) in patients agreeing to participate. We assess those in a 4-week prospective study including, consecutively, all patients with symptomatic disease for whom a treatment change was required. In addition, we performed a 6-month retrospective study to further evaluate reasons for SF. RESULTS: A total of 106 patients (60 male (56.6%), 63 Crohn's disease [CD] (59.4%)), from 10 centers across the world, were included in the prospective study. A RCT has not been proposed to 65 of them (mainly due to eligibility criteria). Of the 41 patients to whom a RCT was offered, 8 refused (mainly due to reluctance to receive placebo) and 28 agreed to participate. Among these 28 patients, 5 failed their screening and 23 were finally included in a RCT. A total of 107 patients (61 male (57%), 67 CD (62.6%)), from 13 centers worldwide, were included in our retrospective study of SFs. The main reason was insufficient disease activity. CONCLUSION: This first multicenter study analyzing reasons for non-enrollment in IBD RCTs shown that we lose patients at each step. Eligibility criteria, the risk of placebo assignment and insufficient disease activity were part of the main barriers.

The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population.

Introduction: The imbalance between Th17 and regulatory T cells in inflammatory bowel diseases (IBD) promotes intestinal epithelial cell damage. In this scenario, T helper cell lineage commitment is accompanied by dynamic changes to the chromatin that facilitate or repress gene expression. Methods: Here, we characterized the chromatin landscape and heterogeneity of intestinal and peripheral CD4 T cellsfrom IBD patients using in house ATAC-Seq and single cell RNA-Seq libraries. Results: We show that chromatin accessibility profiles of CD4 T cells from inflamed intestinal biopsies relate to genes associated with a network of inflammatory processes. After integrating the chromatin profiles of tissue-derived CD4 T cells and in-vitro polarized CD4 T cell subpopulations, we found that the chromatin accessibility changes of CD4 T cells were associated with a higher predominance of pathogenic Th17 cells (pTh17 cells) in inflamed biopsies. In addition, IBD risk loci in CD4 T cells were colocalized with accessible chromatin changes near pTh17-related genes, as shown in intronic STAT3 and IL23R regions enriched in areas of active intestinal inflammation. Moreover, single cell RNA-Seq analysis revealed a population of pTh17 cells that co-expresses Th1 and cytotoxic transcriptional programs associated with IBD severity. Discussion: Altogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients.

Third and Fourth Vaccine Doses Broaden and Prolong Immunity to SARS-CoV-2 in Adult Patients with Immune-Mediated Inflammatory Diseases.

Previous studies have reported impaired humoral responses after SARS-CoV-2 mRNA vaccination in patients with immune-mediated inflammatory diseases (IMIDs), particularly those treated with anti-TNF biologics. We previously reported that IMID patients diagnosed with inflammatory bowel disease, psoriasis, psoriatic arthritis, ankylosing spondylitis, or rheumatoid arthritis exhibited greater waning of Ab and T cell responses than healthy control subjects after SARS-CoV-2 vaccine dose 2. Fewer data are available on the effects of third and fourth doses. This observational cohort study collected plasma and PBMCs from healthy control subjects and untreated or treated patients with IMIDs prevaccination and after one to four doses of SARS-CoV-2 mRNA vaccine (BNT162b2 or mRNA-1273). SARS-CoV-2-specific Ab levels, neutralization, and T cell cytokine release were measured against wild-type and Omicron BA.1 and BA.5 variants of concern. Third vaccine doses substantially restored and prolonged Ab and T cell responses in patients with IMIDs and broadened responses against variants of concern. Fourth-dose effects were subtle but also prolonged Ab responses. However, patients with IMIDs treated with anti-TNF, especially patients with inflammatory bowel disease, exhibited lower Ab responses even after the fourth dose. Although T cell IFN-γ responses were maximal after one dose, IL-2 and IL-4 production increased with successive doses, and early production of these cytokines was predictive of neutralization responses at 3-4 mo postvaccination. Our study demonstrates that third and fourth doses of the SARS-CoV-2 mRNA vaccines sustain and broaden immune responses to SARS-CoV-2, supporting the recommendation for three- and four-dose vaccination regimens in patients with IMIDs.

Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

Geography Influences Susceptibility to SARS-CoV-2 Serological Response in Patients With Inflammatory Bowel Disease: Multinational Analysis From the ICARUS-IBD Consortium.

BACKGROUND: Beyond systematic reviews and meta-analyses, there have been no direct studies of serological response to COVID-19 in patients with inflammatory bowel disease (IBD) across continents. In particular, there has been limited data from Asia, with no data reported from India. The ICARUS-IBD (International study of COVID-19 Antibody Response Under Sustained immunosuppression in IBD) consortium assessed serological response to SARS-CoV-2 in patients with IBD in North America, Europe, and Asia. METHODS: The ICARUS-IBD study is a multicenter observational cohort study spanning sites in 7 countries. We report seroprevalence data from 2303 patients with IBD before COVID-19 vaccination between May 2020 and November 2021. SARS-CoV-2 anti-spike and anti-nucleocapsid antibodies were analyzed. RESULTS: The highest and lowest SARS-CoV-2 anti-spike seropositivity rates were found in Asia (81.2% in Chandigarh and 57.9% in Delhi, India; and 0% in Hong Kong). By multivariable analysis, country (India: odds ratio [OR], 18.01; 95% confidence interval [CI], 12.03-26.95; P < .0001; United Kingdom: OR, 2.43; 95% CI, 1.58-3.72; P < .0001; United States: OR, 2.21; 95% CI, 1.27-3.85; P = .005), male sex (OR, 1.46; 95% CI, 1.07-1.99; P = .016), and diabetes (OR, 2.37; 95% CI, 1.04-5.46; P = .039) conferred higher seropositivity rates. Biological therapies associated with lower seroprevalence (OR, 0.22; 95% CI, 0.15-0.33; P < .0001). Multiple linear regression showed associations between anti-spike and anti-nucleocapsid titers with medications (P < .0001) but not with country (P = .3841). CONCLUSIONS: While the effects of medications on anti-SARS-CoV-2 antibody titers in patients with IBD were consistent across sites, geographical location conferred the highest risk of susceptibility to serologically detectable SARS-CoV-2 infection. Over half of IBD patients in India were seropositive prior to vaccination. These insights can help to inform shielding advice, therapeutic choices, and vaccine strategies in IBD patients for COVID-19 and future viral challenges.

In this multinational study of SARS-CoV-2 seroprevalence prior to vaccination, including the first data from India, where over half of patients seroconverted, geographical location conferred the highest risk of susceptibility to serologically detectable infection.

Identifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients.

Inflammatory bowel disease (IBD) is a group of chronic digestive tract inflammatory conditions whose genetic etiology is still poorly understood. The incidence of IBD is particularly high among Ashkenazi Jews. Here, we identify 8 novel and plausible IBD-causing genes from the exomes of 4453 genetically identified Ashkenazi Jewish IBD cases (1734) and controls (2719). Various biological pathway analyses are performed, along with bulk and single-cell RNA sequencing, to demonstrate the likely physiological relatedness of the novel genes to IBD. Importantly, we demonstrate that the rare and high impact genetic architecture of Ashkenazi Jewish adult IBD displays significant overlap with very early onset-IBD genetics. Moreover, by performing biobank phenome-wide analyses, we find that IBD genes have pleiotropic effects that involve other immune responses. Finally, we show that polygenic risk score analyses based on genome-wide high impact variants have high power to predict IBD susceptibility.

Genetic coding variant in complement factor B (CFB) is associated with increased risk for perianal Crohn's disease and leads to impaired CFB cleavage and phagocytosis.

OBJECTIVE: Perianal Crohn's disease (pCD) occurs in up to 40% of patients with CD and is associated with poor quality of life, limited treatment responses and poorly understood aetiology. We performed a genetic association study comparing CD subjects with and without perianal disease and subsequently performed functional follow-up studies for a pCD associated SNP in Complement Factor B (CFB). DESIGN: Immunochip-based meta-analysis on 4056 pCD and 11 088 patients with CD from three independent cohorts was performed. Serological and clinical variables were analysed by regression analyses. Risk allele of rs4151651 was introduced into human CFB plasmid by site-directed mutagenesis. Binding of recombinant G252 or S252 CFB to C3b and its cleavage was determined in cell-free assays. Macrophage phagocytosis in presence of recombinant CFB or serum from CFB risk, or protective CD or healthy subjects was assessed by flow cytometry. RESULTS: Perianal complications were associated with colonic involvement, OmpC and ASCA serology, and serology quartile sum score. We identified a genetic association for pCD (rs4151651), a non-synonymous SNP (G252S) in CFB, in all three cohorts. Recombinant S252 CFB had reduced binding to C3b, its cleavage was impaired, and complement-driven phagocytosis and cytokine secretion were reduced compared with G252 CFB. Serine 252 generates a de novo glycosylation site in CFB. Serum from homozygous risk patients displayed significantly decreased macrophage phagocytosis compared with non-risk serum. CONCLUSION: pCD-associated rs4151651 in CFB is a loss-of-function mutation that impairs its cleavage, activation of alternative complement pathway, and pathogen phagocytosis thus implicating the alternative complement pathway and CFB in pCD aetiology.

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.).

Immune response and barrier dysfunction-related proteomic signatures in preclinical phase of Crohn's disease highlight earliest events of pathogenesis.

OBJECTIVE: The measure of serum proteome in the preclinical state of Crohn's disease (CD) may provide insight into biological pathways involved in CD pathogenesis. We aimed to assess associations of serum proteins with future CD onset and with other biomarkers predicting CD risk in a healthy at-risk cohort. DESIGN: In a nested case-control study within the Crohn's and Colitis Canada Genetics Environment Microbial Project (CCC-GEM) cohort, which prospectively follows healthy first-degree relatives (FDRs), subjects who developed CD (n=71) were matched with four FDRs remaining healthy (n=284). Using samples at recruitment, serum protein profiles using the Olink Proximity Extension Assay platform was assessed for association with future development of CD and with other baseline biomarkers as follows: serum antimicrobial antibodies (AS: positive antibody sum) (Prometheus); faecal calprotectin (FCP); gut barrier function using the fractional excretion of lactulose-to-mannitol ratio (LMR) assay. RESULTS: We identified 25 of 446 serum proteins significantly associated with future development of CD. C-X-C motif chemokine 9 (CXCL9) had the highest OR with future risk of CD (OR=2.07 per SD, 95% CI 1.58 to 2.73, q=7.9e-5), whereas matrix extracellular phosphoglycoprotein had the lowest OR (OR 0.44, 95% CI 0.29 to 0.66, q=0.02). Notably, CXCL9 was the only analyte significantly associated with all other CD-risk biomarkers with consistent direction of effect (FCP: OR=2.21; LMR: OR=1.67; AS: OR=1.59) (q<0.05 for all). CONCLUSION: We identified serum proteomic signatures associated with future CD development, reflecting potential early biological processes of immune and barrier dysfunction.

Serum Lipidomic Screen Identifies Key Metabolites, Pathways, and Disease Classifiers in Crohn's Disease.

BACKGROUND: There is an unmet medical need for biomarkers that capture host and environmental contributions in inflammatory bowel diseases (IBDs). This study aimed at testing the potential of circulating lipids as disease classifiers given their major roles in inflammation. METHODS: We applied a previously validated comprehensive high-resolution liquid chromatography-mass spectrometry-based untargeted lipidomic workflow covering 25 lipid subclasses to serum samples from 100 Crohn's disease (CD) patients and 100 matched control subjects. Findings were replicated and expanded in another 200 CD patients and 200 control subjects. Key metabolites were tested for associations with disease behavior and location, and classification models were built and validated. Their association with disease activity was tested using an independent cohort of 42 CD patients. RESULTS: We identified >70 metabolites with strong association (P < 1 × 10-4, q < 5 × 10-4) to CD. Highly performing classification models (area under the curve > 0.84-0.97) could be built with as few as 5 to 9 different metabolites, representing 6 major correlated lipid clusters. These classifiers included a phosphatidylethanolamine ether (O-16:0/20:4), a sphingomyelin (d18:1/21:0) and a cholesterol ester (14:1), a very long-chain dicarboxylic acid [28:1(OH)] and sitosterol sulfate. These classifiers and correlated lipids indicate a dysregulated metabolism in host cells, notably in peroxisomes, as well as dysbiosis, oxidative stress, compromised inflammation resolution, or intestinal membrane integrity. A subset of these were associated with disease behavior or location. CONCLUSIONS: Untargeted lipidomic analyses uncovered perturbations in the circulating human CD lipidome, likely resulting from multiple pathogenic mechanisms. Models using as few as 5 biomarkers had strong disease classifier characteristics, supporting their potential use in diagnosis or prognosis.

This study reports a comprehensive untargeted lipidomic analysis of 600 serum samples from patients with Crohn's disease and matched control subjects, identified and replicated ~70 metabolites associated with Crohn's disease, and developed highly performing classification models (area under the curve > 0.84-0.97) with as few as 5 metabolites.