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Background Serious infections have been observed in patients with inflammatory bowel disease (IBD) on anti-TNF use—but to what extent these infections are due to anti-TNF or the disease activity per se is hard to disentangle. We aimed to describe how the rates of serious infections change over time both before and after starting anti-TNF in IBD. Methods Inflammatory bowel disease patients naïve to anti-TNF treatment were identified at 5 centers participating in the Swedish IBD Quality Register, and their medical records examined in detail. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated. Results Among 980 patients who started their first anti-TNF therapy between 1999 and 2016, the incidence rate of serious infections was 2.19 (95% CI,1.43-3.36) per 100 person years the year before and 2.11 (95% CI, 1.33-3.34) per 100 person years 1 year after treatment start. This corresponded to an incidence rate ratio 1 year after anti-TNF treatment of 0.97 (95% CI, 0.51-1.84). Compared with before anti-TNF therapy, the incidence of serious infection was significantly decreased more than 1 year after treatment (incidence rate ratio 0.56; 95% CI, 0.33-0.95; P = .03). Conclusions In routine clinical practice in Sweden, the incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.

Background Prospectively and systematically collected long-term real-world clinical data on ustekinumab (anti-interleukin-12/23) are still scarce. Aims To assess the long-term effectiveness of ustekinumab in patients with active Crohns disease (CD). Methods This is a prospective multicenter study of adult patients with CD initiating ustekinumab according to recommended doses at 20 Swedish hospitals. The primary outcome was clinical remission (Harvey-Bradshaw Index (HBI) = 3-point-decrease in HBI among patients with initial HBI >= 5 points), treatment retention, and biomarkers (C-reactive protein (CRP), hemoglobin, fecal-calprotectin) at weeks 52 and 104 compared to baseline. We also reported Health-related Quality of Life (HRQoL) measures. Results Of 114 included patients, 107 (94%) had previously failed >= 1 and 58 (51%) >= 2 anti-tumor necrosis factor agents. Forty (35%) had failed anti-integrin agents. Ustekinumab retention rates at weeks 52 and 104 were 70% (n = 80/114) and 61% (n = 69/114), respectively. Clinical response was seen in 36% (n = 25/69) and 29% (n = 20/69) of the patients, and remission was achieved in 32% (n = 31/96) and 29% (n = 28/96) at weeks 52 and 104, respectively. Median HBI and CRP levels decreased significantly at both timepoints as compared to baseline. Significant improvements were also observed in HRQoL. Adverse events were reported in 11% (n = 13/114) of the patients, including five cases of severe adverse events. No malignancies were observed. Conclusions In this nationwide prospective real-world 104-week-follow-up study of adult patients with active CD, ustekinumab was associated with long-term clinical effectiveness and improvement in HRQoL measures when used in routine clinical care. Funding Agencies|Karolinska InstituteKarolinska Institutet; Janssen Cilag AB, Sweden

Supplemental material, sj-docx-1-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-3-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Background Birth cohort studies with linked register-based data on inflammatory bowel disease (IBD) provide opportunities to prospectively study early-life determinants of the disease. However, register-based data often lack information on clinical characteristics and rely on diagnostic algorithms. Within the All Babies in Southeast Sweden (ABIS) cohort, we examined the validity of a register-based definition of IBD, its incidence, and clinical and therapeutic characteristics at diagnosis. Methods We followed 16,223 children from birth (1997–1999) until the end of 2020 for the diagnosis of IBD as defined by a minimum of two diagnostic codes for IBD in the Swedish National Patient Register (NPR). We described the incidence and cumulative incidence of IBD. Through a medical record review of cases diagnosed by the end of 2017, we examined the positive predictive value (PPV) for IBD and described its clinical characteristics and treatment. Results By 2020, at an average age of 22.2 years, 113 participants (0.74%, 95% confidence interval [CI] = 0.61–0.89) had a register-based diagnosis of IBD, corresponding to an incidence of 31.3 per 100,000 person-years of follow-up; the incidence for Crohn’s disease (CD) was 11.1 per 100,000 person-years and 15.8 for ulcerative colitis (UC). Of 77 participants with a register-based definition of IBD by the end of 2017, medical records were identified for 61 participants, of whom 57 had true IBD (PPV = 93%; 95%CI = 0.87–1.00). While oral 5-aminosalicylic acid treatment was equally common in newly diagnosed CD and UC patients, biologics were more often used for newly diagnosed CD. The median faecal calprotectin levels were 1206 mg/kg at diagnosis and 93 mg/kg at the last follow-up (P

Supplemental material, sj-docx-2-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-3-tag-10.1177_17562848231174953 for Long-term outcomes of vedolizumab in inflammatory bowel disease: the Swedish prospective multicentre SVEAH extension study by Isabella Visuri, Carl Eriksson, Sara Karlqvist, Byron Lykiardopoulos, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson in Therapeutic Advances in Gastroenterology

Funder: Kennedy Trust Rheumatology Research Prize Studentship, Funder: DFG Cluster of Excellence ���Precision Medicine in Chronic In-flammation��� (PMI; ID: EXC2167), Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: ���Ideas��� Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): 715772, Funder: NWO-VIDI grant 016.178.056, the Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL, Funder: Li Ka Shing Foundation (Li Ka Shing Foundation Limited); doi: https://doi.org/10.13039/100007421, Irritable bowel syndrome (IBS) results from disordered brain���gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain���gut interactions underlying IBS.

Jonas F Ludvigsson,1– 3 Jiangwei Sun,1,4 Ola Olén,5– 7 Mingyang Song,8– 10 Jonas Halfvarson,11 Bjorn Roelstraete,1 Hamed Khalili,9,10,12 Fang Fang4 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 2Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; 3Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, NY, USA; 4Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 6Sachs’ Children and Youth Hospital, Stockholm South General Hospital, Stockholm, Sweden; 7Department of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 8Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; 9Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 10Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; 11Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 12Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USACorrespondence: Jonas F Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 171 77, Sweden, Email jonasludvigsson@yahoo.comBackground: Normal gastrointestinal (GI) mucosa on endoscopy has been linked to a lower risk of colorectal cancer (CRC) but its association to overall death is unknown.Methods: We identified 466,987 individuals with a first GI biopsy 1965– 2016 with normal mucosa (60.6% upper GI and 39.4% lower GI) through all Swedish pathology departments (n = 28). They were individually matched to 2,321,217 reference individuals without a GI biopsy and also compared to 505,076 full siblings. Flexible parametric models were applied to estimate hazard ratio (HRs) and 95% confidence interval (95% CI) for death.Results: During a median follow-up of ∼ 11 years, 85,859 (18.39%) of individuals with normal mucosa and 377,653 (16.27%) of reference individuals died. This corresponded to incidence rates of 147.56/10,000 vs 127.90/10,000 person-years respectively (rate difference: 19.66/10,000 person-years), with the multivariable-adjusted HR of 1.21 (95% CI: 1.20– 1.22). Excess mortality was seen for both upper and lower biopsy with normal mucosa. Particularly higher HRs for death were seen in males, individuals biopsied when aged < 40 years, those without a prior record of GI disease, and those with high education. Mortality risk was most increased in the first five years after biopsy (HR = 1.34; 95% CI: 1.32– 1.36) but decreased thereafter. Having a GI biopsy with normal mucosa was associated with excess mortality from cardiovascular (CVD)disease (HR = 1.02; 95% CI: 1.01– 1.03), cancer (HR = 1.58; 95% CI: 1.56– 1.61), GI disease (HR = 1.65; 95% CI: 1.58– 1.71), and other causes (HR = 1.10; 95% CI: 1.08– 1.11). Sibling comparisons yielded similar results.Conclusion: Compared with individuals without a GI biopsy, those with a normal GI biopsy due to clinical symptoms had a higher mortality particularly in the first five years after biopsy, and especially from GI disease and cancer.Keywords: normal mucosa, screening, mortality, cohort

Background Inflammatory bowel disease (IBD) is associated with disturbed mucosal innate lymphoid cell (ILC) composition, which is correlated to the degree of intestinal inflammation. However, it remains unclear whether circulating ILCs are dysregulated in patients with IBD. Methods Blood samples from 53 patients with Crohn's disease (CD), 43 patients with ulcerative colitis (UC), and 45 healthy control subjects (HC) were analyzed by flow cytometry for markers of ILC subsets (ILC1, ILC2, and ILC precursors [ILCp]) and selected IBD-relevant proteins, as predicted by previous genome-wide association studies. A dimensionality reduction approach to analyzing the data was used to characterize circulating ILCs. Results The frequency of ILCp expressing the ILC3 activation markers NKp44 and CD56 was increased in CD versus HC and UC (NKp44) or in CD versus HC (CD56), whereas the CD45RA+ ILCp were reduced in CD versus UC. Furthermore, the activation marker HLA-DR was increased on ILC1 and ILC2 in CD versus HC. Interestingly, the IBD-related protein SLAMF1 was upregulated on ILC2 from both CD and UC samples as compared with HC samples. In active CD, SLAMF1+ ILC2 frequency was negatively correlated with disease severity (Harvey-Bradshaw index). The characterization of SLAMF1+ ILC2 revealed a higher expression of the ILC2 markers CRTH2, CD161, and GATA3 as compared with SLAMF1- ILC2. Conclusions In line with the systemic nature of CD inflammation, our findings point toward the activation of ILCs in the blood of patients with CD. Furthermore, in active CD, circulating SLAMF1+ ILC2 are increased in patients with less active disease, introducing SLAMF1+ ILC2 as interesting therapeutic targets deserving further exploration.

Summary Background Comparisons of second‐line anti‐tumour necrosis factor (TNF) agents and vedolizumab are sparse. Aim To evaluate the effectiveness of anti‐TNF agents compared to vedolizumab as second‐line biologics in inflammatory bowel disease (IBD). Methods A propensity score‐matched cohort was created using Swedish nationwide registers. Patients with Crohn's disease or ulcerative colitis, exposed to first‐line anti‐TNF treatment, who initiated a second anti‐TNF agent or vedolizumab in 2014‐2016 (N = 1363) were included. The primary outcome was drug survival at 12 months. Secondarily, we assessed survival without IBD‐related hospitalisation, IBD‐related surgery, antibiotics, or hospitalisation because of infection, and also corticosteroid exposure. Results After 1:1 propensity score matching, 400 patients (Crohn's disease, N = 198; ulcerative colitis, N = 202) remained. For Crohn's disease, drug survival was 73% in the vedolizumab group vs 74% in the anti‐TNF group (difference: 1 percentage point; 95% confidence interval [CI]:‐11‐13; P = 0.87). Survival without IBD‐related hospitalisation (82% vs 88%), surgery (82% vs 89%), antibiotics (65% vs 71%), hospitalisation due to infection (95% vs 88%) and corticosteroids (58% vs 48%) were not statistically significantly different between groups. For ulcerative colitis, drug survival was 69% in the vedolizumab group vs 62% in the anti‐TNF group (difference: −7 percentage points; 95% CI: −20 to 6; P = 0.30). Vedolizumab‐treated patients had lower survival without IBD‐related hospitalisation (82% vs 93%, P = 0.02). Survival without colectomy (93% vs 97%), antibiotics (81% vs 70%), hospitalisation due to infection (92% vs 92%) and corticosteroids (58% vs 48%) were not statistically significantly different. Conclusions Based on Swedish clinical practice, the effectiveness and safety of second‐line anti‐TNF and vedolizumab at 12 months appeared largely similar.

Additional file 1: eTable 1. ICD-7 codes for cancer outcomes. eTable 2. Definitions of endoscopy, colectomy, and proctocolectomy. eTable 3. Incidence rate of cancer in individuals with a GI biopsy result of normal mucosa and their matched population references. eTable 4. Average risk of any cancer during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 5. Risk of specific cancers during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 6. Cumulative incidence and its difference of specific cancers during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 7. Sensitivity analyses for the risk of any cancer during follow-up in individuals with a GI biopsy result of normal mucosa and their matched references. eTable 8. Characteristics of individuals with a gastrointestinal (GI) biopsy result of normal mucosa and their siblings, a nationwide matched cohort study in Sweden, 1965-2016. eTable 9. Association between a GI biopsy result of normal mucosa and risk of any cancer, starting follow-up from 6 months vs. 1 year after biopsy. eFigure 1. Standardized cumulative incidence and 95% confidence intervals of any cancer in individuals with a GI biopsy result of normal mucosa (solid line and orange) and their matched references (dotted line and blue), stratified by age at cohort entry or calendar period of cohort entry. Follow-up was started 6 months after the biopsy. eFigure 2. Hazard ratio (HR) and 95% confidence intervals (CIs) of any cancer as a function of time since biopsy, comparing individuals with a GI biopsy result of normal mucosa with their matched references, stratified by calendar period of cohort entry. eFigure 3. Standardized cumulative incidence and 95% confidence intervals of specific cancers in individuals with a GI biopsy result of normal mucosa (solid line and orange) and their matched references (dotted line and blue). Follow-up was started 6 months after the biopsy. eFigure 4. Average hazard ratio (HR) and 95% confidence intervals (CIs) of specific cancers, comparing individuals with a GI biopsy result of normal mucosa with their matched references, stratified by biopsy location: upper (blue) or lower (orange) GI. Follow-up was started 6 months after the biopsy. eFigure 5. (A). Hazard ratio (HR) and 95% confidence intervals (CIs) of any cancer, comparing individuals with a GI biopsy result of normal mucosa with their siblings; (B). Standardized cumulative incidence and 95% confidence intervals of any cancer in individuals with normal mucosa (solid line and orange) and their siblings (dotted line and blue). Both were estimated from the flexible parametric model and follow-up was started 6 months after the biopsy.

Background and Aims Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohns disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. Methods Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naive [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. Results Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naive IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. Conclusions Immune dysregulation seen in peripheral blood transcriptomes of treatment-naive IBD patients is mainly driven by neutrophil activation. Funding Agencies|European UnionEuropean Commission [733100]; German Research Foundation (DFG) Excellence Cluster Precision Medicine in Chronic Inflammation [PMI]German Research Foundation (DFG) [EXC 2167]; Swedish Foundation for Strategic Research [BIO IBD] [RB13-0160]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-02021]

Supplemental material, sj-docx-2-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-2-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

To investigate absolute and relative risk of serious infections in adult/elderly inflammatory bowel disease (IBD) diagnosed 2002–2017. Nationwide, register-based cohort study of Swedish patients with IBD compared with general population matched reference individuals with regard to time to first serious infection, equal to hospital admission. Multivariable Cox regression estimated hazard ratios (HRs) for any serious infection. Secondary outcomes included site-specific infections, opportunistic infections and sepsis. We identified 47 798 individuals with IBD. During a follow-up of 329 000 person-years, they had 8752 first serious infections (26.6 per 1000 person-years). This compared with an incidence rate of 10.7 per 1000 person-years in matched reference individuals, corresponding to a 2.53-fold increased hazard of serious infections (95%CI = 2.47–2.59). The HR for serious infection in elderly-onset IBD was 2.01 (95%CI = 1.95–2.08). The relative hazard of serious infection was somewhat higher in Crohn’s disease (2.94; 95%CI = 2.81–3.06) than in ulcerative colitis (2.24; 95%CI = 2.17–2.31). The HR for serious infections was high in the first year of follow-up (5.17; 95%CI = 4.93–5.42). Individuals with IBD were at a particularly high relative hazard of gastrointestinal and opportunistic infections. The HR for sepsis was 2.47 (95%CI = 2.32–2.63). The relative rates for serious infections in IBD increased in recent years. Patients with adult-onset IBD are at increased risk of serious infections, particularly gastrointestinal and opportunistic infections. Relative rates were highest just after IBD diagnosis, and seem to have increased in recent years.

Some studies have suggested a reduced life expectancy in patients with Crohn���s disease (CD) compared with the general population. The evidence, however, is inconsistent. Prompted by such studies, we studied survival of CD patients in ��rebro county, Sweden. From the medical records, we identified all patients diagnosed with CD during 1963���2010 with follow-up to the end of 2011. We estimated: overall survival, net and crude probabilities of dying from CD, relative survival ratio (RSR), and excess mortality rate ratios (EMRR) at 10-year follow-up. The study included 492 patients (226 males, 266 females). Median age at diagnosis was 32 years (3���87). Net and crude probabilities of dying from CD increased with increasing age and were higher for women. Net survival of patients aged ���60 at diagnosis was worse for patients diagnosed during 1963���1985 (54%) than for patients diagnosed during 1986���1999 (88%) or 2000���2010 (93%). Overall, CD patients��� survival was comparable to that in the general population [RSR = 0.98; 95% CI: (0.95���1.00)]. However, significantly lower than expected survival was suggested for female patients aged ���60 diagnosed during the 1963���1985 [RSR = 0.47 (0.07���0.95)]. The adjusted model suggested that, compared with diagnostic period 1963���1985, disease-related excess mortality declined during 2000���2010 [EMRR = 0.36 (0.07���1.96)]; and age ���60 at diagnosis [EMRR = 7.99 (1.64���39.00), reference: age 40���59], female sex [EMRR = 4.16 (0.62���27.85)], colonic localization [EMRR = 4.20 (0.81���21.88), reference: ileal localization], and stricturing/penetrating disease [EMRR = 2.56 (0.52���12.58), reference: inflammatory disease behaviour] were associated with poorer survival. CD-related excess mortality may vary with diagnostic period, age, sex and disease phenotype.Key summaryThere is inconsistent evidence on life expectancy of patients with Crohn���s diseaseCrohn���s disease-specific survival improved over time.Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn���s disease-related mortality. There is inconsistent evidence on life expectancy of patients with Crohn���s disease Crohn���s disease-specific survival improved over time. Earlier diagnosis period, older age at diagnosis, female sex, colonic disease and complicated disease behaviour seems to be associated with excess Crohn���s disease-related mortality.

Supplemental material, sj-docx-1-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Supplemental material, sj-docx-1-tag-10.1177_17562848211023386 for Real-world effectiveness of vedolizumab in inflammatory bowel disease: week 52 results from the Swedish prospective multicentre SVEAH study by Carl Eriksson, Sara Rundquist, Vyron Lykiardopoulos, Ruzan Udumyan, Per Karlén, Olof Grip, Charlotte Söderman, Sven Almer, Erik Hertervig, Jan Marsal, Jenny Gunnarsson, Carolina Malmgren, Jenny Delin, Hans Strid, Mats Sjöberg, David Öberg, Daniel Bergemalm, Henrik Hjortswang and Jonas Halfvarson; The SWIBREG SVEAH Study Group in Therapeutic Advances in Gastroenterology

Åsa H Everhov, 1, 2 Michael C Sachs, 2 Jonas F Ludvigsson, 3, 4 Hamed Khalili, 2, 5 Johan Askling, 2 Martin Neovius, 2 Pär Myrelid, 6, 7 Jonas Halfvarson, 8 Caroline Nordenvall, 9, 10 Jonas Söderling, 2 Ola Olén 1, 2, 11on behalf of the SWIBREG study group 1Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden; 2Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 4Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden; 5Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 6Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; 7Department of Surgery, County Council of Östergötland Linköping, Linköping, Sweden; 8Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 9Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 10Center for Digestive Disease, Division of Coloproctology, Karolinska University Hospital, Stockholm, Sweden; 11Department of Pediatric Gastroenterology and Nutrition, Sachs’ Children and Youth Hospital, Stockholm, SwedenCorrespondence: Åsa H EverhovDepartment of Surgery, Stockholm South General Hospital, Stockholm SE 118 61, SwedenTel +46 8 616 2349Email asa.hallqvist-everhov@ki.sePurpose: Patients with Crohn’s disease have increased work loss. We aimed to describe changes in work ability in relation to pharmacological and surgical treatments.Patients and Methods: We linked data from the Swedish National Patient Register, The Swedish Quality Register for Inflammatory Bowel Disease SWIBREG, The Prescribed Drug Register, The Longitudinal Integrated Database for Health Insurance and Labour Market Studies, and the Social Insurance Database. We identified working-age (19– 59 years) patients with incident Crohn’s disease 2006– 2013 and population comparator subjects matched by sex, birth year, region, and education level. We assessed the number of lost workdays due to sick leave and disability pension before and after treatments.Results: Of 3956 patients (median age 34 years, 51% women), 39% were treated with aminosalicylates, 52% with immunomodulators, 22% with TNF inhibitors, and 18% with intestinal surgery during a median follow-up of 5.3 years. Most patients had no work loss during the study period (median=0 days). For all treatments, the mean number of lost workdays increased during the months before treatment initiation, peaked during the first month of treatment and decreased thereafter, and was heavily influenced by sociodemographic factors and amount of work loss before first Crohn’s disease diagnosis. The mean increase in work loss days compared to pre-therapeutic level was ∼ 3 days during the first month of treatment for all pharmacological therapies and 11 days for intestinal surgery. Three months after treatment initiation, 88% of patients treated surgically and 90– 92% of patients treated pharmacologically had the same amount of work loss as before treatment start. Median time to return to work was 2 months for all treatments.Conclusion: In this regular clinical setting, patients treated surgically had more lost workdays than patients treated pharmacologically, but return to work was similar between all treatments.Keywords: inflammatory bowel disease, sick leave, disability pension, TNF inhibitor, aminosalicylate, immunomodulator

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620945949 for The use of 5-aminosalicylate for patients with Crohn’s disease in a prospective European inception cohort with 5 years follow-up – an Epi-IBD study by Johan Burisch, Daniel Bergemalm, Jonas Halfvarson, Viktor Domislovic, Zeljko Krznaric, Adrian Goldis, Jens F Dahlerup, Pia Oksanen, Pekka Collin, Luisa de Castro, Vicent Hernandez, Svetlana Turcan, Elena Belousova, Renata D'Incà, Alessandro Sartini, Daniela Valpiani, Martina Giannotta, Ravi Misra, Naila Arebi, Dana Duricova, Martin Bortlik, Kelly Gatt, Pierre Ellul, Natalia Pedersen, Jens Kjeldsen, Karina W Andersen, Vibeke Andersen, Konstantinos H Katsanos, Dimitrios K Christodoulou, Shaji Sebastian, Luisa Barros, Fernando Magro, Jóngerð MM Midjord, Kári R Nielsen, Riina Salupere, Hendrika AL Kievit, Gediminas Kiudelis, Juozas Kupčinskas, Mathurin Fumery, Corinne Gower-Rousseau, Ioannis P Kaimakliotis, Doron Schwartz, Selwyn Odes, Laszlo Lakatos, Peter L Lakatos, Ebbe Langholz, Pia Munkholm and for the Epi-IBD group in United European Gastroenterology Journal

Supplemental material, sj-pdf-1-ueg-10.1177_2050640620945949 for The use of 5-aminosalicylate for patients with Crohn’s disease in a prospective European inception cohort with 5 years follow-up – an Epi-IBD study by Johan Burisch, Daniel Bergemalm, Jonas Halfvarson, Viktor Domislovic, Zeljko Krznaric, Adrian Goldis, Jens F Dahlerup, Pia Oksanen, Pekka Collin, Luisa de Castro, Vicent Hernandez, Svetlana Turcan, Elena Belousova, Renata D'Incà, Alessandro Sartini, Daniela Valpiani, Martina Giannotta, Ravi Misra, Naila Arebi, Dana Duricova, Martin Bortlik, Kelly Gatt, Pierre Ellul, Natalia Pedersen, Jens Kjeldsen, Karina W Andersen, Vibeke Andersen, Konstantinos H Katsanos, Dimitrios K Christodoulou, Shaji Sebastian, Luisa Barros, Fernando Magro, Jóngerð MM Midjord, Kári R Nielsen, Riina Salupere, Hendrika AL Kievit, Gediminas Kiudelis, Juozas Kupčinskas, Mathurin Fumery, Corinne Gower-Rousseau, Ioannis P Kaimakliotis, Doron Schwartz, Selwyn Odes, Laszlo Lakatos, Peter L Lakatos, Ebbe Langholz, Pia Munkholm and for the Epi-IBD group in United European Gastroenterology Journal

Background We aimed to describe the long-term impact of achieving endoscopic and deep remission among participants in the effect of tight control management on CD (CALM) trial. Methods We analysed medical records from patients with follow-up data since end of CALM. Patients were stratified by outcomes in CALM at 1 year: clinical remission (Crohn’s disease activity index, CDAI Results One hundred twenty-two patients with median age 29 years (IQR 22.5–37) and median disease duration 0.2 years (IQR 0.1–0.8) were included. Median follow-up time from end of CALM was 3.02 years (range 0.05–6.26 years). Fifty per cent were randomised to the tight control arm. There were no significant differences in baseline characteristics in patients with follow-up data and those lost to follow-up with the exception of a slightly higher CDEIS score in patients lost to follow-up (14.6 vs. 12.9, p = 0.04). Thirty-four patients (27.9%) had a major adverse outcome during follow-up. Patients in clinical remission at 1 year did not have significantly lower rates of the composite endpoint (log-rank p = 0.15). Patients in endoscopic and deep remission at the end of CALM were significantly less likely to have a major adverse event over time (Figures 1 and 2). After adjusting for age, disease duration, prior surgery, prior stricture, and randomisation arm, endoscopic remission (aHR 0.44, 95% CI 0.20–0.96, p = 0.038) and deep remission (aHR 0.25, 95% CI 0.09–0.72, p = 0.01) were significantly associated with lower risk of major adverse events. Conclusions Early CD patients who achieve endoscopic or deep remission after 1 year of intensive treatment are less likely to have disease progression over a median of 3 years.

ObjectiveThe Epi-IBD cohort is a prospective population-based inception cohort of unselected patients with inflammatory bowel disease from 29 European centres covering a background population of almost 10 million people. The aim of this study was to assess the 5-year outcome and disease course of patients with Crohn’s disease (CD).DesignPatients were followed up prospectively from the time of diagnosis, including collection of their clinical data, demographics, disease activity, medical therapy, surgery, cancers and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.ResultsIn total, 488 patients were included in the study. During follow-up, 107 (22%) patients received surgery, while 176 (36%) patients were hospitalised because of CD. A total of 49 (14%) patients diagnosed with non-stricturing, non-penetrating disease progressed to either stricturing and/or penetrating disease. These rates did not differ between patients from Western and Eastern Europe. However, significant geographic differences were noted regarding treatment: more patients in Western Europe received biological therapy (33%) and immunomodulators (66%) than did those in Eastern Europe (14% and 54%, respectively, PConclusionDespite patients being treated early and frequently with immunomodulators and biological therapy in Western Europe, 5-year outcomes including surgery and phenotype progression in this cohort were comparable across Western and Eastern Europe. Differences in treatment strategies between Western and Eastern European centres did not affect the disease course. Treatment with immunomodulators reduced the risk of surgery and hospitalisation.

Additional file 1: Table S1. IBD-related surgical procedure codes included in the review process with frequency of validated codes; 2) Table S2. Classification and definitions of coding errors in the NPR with frequency Table S1 includes all surgical procedure codes included in the review process with frequency of validated codes. Table S2 shows the classification and definitions of coding errors used in the validation process together with frequency of identified errors.

Background: Non-invasive markers for predicting relapse would be a useful tool for the management of patients with inflammatory bowel disease. Eosinophil granulocytes and their granule proteins eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) have previously been shown to reflect disease activity in Crohn’s disease and ulcerative colitis. Aim: To examine the capacity of faecal ECP and EDN to predict relapse in ulcerative colitis and Crohn's disease, and to compare these proteins with faecal calprotectin. Methods: Patients with Crohn's disease (n = 49) and ulcerative colitis (n = 55) were followed prospectively until relapse or end of the two-year study period. Faecal samples were obtained every third month. The predictive value of ECP and EDN was assessed in Cox regression models. Results: In ulcerative colitis, a doubled EDN or ECP concentration was associated with a 31% and 27% increased risk of relapse, respectively. EDN levels were increased both at relapse and three months prior. By contrast, in Crohn's disease, the concentration of EDN was higher among patients in remission than in those who relapsed. Correlations between faecal calprotectin, ECP and EDN were observed in both diseases. Conclusions: We demonstrate that the risk of relapse in ulcerative colitis can be predicted by consecutively measuring faecal EDN every third month, and suggest EDN as a complementary faecal marker to calprotectin to predict future relapse in ulcerative colitis. Our finding of higher EDN in Crohn’s disease-patients staying in remission than in those who relapsed indicates different functions of the protein in ulcerative colitis and Crohn’s disease.

Background and Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, >= 50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls.Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1 x 10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4 x 10(-9), odds ratio 3.1).Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

Background: The precise diagnosis of inflammatory bowel disease (IBD) cannot always be established. Thus, a proportion of patients will be diagnosed as IBD Unclassified (IBDU). A significant proportion of these patients will remain unclassified throughout their disease course. Only very few population-based cohorts have investigated the disease course of IBDU. Methods: The Epi-IBD cohort is a prospective population-based cohort of 1289 unselected, uniformly diagnosed patients with IBD diagnosed in 2010 in centres from Western and Eastern European countries. Clinical data were captured prospectively throughout the follow-up period. The aim of the study was to investigate the disease course and prognosis of patients diagnosed with IBDU from diagnosis and during the first 5 years of follow-up. Results: A total of 112 (9%) patients were initially diagnosed with IBD). Patient characteristics are shown in Table 1. After 5 years of follow-up, 28 (25%) patients changed diagnosis to either ulcerative colitis (UC) (n = 20, 71%) or Crohn’s disease (CD) (n = 8, 29%) while 84 (7% of the total cohort) remained as IBDU. The median time to a definite IBD diagnosis was 7 months (range: 1–63) with no difference between those changing to UC or CD. A total of 17 (15%) patients were hospitalised for their IBD during follow-up after a median of 10 months (range: 0–63). Of those, 9 (45%) patients changed diagnosis to UC during follow-up, while no patient changing diagnosis to CD was hospitalised. 8 (7%) patients had surgery (7 colectomies, 1 resection) after a median of 19 months (range: 3–63). Most surgeries (n = 6, 75%) were performed in patients who changed diagnosis to UC, and 3 of those led to a definite diagnosis of UC where the other 3 were performed after the change of diagnosis. No patient changing diagnosis to CD had surgery. The cumulative exposure to medical treatments in IBDU patients including t[...].

Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

Objective To determine if low psychosocial stress resilience in adolescence (increasing chronic stress arousal throughout life) is associated with an increased inflammatory bowel disease (IBD) risk in adulthood. Subclinical Crohn's disease (CD) and ulcerative colitis (UC) can exist over many years and we hypothesise that psychosocial stress may result in conversion to symptomatic disease through its proinflammatory or barrier function effects. Design National register-based cohort study of men followed from late adolescence to middle age. Setting A general population cohort of men in Sweden. Participants Swedish population-based registers provided information on all men born between 1952 and 1956 who underwent mandatory Swedish military conscription assessment (n=239 591). Men with any gastrointestinal diagnoses (except appendicitis) prior to follow-up were excluded. Primary outcome measures An inpatient or outpatient diagnosis of CD or UC recorded in the Swedish Patient Register (1970–2009). Results A total of 938 men received a diagnosis of CD and 1799 UC. Lower stress resilience in adolescence was associated with increased IBD risk, with unadjusted HRs (95% CIs) of 1.54 (1.26 to 1.88) and 1.24 (1.08 to 1.42), for CD and UC, respectively. After adjustment for potential confounding factors, including markers of subclinical disease activity in adolescence, they are 1.39 (1.13 to 1.71) and 1.19 (1.03 to 1.37). Conclusions Lower stress resilience may increase the risk of diagnosis of IBD in adulthood, possibly through an influence on inflammation or barrier function.

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10(-7), odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.

Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods: This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohn's disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29 838 patients (16 902 with Crohn's disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

Background & aimsGenome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.MethodsWe sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.ResultsWe identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 × 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 × 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor κB activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.ConclusionsWe have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.

Genome-wide association studies and follow-up meta-analyses in Crohn's disease (CD) and ulcerative colitis (UC) have recently identified 163 disease-associated loci that meet genome-wide significance for these two inflammatory bowel diseases (IBD). These discoveries have already had a tremendous impact on our understanding of the genetic architecture of these diseases and have directed functional studies that have revealed some of the biological functions that are important to IBD (e.g. autophagy). Nonetheless, these loci can only explain a small proportion of disease variance (~14% in CD and 7.5% in UC), suggesting that not only are additional loci to be found but that the known loci may contain high effect rare risk variants that have gone undetected by GWAS. To test this, we have used a targeted sequencing approach in 200 UC cases and 150 healthy controls (HC), all of French Canadian descent, to study 55 genes in regions associated with UC. We performed follow-up genotyping of 42 rare non-synonymous variants in independent case-control cohorts (totaling 14,435 UC cases and 20,204 HC). Our results confirmed significant association to rare non-synonymous coding variants in both IL23R and CARD9, previously identified from sequencing of CD loci, as well as identified a novel association in RNF186. With the exception of CARD9 (OR = 0.39), the rare non-synonymous variants identified were of moderate effect (OR = 1.49 for RNF186 and OR = 0.79 for IL23R). RNF186 encodes a protein with a RING domain having predicted E3 ubiquitin-protein ligase activity and two transmembrane domains. Importantly, the disease-coding variant is located in the ubiquitin ligase domain. Finally, our results suggest that rare variants in genes identified by genome-wide association in UC are unlikely to contribute significantly to the overall variance for the disease. Rather, these are expected to help focus functional studies of the corresponding disease loci. © 2013 Beaudoin et al., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

OBJECTIVES: Physical fitness may reduce systemic inflammation levels relevant to the risk of symptomatic Crohn's disease (CD) and ulcerative colitis (UC); we assessed if fitness in adolescence is associated with subsequent inflammatory bowel disease (IBD) risk, independent of markers of risk and prodromal disease activity. METHODS: Swedish registers provided information on a cohort of 240,984 men (after exclusions) who underwent military conscription assessments in late adolescence (1969–1976). Follow-up started at least 4 years after the conscription assessment until 31 December 2009 (up to age 57 years). Cox's regression assessed the association of physical fitness with CD (n=986) and UC (n=1,878) in separate models, with adjustment including: socioeconomic conditions in childhood; physical fitness, height, body mass index, and erythrocyte sedimentation rate (ESR) in adolescence; and subsequent diagnoses of IBD. RESULTS: Low fitness was associated with a raised risk of IBD, with unadjusted hazard ratios (and 95% confidence intervals) of 1.62 (1.31–2.00) for CD and 1.36 (1.17–1.59) for UC. The results were attenuated by adjustment, particularly for markers of prodromal disease activity to 1.32 (1.05–1.66) and 1.25 (1.06–1.48), respectively. Raised ESR in adolescence was associated with increased risks for subsequent CD (5.95 (4.47–7.92)) and UC (1.92 (1.46–2.52)). CONCLUSIONS: The inverse association of physical fitness with IBD risk is consistent with a protective role for exercise. However, evidence of disease activity before diagnosis was already present in adolescence, suggesting that some or all of the association between fitness and IBD may be due to prodromal disease activity reducing exercise capacity and therefore fitness.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration. Aim was to construct and validate a web-based inception cohort database available in both English and Russian language. The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments. The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database. A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

International audience; Background The long-term efficacy of infliximab as rescue therapy in steroid-refractory ulcerative colitis is not well described. Aim We report a 3-year follow-up of a previous placebo-controlled trial of infliximab in acute steroid-refractory ulcerative colitis. Method In the original study, 45 patients were randomised to a single infusion of infliximab 5 mg/kg or placebo, and at three months 7/24 patients given infliximab were operated versus 14/21 patients given placebo. Three years or later patients were asked to participate in a clinical follow-up. Results Another 7 patients underwent colectomy during follow-up; 5 in the infliximab group and 2 in the placebo group. After 3 years, a total of 12/24 (50 %) patients given infliximab and 16/21 (76 %) given placebo (p=0.012) had had a colectomy. None of 8 patients in endoscopic remission at 3 months later had a colectomy compared with 7/14 (50%) patients not being in remission (p=0.02). There was no mortality. Conclusion The benefit of rescue therapy with infliximab in steroid-refractory acute ulcerative colitis remained after 3 years. The main advantage of infliximab treatment occurred during the first 3 months, whereas subsequent colectomy rates were similar in the two groups. Mucosal healing at 3 months influenced later colectomy risk.

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn's disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Crohn Disease (CD) is a complex genetic disorder for which more than 140 genes have been identified using genome wide association studies (GWAS). However, the genetic architecture of the trait remains largely unknown. The recent development of machine learning (ML) approaches incited us to apply them to classify healthy and diseased people according to their genomic information. The Immunochip dataset containing 18,227 CD patients and 34,050 healthy controls enrolled and genotyped by the international Inflammatory Bowel Disease genetic consortium (IIBDGC) has been re-analyzed using a set of ML methods: penalized logistic regression (LR), gradient boosted trees (GBT) and artificial neural networks (NN). The main score used to compare the methods was the Area Under the ROC Curve (AUC) statistics. The impact of quality control (QC), imputing and coding methods on LR results showed that QC methods and imputation of missing genotypes may artificially increase the scores. At the opposite, neither the patient/control ratio nor marker preselection or coding strategies significantly affected the results. LR methods, including Lasso, Ridge and ElasticNet provided similar results with a maximum AUC of 0.80. GBT methods like XGBoost, LightGBM and CatBoost, together with dense NN with one or more hidden layers, provided similar AUC values, suggesting limited epistatic effects in the genetic architecture of the trait. ML methods detected near all the genetic variants previously identified by GWAS among the best predictors plus additional predictors with lower effects. The robustness and complementarity of the different methods are also studied. Compared to LR, non-linear models such as GBT or NN may provide robust complementary approaches to identify and classify genetic markers.