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Saeed Shakibfar,1 Kristine H Allin,2 Tine Jess,2 Maria Antonietta Barbieri,1,3 Vera Battini,1,4 Eva Simoncic,1 Julien Kirchgesner,5 Trond Ulven,1,* Maurizio Sessa1,* 1Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark; 2Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark; 3Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy; 4Pharmacovigilance & Clinical Research, International Centre for Pesticides and Health Risk Prevention, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università Degli Studi Di Milano, Milan, Italy; 5Department of Gastroenterology, INSERM, Institut Pierre Louis d’Epidémiologie Et de Santé Publique, AP-HP, Hôpital Saint-Antoine, Sorbonne Université, Paris, France*These authors contributed equally to this workCorrespondence: Saeed Shakibfar, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark, Email saeed.shakibfar@sund.ku.dkAim: Drug repurposing, utilizing electronic healthcare records (EHRs), offers a promising alternative by repurposing existing drugs for new therapeutic indications, especially for patients lacking effective therapies. Intestinal fibrosis, a severe complication of Crohn’s disease (CD), poses significant challenges, increasing morbidity and mortality without available pharmacological treatments. This article focuses on identifying medications associated with an elevated or reduced risk of fibrosis in CD patients through a population-wide real-world data and artificial intelligence (AI) approach.Methods: Patients aged 65 or older with a diagnosis of CD from 1996 to 2019 in the Danish EHRs were followed for up to 24 years. The primary outcome was the need of specific surgical procedures, namely proctocolectomy with ileostomy and ileocecal resection as proxies of intestinal fibrosis. The study explored drugs linked to an increased or reduced risk of the study outcome through machine-learning driven survival analysis.Results: Among the 9179 CD patients, 1029 (11.2%) underwent surgery, primarily men (58.5%), with a mean age of 76 years, 10 drugs were linked to an elevated risk of surgery for proctocolectomy with ileostomy and ileocecal resection. In contrast, 10 drugs were associated with a reduced risk of undergoing surgery for these conditions.Conclusion: This study focuses on repurposing existing drugs to prevent surgery related to intestinal fibrosis in CD patients, using Danish EHRs and advanced statistical methods. The findings offer valuable insights into potential treatments for this condition, addressing a critical unmet medical need. Further research and clinical trials are warranted to validate the effectiveness of these repurposed drugs in preventing surgery related to intestinal fibrosis in CD patients.Keywords: Crohn’s disease, drug repurposing, inflammatory bowel disease, intestinal fibrosis, machine-learning, real-world data

Plastics, encompassing a wide range of polymeric materials, and their downstream products (micro- and nanoplastics, MNPs) are accumulating in the environment at an alarming rate, and they are linked to adverse human health outcomes. Considering that ingestion is a main source of MNPs exposure, the impact of plastics is particularly relevant towards intestinal inflammation and inflammatory bowel disease (IBD). However, the study of MNPs has been limited by obstacles relating to sample collection, preparation, and microplastics analysis based on optical microscopy and chemical analysis, which we detail in this review alongside potential solutions. We summarize available data on human exposure to MNPs and overall health outcomes, with particular focus on data pertaining to intestinal inflammation, microbiome perturbations, and related outcomes. We include ecologic perspectives, and human, in vitro, and animal model studies. We discuss the way forward in MNPs and IBD research, including knowledge gaps and future research., Competing Interests: Declaration of competing interest The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. MA reports consulting for Douglas Pharmaceutical. AV reports no conflict of interest. MP reports no conflict of interest. LSS reports no conflict of interest. RC reports no conflict of interest. MME reports no conflict of interest. KW reports no conflict of interest. JL reports no conflict of interest. TJ reports consulting for Ferring and Pfizer. IP reports no conflict of interest. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix,; and hold stock options in Intestinal Biotech Development. KHA reports no conflict of interest. JV reports no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Epidemiological and translational data increasingly implicate environmental pollutants in inflammatory bowel disease (IBD). Indeed, the global incidence of IBD has been rising, particularly in developing countries, in parallel with the increased use of chemicals and synthetic materials in daily life and escalating pollution levels. Recent nationwide and ecological studies have reported associations between agricultural pesticides and IBD, particularly Crohn's disease. Exposure to other chemical categories has also been linked with an increased risk of IBD. To synthesise available data and identify knowledge gaps, we conducted a systematic review of human studies that reported on the impact of environmental pollutants on IBD risk and outcomes. Furthermore, we summarised in vitro data and animal studies investigating mechanisms underlying these associations. The 32 included human studies corroborate that heavy and transition metals, except zinc, air pollutants, per- and polyfluorinated substances, and pesticides are associated with an increased risk of IBD, with exposure to air pollutants being associated with disease-related adverse outcomes as well. The narrative review of preclinical studies suggests several overlapping mechanisms underlying these associations, including increased intestinal permeability, systemic inflammation and dysbiosis. A consolidated understanding of the impact of environmental exposures on IBD risk and outcomes is key to the identification of potentially modifiable risk factors and to inform strategies towards prediction, prevention and mitigation of IBD., Competing Interests: Competing interests: MF reports receiving lecture/consultant fees from Abbvie, Ferring, Tillots, MSD, Biogen, Amgen, Fresenius, Hospira, Sandoz, Pfizer, Bristol Myers Squibb, Celgene, Gilead, Boehringer, Eli Lilly, Nordic-Pharma, Arena, Galapagos, Janssen and Takeda. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Ferring Pharmaceuticals, Shire and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix and hold stock options in Intestinal Biotech Development.MA reports consulting for Douglas Pharmaceutical., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In utero exposure to maternal inflammation may impact immune system development and subsequent risk of disease. We investigated whether a maternal diagnosis of IBD before childbirth is linked to a higher risk of IBD in offspring compared with a diagnosis after childbirth. Further, we analysed paternal IBD status for comparison., Design: Using Danish health registers, we identified all individuals born in Denmark between 1997 and 2022 and their legal parents, as well as their IBD status. Cox proportional hazards regression analyses adjusted for calendar period and mode of delivery were used to estimate offspring IBD risk by maternal and paternal IBD status before and after childbirth., Results: Of 1 290 358 children, 10 041 (0.8%) had mothers with IBD diagnosis before childbirth and 9985 (0.8%) had mothers with IBD diagnosis after childbirth. Over 18 370 420 person-years, 3537 individuals were diagnosed with IBD. Offspring of mothers with IBD before childbirth had an adjusted HR of IBD of 6.27 (95% CI 5.21, 7.54) compared with those without maternal IBD, while offspring of mothers with IBD after childbirth had an adjusted HR of 3.88 (95% CI 3.27, 4.60). Corresponding adjusted HRs were 5.26 (95% CI 4.22, 6.56) among offspring with paternal IBD before childbirth and 3.73 (95% CI 3.10, 4.50) for paternal IBD after childbirth., Conclusion: Offspring had a greater risk of IBD when either parent was diagnosed before childbirth rather than later, emphasising genetic predisposition and environmental risk factors rather than maternal inflammation in utero as risk factors for IBD., Competing Interests: Competing interests: The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. The authors disclose the following: MA is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK129762-03). MA reports consulting for Douglas Pharmaceutical. MJ has received research grants for other investigator-driven studies from Takeda, and the NOVO Nordisk Foundation (grant no. NNF23OC0081717), has been on the advisory board of Pharmacosmos, has received consultation fee from Ferring and Takeda, and has received speaker’s fees from Tillotts Pharma, MSD, Ferring and Takeda. JT has received grant support from Abbvie and Janssen, consulting fees from Janssen, Abbvie and Pfizer, and speaker fees from Janssen, Abbvie, Pfizer and Sandoz. TJ reports having consulted for Ferring and Pfizer. The other authors disclose no conflicts., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Breastfeeding is critical for offspring health and development. Although many observational studies report a protective effect between breastfeeding and inflammatory bowel disease (IBD), the relationship is not well-understood., Methods: We used prospectively collected data from 3 population-based birth cohorts (Danish National Birth Cohort, Norwegian Mother, Father, and Child Cohort, and All Babies in Southeast Sweden) and cross-linked national registers to ascertain the impact of breastfeeding duration on offspring IBD risk in each country, using adjusted Cox proportional regression analyses. We performed meta-analyses to determine pooled estimates., Results: We included 148,737 offspring and 169,510 offspring in analyses of exclusive and any breastfeeding duration, respectively. During median follow-up of 16.3-22.3 years, between 1996 and 2021, 543 offspring were diagnosed with IBD. In each country, there was no association between exclusive breastfeeding duration and offspring IBD risk after adjusting for birth year (Denmark), offspring sex, parental IBD status, maternal education, smoking during pregnancy, age at delivery, mode of delivery, preterm birth, and small for gestational age. The pooled adjusted hazard ratio for IBD was 1.24 (95% confidence interval, 0.94-1.62; Q = 0.16, I 2  = 0.0%) and 1.02 (95% confidence interval, 0.85-1.21; Q = 1.45, I 2 = 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared with 4-5 months. Similarly, we found null associations in pooled analyses of any breastfeeding duration and IBD, subtypes Crohn's disease and ulcerative colitis, as well as in cohort-specific analyses., Conclusions: In prospectively collected data from 3 population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Specific pollutants and environmental exposures are implicated in modulating inflammatory bowel disease (IBD) risk. However, the role of environmental exposures, particularly during the early life period, towards IBD risk, has not been systematically evaluated., Methods: We conducted a nationwide population-based cohort study during the study period extending from January 1, 1995, to September 1, 2020, using cross-linked Danish registers, maps, and inventories to ascertain the impact of agricultural land use, biodiversity, green space, urban space, blue space, and normalized difference vegetation index during pregnancy and the first two years of life on IBD, Crohn's disease (CD), and ulcerative colitis (UC) risk, using adjusted Cox proportional hazards regression analyses. We adjusted for covariates sex, maternal age at delivery, calendar year of birth, municipal-level socioeconomic status, and first-degree relative with IBD., Findings: Of 1,438,487 individuals included in the study who were followed from age 2 years until a median (IQR) age of 14 (8-20) years, 3768 individuals were diagnosed with IBD. Exposure to the second, third and highest quartiles of agriculture land use during early life, relative to the lowest quartile, were associated with increased CD risk (aHR 1.12, 95% CI 1.01, 1.26, 1.19, 95% CI 1.05, 1.34 and, 1.24 95% CI 1.06, 1.46, respectively). There was no association of agriculture land use with UC risk. Conversely, exposure to the third quartile of biodiversity in early life, compared to the lowest quartile, were associated with a lower CD risk (aHR 0.86, 95% CI 0.75, 0.98). A protective effect of greenspace was noted in the highest quartile for CD (aHR 0.87, 95% CI 0.78, 0.98)., Interpretation: In a nationwide cohort with long-term follow up data, early life environmental exposures were associated with modulation of CD risk, with a harmful effect of agriculture land use and protective effect of biodiversity and green space., Funding: Danish National Research Foundation, the International Organization for the Study of Inflammatory Bowel Disease, the National Institute of Diabetes and Digestive and Kidney Diseases., Competing Interests: The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. MA reports having consulted for Douglas Pharmaceuticals. AVH reports no conflict of interest. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix,; and hold stock options in Intestinal Biotech Development. TJ reports having consulted for Ferring. KHA reports no conflict of interest., (© 2024 The Author(s).)

Objective: Patients with Crohn's disease (CD) exhibit great heterogeneity in disease presentation and treatment responses, where distinct gut bacteria and immune interactions may play part in the yet unresolved disease aetiology. Given the role of antibodies in the barrier defence against microbes, we hypothesised that gut bacterial antibody-coating patterns may influence underlying disease-mediated processes., Design: Absolute and relative single and multicoating of gut bacteria with IgA, IgG1, IgG2, IgG3 and IgG4 in patients with CD and healthy controls were characterised and compared with disease activity. IgG2-coated and non-coated taxa from patients with severe CD were identified, profiled for pathogenic characteristics and monitored for enrichment during active disease across cohorts., Results: Patients with severe CD exhibited higher gut bacterial IgG2-coating. Supervised clustering identified 25 bacteria to be enriched in CD patients with high IgG2-coating. Sorting, sequencing and in silico -based assessments of the virulent potential of IgG2-coated and bulk stool bacteria were performed to evaluate the nature and pathogenicity of IgG2-coated and non-coated bacteria. The analyses demonstrated IgG2-coating of both known pathogenic and non-pathogenic bacteria that co-occurred with two non-coated pathobionts, Campylobacter and Mannheimia . The two non-coated pathobionts exhibited low prevalence, rarely coincided and were strongly enriched during disease flares in patients with CD across independent and geographically distant cohorts., Conclusion: Distinct gut bacterial IgG2-coating was demonstrated in patients with severe CD and during disease flares. Co-occurrence of non-coated pathobionts with IgG2-coated bacteria points to an uncontrolled inflammatory condition in severe CD mediated via escape from antibody coating by two gut pathobionts., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), affect millions of people worldwide with increasing incidence., Objectives: Several studies have shown a link between gut microbiota composition and IBD, but results are often limited by small sample sizes. We aimed to re-analyze publicly available fecal microbiota data from IBD patients., Methods: We extracted original fecal 16S rRNA amplicon sequencing data from 45 cohorts of IBD patients and healthy individuals using the BioProject database at the National Center for Biotechnology Information. Unlike previous meta-analyses, we merged all study cohorts into a single dataset, including sex, age, geography, and disease information, based on which microbiota signatures were analyzed, while accounting for varying technical platforms., Results: Among 2518 individuals in the combined dataset, we discovered a hitherto unseen number of genera associated with IBD. A total of 77 genera associated with CD, of which 38 were novel associations, and a total of 64 genera associated with UC, of which 28 represented novel associations. Signatures were robust across different technical platforms and geographic locations. Reduced alpha diversity in IBD compared to healthy individuals, in CD compared to UC, and altered microbiota composition (beta diversity) in UC and especially in CD as compared to healthy individuals were found., Conclusions: Combining original microbiota data from 45 cohorts, we identified a hitherto unseen large number of genera associated with IBD. Identification of microbiota features robustly associated with CD and UC may pave the way for the identification of new treatment targets., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Introduction: There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis., Methods: Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching., Results: The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication ( P -value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis ( P -value < 0.0001)., Discussion: Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD., (Copyright © 2023 by The American College of Gastroenterology.)

Understanding the biological changes that precede a diagnosis of inflammatory bowel disease (IBD) could facilitate pre-emptive interventions, including risk factor modification, but this pre-clinical phase of disease remains poorly characterized. Using measurements from 17 hematological and biochemical parameters taken up to 10 years before diagnosis in over 20,000 IBD patients and population controls, we address this at massive scale. We observe widespread significant changes in multiple biochemical and hematological parameters that occur up to 8 years before diagnosis of Crohn's disease (CD) and up to 3 years before diagnosis of ulcerative colitis. These changes far exceed previous expectations regarding the length of this pre-diagnostic phase, revealing an opportunity for earlier intervention, especially in CD. In summary, using a nationwide, case-control dataset-obtained from the Danish registers-we provide a comprehensive characterization of the hematological and biochemical changes that occur in the pre-clinical phase of IBD., Competing Interests: Declaration of interests J.C.L. reports financial support for research from GSK and consultancy fees from Abbvie, AgPlus Diagnostics, PredictImmune, and C4X Discovery., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Early Crohn's disease (CD) treatment involves anti-tumor necrosis factor (TNF) agents, whereas ileocecal resection (ICR) is reserved for complicated CD or treatment failure. We compared long-term outcomes of primary ICR and anti-TNF therapy for ileocecal CD., Methods: Using cross-linked nationwide registers, we identified all individuals diagnosed with ileal or ileocecal CD between 2003 and 2018 and treated with ICR or anti-TNF agents within 1 year of diagnosis. The primary outcome was a composite of ≥1 of the following: CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD. We conducted adjusted Cox's proportional hazards regression analyses and determined the cumulative risk of different treatments after primary ICR or anti-TNF therapy., Results: Of 16,443 individuals diagnosed with CD, 1279 individuals fulfilled the inclusion criteria. Of these, 45.4% underwent ICR and 54.6% received anti-TNF. The composite outcome occurred in 273 individuals (incidence rate, 110/1000 person-years) in the ICR group and in 318 individuals (incidence rate, 202/1000 person-years) in the anti-TNF group. The risk of the composite outcome was 33% lower with ICR compared with anti-TNF (adjusted hazard ratio, 0.67; 95% confidence interval, 0.54-0.83). ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not other secondary outcomes. The proportion of individuals on immunomodulator, anti-TNF, who underwent subsequent resection, or were on no therapy 5 years post-ICR was 46.3%, 16.8%, 1.8%, and 49.7%, respectively., Conclusion: These data suggest that ICR may have a role as first-line therapy in CD management and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Yet, given inherent biases associated with observational data, our findings should be interpreted and applied cautiously in clinical decision making., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The appendix is thought to have a role in the pathogenesis of ulcerative colitis, but the nature and basis of this association remains unclear. In this Perspective, we consider the biology of the appendix with respect to its immunological function and the microbiome, and how this relates to evidence that supports the involvement of the appendix in ulcerative colitis. In experimental models, removal of the inflamed appendix prevents colitis, and in human observational studies, appendectomy is associated with protection against ulcerative colitis. Further, among people who develop ulcerative colitis, appendectomy before diagnosis might influence the course and outcomes of the disease - some evidence suggests that it protects against colectomy but could increase the risk of colorectal cancer. Appendectomy after onset of ulcerative colitis seems to have disparate consequences. Clinical trials to understand whether appendectomy has a role in the treatment of ulcerative colitis are ongoing. Major questions about the role of the appendix in the pathogenesis of ulcerative colitis remain unanswered, and further research is needed to establish whether the connection is clinically relevant., (© 2023. Springer Nature Limited.)

We evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue., (© 2023. Springer Nature Limited.)

Objective: Inflammatory bowel disease (IBD) is associated with anxiety and depression, but the magnitude and directionality of risk remains uncertain. This study quantifies the risk of anxiety or depression following a diagnosis of IBD, and the risk of IBD in individuals with anxiety or depression, using population representative data., Method: We performed a systematic literature search using MEDLINE and Embase and included unselected cohort studies reporting risk of anxiety or depression in patients with IBD or risk of IBD in patients with anxiety or depression. We undertook Random Effect Model meta-analysis to calculate pooled Hazard Ratios (HR) for the risk of anxiety and depression in IBD and subgroup meta-analysis to calculate risk by IBD subtype and in pediatric-onset IBD., Results: Nine studies were included; seven of which examined incidence of anxiety or depression among a total of >150,000 IBD patients. Meta-analysis showed an increased risk of both anxiety (HR: 1.48, 95% CI: 1.29-1.70) and depression (HR: 1.55, 95% CI: 1.35-1.78) following IBD diagnosis. Two studies investigating >400,000 individuals with depression showed a 2-fold increased risk of IBD., Conclusions: The bidirectional association between IBD and anxiety and depression is clinically relevant and could indicate shared or mutually dependent disease mechanisms., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: Patients with Crohn's disease (CD) often suffer from perianal fistulizing disease. Their risk of anorectal cancer remains uncertain. We aimed to examine the long-term risk of anorectal cancer in a population-based cohort of CD patients with anorectal fistula., Method: Our study population covered all individuals (n = 7 987 520) aged 15+ years living in Denmark from 1978 to 2018. We identified all patients with CD and anorectal fistula in the Danish National Patient Register (NPR) and 50 matched noninflammatory bowel disease (IBD) individuals from the general population. Using Cox regression analyses, we examined the risk of anorectal cancer in CD fistula patients versus non-IBD individuals. All patients with CD were identified using codes from the International Classification of Diseases and their data extracted from the NPR. The main outcome measure was cases of anorectal cancer., Results: A total of 2786 CD patients with anorectal fistula and 139 300 non-IBD individuals were followed for 1 553 917 person-years. During follow-up, anorectal cancer was observed in 19 CD patients (0.68%) and 340 non-IBD individuals (0.24%), corresponding to a 2.9-fold increased hazard ratio (HR) of anorectal cancer in CD fistula patients (95% CI 1.80-4.53), with a particularly high risk of anal cancer (HR 15.13, 95% CI 6.88-33.31) and a mean time from CD fistula diagnosis to anorectal cancer of 6.7 (SD 6.5) years. The risk was slightly higher in women than men and had no apparent relation to treatment with tumour necrosis factor-α inhibitors. Sensitivity analyses using CD nonfistula patients for comparison revealed similar results. Individual data on smoking and infection with human papilloma virus were not available., Conclusion: Patients with CD and anorectal fistula have a three-fold increased risk of anorectal cancer compared with the general population. The number needed to surveil to detect one case of anorectal cancer in this patient population was 2160 patients per year in patients with long-standing fistula (>6 years)., (© 2023 Association of Coloproctology of Great Britain and Ireland.)

Background and Aims: Selected patient groups with ulcerative colitis and Crohn's disease are at increased risk of colorectal cancer. Surveillance guidelines rarely cover patients after colectomy. We performed a nationwide population-based cohort study to estimate the risk of developing rectal cancer in patients with inflammatory bowel disease after subtotal colectomy., Methods: Through the Danish Civil Registration System, a source population of all individuals living in Denmark between 1978 and 2018 was retrieved. The risk of rectal cancer in patients with diverted rectum was assessed using Cox regression analyses with comparison to both the individuals with inflammatory bowel diseases without subtotal colectomy and the background population., Results: Rectal cancer occurred in 42 of 4931 patients (0.9%) after subtotal colectomy and diverted rectum, compared to 209 of 49,251 (0.4%) in the matched inflammatory bowel diseases cohort without colectomy and 941 of 246,550 (0.4%) in the background population. The hazard ratio (HR) for rectal cancer in patients with inflammatory bowel disease and diverted rectum vs patients without colectomy was 0.76 (95% CI, 0.28, 2.07) before 10 years and 7.56 (95% CI, 5.21, 10.86) 10 years after colectomy. The HR for patients with diverted rectum compared to the background population was 0.84 (95% CI, 0.31, 2.24) and 10.01 (95% CI, 7.20, 13.94) respectively., Conclusion: In our nationwide population-based Danish cohort study, we found the risk of rectal cancer in the diverted rectum to be markedly increased 10 years postcolectomy. This calls for better long-term surveillance of colectomized patients with inflammatory bowel diseases., (© 2023 The Authors.)

Background: Inflammatory bowel disease (IBD) is associated with psychiatric diseases, but it is unclear to what degree patients with IBD are affected over their lifetime. We aimed to longitudinally investigate the risk of anxiety, depression, and bipolar disorder before and after IBD diagnosis to understand the full burden of these diseases in patients with IBD., Methods: In this population based cohort study, we identified 22,103 patients diagnosed with IBD between January 1, 2003 and December 31, 2013 in the Danish National registers and 110,515 matched reference individuals from the general population. We calculated yearly prevalence of hospital contacts for anxiety, depression, and bipolar disorder and dispensed prescriptions for antidepressants from five years before to ten years after IBD diagnosis. We used logistic regression to calculate prevalence odds ratios (OR) for each outcome prior to IBD diagnosis, and Cox regression to calculate hazard ratios (HR) of new outcomes after IBD diagnosis., Findings: During >150,000 person years follow-up, patients with IBD had higher risk of anxiety (OR 1.4; 95% confidence interval (CI) 1.2-1.7) and depression (OR 1.4; 95% CI 1.3-1.6) starting at least five years before and continuing until at least ten years after IBD diagnosis (HR 1.3; 95% CI 1.1-1.5 for anxiety and HR 1.5; 95% CI 1.4-1.7 for depression). The risk was particularly high around IBD diagnosis and in patients diagnosed with IBD after the age of 40 years. We found no association between IBD and bipolar disorder., Interpretation: This population-based study suggests that anxiety and depression are clinically significant comorbidities of IBD both before and after IBD diagnosis, which warrant thorough evaluation and management, particularly around the time of IBD diagnosis., Funding: The Danish National Research Foundation [DNRF148], the Lundbeck Foundation [R313-2019-857], and Aage og Johanne Louis-Hansens Fond [9688-3374 TJS]., Competing Interests: TB: None. GP: None. KA: Board member, the Epidemiological Committee of the European Crohn's and Colitis Organization and the Danish Society for Pharmacoepidemiology. LK: LK is co-founder, consultant, and equity owner of Trellus Health. LK is a consultant to AbbVie, Pfizer, Takeda, and Eli Lilly. LK is on the Board of directors at the Rome Foundation. AA: AA has received payment or honoraria from Takeda and Pfizer. TJ: TJ has received support for the present manuscript from the 10.13039/501100001732Danish National Research Foundation, the 10.13039/501100003554Lundbeck Foundation, and the Aage og Johanne Louis-Hansen Fond. TJ is a member of the Board of the Danish medical society Selskab for Teoretisk og Anvendt Terapi., (© 2023 The Author(s).)

Background: There is an increasing incidence of inflammatory bowel disease (IBD) for which environmental factors are suspected. Antibiotics have been associated with development of IBD in earlier generations, but their influence on IBD risk in adults is uncertain., Objective: To assess the impact of antibiotic exposure, including dose-response, timing and antibiotic class, on the risk of IBD in all individuals aged ≥10 years., Design: Using Denmark nationwide registries, a population-based cohort of residents aged ≥10 years was established between 2000 and 2018. Incidence rate ratios (IRRs) for IBD following antibiotic exposure were calculated using Poisson regression., Results: There were a total of 6 104 245 individuals, resulting in 87 112 328 person-years of follow-up, and 52 898 new cases of IBD. Antibiotic exposure was associated with an increased risk of IBD as compared with no antibiotic exposure for all age groups, although was greatest among individuals aged 40-60 years and ≥60 years (age 10-40 years, IRR 1.28, 95% CI 1.25 to 1.32; age 40-60 years, IRR 1.48, 95% CI 1.43 to 1.54; age ≥60 years, IRR 1.47, 95% CI 1.42 to 1.53). For all age groups a positive dose-response was observed, with similar results seen for both ulcerative colitis and Crohn's disease. The highest risk of developing IBD was seen 1-2 years after antibiotic exposure, and after use of antibiotic classes often prescribed to treat gastrointestinal pathogens., Conclusion: Antibiotic exposure is associated with an increased risk of IBD, and was highest among individuals aged 40 years and older. This risk increased with cumulative antibiotic exposure, with antibiotics targeting gastrointestinal pathogens and within 1-2 years after antibiotic exposure., Competing Interests: Competing interests: ASF: Research support from Crohn’s and Colitis Foundation; consultant for GLG, M3, Janssen, Guidepoint. JF: consultant Vedanta Biosciences and Innovation Pharmaceuticals; Scientific Advisory Board Vedanta Biosciences. JC: research grants from AbbVie, Janssen Pharmaceuticals and Takeda; payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire and Takeda; consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microba, Novartis, PBM Capital, Pfizer, Sanofi, Takeda, TiGenix, Vifor; holds stock options in Intestinal Biotech Development., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To review studies examining the appendiceal microbiota and microbial changes in acute appendicitis. Methods: After a systematic literature search, 11 studies examining the appendiceal microbiota (414 samples) using non-culture-based methods were included. Results: The appendiceal microbiota showed decreased α-diversity compared with fecal microbiota. Inflamed and uninflamed appendices showed differences in β-diversity, and there was an increased abundance of oral-associated bacteria in inflamed versus uninflamed appendices. Conclusion: The appendiceal microbiota exhibits lower α-diversity than the fecal microbiota, with an increased abundance of oral-associated bacteria. Compared with uninflamed appendices, the appendix microbiota in acute appendicitis also showed increased abundance of oral-associated bacteria, but no bacterial profile unique to either complicated or uncomplicated appendicitis was found.

Introduction: A family history of inflammatory bowel disease [IBD] is the strongest risk factor for disease. However, some first-degree relatives (FDRs) will develop disease, while others will not., Methods: Using the nationwide Danish National Patient Register, we examined risk factors in families with two or more affected FDRs. First, we compared exposures between siblings with and without IBD within the same family [within-family analysis]. Second, we compared exposures between individuals with and without IBD across all families [across-family analysis]. Exposures included sex, birth order, mode of delivery, antibiotics, personal and family history of immune-mediated diseases, gastrointestinal infections, and surgical history preceding diagnosis. Uni- and multivariable conditional logistic regression analyses were conducted., Results: In the 'within-family analysis', 1669 families were included [1732 cases, 2447 controls]. Female sex (adjusted odds ratio [aOR]: 1.40, 95% confidence interval [CI] 1.23, 1.59), history of ankylosing spondylitis [aOR: 2.88, 95% CI 1.05, 7.91] and exposure to antibiotics [aOR: 1.28, 95% CI 1.02, 1.61] increased the risk for IBD. In the 'across-family analysis', 1254 cases and 37 584 controls were included, confirming an association with prior ankylosing spondylitis [aOR: 3.92, 95% CI 1.38, 11.12] and exposure to antibiotics [aOR: 1.29, 95% CI 1.04, 1.60]. Having two or more relatives [aOR: 6.26, 95% CI 1.34, 29.29] or a sibling with IBD [aOR: 1.36, 95% CI 1.18, 1.57] increased the risk of IBD. Appendectomy reduced the risk of ulcerative colitis [aOR: 0.32, 95% CI 0.14, 0.72]., Conclusion: In families with IBD, we identified risk factors for the unaffected FDR to develop disease. These findings provide an opportunity for counselling IBD relatives., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Current knowledge regarding the epidemiology of pouchitis is based on highly selected, mostly single-center, patient cohorts. Our objective was to prospectively determine the population-based incidence of pouchitis in patients with ulcerative colitis in the first 2 years after ileal pouch-anal anastomosis and analyze time trends of the incidence of pouchitis., Methods: Using national registries, we established a population-based cohort of all Danish patients undergoing proctocolectomy with ileal pouch-anal anastomosis for ulcerative colitis between 1996 and 2018. The primary outcome was the development of pouchitis within the first 2 years after surgery, evaluated by time period. We used Kaplan-Meier and Cox proportional hazard modeling to evaluate the time to development of pouchitis., Results: Overall, 1664 patients underwent an ileal pouch-anal anastomosis. The cumulative incidence of pouchitis in the 2 years after ileal pouch-anal anastomosis increased throughout the study period, from 40% in the period from 1996 to 2000 (95% CI, 35%-46%) to 55% in the period from 2015 to 2018 (95% CI, 48%-63%). Patients undergoing surgery between 2015 and 2018 also showed an increased risk of pouchitis compared with the earliest study period (1996-2000) after adjusting for sex, age, and socioeconomic status (hazard ratio, 1.57; 95% CI, 1.20-2.05)., Conclusions: This population-based study showed a 15% absolute and 38% relative increase in the incidence of pouchitis among patients undergoing surgery between 1996 and 2018, with the greatest cumulative incidence of pouchitis shown in the most recent era (2015-2018). The striking increase in the incidence of pouchitis highlights the need for further research into causes and prevention of pouchitis., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Shifts in epidemiological stages of inflammatory bowel disease (IBD) carry implications toward understanding IBD etiology and managing clinical care. We conducted a temporal analysis of the epidemiology of IBD between 1995 and 2016 in the Danish nationwide cohort., Methods: We used the Danish registers to obtain data on demographics and IBD-related outpatient and inpatient contacts between 1995 and 2016. IBD diagnosis was defined as having ≥2 registrations related to Crohn's disease (CD) or ulcerative colitis (UC) within a 2-year period. We estimated overall and annual incidence rates and prevalence of CD and UC standardized with respect to age and sex., Results: A total of 47,830 individuals met the criteria for IBD diagnosis, of which 33% were diagnosed with CD and 67% with UC. Between 1995 and 2016, the incidence rate (95% confidence interval) per 100,000 person-years rose from 9.1 (8.3-10.0) to 17.8 (16.8-19.0) for CD, and from 21.0 (19.8-22.3) to 28.4 (27.0-29.8) for UC. The highest increase in CD and UC incidence rates occurred in children and young adults, respectively. The prevalence of IBD doubled from 1995 to 2016; the greatest increase (2.5-fold) was in UC prevalence among individuals aged >40 years. During this period, the median age of the IBD population increased by 6 to 7 years., Conclusions: In Denmark, the incidence and prevalence of IBD have increased during the last 2 decades. The IBD population is shifting toward an older age. These findings have implications towards understanding environmental shifts as well as preparing health care systems for an aging IBD population., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The prevalence of inflammatory diseases is increasing in populations throughout the industrialized world. An increasing proportion of human populations grow up and live in urban areas, probably with reduced exposure to biodiversity, including diverse soil biotas. Decreased exposure to microorganisms from natural environments, in particular in early childhood, has been hypothesized to hamper development of the human immune system and lead to increasing risks of inflammatory diseases, such as asthma. We investigated 40,249 Danish individuals born 1995-2015. Percentage greenspace was assessed in a 2 km buffer around home addresses of individuals. The Danish Biodiversity Map, charting occurrence density of red-listed animals, plants and macrofungi, was used as a proxy for multi-taxon biodiversity. For asthma defined broadly, we found no evidence of decreasing risk of developing asthma with higher levels of biodiversity, while greenspace exposure was associated with higher risk of asthma. In contrast, exposure to total and biodiverse greenspace was associated with reduced risk of developing severe asthma. Exposure to farmland, which in Denmark is heavily industrialized cropland, also showed association with elevated risk of developing asthma, even at relatively low agricultural landcover. In the subset of children growing up in highly urbanized settings, we found high exposures to urban greenspace to be associated with reduced risk of developing asthma. Our results lend limited support to the hypothesis that childhood exposure to biodiverse environments reduces the risk of acquiring inflammatory diseases later in life. However, access to urban greenspace, such as parks, which typically harbour low levels of biodiversity, seems to reduce asthma risk, potentially through exposure to common soil microbiota. Our results suggest that effects of biodiversity exposure on human health is set by a balance between ecosystem services and disservices and that biodiversity conservation is best motivated with other arguments than reduction of risks from inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: According to the hygiene hypothesis, exposure to parasites may protect against inflammatory bowel disease (IBD). Our aim was to examine the risk of IBD with childhood exposure to mebendazole, a broad-spectrum antihelminthic agent., Methods: We conducted a population-based cohort study using prospectively collected historical data of all individuals born in Denmark between 1995 and 2018. We identified mebendazole exposure at age younger than 18 years and during early life (younger than 5 years). We performed adjusted Cox proportional hazards regression analysis to determine the risk of IBD, ulcerative colitis (UC), and Crohn's disease with mebendazole exposure after adjusting for potential confounders., Results: Of 1,520,290 individuals in the cohort, 615,794 had childhood or adolescence mebendazole exposure. One thousand five hundred fifty-five and 1,499 individuals were subsequently diagnosed with pediatric-onset and adult-onset IBD, respectively. On multivariable analysis, mebendazole exposure at age younger than 18 years did not affect pediatric-onset or adult-onset IBD risk (adjusted hazard ratio [aHR] 0.97, 95% confidence interval [CI] 0.87, 1.07, and 1.08, 95% CI 0.97, 1.19, respectively). On limiting mebendazole exposure to age younger than 5 years while there was no association with pediatric-onset IBD (aHR 0.98, 95% CI 0.87, 1.11), adult-onset IBD risk was increased (aHR 1.17, 95% CI 1.04, 1.31). This increase in risk was driven by UC (aHR 1.32, 95% CI 1.12, 1.55), but not Crohn's disease (1.03, 95% CI 0.87, 1.22)., Discussion: Early-life mebendazole exposure is associated with an increase in the risk of adult-onset UC. These findings suggest the importance of early-life exposures in shaping the risk of IBD later in life., (Copyright © 2022 by The American College of Gastroenterology.)

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a chronic, relapsing immune-mediated disease with a varying and sometimes severe disease course. IBD is often diagnosed in early adulthood and can lead to a substantial decline in quality of life. It has been suggested that patients with IBD are at increased risk of depression and anxiety, but it is still unclear to what extent these diseases co-occur and in what sequence they arise. This Review summarizes the literature on the degree of co-occurrence of IBD with depression and anxiety and the temporal relationship between these diseases. We also discuss the effect of psychological stress on the onset and course of IBD. In addition, we outline the possible mechanisms underlying the co-occurrence of IBD and depression and anxiety, which include changes in brain signalling and morphology, increases in peripheral and intracerebral pro-inflammatory cytokines, impairment of the nitric oxide pathway, changes in vagal nerve signalling, gut dysbiosis and genetics. Finally, we examine the possible effects of treatment of depression and anxiety on the risk and course of IBD, the influence of psychological interventions on IBD, and the effects of IBD treatment on psychiatric comorbidity., (© 2022. Springer Nature Limited.)

Background: Metformin has pleiotropic effects including anti-inflammatory properties and effects on the gut microbiome. It is primarily used in the older population, where the occurrence of inflammatory bowel disease (IBD) is increasing. The aim of this study was to examine whether metformin protects against development of IBD., Methods: In the setting of a Danish nationwide population-based cohort, we conducted a nested case-control study using a new-user active comparator design. For each patient with IBD, we selected 10 IBD-free individuals matched on age, sex, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) of IBD. Adjustment included educational level, other immune-mediated inflammatory diseases, and use of dipeptidyl peptidase (DPP)-4 inhibitors and statins., Results: Among 302,863 IBD-free new users of oral glucose-lowering drugs, we identified 1271 patients who developed IBD and 12,676 matched IBD-free individuals. Mean age at IBD diagnosis was 66 (SD, 11) years. We found no association between ever use of metformin and risk of IBD, Crohn's disease or ulcerative colitis, adjusted OR 0.95 (95% CI 0.78-1.15), 0.87 (95% CI 0.60-1.26), and 1.04 (95% CI 0.83-1.31), respectively. Neither was the cumulative dose of metformin or the treatment duration with metformin associated with risk of IBD., Conclusions: In this population-based study, we report that despite anti-inflammatory effects and a notable impact on the gut microbiome, metformin use is not associated with reduced risk of older onset IBD., (© 2022. Japanese Society of Gastroenterology.)

Background: Eosinophilic oesophagitis (EoE) is a chronic immune-mediated or antigen-mediated oesophageal disease characterised by symptoms related to oesophageal dysfunction and eosinophil-predominant inflammation., Objective: We aimed to estimate the incidence and prevalence of EoE in Denmark during the period 2008-2018., Methods: Based on data from nationwide registers we identified cases of EoE using two definitions: a broad definition based solely on oesophageal biopsies registered in the Danish Pathology Register and a narrow definition also including symptoms of oesophageal dysfunction registered in the Danish National Patient Registry. The annual incidence and prevalence were standardised by sex and age in 5-year intervals to the 2013 study population., Results: From 2008 to 2011, the standardised incidence of EoE was stable, but from 2011 to 2018 it increased from 3.9 (95% CI 3.3-4.4) to 11.7 (95% CI 10.8-12.6) per 100,000 person-years. Similar temporal trends were observed when using the narrow EoE definition. The increase in incidence was most pronounced in men and in individuals above 40 years of age. In children, the EoE incidence was a fourth of the incidence in adults aged 40-64 years: 4.4 (95% CI 3.2-5.6) versus 17.6 (95% CI 15.7-19.5) per 100,000 person-years. The EoE incidence varied substantially across the five regions in Denmark. Overall, the biopsy rate as well as the proportion of oesophageal biopsies with detected eosinophilia increased during the study period., Conclusion: This study of the entire population of Denmark during the period 2008 to 2018 shows that the incidence and prevalence of EoE is not yet plateauing and that EoE could be severely underdiagnosed, especially in children., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Importance: Observational comparative effectiveness studies can inform the positioning of biologic therapies for older patients with inflammatory bowel disease (IBD) who are underrepresented in clinical trials., Objective: To compare the effectiveness and safety of vedolizumab vs tumor necrosis factor (TNF) for older patients with IBD., Design, Setting, and Participants: This active comparator, new-user design, comparative effectiveness study was conducted between January 1, 2005, and December 31, 2018, among 754 older patients (aged ≥50 years) with IBD from the Danish National Patient Register. The mean follow-up after treatment initiation took place at 32 to 40 weeks. Statistical analysis was performed from February 1 to April 27, 2022., Interventions: Treatment with vedolizumab or TNF antagonists., Main Outcomes and Measures: The primary effectiveness outcome was treatment failure, defined as the composite risk of IBD-related hospitalization, IBD-related surgery, or a new corticosteroid prescription more than 6 weeks after initiation of treatment with biologic therapy. Secondary effectiveness outcomes were time to each individual component of the composite effectiveness outcome. The primary safety outcome was the risk of serious infections, defined as infections requiring hospitalization. A 1:1 propensity score-matched analysis was conducted, accounting for patient-, disease-, and treatment-associated factors., Results: The study compared 377 older patients with IBD with incident use of vedolizumab (202 women [53.6%]; mean [SD] age, 61.2 [8.3] years; 177 [46.9%] with Crohn disease) vs 377 patients with incident use of TNF antagonists (206 women [54.6%]; mean [SD] age, 61.3 [8.1] years; 182 [48.3%] with Crohn disease). Overall, vedolizumab was associated with an increased risk of treatment failure compared with TNF antagonists (1-year risk, 45.4% vs 34.7%; adjusted hazard ratio [HR], 1.31; 95% CI, 1.02-1.69), including higher risk of IBD-related hospitalization (1-year risk, 27.8% vs 16.3%; adjusted HR, 1.48; 95% CI, 1.03-2.15) and IBD-related major abdominal surgery (1-year risk, 21.3% vs 8.0%; adjusted HR, 2.39; 95% CI, 1.45-3.94). In subgroup analysis by IBD phenotype, among patients with Crohn disease, vedolizumab was associated with a 77% higher risk of treatment failure (adjusted HR, 1.77; 95% CI, 1.21-2.58), while no difference in risk of treatment failure was seen among patients with ulcerative colitis (adjusted HR, 1.04; 95% CI, 0.75-1.43; P = .03 for interaction). There was no significant difference in the risk of serious infections, overall (1-year risk, 8.2% vs 8.7%; adjusted HR, 1.04; 95% CI, 0.58-1.85) and by IBD phenotype., Conclusions and Relevance: In this comparative effectiveness study of older patients with IBD, vedolizumab was associated with a higher risk of treatment failure compared with TNF antagonists, particularly among patients with Crohn disease, without offering a significant safety advantage.

Aims: We examined associations between five body mass index (BMI) trajectories from ages 6-15 years and register-based adult-onset type 2 diabetes mellitus (T2D) and coronary heart disease (CHD) with and without adjustment for adult BMI., Methods: Child and adult BMI came from two Danish cohorts and 13,205 and 13,438 individuals were included in T2D and CHD analyses, respectively. Trajectories were estimated by latent class modelling. Incidence rate ratios (IRRs) were estimated with Poisson regression., Results: In models without adult BMI, compared to the lowest trajectory, among men the T2D IRRs were 0.92 (95 %CI:0.77-1.09) for the second lowest trajectory and 1.51 (95 %CI:0.71-3.20) for the highest trajectory. The corresponding IRRs in women were 0.92 (95 %CI:0.74-1.16) and 3.58 (95 %CI:2.30-5.57). In models including adult BMI, compared to the lowest trajectory, T2D IRRs in men were 0.57 (95 %CI:0.47-0.68) for the second lowest trajectory and 0.26 (95 %CI:0.12-0.56) for the highest trajectory. The corresponding IRRs in women were 0.60 (95 %CI:0.48-0.75) and 0.59 (95 %CI:0.36-0.96). The associations were similar in direction, but not statistically significant, for CHD., Conclusions: Incidence rates of adult-onset T2D were greater for a high child BMI trajectory than a low child BMI trajectory, but not in models that included adult BMI., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Although clinical guidelines exist, the diagnostic work-up for diagnosing inflammatory bowel disease (IBD) is complex and varies in clinical practice. This study used real-life data to characterise the current diagnostic procedures used to establish IBD diagnoses in a Danish nationwide setting., Design: Person-level data on patients diagnosed with IBD between 1 January 2014 and 30 June 2018 were linked between Danish health registers. Information on age, sex, registration of other gastrointestinal diseases, and diagnostic procedures (endoscopies, biopsies, and imaging) performed in relation to the first IBD hospital admission was analysed for the total study population and was stratified by IBD type, sex, and age., Results: The majority of the 12 871 patients with IBD included underwent endoscopy (84%), had a biopsy taken (84%), and/or underwent imaging procedures (44%). In total, 7.5% of the population (6% for Crohn's disease and 8% for ulcerative colitis) were diagnosed with IBD despite not undergoing any of these diagnostic procedures. Patients with Crohn's disease underwent more procedures than patients with ulcerative colitis (94% vs 92%, p<0.001). Children underwent slightly fewer diagnostic procedures than adults (92% vs 93%, p=0.004). Slightly more men underwent at least one procedure than women (92% vs 94%, p<0.001)., Conclusion: For 7.5% of patients with IBD, this study did not detect any registrations of the recommended diagnostic procedures for establishing an IBD diagnosis. Further research is needed to examine whether these findings are mainly explained by limitations of the register data or also indicate shortcomings of the general approach to IBD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammatory bowel disease (IBD) is an immune-mediated disease of the intestinal tract, with complex pathophysiology involving genetic, environmental, microbiome, immunological and potentially other factors. Epidemiological data have provided important insights into risk factors associated with IBD, but are limited by confounding, biases and data quality, especially when pertaining to risk factors in early life. Multiomics platforms provide granular high-throughput data on numerous variables simultaneously and can be leveraged to characterize molecular pathways and risk factors for chronic diseases, such as IBD. Herein, we describe omics platforms that can advance our understanding of IBD risk factors and pathways, and available omics data on IBD and other relevant diseases. We highlight knowledge gaps and emphasize the importance of birth, at-risk and pre-diagnostic cohorts, and neonatal blood spots in omics analyses in IBD. Finally, we discuss network analysis, a powerful bioinformatics tool to assemble high-throughput data and derive clinical relevance., (© 2022. Springer Nature Limited.)

Background: Escalation to anti-tumour necrosis factor (anti-TNF) in inflammatory bowel disease (IBD) patients on thiopurine is a common clinical scenario. However, the impact of discontinuing thiopurine at escalation is unclear., Aim: To assess the impact of discontinuing versus continuing thiopurine therapy at anti-TNF initiation., Methods: We used the Danish registries to establish a national cohort of patients with IBD on thiopurine therapy prior to initiating anti-TNF from 2003 to 2018. We compared patients discontinuing thiopurine therapy within 90 days of anti-TNF initiation to those continuing. Our primary outcome was a composite of any new oral corticosteroid use, IBD-related hospitalization, surgery or death. We used Cox regression models to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI)., Results: Of the 10,352 anti-TNF exposed patients, 2,630 (1590 Crohn's disease (CD) and 1040 ulcerative colitis (UC)) received thiopurines prior to anti-TNF. After anti-TNF initiation, 979 patients discontinued thiopurines. Discontinuing thiopurines within 90 days of anti-TNF initiation, increased the risk of the primary outcome (aHR: 1.22; 95% CI: 1.10-1.36), particularly for IBD-related hospitalization (aHR: 1.14; 95% CI: 1.00-1.31) and oral corticosteroid use (aHR: 1.27; 95% CI: 1.13-1.44). This increased risk of the primary outcome was seen in both CD (aHR: 1.17; 95% CI 1.02-1.34) and UC (aHR: 1.32; 95% CI: 1.12-1.55)., Conclusions: In a nationwide cohort study of IBD patients, we observed that discontinuing thiopurines after anti-TNF initiation was associated with an increased risk of adverse outcomes, in particular an increase in hospitalizations. Further interventional studies exploring this common clinical scenario are required., (© 2022 John Wiley & Sons Ltd.)

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of human papillomavirus (HPV) related cancers such as anal squamous cell carcinoma. However, risk of non-malignant HPV infection has never been systematically studied in IBD. This study aims to assess the risk of genital warts (GW) in IBD patients., Methods: Using the Danish nationwide registries, we identified 49,163 patients with IBD between 1996 and 2018 and matched them to 491,665 individuals from the general population by age, sex, and HPV immunisation. Cumulative incidence rates for GW in IBD and non-IBD patients were calculated by age. Cox proportional regression analysis was used to calculate hazard ratios (HR) for GW in IBD compared to matched population and in Crohn's disease (CD) compared to ulcerative colitis (UC). We undertook subgroup analysis for risk of GW by sex, year of IBD diagnosis, contraceptive exposure and IBD treatment exposure., Results: The fully adjusted HR for GW in IBD patients compared to the matched non-IBD population was 1.33 (95% CI: 1.19-1.49) and 1.13 (95% CI: 1.01, 1.27) in CD as compared to UC. This increased risk was particularly observed in female (HR: 1.54, 95% CI: 1.33-1.79) over male (HR: 1.14, 95% CI: 0.97-1.34) IBD patients, but was also found across all periods of diagnosis with IBD, regardless of contraceptive treatment exposure, and also seen in IBD patients who had never been exposed to immunosuppressive treatment (HR: 1.33, 95% CI: 1.19-1.49)., Conclusion: In this nationwide, population-representative cohort study, we observed a 33% increased risk of GW in patients with IBD compared to the matched population and a 13% increased risk of GW in CD compared with UC. This risk was particularly increased in female over male IBD patients and seen independent of IBD treatment exposure., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Importance: Because the incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing, knowledge of the long-term risk of cancer in this patient population is required., Objective: To evaluate the relative rate of cancer among patients with pediatric-onset IBD., Data Sources: A comprehensive systematic search was performed of MEDLINE and Embase from the date of database inception to October 31, 2021., Study Selection: All unselected, population-based cohort studies of pediatric-onset IBD assessing the risk of cancer were included. Tertiary center referrals and insurance database studies were excluded. All articles were assessed by 2 independent reviewers., Data Extraction and Synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline for data extraction and used the Newcastle-Ottawa Scale for assessment of the risk of bias and the quality of included articles., Main Outcomes and Measures: A random-effects model meta-analysis was conducted of included studies using the inverse-variance method to assess the relative rate of cancer overall and by IBD subtype (Crohn disease or ulcerative colitis), sex, and thiopurine exposure among patients with pediatric-onset IBD. Pooled relative rates (pRRs) along with 95% CIs were calculated for combined studies., Results: Of 4628 articles screened, 5 population-based studies from North America and Europe were eligible for inclusion. These studies comprised 19 812 individuals with pediatric-onset IBD followed up for 283 540 person-years in which 715 cases of cancer were identified. Meta-analysis of pRR estimates showed a 2.4-fold increased rate of cancer among patients with pediatric-onset IBD (pRR, 2.46; 95% CI, 2.06-2.93), seen among patients with Crohn disease (pRR, 2.03; 95% CI, 1.67-2.46) and those with ulcerative colitis (pRR, 2.61; 95% CI, 2.00-3.40). This increased rate is primarily due to an increased rate of liver (pRR, 55.45; 95% CI, 19.59-156.99), colorectal (pRR, 20.29; 95% CI, 15.90-25.90), and small bowel (pRR, 16.20; 95% CI, 3.52-74.66) cancers. The incidence rate of cancer among patients with pediatric-onset IBD was reported by 4 studies and ranged from 1.0 to 3.3 cases per 1000 person-years., Conclusions and Relevance: This meta-analysis of unselected, population-based studies showed a greater than 2-fold increased rate of cancer among patients with pediatric-onset IBD compared with the general pediatric populations, primarily owing to an increased rate of gastrointestinal cancers.

Background and Aims: Patients with inflammatory bowel disease (IBD) are at increased risk of type 2 diabetes (T2D), but the underlying mechanisms remain elusive. We aimed to determine the impact of small and large bowel resections on the risk of developing T2D in patients with IBD., Methods: We conducted a nationwide, prospective study of all IBD patients undergoing small bowel resection (Crohn's disease [CD]) and large bowel resection (CD and ulcerative colitis [UC]) in Denmark (1996-2018). Each patient was matched with up to 5 patients with IBD and no history of bowel resection. We used Cox proportional hazards regression models to estimate adjusted hazard ratios (aHRs) of T2D., Results: We included 2469 patients with CD and small bowel resection, 1361 patients with CD and large bowel resection, and 3787 patients with UC and large bowel resection. Small bowel resection in CD patients was associated with lower risk of T2D (aHR 0.65, 95% CI, 0.44-0.92), compared with matched patients with CD and no bowel resection. Large bowel resection in patients with CD or UC was associated with aHRs of 0.95 (95% CI, 0.67-1.31) and 1.25 (95% CI, 1.03-1.51), respectively, compared with matched patients with CD or UC and no bowel resection., Conclusion: Patients with CD and small bowel resection have a lower risk of T2D, whereas patients with UC and large bowel resection have a higher risk of T2D, compared with patients with IBD and no bowel resection history. The underlying mechanisms remain to be explored., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.

Background and Aims: Human immunodeficiency virus (HIV) infection is associated with several immune-mediated disorders. However, the risk of inflammatory bowel disease (IBD) in people living with HIV (PLWH) remains unclear. We aimed to assess the risk of IBD among PLWH using a nationwide, population-based Danish cohort and to validate findings in a large American insurance-based database., Methods: Using Danish registries (1983-2018), we identified 8995 PLWH and age- and sex-matched them to 449,750 HIV-negative individuals. Cox regression analysis was undertaken to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for IBD diagnosis. Results were stratified by sex, age, and year of HIV diagnosis. Using an American insurance-based cohort, Explorys (1999-2018), we assessed the prevalence odds ratio (OR) and 95% CI of IBD diagnosis in PLWH compared with HIV-negative individuals., Results: IBD diagnosis among PLWH in Denmark was increased (HR: 2.25, 95% CI: 1.78-2.83) compared with matched HIV-negative individuals. This was seen for both Crohn's disease (HR: 2.25, 95% CI: 1.47-3.44) and ulcerative colitis (HR: 2.24, 95% CI: 1.70-2.96) and in male (HR: 2.75, 95% CI: 2.15-3.52) but not female (HR: 0.93, 95% CI: 0.48-1.79) PLWH. Explorys analysis also showed an increased odds of IBD diagnoses among PLWH (OR: 1.41; 95% CI: 1.35-1.49)., Conclusion: This study finds an increased risk of IBD diagnosis among PLWH in both a Danish and US cohort, highlighting a need to consider IBD in PLWH with new-onset gastrointestinal symptoms. Further research into the role of antiretroviral therapy in this relationship is required., Competing Interests: Conflicts of Interest: The authors disclose no conflicts.