Breastfeeding duration is not associated with offspring inflammatory bowel disease risk in three population-based birth cohorts.

BACKGROUND AND AIMS: Breastfeeding is critical for offspring health and development. While 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 three 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 to 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% CI 0.94, 1.62, Q =0.16, I2= 0.0%) and 1.02 (95% CI 0.85, 1.21, Q=1.45, I2= 0.0%) among offspring breastfed exclusively for ≥6 months and <4 months, respectively, compared to 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. CONCLUSION: In prospectively collected data from three population-based birth cohorts, the duration of exclusive or any breastfeeding was not associated with offspring IBD risk.

Association between early life exposure to agriculture, biodiversity, and green space and risk of inflammatory bowel disease: a population-based cohort study.

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.

Drug Repurposing in Crohn's Disease Using Danish Real-World Data.

Aim: 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.

Gut microbiota signatures in inflammatory bowel disease.

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.

Characterizing the pre-clinical phase of inflammatory bowel disease.

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.

Genetic analysis of blood molecular phenotypes reveals common properties in the regulatory networks affecting complex traits.

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.

Medication-Wide Study: Exploring Medication Use 10 Years Before a Diagnosis of Inflammatory Bowel Disease.

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.

Early Ileocecal Resection for Crohn's Disease Is Associated With Improved Long-term Outcomes Compared With Anti-Tumor Necrosis Factor Therapy: A Population-Based Cohort Study.

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.

The bidirectional risk of inflammatory bowel disease and anxiety or depression: A systematic review and meta-analysis.

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.

Longitudinal trajectories of anxiety, depression, and bipolar disorder in inflammatory bowel disease: a population-based cohort study.

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].

The appendix and ulcerative colitis - an unsolved connection.

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.

Non-culture-based studies of the appendiceal microbiota: a systematic review.

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 ß-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.

This article represents a summary of the current literature examining the bacteria in the human appendix. We aimed to describe the bacterial community in the appendix and look for evidence of bacterial differences between diseased and healthy appendices, as well as evidence of bacteria being the cause of acute appendicitis. We found that the bacteria in the appendix are different from the bacteria in stool. Furthermore, bacteria are different when comparing diseased and healthy appendices. The diseased appendix had more types of bacteria that are normally found in the mouth than the healthy appendix. Our summary did not find any evidence that bacteria are the main cause of developing acute appendicitis.

Risk Factors for Developing Inflammatory Bowel Disease Within and Across Families with a Family History of IBD.

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.

Increasing Incidence of Pouchitis Between 1996 and 2018: A Population-Based Danish Cohort Study.

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.

Development of Inflammatory Bowel Disease in HIV Patients: A Danish Cohort Study (1983-2018) With American Validation (1999-2018).

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.

Comparative Outcomes and Safety of Vedolizumab vs Tumor Necrosis Factor Antagonists for Older Adults With Inflammatory Bowel Diseases.

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.

The Risk of Type 2 Diabetes in Patients With Inflammatory Bowel Disease After Bowel Resections: A Nationwide Cohort Study.

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.

Body mass index trajectories in childhood and incidence rates of type 2 diabetes and coronary heart disease in adulthood: A cohort study.

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.