Risk of inflammatory bowel disease following hospitalisation with infectious mononucleosis: nationwide cohort study from Denmark.

Infectious mononucleosis (IM) is suspected to be associated with inflammatory bowel disease (IBD) development. Using a Danish nationwide cohort of people developing severe IM and their age-, sex-, and socioeconomic (SES) index-matched counterparts, we investigated the subsequent risk of IBD, Crohn's disease (CD), or ulcerative colitis (UC) development from 1977 to 2021. Among 39,684 severe IM patients we find a sex-, age-, and SES index-adjusted HR for IBD of 1.35 (95% CI: 1.22-1.49). This significantly increased risk was seen for both CD (HR: 1.56; 95% CI: 1.34-1.83) and to a lesser extent UC (HR: 1.23; 95% CI: 1.08-1.40) and remains following negative control matching with a cohort diagnosed with Chlamydia trachomatis infection (HR: 1.39; 95% CI: 1.01-1.91). Those with severe IM at 0-9 years had a particularly increased risk for CD (HR: 1.77; 95% CI: 1.26-2.49). Here we show an increased risk for IBD diagnosis following IM hospitalisation, indicating an association between severe EBV disease and later IBD development. Further exploration of the potential factors contributing to IBD susceptibility following EBV disease is warranted.

Epidemiology of Elderly Onset IBD: A Nationwide Population-Based Cohort Study.

BACKGROUND AND AIMS: We examined the incidence and natural history of patients with very elderly onset (herein referred to as very late-onset) inflammatory bowel diseases (IBDs) (≥ 70 years of age at diagnosis), compared with patients diagnosed between 60 and 69 years of age in Denmark. METHODS: In the Danish National Patient Register, between 1980 and 2018, we identified all individuals ≥ 60 years of age with newly diagnosed Crohn's disease (CD) and ulcerative colitis (UC) and examined trends in incidence, cumulative risk of hospitalization, treatment patterns, IBD-related surgery, serious infection, cancer and cardiovascular and venous thromboembolic risks among very late-onset (70-79 years of age or 80+ years) vs late-onset (60-69 years of age) IBD, using nonparametric competing risk analysis treating death as competing risk. RESULTS: We identified 3459 patients with onset of CD at ≥60 years of age (47% ≥ 70 years of age) and 10,774 patients with onset of UC ≥60 years of age (51% ≥ 70 years of age). Over the last 3 decades, incidence changes for very late-onset and late-onset IBD have followed the same patterns. Also, both for CD and UC, cumulative incidence of IBD-related hospitalization and corticosteroid use was comparable in very late-onset vs late-onset patients. However, the burden of disease-modifying therapy, either immunomodulator or tumor necrosis factor antagonist use, and major IBD-related surgery was significantly lower in patients with very late-onset than in late-onset IBD. On the other hand, the 5-year risk of serious infections and cardiovascular events was higher in patients with very late-onset IBD. CONCLUSIONS: This nationwide cohort study shows that patients diagnosed with very late-onset (≥ 70 years of age) IBD have a higher relative burden of disease- and aging-related complications, with limited use of steroid-sparing strategies and surgery, compared with late-onset IBD.

Impact of sex and socioeconomic status on the likelihood of surgery, hospitalization, and use of medications in inflammatory bowel disease: a systematic review and meta-analysis.

BACKGROUND: Inflammatory bowel diseases (IBDs) are associated with high healthcare utilization. This systematic review aimed to summarize what is known about the impact of sex, income, and education on the likelihood of bowel surgery, hospitalization, and use of corticosteroids and biologics among patients with IBD. METHODS: We used EMBASE, MEDLINE, CINAHL, and Web of Science to perform a systematic literature search. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects meta-analysis for the impact of sex on the likelihood of surgery and hospitalization. In addition, we performed subgroup analyses of the effect of IBD type (Crohn's disease or ulcerative colitis) and age. Finally, meta-regression was undertaken for the year of publication. RESULTS: In total, 67 studies were included, of which 23 studies were eligible for meta-analysis. In the main meta-analysis, male sex was associated with an increased likelihood of bowel surgery (HR 1.42 (95% CI 1.13;1.78), which was consistent with the subgroup analysis for UC only (HR 1.78, 95% CI 1.16; 2.72). Sex did not impact the likelihood of hospitalization (OR 1.05 (95% CI 0.86;1.30), although the subgroup analysis revealed an increased likelihood of hospitalization in CD patients (OR 1.42, 95% CI 1.28;1.58). In 9 of 10 studies, no significant sex-based differences in the use of biologics were reported, although in 6 of 6 studies, female patients had lower adherence to biologics. In 11 of 13 studies, no significant sex-based difference in the use of corticosteroids was reported. The evidence of the impact of income and education on healthcare utilization was sparse and pointed in different directions. The substantial heterogeneity between studies was explained, in part, by differences in IBD type and age. CONCLUSIONS: The results of this systematic review indicate that male patients with IBD are significantly more likely to have surgery than female patients with IBD but are not, overall, more likely to be hospitalized, whereas female patients appear to have statistically significantly lower adherence to biologics compared to male patients. Thus, clinicians should not underestimate the impact of sex on healthcare utilization. Evidence for income- and education-based differences remains sparse. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022315788.

Breastfeeding Duration Is Not Associated With Offspring Inflammatory Bowel Disease Risk in Three Population-Based Birth Cohorts.

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, I2 = 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.

Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

Risk of cancer in patients with bile acid diarrhoea: a Danish nationwide matched cohort study.

OBJECTIVE: Bile acid diarrhoea is a common cause of chronic diarrhoea. Increased levels of potentially carcinogenic bile acids in faeces, theoretically, may increase the risk of colorectal cancer in particular, but the long-term disease course is unknown. We aimed to investigate the overall and site-specific cancer risk in bile acid diarrhoea. DESIGN: Adult patients with bile acid diarrhoea were identified using nationwide Danish registries from 2003 to 2020 by a diagnostic gold-standard 75-selenium tauroselcholic acid procedure followed within 6 months by sequestrant prescription. The risk of overall and site-specific cancers in cases with bile acid diarrhoea was compared with sex, age and comorbidity-adjusted matched controls. A competing risk model estimated cumulative incidence functions and cause-specific HRs. RESULTS: We identified 2260 patients with bile acid diarrhoea with a mean follow-up of 5.5 years (SD 4.2). The overall cancer risk was increased by an HR of 1.32 (95% CI 1.12 to 1.54). The risk of site-specific cancer was increased in 3 of 10 cancer groups: haematological, HR 2.41 (1.36 to 4.02); skin, HR 1.33 (1.01 to 1.71); and male genital cancers, HR 1.85 (1.11 to 2.92). No increased risk of colorectal cancer was detected in patients with bile acid diarrhoea, HR 0.73 (0.34 to 1.63). CONCLUSIONS: Bile acid diarrhoea was associated with an increased overall risk of cancer, especially haematological cancers, but the risk of colorectal cancer was not increased. The lack of a diagnostic code for bile acid diarrhoea and potential residual confounding are limitations, and the findings should be replicated in other cohorts.

Antibiotic Use in the 12 Months Prior to Ileal Pouch-Anal Anastomosis Increases the Risk for Pouchitis.

BACKGROUND & AIMS: Pouchitis is the most common complication after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC); however, clinical and environmental risk factors for pouchitis remain poorly understood. We explored the relationship between specific clinical factors and the incidence of pouchitis. METHODS: We established a population-based cohort of all adult persons in Denmark undergoing proctocolectomy with IPAA for UC from 1996-2020. We used Cox proportional hazard modeling to assess the impact of antibiotic, nonsteroidal anti-inflammatory drug (NSAID) exposure, and appendectomy on diagnosis of acute pouchitis in the first 2 years after IPAA surgery. RESULTS: Among 1616 eligible patients, 46% developed pouchitis in the first 2 years after IPAA. Antibiotic exposure in the 12 months before IPAA was associated with an increased risk of pouchitis (adjusted hazard ratio [aHR], 1.41; 95% confidence interval [CI], 1.22-1.64) after adjusting for anti-tumor necrosis factor alpha use and sex. Compared with persons without any antibiotic prescriptions in the 12 months before IPAA, the risk of pouchitis was increased in those with 1 or 2 courses of antibiotics in that period (aHR, 1.30; 95% CI, 1.11-1.52) and 3 or more courses (aHR, 1.77; 95% CI, 1.41-2.21). NSAID exposure in the 12 months before IPAA and appendectomy were not associated with risk of acute pouchitis (P = .201 and P = .865, respectively). CONCLUSIONS: In this population-based cohort study, we demonstrated that antibiotic exposure in the 12 months before IPAA is associated with an increased risk of acute pouchitis. Future prospective studies may isolate specific microbial changes in at-risk patients to drive earlier interventions.

Spondyloarthritis in First-Degree Relatives and Spouses of Patients with Inflammatory Bowel Disease: A Nationwide Population-based Cohort Study from Sweden.

BACKGROUND AND AIMS: Register-based research suggests a shared pathophysiology between inflammatory bowel disease [IBD] and spondyloarthritis [SpA], but the role of familial [genetic and environmental] factors in this shared susceptibility is largely unknown. We aimed to compare the risk of SpA in first-degree relatives [FDRs] and spouses of IBD patients with FDRs and spouses of matched, population-based, reference individuals. METHODS: We identified 147 080 FDRs and 25 945 spouses of patients with incident IBD [N = 39 203] during 2006-2016, and 1 453 429 FDRs and 258 098 spouses of matched reference individuals [N = 390 490], by linking nationwide Swedish registers and gastrointestinal biopsy data. Study participants were followed 1987-2017. Cox regression was used to estimate hazard ratios [HRs] of SpA. RESULTS: During follow-up, 2430 FDRs of IBD patients [6.5/10 000 person-years] and 17 761 FDRs of reference individuals [4.8/10 000 person-years] were diagnosed with SpA, corresponding to an HR of 1.35 [95% CI:1.29, 1.41]. In subgroup analyses, the increased risk of SpA was most pronounced in FDRs of Crohn's disease patients [HR = 1.44; 95% CI:1.34,1.5 6] and of IBD patients aged <18 years at diagnosis [HR = 1.46; 95% CI: 1.27, 1.68]. IBD patients' spouses also had a higher SpA rate than reference individuals' spouses, but the difference was less pronounced [4.3 vs 3.5/10 000 person-years; HR = 1.22; 95% CI:1.09, 1.37]. No subgroup-specific risk pattern was identified among spouses. CONCLUSIONS: The observed shared familial risks between IBD and SpA support shared genetic factors in their pathogenesis. However, spouses of IBD patients were also at increased risk for SpA, reflecting the influence of environmental exposures or similarities in health-seeking patterns.

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.

Impact of immunosuppressive therapy on SARS-CoV-2 mRNA vaccine effectiveness in patients with immune-mediated inflammatory diseases: a Danish nationwide cohort study.

OBJECTIVE: Patients receiving immunosuppressives have been excluded from trials for SARS-CoV-2 vaccine efficacy. Investigation of immunosuppressants' impact on effectiveness of vaccines, particularly in patients with immune-mediated inflammatory diseases (IMID), is therefore required. DESIGN: We performed a nationwide cohort study to assess the risk of COVID-19 infection in vaccinated patients with IMID exposed to immunosuppressives compared with IMID unexposed to immunosuppressives. Exposure to immunosuppressives in the 120 days before receiving the second SARS-CoV-2 mRNA vaccination was assessed. Patients were followed from date of second vaccination and weighted Cox models were used to estimate the risk of infection associated with immunosuppressives. Secondary outcomes included hospitalisation and death associated with a positive SARS-CoV-2 test. Risk of infection by immunosuppressant drug class was also analysed. SETTING: This study used population-representative data from Danish national health registries in the period from 1 January to 30 November 2021. RESULTS: Overall, 152 440 patients were followed over 19 341 person years. Immunosuppressants were associated with a significantly increased risk of infection across IMID (HR: 1.4, 95% CI 1.2 to 1.5), in inflammatory bowel disease (IBD) (HR: 1.6, 95% CI 1.4 to 1.9) and arthropathy (HR: 1.3, 95% CI 1.1 to 1.4) but not psoriasis (HR: 1.1, 95% CI 0.9 to 1.4). Immunosuppressants were also associated with an increased risk of hospitalisation across IMID (HR: 1.4, 95% CI 1.1 to 2.0), particularly in IBD (HR: 2.1, 95% CI 1.0 to 4.1). No significantly increased risk of death in immunosuppressant exposed patients was identified. Analyses by immunosuppressant drug class showed increased COVID-19 infection and hospitalisation with anti-tumour necrosis factor (TNF), systemic corticosteroid, and rituximab and other immunosuppressants in vaccinated patients with IMID. CONCLUSION: Immunosuppressive therapies reduced effectiveness of mRNA SARS-CoV-2 vaccination against infection and hospitalisation in patients with IMID. Anti-TNF, systemic corticosteroids, and rituximab and other immunosuppressants were particularly associated with these risks.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). METHODS: We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. RESULTS: The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). CONCLUSIONS: In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

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.

Deciphering the different phases of preclinical inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disease (IMID) of the gastrointestinal tract and includes two subtypes: Crohn's disease and ulcerative colitis. It is well-recognized that IBD is associated with a complex multifactorial aetiology that includes genetic predisposition and environmental exposures, with downstream dysregulation of systemic immune function and host-microbial interactions in the local environment in the gut. Evidence to support the notion of a multistage development of IBD is growing, as has been observed in other IMIDs such as rheumatoid arthritis and systemic lupus erythematosus. With the rising worldwide incidence of IBD, it is increasingly important to understand the complex interplay of pathological events during the different stages of disease development to enable IBD prediction and prevention strategies. In this article, we review comprehensively the current evidence pertaining to the preclinical phase of IBD, including at-risk, initiation and expansion phases. We also discuss the framework of preclinical IBD, expanding on underlying pathways in IBD development, future research directions and IBD development in the context of other IMIDs.

Specific gut pathobionts escape antibody coating and are enriched during flares in patients with severe Crohn's disease.

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.

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.

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.

Autoimmune Pancreatitis in Patients with Inflammatory Bowel Disease: A Real-World Multicentre Collaborative ECCO CONFER Study.

BACKGROUND: Autoimmune pancreatitis [AIP] is rarely associated with inflammatory bowel disease [IBD]. The long-term outcomes of AIP and IBD in patients with coexisting AIP-IBD and predictors of complicated AIP course have rarely been reported. METHODS: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collected cases of AIP diagnosed in patients with IBD. Complicated AIP was defined as a composite of endocrine and/or exocrine pancreatic insufficiency, and/or pancreatic cancer. We explored factors associated with complicated AIP in IBD. RESULTS: We included 96 patients [53% males, 79% ulcerative colitis, 72% type 2 AIP, age at AIP diagnosis 35 ±â€…16 years]. The majority of Crohn's disease [CD] cases [78%] had colonic/ileocolonic involvement. In 59%, IBD preceded AIP diagnosis, whereas 18% were diagnosed simultaneously. Advanced therapy to control IBD was used in 61% and 17% underwent IBD-related surgery. In total, 82% of patients were treated with steroids for AIP, the majority of whom [91%] responded to a single course of treatment. During a mean follow-up of 7 years, AIP complications occurred in 25/96 [26%] individuals. In a multivariate model, older age at AIP diagnosis was associated with a complicated AIP course (odds ratio [OR] = 1.05, p = 0.008), whereas family history of IBD [OR = 0.1, p = 0.03], and CD diagnosis [OR = 0.2, p = 0.04] decreased the risk of AIP complications. No IBD- or AIP-related deaths occurred. CONCLUSIONS: In this large international cohort of patients with concomitant AIP-IBD, most patients have type 2 AIP and colonic IBD. AIP course is relatively benign and long-term outcomes are favourable, but one-quarter develop pancreatic complications. Age, familial history of IBD, and CD may predict uncomplicated AIP course.

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.

Risk of anorectal cancer in patients with Crohn's disease and perianal fistula: a nationwide Danish cohort study.

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).