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.

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).

Antibiotic use as a risk factor for inflammatory bowel disease across the ages: a population-based cohort study.

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.

Eosinophilic oesophagitis in Denmark: Population-based incidence and prevalence in a nationwide study from 2008 to 2018.

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.

Does childhood exposure to biodiverse greenspace reduce the risk of developing asthma?

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.

Clinical procedures used to diagnose inflammatory bowel disease: real-world evidence from a Danish nationwide population-based study.

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.

GLP-1 based therapies and disease course of inflammatory bowel disease.

BACKGROUND: The disease course of inflammatory bowel disease (IBD) following treatment with glucagon-like peptide (GLP)-1 based therapies is unclear. The aim of this study was to examine the disease course of IBD in patients treated with GLP-1 based therapies compared with treatment with other antidiabetics. METHODS: Using nationwide Danish registries, we identified patients with IBD and type 2 diabetes who received antidiabetic treatment between 1 January 2007 and 31 March 2019. The primary outcome was a composite of the need for oral corticosteroids, tumour necrosis factor-α inhibitors, IBD-related hospitalisation, or IBD-related surgery. In the setting of a new-user active comparator design, we used Poisson regression to estimate incidence rate ratios (IRR) comparing treatment with GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors with other antidiabetic therapies. The analyses were adjusted for age, sex, calendar year, IBD severity, and metformin use. FINDINGS: We identified 3751 patients with a diagnosis of IBD and type 2 diabetes and with a prescription of an antidiabetic drug (GLP-1 receptor agonists/DPP-4 inhibitors: 982 patients; other antidiabetic treatment: 2769 patients). The adjusted IRR of the composite outcome was 0·52 (95% CI: 0·42-0·65) for patients exposed to GLP-1 receptor agonists/DPP-4 inhibitors compared with patients exposed to other antidiabetics. INTERPRETATION: In patients with IBD and type 2 diabetes, we observed a lower risk of adverse clinical events amongst patients treated with GLP-1 based therapies compared with treatment with other antidiabetics. These findings suggest that treatment with GLP-1 based therapies may improve the disease course of IBD.

Fractures and Osteoporosis in Patients With Diabetes With Charcot Foot.

OBJECTIVE: Charcot foot is a serious complication of diabetes, with degeneration of the bones and joints in the foot and ankle. It is unknown whether patients with diabetes with a Charcot foot have an increased risk of osteoporosis and fractures. The aim of this study was to investigate whether patients with diabetes with a Charcot foot have an increased risk of fracture and/or osteoporosis compared with patients with diabetes without Charcot foot. RESEARCH DESIGN AND METHODS: A Danish register-based, nationwide population-based matched cohort study was conducted. During 1995-2018, we identified 1,602 patients with diabetes with Charcot foot and matched them on sex and date of diagnosis of diabetes with 16,296 patients with diabetes without Charcot foot. We used logistic regression to estimate odds ratios (ORs) with 95% CIs for fracture and osteoporosis. Information about exposure, outcome, and comorbidities was retrieved from the Danish National Patient Register. RESULTS: Diabetes patients with Charcot foot had higher risk of fractures compared with those without Charcot foot (i.e., ORs for any fracture, lower-leg fracture, foot fracture, and osteoporotic fracture were 1.8 [95% CI 1.6-2.0], 2.4 [2.0-2.8], 2.9 [2.6-3.3], and 1.3 [1.1-1.4], respectively). Furthermore, patients with diabetes with Charcot foot had higher risk of osteoporosis compared with the patients without Charcot foot, with an OR of 1.3 (95% CI 1.1-1.5). CONCLUSIONS: Patients with diabetes with a Charcot foot have an increased risk of fractures and osteoporosis compared with patients with diabetes without a Charcot foot.

Risk of Urolithiasis in Patients With Inflammatory Bowel Disease: A Nationwide Danish Cohort Study 1977-2018.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) are suggested to be at increased risk of urolithiasis, but the magnitude of risk and the impact of medical and surgical treatment on this risk remain unknown. We therefore aimed to determine overall and treatment-related risk of urolithiasis in patients with IBD in a nationwide population-based cohort study. METHODS: Using national registers, we identified all patients with IBD and all cases of urolithiasis in Denmark during 1977-2018. We obtained information on all IBD medications and surgical procedures during 1995-2018. IBD cases were matched 1:10 on age and sex to non-IBD individuals. RESULTS: In total, 2,549 (3%) of 75,236 IBD patients and 11,258 (2%) of 767,403 non-IBD individuals developed urolithiasis, resulting in a 2-fold increased risk of urolithiasis (HR, 2.27; 95% CI, 2.17-2.38) in patients with IBD. The patients were also at increased risk of repetitive urolithiasis events (RR, 1.09; 95% CI: 1.04-1.15) and had increased risk of urolithiasis prior to IBD diagnosis (OR, 1.42; 95% CI: 1.34-1.50). After IBD diagnosis, risk of urolithiasis was associated with anti-TNF therapy and surgery. CONCLUSION: Patients with IBD had a 2-fold increased risk of urolithiasis after IBD diagnosis and a 42% increased risk prior to IBD diagnosis. Risk was increased in anti-TNF exposed patients, and after surgery, suggesting that IBD severity per se and surgery, with altered intestinal absorption, increase risk of urolithiasis. Since stone formation is associated with adverse outcomes including sepsis, subpopulations of IBD patients, especially those undergoing strong immunosuppression might benefit from additional urolithiasis screening.

Comparative Studies of the Gut Microbiota in the Offspring of Mothers With and Without Gestational Diabetes.

Background: Offspring of mothers with gestational diabetes mellitus (GDM) have increased risk of developing metabolic disorders as they grow up. Microbial colonization of the newborn gut and environmental exposures affecting the configuration of the gut microbiota during infancy have been linked to increased risk of developing disease during childhood and adulthood. In a convenience sample, we examined whether the intestinal tract of children born to mothers with GDM is differentially colonized in early life compared to offspring of mothers with normal gestational glucose regulation. Secondly, we examined whether any such difference persists during infancy, thus potentially conferring increased risk of developing metabolic disease later in life. Methods: Fecal samples were collected from children of mothers with (n = 43) and without GDM (n = 82) during the first week of life and again at an average age of 9 months. The gut microbiota was characterized by 16S rRNA gene amplicon sequencing (V1-V2). Differences in diversity and composition according to maternal GDM status were assessed, addressing potential confounding by mode of delivery, perinatal antibiotics treatment, feeding and infant sex. Results: Children of mothers with GDM were featured by a differential composition of the gut microbiota, both during the first week of life and at 9 months, at higher taxonomic and OTU levels. Sixteen and 15 OTUs were differentially abundant after correction for multiple testing during the first week of life and at 9 months, respectively. Two OTUs remained differentially abundant after adjustment for potential confounders both during the first week of life and at 9 months. Richness (OTU) was decreased in neonates born to mothers with GDM; however, at 9 months no difference in richness was observed. There was no difference in Shannon's diversity or Pielou's evenness at any timepoint. Longitudinally, we detected differential changes in the gut microbiota composition from birth to infancy according to GDM status. Conclusion: Differences in glycaemic regulation in late pregnancy is linked with relatively modest variation in the gut microbiota composition of the offspring during the first week of life and 9 months after birth.

Antibiotic treatment during early childhood and risk of type 1 diabetes in children: A national birth cohort study.

OBJECTIVE/BACKGROUND: Antibiotics are widely used during childhood infections and influence the composition of the microbiota, which is established during the first years of life. Evidence from animal models of type 1 diabetes shows that antibiotics might accelerate disease progression, and altered intestinal microbiota has been reported in association with type 1 diabetes in humans. We aimed to test the hypothesis that early exposure to antibiotics (0-24 months of age) was associated with an increased risk of childhood type 1 diabetes development. METHODS: We studied 75 615 mother-child dyads from the Danish National Birth Cohort. Information on the use of antibiotics during early childhood and type 1 diabetes development in childhood was available for all children via linkage to the Danish National Prescription Registry and the Danish National Patient Register, respectively. The mean follow-up time was 14.3 years (range 11.5 to 18.4 years, SD 1.4). RESULTS: After adjustment for confounders, we found no association between antibiotic exposure and risk of type 1 diabetes (HR 1.26, 95% CI 0.89-1.79). The number of antibiotic courses during early childhood was not associated with type 1 diabetes development when analyzing for one (HR 1.31, 95% CI 0.87-1.99), two (HR 0.99, 95% CI 0.61-1.63), or 3 or more (HR 1.42, 95% CI 0.95-2.11) courses. Furthermore, no specific types of antibiotics (penicillins/beta-lactam antibacterials, sulfonamide/trimethroprim, or macrolides/lincosamides/streptogramins) were associated with increased risk of type 1 diabetes. CONCLUSION: Our nationwide cohort study suggests that postnatal exposure to antibiotics does not influence the development of childhood type 1 diabetes.

Outcome of concomitant treatment with thiopurines and allopurinol in patients with inflammatory bowel disease: A nationwide Danish cohort study.

BACKGROUND: Thiopurine and allopurinol in combination are associated with clinical remission in inflammatory bowel diseases but their influence on subsequent outcomes is unclear. We compared outcomes during exposure to both thiopurines and allopurinol versus thiopurines alone. METHODS: We established a nationwide cohort of patients with inflammatory bowel diseases exposed to thiopurines ± allopurinol during 1999-2014, using registry data. Patients were followed until hospitalization, surgery, anti-TNFα, or death (as a primary composite outcome). We used Poisson regression analyses to calculate incidence rate ratios overall and stratified by calendar period (assuming the combined exposure was unintended before 2009). RESULTS: A total of 10,367 patients with inflammatory bowel diseases (Crohn's disease, n = 5484; ulcerative colitis, n = 4883) received thiopurines. Of these, 217 (2.1%) also received allopurinol. During 24,714 person years of follow-up, we observed 40 outcomes among thiopurine-allopurinol-exposed patients, and 4745 outcomes among those who were thiopurine exposed; incidence rate ratio, 1.26 (95% confidence interval, 0.92-1.73). The incidence rate ratios decreased over time: 4.88 (95% confidence interval 2.53-9.45) for 1999-2003, 2.19 (95% confidence interval, 1.17-4.09) for 2004-2008 and 0.80 (95% confidence interval, 0.52-1.23) for 2009-2014. CONCLUSION: Our nationwide inflammatory bowel disease cohort study shows that concomitant thiopurine-allopurinol is as safe to use as thiopurines alone, with a tendency towards a positive effect on clinical outcomes in recent calendar periods when combined use was intended.

COPD exacerbations: the impact of long versus short courses of oral corticosteroids on mortality and pneumonia: nationwide data on 67 000 patients with COPD followed for 12 months.

Introduction: A large group of patients with chronic obstructive pulmonary disease (COPD) are exposed to an overload of oral corticosteroids (OCS) due to repeated exacerbations. This is associated with potential serious adverse effects. Therefore, we evaluated the impact of a recommended reduction of OCS duration in 2014 on the risk of pneumonia hospitalisation and all-cause mortality in patients with acute exacerbation of COPD (AECOPD). Methods: This was a nationwide observational cohort study that was based on linked administrative registry data between 1 January 2010 and 31 October 2017. 10 152 outpatients with COPD (median age 70 years) treated with either a short (≤250 mg) or long course (>250 mg) of OCS for AECOPD were included in the study. Cox proportional hazards regression models were used to derive an estimation of multivariable adjusted HRs (aHRs) for pneumonia hospitalisation or all-cause mortality combined and pneumonia hospitalisation and all-cause mortality, separately. Results: The long course of OCS treatment for AECOPD was associated with an increased 1-year risk of pneumonia hospitalisation or all-cause mortality (aHR 1.3, 95% CI 1.1 to 1.4; p<0.0001), pneumonia hospitalisation (aHR 1.2, 95% CI 1.0 to 1.3; p=0.0110) and all-cause mortality (aHR 1.8, 95% CI 1.5 to 2.2; p<0.0001) as compared with the short course of OCS treatment. These results were confirmed in several sensitivity analyses. Conclusion: The change of recommendations from long courses to short courses of OCS for AECOPD in 2014 was strongly associated with a decrease in pneumonia admissions and all-cause mortality, in favour of short courses of OCS.