Association Between the Clinical, Biochemical, and Endoscopic Activity of Inflammatory Bowel Diseases and Severity and Long-term Outcomes of Coronavirus Disease 2019-A Population-based Study.

This brief report investigated the impact of clinical, biochemical, and endoscopic activity of IBD on the severity and long-term outcomes of COVID-19 in a prospective population-based cohort. The study did not identify any association between IBD activity and COVID-19 outcomes.

Outcomes and Long-Term Effects of COVID-19 in Patients with Inflammatory Bowel Diseases - A Danish Prospective Population-Based Cohort Study with Individual-Level Data.

BACKGROUND AND AIMS: The health consequences of coronavirus disease 2019 [COVID-19] among patients with ulcerative colitis [UC] and Crohn's disease [CD] remain largely unknown. We aimed to investigate the outcomes and long-term effects of COVID-19 in patients with UC or CD. METHODS: We conducted a prospective, population-based study covering all Danish patients with CD or UC and confirmed COVID-19 between January 28, 2020 and April 1, 2021, through medical records and questionnaires. RESULTS: All 319 patients with UC and 197 patients with CD who developed COVID-19 in Denmark were included in this study and compared with the Danish background population with COVID-19 [N = 230 087]. A significantly higher risk of COVID-19-related hospitalization was observed among patients with UC (N = 46 [14.4%], relative risk [RR] = 2.49 [95% confidence interval, CI, 1.91-3.26]) and CD (N = 24 [12.2%], RR = 2.11 [95% CI 1.45-3.07]) as compared with the background population (N = 13 306 [5.8%]). A similar pattern was observed for admission to intensive care (UC: N = 8 [2.51%], RR = 27.88 [95% CI 13.88-56.00]; CD: N = 3 [1.52%], RR = 16.92 [95% CI 5.46-52.46]). After a median of 5.1 months (interquartile range [IQR] 4.5-7.9), 58 [42.3%] and 39 [45.9%] patients with UC and CD, respectively, reported persisting symptoms which were independently associated with discontinuation of immunosuppressive therapies during COVID-19 (odds ratio [OR] = 1.50 [95% CI 1.07-10.22], p = 0.01) and severe COVID-19 (OR = 2.76 [95% CI 1.05-3.90], p = 0.04), but not with age or presence of comorbidities. CONCLUSION: In this population-based study of 516 patients with IBD and COVID-19, 13.6% needed hospitalization and 2.1% required intensive care. Furthermore, sequelae were frequent, affecting 43.7% of COVID-19-infected patients. These findings might have implications for planning the healthcare of patients in the post-COVID-19 era.

Validation of ulcerative colitis and Crohn's disease and their phenotypes in the Danish National Patient Registry using a population-based cohort.

INTRODUCTION: The Danish National Patient Registry (DNPR) has been the source of several epidemiological studies of inflammatory bowel disease (IBD). However, the validation dates back to 1996 and lacks outpatient records and disease classification. The aim of this study was to update the validation and assess the validity and reliability of using the registry in disease classification. METHODS: Validation of the registry was done using a population-based inception cohort of IBD patients from 2003 to 2011 consisting of 513 patients. Specificity and sensitivity were calculated for the diagnoses of Crohn's disease (CD) and ulcerative colitis (UC), age at diagnosis and disease classification according to the Montreal Classification at both time of diagnosis and end of follow-up. RESULTS: The registry showed high validity and reliability in identifying CD and UC patients concerning correct age classification and identifying perianal disease. The registry showed inconsistent, unreliable results in further disease classification. CONCLUSIONS: The DNPR has good validity and reliability in identifying patients with CD and UC, and defining the age of patients at diagnosis. However, categorising IBD patients according to the Montreal Classification should not be carried out using DNPR data in their current form, except when identifying CD patients with perianal disease.

Incidence, Risk Factors and Evaluation of Osteoporosis in Patients With Inflammatory Bowel Disease: A Danish Population-Based Inception Cohort With 10 Years of Follow-Up.

BACKGROUND: Patients with inflammatory bowel disease [IBD] including Crohn's disease [CD] and ulcerative colitis [UC] are at risk of developing metabolic bone disease. The aims here were to investigate the screening strategy, incidence and risk factors of osteoporosis in a prospective population-based inception cohort. METHOD: Between 2003 and 2004 all incident patients diagnosed with CD and UC in a well-defined Copenhagen area were included and followed until 2015. Data were compared with a control population [at a ratio of 1:20]. Regression models were performed with several covariates. The sensitivity of the Danish registries for osteoporosis was also assessed. RESULTS: A total of 513 patients were included [213 CD, 300 UC]. Overall, 338 (66%, CD: 164 [77%], UC: 174 [58%], p < 0.001] patients received ≥ 500 mg corticosteroid within a year, resulting in 781 patient-years at risk of osteoporosis. Of those, only 83 [10.6%] patient-years were followed by a dual-energy X-ray absorptiometry scan within the same or the following 2 years.Overall, 73 [14.2%] IBD patients (CD: 31 [14.6%], UC: 42 [14%]) and 680 [6.6%, p < 0.001] controls were diagnosed with osteoporosis during follow-up. The risk of osteoporosis was increased compared to the control population (odds ratio: CD: 2.9 [95% confidence interval: 2.0-4.1], UC: 2.8 [2.1-3.9]). CONCLUSION: In this population-based inception cohort, the incidence of osteoporosis was significantly higher compared to a control population. Measurement of bone mineral density is infrequent, especially in patients at high risk of developing osteoporosis. These results demonstrate the need of further awareness of the risk of osteoporosis among IBD patients, and prospective population-based studies are warranted.

Direct and Indirect Costs of Inflammatory Bowel Disease: Ten Years of Follow-up in a Danish Population-based Inception Cohort.

BACKGROUND: Inflammatory bowel disease [IBD], encompassing Crohn's disease [CD] and ulcerative colitis [UC], places a high burden on health care resources. To date, no study has assessed the combined direct and indirect cost of IBD in a population-based setting. Our aim was to assess this in a population-based inception cohort with 10 years of follow-up. METHODS: All incident patients diagnosed with CD or UC, 2003-2004, in a well-defined area of Copenhagen, were followed prospectively until 2015. Direct and indirect costs were retrieved from Danish national registries. Data were compared with a control population [1:20]. Associations between the costs and multiple variables were assessed. RESULTS: A total of 513 (CD: 213 [42%], UC: 300 [58%]) IBD patients were included. No significant differences were found in indirect costs between CD, UC, and the control population. Costs for CD patients were significantly higher than those for UC regarding all direct expenditures (except for5-aminosalicylates [5-ASA] and diagnostic expenses). Biologics accounted for €1.6 and €0.3 million for CD and UC, respectively. The total costs amounted to €42.6 million. Only patients with extensive colitis had significantly higher direct costs (proctitis: €2273 [1341-4092], left-sided: €3606 [2354-5311], extensive: €4093 [2313-6057], p <0.001). No variables were significantly associated with increased total costs in CD or in UC patients. CONCLUSIONS: In this prospective population-based cohort, direct costs for IBD remain high. However, indirect costs did not surpass the control population. Total costs were mainly driven by hospitalisation, but indirect costs accounted for a higher percentage overall, although these did decrease over time. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Disease activity, steroid use and extraintestinal manifestation are associated with increased disability in patients with inflammatory bowel disease using the inflammatory bowel disease disability index: a cross-sectional multicentre cohort study.

BACKGROUND: The inflammatory bowel disease disability index (IBD-DI) was developed recently. The aim was to translate the IBD-DI into Danish and validate it for future clinical studies and practice, and to assess the level of disability among IBD patients. PATIENTS AND METHODS: The IBD-DI was translated using a transcultural adaptation method. Between January and December 2017, patients from three outpatient clinics in three different regions in Denmark were given the final version of the IBD-DI for self-completion. Validation was carried out according to guidelines. Disability level was assessed among the entire cohort and in various subgroups. RESULTS: A total of 200 patients were included in the study, including 112 Crohn's disease (CD) and 88 ulcerative colitis (UC) patients. The response rate was 90%. The IBD-DI showed excellent reliability and validity. CD patients showed worse disability levels than UC patients [mean (SD): CD: 37.3 (20.2) vs. UC: 21.7 (16.4); P=0.04]. In both CD and UC, significantly increased disability levels were found between patients with active disease, use of steroid and extraintestinal manifestation (P<0.05). CONCLUSION: A valid and reliable version of the IBD-DI is now available in Danish for future studies. Several clinical factors are shown to affect the levels of disability among patients with CD and UC. The disability levels are significantly increased in patients with active disease, treated with systemic steroids, and extraintestinal manifestations are present in both CD and UC. Further testing of the Danish IBD-DI is needed to assess its responsiveness and interpretability.

NKG2D ligand expression in Crohn's disease and NKG2D-dependent stimulation of CD8+ T cell migration.

Interaction between the activating NKG2D receptor on lymphocytes and its ligands MICA, MICB, and ULBP1-6 modulate T and NK cell activity and may contribute to the pathogenesis of Crohn's disease (CD). NKG2D ligands are generally not expressed on the cell surface of normal, non-stressed cells, but expression of MICA and MICB in CD intestine has been reported. In this exploratory study, we further characterize the expression of NKG2D and its ligands, including the less well-described ULBP4-6, in CD, and test if NKG2D ligand interactions are involved in the migration of activated T cells into the affected mucosal compartments. Intestinal tissue from CD patients and healthy controls were analyzed by flow cytometry, mass cytometry, and immunohistochemistry for expression of NKG2D and ligands, and for cytokine release. Furthermore, NKG2D-dependent chemotaxis of activated CD8+ T cells across a monolayer of ligand-expressing human intestinal endothelial cells was examined. Activated lymphocytes down-regulated NKG2D expression upon accumulation in inflamed CD intestine. NKG2D expression on CD56+ T and γδ T cells from inflamed tissue seemed inversely correlated with CRP levels and cytokine release. B cells, monocytes, mucosal epithelium, and vascular endothelium expressed NKG2D ligands in inflamed CD intestine. The expression of NKG2D ligands was correlated with cytokine release, but was highly variable between patients. Stimulation of vascular intestinal endothelial cells in vitro induced expression of NKG2D ligands, including MICA/B and ULBP2/6. Blockade of NKG2D on CD8+ T cells inhibited the migration over ligand-expressing endothelial cells. Intestinal induction of NKG2D ligands and ligand-induced down-regulation of NKG2D in CD suggest that the NKG2D-ligand interaction may be involved in both the activation and recruitment of NKG2D+ lymphocytes into the inflamed CD intestine.

Validation and Optimization of an Ex Vivo Assay of Intestinal Mucosal Biopsies in Crohn's Disease: Reflects Inflammation and Drug Effects.

Crohn's disease (CD) is a chronic illness demanding better therapeutics. The marketed biologics only benefit some patients or elicit diminishing effect over time. To complement the known methods in drug development and to obtain patient specific drug responses, we optimized and validated a known human explant method to test drug candidates and pathophysiological conditions in CD intestinal biopsies. Mucosal biopsies from 27 CD patients and 6 healthy individuals were collected to validate an explant assay test where the polarized tissue was cultured on a novel metal mesh disk, slightly immersed in medium imitating an air-liquid interphase. After culture in high oxygen for 24 hours with or without biological treatment in the medium, biopsy integrity and penetration of antibodies was measured by immunohistochemistry (IHC). Nine cytokines were quantified in the conditioned medium as a read-out for degree of inflammation in individual biopsies and used to evaluate treatment efficacy. The biopsies were well-preserved, showing few structural changes. IHC revealed tissue penetration of antibodies demonstrating ability to test therapeutic antibodies. The cytokine release to the medium showed that the assay can distinguish between inflammation states and then validate the known effect of two treatment biologics confirmed by a detection panel of five specific cytokines. Our data also suggest that the assay would be able to indicate which patients are responders to anti-TNF-α therapeutics, and which are non-responders. This study demonstrates this version of an ex vivo culture as a valid and robust assay to assess inflammation in mucosal biopsies and test of the efficacy of novel drug candidates and current treatments on individual patients-potentially for a personalized medicine approach.