May-Bente Bengtson

Background: This study aimed to compare the proportion of Crohn’s disease (CD) and ulcerative colitis (UC) patients receiving work disability (WD) benefits with the corresponding proportion in the background population at diagnosis and after 1 year, and to assess associations between selected variables and WD. Methods: Adults from a population-based inception cohort with WD data at diagnosis and/or 1-year follow-up were included. WD was defined as receiving work assessment allowance (AAP) or disability pension (DP). Relative risks (RRs) for AAP and DP were calculated vs. national registry proportions stratified by age and sex, overall RRs were age standardized. Multivariable logistic regression assessed associations between WD and selected variables. Results: At diagnosis, risk of AAP was increased for UC (RR, 1.5; 95% confidence interval [CI], 1.1-2.1) and CD patients between 30-39 years old (RR, 2.8; 95% CI, 1.1-5.8). AAP risk was increased at 1-year for both UC (RR, 1.6; 95% CI, 1.1-2.4) and CD (RR, 3.6; 95% CI, 2.4-5.2). DP risk was comparable with the background population. Higher general self-efficacy and health-related quality of life were associated with lower odds of WD, whereas disease-activity variables were not. Older age, comorbidities, and lower education were also associated with increased odds of WD in UC. Conclusions: After 1 year, patients with UC and CD had increased risk of AAP. Lower general self-efficacy and poorer health-related quality of life were associated with higher WD, suggesting a potential window for targeted interventions to reduce AAP and prevent or delay DP.

Background: Evidence for the clinical importance of changes in health-related quality of life (HRQoL) over time in unselected patients with ulcerative colitis (UC) and Crohn’s disease (CD) is limited. We aimed to describe HRQoL trajectories, determine clinically meaningful HRQoL improvement, and identify factors associated with such improvement during the first 3 years after diagnosis. Methods: Adults with UC and CD from a population-based inception cohort completed the Inflammatory Bowel Disease Questionnaire (IBDQ) and the 36-Item Short Form Survey (SF-36) at inclusion and at the 1-year and 3-year follow-ups. HRQoL trajectories were estimated using linear mixed-effects models. Clinically meaningful improvement was defined using established minimal clinically important difference (MCID) thresholds (IBDQ ≥16; SF-36 physical and mental component summary scores ≥3). Associations between prespecified variables and MCID achievement at follow-up were assessed using multivariable logistic regression. Results: Among 1016 patients (UC: 68%; CD: 32%), IBDQ and SF-36 physical and mental component summary scores improved at both follow-ups, and approximately half of the patients achieved the corresponding MCID thresholds. HRQoL scores remained below general Norwegian population norms, and trajectories were similar for UC and CD. Symptomatic remission was consistently associated with higher odds of clinically meaningful HRQoL improvement, whereas depressive symptoms, substantial fatigue, and irritable bowel–like symptoms were associated with lower odds. Endoscopic remission, biologic therapy, and bowel surgery during the first year were not significantly associated with clinically meaningful improvement. Conclusions: Clinically meaningful HRQoL improvement was achieved by about half of the patients and was consistently associated with lower symptom and psychosocial burden.

Background and Aim: Despite the well-established involvement of the gut microbiome in inflammatory bowel disease (IBD), less is known about how the gut microbiome changes over time and how it varies with clinical disease activity and fecal calprotectin (f-calprotectin). To address this gap, we utilized samples from the population-based inception cohort of the Inflammatory Bowel Disease in South-Eastern Norway III (IBSEN III) study. Methods: Data and stool samples from study participants with IBD and symptomatic controls were collected at diagnosis and after 3, 6, and 12 months. Microbiome profiling of stool samples was performed targeting the V3-V4 region of the 16S rRNA gene, and a consensus-based approach of mixed models was employed for the longitudinal microbiome analysis. Results: We included 1251 samples from 744 patients with ulcerative colitis, 618 samples from 356 patients with Crohn’ s disease and 266 samples from 164 symptomatic non-IBD controls. In the IBD population, we observed that levels of f-calprotectin decreased over time, as did the patient-reported disease activity (P < .001). Distinct changes in the gut microbiome of IBD patients were observed throughout the first year, such as increased alpha diversity (P < .001) and significant taxonomic changes. Notably, there was no covariation between the changes in alpha diversity and f-calprotectin or symptom score. Conclusion: The gut microbiome during the first year after IBD diagnosis showed changes that paralleled inflammation and clinical disease activity, albeit without covariation, suggesting that there may be a disease-driving impact of gut microbiome independent of inflammation and inflammation-driven symptoms.

Background: Inflammatory bowel diseases (IBDs) are complex conditions marked by chronic inflammation in the gastrointestinal tract. Traditional classification separates IBD into Crohn’s disease and ulcerative colitis, but this division may not fully capture disease heterogeneity. Here, we examine whether microbiome-driven subtyping can describe novel clinical IBD phenotypes. To achieve this, we applied unsupervised clustering to fecal microbiota profiles from the population-based Inflammatory Bowel Disease in South-Eastern Norway III (IBSEN III) cohort. Methods: A Gaussian Mixture Model (GMM) was used to cluster participants with IBD based on microbiome composition and examine associations between clusters and clinical outcomes, including inflammatory markers and disease severity during the first year after inclusion. Results: Three microbiome-based clusters were identified: CLO (dominated by Clostridia UCG-014), ALF (Agathobacter, Lachnoclostridium, and Faecalibacterium), and RUM (Ruminococcus gnavus). Participants in the RUM cluster had a higher risk of future severe disease than those in the CLO cluster, even among participants with remission-to-mild disease at inclusion (21% vs. 6%, P < 0.00001). This association could not be explained by antibiotic use or baseline disease severity. Cluster membership alone performed comparably to fecal calprotectin in distinguishing severe disease, and a combined model significantly improved accuracy (P < 0.0001). Conclusion: Our findings demonstrate a connection between microbiome composition and the risk of severe disease development, which is partly independent of inflammation levels at the time of sampling. Microbiome-informed subgrouping could lead to more personalized treatment strategies. Further validation is needed to determine the clinical utility of these clusters.

Symptoms of anxiety and depression are common in inflammatory bowel disease (IBD); the aim of this study was to assess the proportion of anxiety and depression in patients newly diagnosed with IBD, compare the rates with the Norwegian general population (NGP), and examine associations with selected sociodemographic, psychological, and disease-related factors. This prospective cohort study included newly diagnosed patients with IBD, and data from the HUNT4 survey of the NGP. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Crude statistical comparisons were performed using t-tests, Mann–Whitney U test, chi-square tests, or Fisher’s exact tests. Adjusted associations were modeled using multiple robust linear regression and multiple logistic regression. In total, 938/1562 (62.1%) patients with IBD completed the Hospital Anxiety and Depression Scale (Crohn’s disease [CD]: n = 297, ulcerative colitis [UC]: n = 641). The proportion of anxiety was 37.4% in CD and 32.1% in UC, while depression was reported by 21.9% and 16.8%, respectively. Both rates were significantly higher than those observed in the NGP (17.5% for anxiety and 9.4% for depression). Compared with the NGP, males with CD had significantly higher levels of anxiety and depression, males with UC had elevated anxiety only, while females with CD and UC showed increased anxiety and depression. Both substantial fatigue and general self-efficacy were significantly associated with anxiety and depression in IBD. Newly diagnosed patients with IBD experienced significant psychological challenges compared with the NGP. Early identification of anxiety and depression may enable targeted interventions.

Background Fatigue is common in Crohn’s disease (CD) and ulcerative colitis (UC), but the pathogenesis remains poorly understood. Aims This study aimed to assess changes in fatigue prevalence during the first year after diagnosis and examine the association between disease course and substantial fatigue (SF) at the 1-year follow-up. Methods Adults with newly diagnosed CD or UC were recruited from the population-based IBSEN III cohort. Fatigue was assessed at diagnosis and the 1-year follow-up using the Fatigue Questionnaire. Associations between SF at the 1-year follow-up and disease-related factors were quantified using multivariate logistic regression adjusted for sex, age and comorbidities. Results In total, 596 patients were included (CD: 196, UC: 400). SF was present at both baseline and after one year of disease for 46.9% (n = 92/196) and 40.5% (n = 162/400) of patients with CD and UC, respectively. In CD, development of endoscopically non-passable stricture and/or surgically treated stricture within first year of disease (OR = 4.52, 95%CI [1.61;12.68]), self-reported flares since diagnosis (OR = 2.55, 95%CI [1.26;5.16]), female sex (OR = 3.12, 95%CI [1.53;6.37]) and comorbidities (OR = 4.05, 95%CI [1.89;8.69]) were independently associated with SF at the 1-year follow-up. In UC, SF was associated with current biological treatment (OR = 5.14, 95%CI [1.56;16.96]), increasing Mayo endoscopic score at the 1-year follow-up (OR = 1.54, 95%CI [1.01;2.35]), self-reported flares since diagnosis (OR = 2.66, 95%CI [1.24;5.72]) and female sex (OR = 2.20, 95%CI [1.06;4.57]). Conclusions Fatigue frequently persists through the first year after IBD diagnosis. Clinical factors reflecting a more severe disease course were associated with SF one year after diagnosis in both CD and UC.

Identifying patients at risk of developing severe inflammatory bowel disease (IBD) can aid treatment decisions. However, predicting disease course remains challenging. We aimed to identify predictive factors associated with severe disease course in the first year after IBD diagnosis. Newly diagnosed adult (≥18 years) patients with IBD were recruited from a population-based inception cohort (IBSEN III study). Preselected baseline factors were tested for associations with severe disease course, defined as IBD-related hospitalisation, surgery, treatment with ≥2 steroid courses, >2 biologics and/or new event of complication (stricture, fistula, abscess only applicable Crohn's disease (CD)). From a best fitted multivariable logistic regression model stratified by diagnosis and age (18-40/>40 years), probability of severe disease for given combinations of predictive factors was summarised in prediction matrices. At one-year follow-up, 90/559 (16%) patients with ulcerative colitis (UC) and 74/312 (24%) with CD had severe disease. Treatment with systemic steroids, vitamin D deficiency, Simple Clinical Colitis Activity Index >2, and hypoalbuminemia at diagnosis were all significantly associated with severe disease in UC patients. CD patients with stricturing or penetrating disease behaviour, systemic steroids and hypoalbuminemia at diagnosis were associated with severe disease course. The least favourable combination of these factors increased the probability of severe disease from 3% (95%CI[0-5%]) to 72% (95%CI[66-79%]) for UC and from 8% (95%CI[3-13%]) to 88% (95%CI[84-93%]) for CD. Our study identified predictive factors associated with severe disease the first year after diagnosis. The probability of severe disease summarised in matrices enables easy risk stratification.

Introduction: IBD is an incurable immune-mediated inflammatory disease (IMID), affecting the gut with a high rate of primary- and secondary-loss-of-response to therapy. By investigating the T cell receptor repertoire of individuals with IBD, novel therapeutic and preventive strategies can be identified, and a better understanding of IBD can be obtained. Methods: Whereas most studies have so far focused on the more diverse T cell receptor beta (TRB) repertoire, we here profiled the alpha (TRA) repertoire of three cohorts containing treatment-naïve and treated individuals in addition to individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 2,151 individuals. Results: Using the generated datasets, we were able to replicate previous findings describing the expansion of Crohn’s-associated invariant T (CAIT) cells in individuals with Crohn’s disease (CD) in the three cohorts. Using a hypothesis-free statistical testing framework, we identified clonotypes that were associated with the disease at its different stages, e.g., at the time of diagnosis and decades post-diagnosis. By conducting a meta-analysis across the three cohorts, we were able to identify a set of clonotypes that were associated with the disease regardless of its stage. We validated our findings in a previously published independent test dataset from a German cohort, showing the robustness of the identified sets of clonotypes. Conclusion: The identified clonotypes are potential novel therapeutic targets to treat IBD, e.g., through targeted depletion. These clonotypes are also of major interest as they can be investigated in a targeted fashion to identify culprit antigen(s) in IBD.

Introduction: We aimed to determine the diagnostic and prognostic potential of baseline microbiome profiling in inflammatory bowel disease (IBD). Methods: Participants with ulcerative colitis (UC), Crohn’s disease (CD), suspected IBD, and non-IBD symptomatic controls were included in the prospective population-based cohort Inflammatory Bowel Disease in South-Eastern Norway III (third iteration) based on suspicion of IBD. The participants donated fecal samples that were analyzed with 16S rRNA sequencing. Disease course severity was evaluated at the 1-year follow-up. A stringent statistical consensus approach for differential abundance analysis with 3 different tools was applied, together with machine learning modeling. Results: A total of 1404 individuals were included, where n = 1229 samples from adults were used in the main analyses (n = 658 UC, n = 324 CD, n = 36 IBD-U, n = 67 suspected IBD, and n = 144 non-IBD symptomatic controls). Microbiome profiles were compared with biochemical markers in machine learning models to differentiate IBD from non-IBD symptomatic controls (area under the receiver operating curve [AUC] 0.75-0.79). For UC vs controls, integrating microbiome data with biochemical markers like fecal calprotectin mildly improved classification (AUC 0.83 to 0.86, P < .0001). Extensive differences in microbiome composition between UC and CD were identified, which could be quantified as an index of differentially abundant genera. This index was validated across published datasets from 3 continents. The UC-CD index discriminated between ileal and colonic CD (linear regression, P = .008) and between colonic CD and UC (P = .005), suggesting a location-dependent gradient. Microbiome profiles outperformed biochemical markers in predicting a severe disease course in UC (AUC 0.72 vs 0.65, P < .0001), even in those with a mild disease at baseline (AUC 0.66 vs 0.59, P < .0001). Conclusions: Fecal microbiome profiling at baseline held limited potential to diagnose IBD from non-IBD compared with standard-of-care. However, microbiome shows promise for predicting future disease courses in UC.

Background and Aims: The diagnostic and prognostic properties of anti-integrin αvβ6 immunoglobulin G (IgG) autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin αvβ6 autoantibodies and examine their association with disease outcomes. Methods: Serum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n = 473) were analyzed using an in-house fluorescence enzyme immunoassay based on EliA technology. Findings were validated in a Norwegian population-based inception cohort (n = 570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index. Results: In the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn’s disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC = 0.92, 95% CI, 0.89-0.95) was superior to hs-CRP (AUC = 0.65, 95% CI, 0.60-0.70, P < .001) and faecal calprotectin (fcalpro) (AUC = 0.88, 95% CI, 0.84-0.92, P = .09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC = 0.97, 95% CI, 0.95-0.98) and patient reclassification (P < .001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P = .003). Conclusions: Anti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.