BACKGROUND:Iron deficiency is common in patients with inflammatory bowel disease (IBD) and may lead to a variety of distressing symptoms negatively impacting quality of life. AIMS:This prospective observational cohort study aimed to assess quality of life, measured using the Short Form-36 (SF-36) questionnaire before and after treatment with high-dose intravenous iron in patients with IBD and iron deficiency. MATERIALS AND METHODS:Over a 15-month period, 130 patients with a well-established diagnosis of IBD (either ulcerative colitis (UC) or Crohns disease (CD)) and confirmed iron deficiency were consecutively assessed for study eligibility at two university hospitals in South-Eastern Norway. Of these, 112 patients were included in the per protocol set. Demographic characteristics were recorded at study inclusion. Clinical, and biochemical variables, as well as SF-36 questionnaires were collected just before and 5-7 weeks after treatment with intravenous iron. RESULTS:An improvement was observed in six of the eight SF-36 domains six weeks after treatment with intravenous iron. Females had lower scores compared to males at both visits, but there were no differences between UC and CD patients. Both sexes and the two diagnoses had a significant increase in vitality scores. Haemoglobin level was a significant predictor for improvement of quality of life. CONCLUSIONS:Treatment with high dose intravenous iron improves quality of life in IBD patients and iron deficiency and particularly in those with anaemia. The most significant improvements were observed in vitality and energy levels, suggesting a clinically meaningful change.

BackgroundFatigue is common in Crohn's disease (CD) and ulcerative colitis (UC), but the pathogenesis remains poorly understood.AimsThis 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.MethodsAdults 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.ResultsIn 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]).ConclusionsFatigue 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.

Introduction The members of the human gut microbiota contain a large diversity of genes, including antimicrobial resistance genes (ARGs) known as the gut resistome. The resistome is susceptible to alterations when compositional changes occur in the fecal and gut microbiome. Medical treatment may affect members of the gut microbiota. This study hypothesizes that medication used by patients with inflammatory bowel disease (IBD) leads to an increased prevalence and diversity of ARGs in the gut and a corresponding change in the taxonomic composition of the fecal microbiome. Methods Fecal samples from 16 Crohn's Disease (CD) and 16 Ulcerative Colitis (UC) patients, and 13 symptomatic controls (patients experiencing gastrointestinal symptoms, but with no endoscopic or histologic signs of IBD at inclusion, and no evidence of IBD during follow-up, were classified as symptomatic non-IBD controls) were subjected to metagenomic sequencing. The samples were collected before initiation of IBD medication, and after one year of treatment. Patients were treated with 5- Amino Salicylic Acid, Biological treatment, and Corticosteroids, or a combination of the three. Resistance Gene Identifier Comprehensive Antibiotic Resistance Database (RGI CARD) and regression modelling were used to analyze the abundance and diversity changes in the ARGs and the taxonomy. Results We found significant associations with medicine use and abundance changes for eight resistance genes (Antibiotic Resistance Ontology (ARO) terms), four AMR gene families and 14 AMR drug classes. The use of 5-ASA was associated with abundance changes for the efflux pump efpA. This medication was also associated with significant changes in the "pyrazinamide resistant rpsA" gene family and with six drug classes (cephamycin, diaminopyrimidine, mupirocin, penem, pyrazinamide and rifamycin). Biological treatment was associated with changes in abundance of five drug classes (Zoliflodacin, lincosamide, macrolide, streptogramin and tetracycline). Corticosteroids were associated with changes in the ARO terms sul2, OXA beta-lactamase AMR gene family, and three drug classes (carbapenem, glycylcycline, and triclosan). Conclusions All IBD medication groups were found to be associated with significant abundance changes within the fecal resistome between inclusion and follow-up time points, where corticosteroid treatment resulted in less resistance in the microbiota compared to in the persons not treated with corticosteroids (either 5-Aminosalicylic Acid or Biological treatments).

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:Tryptophan (Trp) metabolism is a central immunometabolic axis in inflammatory bowel disease (IBD) and has been linked to inflammatory activity and immune regulation. While individual Trp metabolites have been associated with disease severity and treatment response, systems-level frameworks to define metabolic subtypes in IBD are lacking. Objective:To identify reproducible Trp-related metabolic subtypes ("metabotypes") in IBD and assess their association with disease activity, clinical outcomes, and early disease development. Design:We applied unsupervised clustering to serum concentrations of 16 Trp-related metabolites in a discovery cohort of patients with IBD undergoing biologic induction therapy (n=134). Metabotypes were validated in three independent IBD cohorts (total n>2,800), a healthy reference population, and a prospective cohort of first-degree relatives at risk for Crohn's disease. Associations with disease activity, longitudinal outcomes, and metabolic pathways were assessed using multivariable regression and survival analysis. Results:Four reproducible metabotypes with distinct metabolite profiles were identified across cohorts: Low Kyna, High Kyna, High Quin, and Balanced. Low Kyna and High Quin metabotypes were consistently associated with increased inflammatory activity and adverse clinical outcomes, including increased risk of treatment escalation and disease progression. Pathway-level analyses revealed alterations in NAD-related, lipid, and amino acid pathways between inflammatory metabotypes. A metabotype resembling inflammatory disease states was enriched in individuals who later developed Crohn's disease in a prospective pre-disease cohort. Conclusion:Trp-linked metabotypes define reproducible immunometabolic states in IBD that associate with disease activity and clinical outcomes and may precede disease onset. These findings provide a framework for metabolic stratification and biomarker-guided clinical trials targeting immunometabolic pathways.

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.

BACKGROUND AND AIMS: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. METHODS: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. RESULTS: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. CONCLUSIONS:Newly diagnosed patients with IBD experienced significant psychological challenges compared with the NGP. Early identification of anxiety and depression may enable targeted interventions.

Inflammatory bowel disease (IBD) is an incurable immune-mediated inflammatory disease, 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. To identify and validate T cell clonotypes implicated in the pathogenesis of IBD, we profiled the T cell receptor alpha (TRA) repertoire of three cohorts containing treatment-naive, treated individuals, and individuals living with the disease for >20 years, resulting in an exhaustive dataset containing the TRA repertoire of 1,732 individuals. 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 clonotypes. The identified clonotypes are novel therapeutic targets to treat IBD, for example, through targeted depletion. By identifying antigens recognized by these T cells, a better understanding of the etiopathology of IBD, particularly CD, can be obtained.

BACKGROUND AND AIMS: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

BACKGROUND AND AIMS:The emergence of biologic therapy has coincided with a decline in surgery rates for Crohn's disease (CD). This study aims to describe the disease course, including intra-abdominal surgery rates, biologic therapy use, and variables associated with biologic therapy initiation in a cohort of newly diagnosed CD patients. METHODS:The Inflammatory Bowel Disease in South-Eastern Norway (IBSEN) III study is a population-based inception cohort study. From 2017 to 2019, newly diagnosed inflammatory bowel disease patients were included for prospective follow-up. The present study included CD patients ≥ 18 years. Clinical, endoscopic, and demographic data were collected at diagnosis and 1-year follow-up. Data were analyzed by using the Kaplan-Meier method and regression analyses. RESULTS:In total, 424 CD patients (median age 37.0 years (range 18-80), female 55.0%) were included. At diagnosis, 50.5% presented with ileal disease and 80.7% with inflammatory behavior. Within a 1-year follow-up, 39.6% of patients received their first biologic therapy and 5.2% required intra-abdominal surgery. Systemic steroid treatment, CRP ≥ 5.0 mg dL-1, Harvey-Bradshaw Index score > 4, ileocolonic disease and penetrating disease behavior at diagnosis were independently associated with increased risk of initiation of biologic therapy, while age > 40 years was associated with decreased risk. CONCLUSION:A high proportion of patients had ileal disease and inflammatory behavior at diagnosis. Still, nearly 40% started biologic therapy within the 1-year follow-up, while only 5% required intra-abdominal surgery.

Whereas altered immune processes have been identified in individuals with inflammatory bowel disease (IBD), potentially causative antigens remain to be identified. By interrogating the immune repertoire of individuals with IBD, an identification of common antigenic exposures associated with the disease can be obtained. We analyzed the T cell receptor beta (TRB) chain repertoire of 1,890 individuals with Crohn’s disease (CD) and 914 individuals with ulcerative colitis (UC), enabling the identification of 327 TRB clonotypes associated with CD and 130 with UC. We validated the expansion of these clonotypes in a cohort of treatment-naïve individuals with either CD, UC or symptomatic control (n=855). These disease-associated clonotypes were restricted to disease-associated risk HLA alleles and their expansion correlated with disease-severity but not with surgery or treatment trajectory. In conclusion, we identified and validated TRB clonotypes that are associated with either CD or UC, these clonotypes are a novel therapeutic target in IBD. ### Competing Interest Statement H.E. did an internship at Adaptive Biotechnologies from July 2023 to September 2023. G.P. has served as a speaker and/or advisory board member for AbbVie. She has also received grant support from Ferring, Tillotts Pharma, and Takeda. V.A.K. received speaker honoraria from Thermo Fischer Scientific, is a consultant for Janssen-Cilag AS, and is on the advisory Board of Tillotts Pharma AG and Takeda AS. J.R.H. received a research grant from Biogen and speaker honoraria from Roche, Novartis, Amgen, and has been a consultant for Novartis and Orkla Health, all unrelated to the present work. M.L.H. received investigator-initiated research grants from Takeda, Pfizer, Tilllotts, Ferring, and Janssen. Speaker honoraria from Takeda, Tillotts, Ferring, AbbVie, Galapagos, and Meda. She is also on the advisory board of Takeda, Galapagos, MSD, Lilly, and AbbVie. All other co-authors declare no competing interests. EU Horizon Europe Program, miGut-Health: Personalized blueprint of intestinal health (101095470) German Research Foundation (DFG), Research Unit 5042: miTarget – The Microbiome as a Therapeutic Target in Inflammatory Bowel Diseases German Research Foundation (DFG), Cluster of Excellence 2167 “Precision Medicine in Chronic Inflammation (PMI)”.

Abstract Background The kynurenine pathway is upregulated in inflammatory bowel disease (IBD) in a disease-activity induced manner. This route of tryptophan (Trp) degradation leads to a variety of bioactive compounds, including several with anti-inflammatory (e.g., kynurenic acid (Kyna), xanthurenic acid (Xana)) or cytotoxic (quinolinic acid (Quin)) effects. Our aim was to stratify patients with IBD into distinct subgroups based on their Trp metabolic profiles (Trp metabotypes) and to assess their prognostic capacity regarding disease progression. Methods We measured 16 Trp-related metabolites with particular attention to kynurenine pathway metabolites in the serum of a longitudinal German cohort (hypothesis generation) of 82 Ulcerative Colitis (UC) and 52 Crohn’s Disease (CD) patients. We used unsupervised k-means clustering to identify distinct clusters of patients based on their metabolite profiles and employed regression analysis to identify associations between the metabotypes and disease activity and progression. The analysis was expanded to three independent prospective validation cohorts recruited in France (n = 281 UC, 788 CD), the USA (n = 329 controls, 470 UC, 374 CD) and an inception cohort in Norway (n = 179 UC, 340 CD). Results We found four highly stable metabotypes within the discovery cohort (Fig 1A). Strong signals from the anti-inflammatory compounds Kyna and Xana characterized the first two metabotypes (High/Low Kyna metabotypes), which exhibited opposing associations with clinical, biochemical, and endoscopic disease activity. The third is characterized by high Quin levels and increased disease activity, while the fourth is metabolically heterogeneous and has lower disease activity (Fig 1B). These metabotypes were present in both UC and CD, albeit with differing proportions. Associations with disease activity were confirmed in three validation cohorts. Furthermore, we found differential probabilities between the metabotypes regarding future escalation to biologic therapies, requirement for steroid courses, IBD-related hospitalization and surgery. This was particularly evident when comparing individuals in the Low Kyna group with the lower incidence rates observed in the High Kyna group (Fig. 1C). Conclusion A distinct pattern of Trp degradation occurs in a subset of IBD patients that is strongly and consistently linked with disease activity and longitudinal outcomes of disease progression across multiple recruitment sites spanning two continents. Further work will focus on metabolic characterization of the metabotypes to understand the physiological processes driving the differentiation. This work may lead to the design of new therapeutic modalities targeting Trp metabolism in distinct patient groups.

PURPOSE:Almost a third of patients with inactive inflammatory bowel disease (IBD) suffer from symptoms compatible with irritable bowel syndrome (IBS-like symptoms). The relation between these symptoms and diet in patients with IBD is not fully established. We aimed to assess associations between IBS-like symptoms and intake of macronutrients and fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) in patients with inactive IBD compared to an IBD-free background population. METHODS:Patients with IBD at one-year follow-up from the IBSEN III (Inflammatory bowel disease in South-Eastern Norway) study were compared to an IBD-free Norwegian background population (Tromsø7). A food frequency questionnaire (FFQ) was used to collect dietary data including FODMAP intake, which was compiled as gram/100 g of food and assessed in patients with active versus inactive IBD. Rome IV criteria were applied to define IBS-like symptoms in patients with inactive IBD. RESULTS:A sample of 154 patients ≥40 years with inactive IBD was compared to 11078 adults from the IBD-free background population (Tromsø7). There were no significant associations between IBS-like symptoms and FODMAP and macronutrient intake, neither in patients with inactive IBD nor in the IBD-free background population. Patients with IBD ≥40 years had higher intake of fructans and total FODMAPs compared to the Tromsø7 sample. Intake of nutrients and FODMAPs was similar in patients with active IBD (n = 105), inactive IBD with IBS-like symptoms (n = 55), and without IBS-like symptoms (n = 197). CONCLUSION:FODMAP and macronutrient intake were not associated with IBS-like symptoms in patients with inactive IBD one-year after diagnosis.

BACKGROUND:Distinguishing irritable bowel syndrome (IBS) from inflammatory bowel disease (IBD) flare-ups is challenging. This study used objective remission markers to accurately determine IBS prevalence in a population-based cohort of patients with IBD. METHODS:Adults with ulcerative colitis and Crohn's disease were recruited from the IBD in South-Eastern Norway III cohort study. Irritable bowel-like symptoms were assessed using the Rome IV criteria for patients in remission from IBD at 1- and 3-year follow-ups. Remission was defined objectively using the biochemical marker fecal calprotectin (FC) ≤ 250 µg/g, and comparisons to remission based on endoscopic indices were made at 1-year follow-up. RESULTS:Among patients with FC ≤ 250 µg/g, IBS prevalences were 21.9% (n = 62/283) and 16.1% (n = 49/304) at the 1- and 3-year follow-ups, respectively, which were higher than that in the Norwegian population (9.5%; P < .005). Of patients in endoscopic remission at 1-year follow-up, 19.2% (n = 43/224) reported IBS-like symptoms, which was not significantly different from IBS prevalence for patients with FC ≤ 250 µg/g. Irritable bowel syndrome was independently associated with substantial fatigue (odds ratio: 3.05 [95% CI, 1.48-6.27]) and female sex (odds ratio: 2.67 [95% CI, 1.34-5.32]) at the 1-year follow-up. Patients with IBS reported significantly reduced health-related quality of life (HRQoL) scores. CONCLUSIONS:The prevalence of IBS among patients in remission from IBD was approximately twice as common as that in the Norwegian population. Irritable bowel syndrome was independently associated with substantial fatigue, female sex, and reduced HRQoL.

Background:As part of the IBD Character initiative, we examined an inception cohort and investigated mucosal microbiota composition and transcriptional activity in relation to clinical outcomes. Methods:A cohort of 237 individuals were included from five countries: Crohn's disease (CD, n = 72), ulcerative colitis (UC, n = 57), symptomatic non-IBD controls (SC, n = 78) and healthy controls (HC, n = 30). Rectal/colonic biopsies were obtained at inclusion, and DNA and RNA were extracted from the same biopsy and examined by sequencing the 16S rRNA V4 region. Results:Beta diversity measurements separated IBD from both HC and SC. IBD and SC exhibited reduced intra-individual diversity compared with HC. When comparing taxonomy at DNA and RNA level, six bacteria were found to differ in abundance and/or transcriptional activity between IBD and symptomatic control, while there were 14 and three between symptomatic control and CD and UC, respectively. A limited number of bacterial taxa were responsible for the largest difference between presence and activity, separating patients and controls. Multiple bacterial taxa were associated with treatment escalation in both UC and CD. Machine-learning models separated IBD from symptomatic controls and treatment escalators from non-escalators (AUC >0.8). However, the differential effects were mainly driven by clinical biomarkers, such as f-calprotectin, s-albumin, and b-hemoglobin. Conclusion:Differences between presence and transcriptional activity were found among multiple taxa when assessing 16S rRNA at DNA and RNA level. Symptomatic controls were more similar to the IBD patients compared to HC. The analyses suggest that the mucosal microbiota carries a moderate diagnostic and predictive potential, outcompeted by f-calprotectin.

AIMS:Iron deficiency anemia (IDA) is among the most common extraintestinal sequelae of inflammatory bowel disease (IBD). Intravenous iron is often the preferred treatment in patients with active inflammation with or without active bleeding, iron malabsorption, or intolerance to oral iron. The aim of the present study was to evaluate the cost-utility of ferric derisomaltose (FDI) versus ferric carboyxymaltose (FCM) in patients with IBD and IDA in Norway. MATERIALS AND METHODS:A published patient-level simulation model was used to evaluate the cost-utility of FDI versus FCM in patients with IBD and IDA from a Norwegian national payer perspective. Iron need was modelled based on bivariate distributions of hemoglobin and bodyweight combined with simplified tables of iron need from the FDI and FCM summaries of product characteristics. Patient characteristics and disease-related quality of life data were obtained from the PHOSPHARE-IBD trial. Cost-utility was evaluated in Norwegian Kroner (NOK) over a five-year time horizon. RESULTS:Patients required 1.64 fewer infusions of FDI than FCM over five years (5.62 versus 7.26), corresponding to 0.41 fewer infusions per treatment course. The reduction in the number of infusions resulted in cost savings of NOK 5,236 (NOK 35,830 with FDI versus NOK 41,066 with FCM). The need for phosphate testing in patients treated with FCM resulted in further cost savings with FDI (no costs with FDI versus NOK 4,470 with FCM). Total cost savings with FDI were therefore NOK 9,707. FDI also increased quality-adjusted life expectancy by 0.071 quality-adjusted life years (QALYs) driven by reduced incidence of hypophosphatemia and fewer interactions with the healthcare system. CONCLUSIONS:FDI resulted in cost savings and improved quality-adjusted life expectancy versus FCM in patients with IDA and IBD in Norway. FDI therefore represents the economically preferable iron formulation in Norwegian patients with IBD and IDA in whom it is indicated.

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. ### Competing Interest Statement MP, DM, BH, and HR acknowledge employment by, and equity ownership in, Adaptive Biotechnologies Corp. H.E. did an internship at Adaptive Biotechnologies from July 2023 to September 2023. JH has received consulting and/or advisory board fees from: AbbVie, Alfasigma, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Index Pharma, Janssen, Johnson & Johnson, MEDA, Medivir, Medtronic, Merck, Merck Sharp & Dohme, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, STADA, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma, UCB; and speaker's fees from: AbbVie, Alfasigma, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Hospira, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma; and research grant support from Janssen, Merck Sharp & Dohme and Takeda. G.P. has served as a speaker and/or advisory board member for AbbVie. She has also received grant support from Ferring, Tillotts Pharma, and Takeda. V.A.K. received speaker honoraria from Thermo Fischer Scientific, is a consultant for Janssen-Cilag AS, and is on the advisory Board of Tillotts Pharma AG and Takeda AS. J.R.H. received a research grant from Biogen and speaker honoraria from Roche, Novartis, Amgen, and has been a consultant for Novartis and Orkla Health, all unrelated to the present work. M.L.H. received investigator-initiated research grants from Takeda, Pfizer, Tilllotts, Ferring, and Janssen. Speaker honoraria from Takeda, Tillotts, Ferring, AbbVie, Galapagos, and Meda. She is also on the advisory board of Takeda, Galapagos, MSD, Lilly, and AbbVie. All other co-authors declare no competing interests. Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, Research Unit 5042: miTarget, The Microbiome as a Therapeutic Target in Inflammatory Bowel Diseases, Cluster of Excellence 2167 Precision Medicine in Chronic Inflammation (PMI), Collaborative Research Unit 1526 Pathomechanisms of Antibody-mediated Autoimmunity (PANTAU) Insights from Pemphigoid Diseases European Union, miGut-Health: Personalized blueprint of intestinal health (101095470) Innovative Medicines Initiative, https://ror.org/019af4n30, 831434 (3TR)

BACKGROUND:Antiplatelet and anticoagulant therapy are associated with a significant risk of upper gastrointestinal bleeding (UGIB), as is the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Concomitant treatment with proton pump inhibitors (PPIs) has been shown to reduce the risk of this complication. AIMS:To compare the use of risk medications and PPIs in a cohort of adult patients with bleeding peptic ulcers or erosions in the stomach or duodenum with the background population. MATERIALS AND METHODS:We performed a prospective observational study including 543 patients with endoscopically verified bleeding ulcers and/or erosions at two large hospitals in Norway. Information on risk medications taken prior to study enrolment was collected prospectively through structured interviews with patients and with the review of their medical records, whereas for the background population the information was obtained from The Norwegian Prescription Database (NorPD). RESULTS:Overall, 434 (80%) of the patients used risk medications, compared to 34% in the background population (p < 0.001). Only 39 (8.9%) of the patients received PPIs as co-medication, and 150 (34.6%) tested positive for Helicobacter pylori (H. pylori) infection. CONCLUSIONS:Among patients with bleeding ulcers and erosions, we found a high prevalence of risk medication use and an underutilization of prophylactic PPIs. H. pylori infection appears to play a minor role. CLINICAL TRIAL REGISTRATION:Bleeding Ulcer and Erosions Study "BLUE Study", ClinicalTrials.gov Identifier: NCT03367897.