Inflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that ...cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data generated from the same IBD patients.
We initiated the 1000IBD project ( https://1000ibd.org ) to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1215 participants have been enrolled in the project and enrolment is on-going. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.
All molecular data generated within the 1000IBD project will be shared on the European Genome-Phenome Archive ( https://ega-archive.org , accession no: EGAS00001002702). The first data release, detailed in this announcement and released simultaneously with this publication, will contain basic phenotypes for 1215 participants, genotypes of 314 participants and gut microbiome data from stool samples (315 participants) and biopsies (107 participants) generated by tag sequencing the 16S gene. Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.
We report on the establishment and future development of the 1000IBD project: the first comprehensive multi-omics dataset aimed at discovering IBD biomarker profiles and treatment targets.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background and Aims
Inflammatory bowel disease IBD phenotypes are very heterogeneous between patients, and current clinical and molecular classifications do not accurately predict the course ...that IBD will take over time. Genetic determinants of disease phenotypes remain largely unknown but could aid drug development and allow for personalised management. We used genetic risk scores GRS to disentangle the genetic contributions to IBD phenotypes.
Methods
Clinical characteristics and imputed genome-wide genetic array data of patients with IBD were obtained from two independent cohorts cohort A, n = 1097; cohort B, n = 2156. Genetic risk scoring GRS was used to assess genetic aetiology shared across traits and IBD phenotypes. Significant GRS–phenotype (false-discovery rate FDR corrected p <0.05) associations identified in cohort A were put forward for replication in cohort B.
Results
Crohn’s disease CD GRS were associated with fibrostenotic CD R2 = 7.4%, FDR = 0.02 and ileocaecal resection R2 = 4.1%, FDR = 1.6E-03, and this remained significant after correcting for previously identified clinical and genetic risk factors. Ulcerative colitis UC GRS R2 = 7.1%, FDR = 0.02 and primary sclerosing cholangitis PSC GRS R2 = 3.6%, FDR = 0.03 were associated with colonic CD, and these two associations were largely driven by genetic variation in MHC. We also observed pleiotropy between PSC genetic risk and smoking behaviour R2 = 1.7%, FDR = 0.04.
Conclusions
Patients with a higher genetic burden of CD are more likely to develop fibrostenotic disease and undergo ileocaecal resection, whereas colonic CD shares genetic aetiology with PSC and UC that is largely driven by variation in MHC. These results further our understanding of specific IBD phenotypes.
Abstract
Background
Oxidative stress is a key pathophysiological mechanism in inflammatory bowel diseases (IBD). Systemic levels of oxidative stress are reflected by reduced levels of free thiols ...(FT) in circulating proteins, especially those in albumin, which associates with disease activity in IBD. Yet, clinal value of circulating FT level as biomarkers of disease and therapy response remains largely unexplored. Here we investigated the association between plasma FT levels and clinical parameters, the plasma inflammatory proteome and medication use.
Methods
Plasma samples from 1,028 patients with IBD (567 Crohn's disease CD and 461 ulcerative colitis UC), and 500 healthy controls (HCs) participating in the 1000IBD and LifeLines projects were profiled for free thiols (FT), uric acid, bilirubin and 92 inflammation-related proteins (Olink Inflammation panelÒ). All biomarkers were associated with clinical phenotypes using general linear models adjusting for age, sex, body mass index, smoking and medication use.
Results
Plasma FT levels were significantly lower in IBD compared to HCs (p<0.05) (Figure 1A), with patients with UC showing even lower levels than patients with CD (p<0.05). Patients with UC on induction therapy had lower FT levels compared to patients on maintenance therapy (p<0.05). Furthermore, FT levels of patients with IBD were strongly associated with systemic inflammation (C-reactive protein CRP, p<0.05) (Figure 1B). In both patients withCD and UC, reduced FT levels were associated with elevated levels of inflammation-, apoptosis-, and growth factor-related proteins, including C-X-C motif chemokine 9 (CXCL9) (Figure 1C-D), CUB domain-containing protein 1 (CDCP1) and caspase-8 (CASP8), proteins previous associated with preclinical IBD1-3. Furthermore, specifically for patients with UC, reduced FT levels were associated with elevated eotaxin-1 (CCL11) (Figure 1C), monocyte chemotactic protein-1 (MCP-1), and several cytokine biomarkers like Interleukine-6 (IL6) and Interleukin-17A (IL17A).
Conclusion
Systemic FT levels associate with inflammatory disease activity and clinical therapy and may offer potential utility in clinical assessments. This study highlights the intricate involvement of oxidative stress in various inflammatory pathways and components, particularly in innate/adaptive immune balance, cell damage, and apoptosis. These findings contribute to a deeper understanding of the interplay between oxidative stress, inflammation, and IBD.
Funding: This study was supported by Janssen Research & Development LLC.
References:
1. Leibovitzh H, et al. Gut. 2023
2. Chen J, et al. JCC. 2023
3. Bergemalm D, et al. Gastroenterology, 2021
The number of patients with inflammatory bowel disease IBD, of non-Caucasian descent in Western Europe, is increasing. We aimed to explore the impact of ethnicity and country of birth on IBD ...phenotype.
IBD patients treated in the eight University Medical Centers in The Netherlands Dutch IBD Biobank were divided into two groups according to their ethnicity: 1 Caucasian patients of Western and Central European descent CEU; and 2 patients of non-Caucasian descent non-CEU. The non-CEU group was subdivided according to country of birth, into: born in The Netherlands or Western Europe non-CEU European born; or born outside Western-Europe who migrated to The Netherlands non-CEU non-European born. Both comparisons were analysed for phenotype differences by chi-square test.
The Dutch IBD Biobank included 2921 CEU patients and 233 non-CEU patients. Non-CEU Crohn's disease CD patients more often had upper gastro-intestinal disease 16% vs 8%, p = 0.001 and anal stenosis 10% vs 4%, p = 0.002 than CEU CD patients. The use of anti-tumour necrosis factor TNF agents and immunomodulators was higher in non-CEU IBD patients than in CEU IBD patients 45% vs 38%, p = 0.042 and 77% vs 66%, p = 0.001, respectively. Non-CEU IBD patients born in Europe n = 116 were diagnosed at a lower age than non-CEU IBD patients born outside Europe n = 115 at 22.7 vs 28.9 years old, p < 0.001.
Non-Caucasians had more severe disease behaviour than Caucasians. Non-CEU patients born in Europe were diagnosed at a lower age with IBD than those born outside Europe who migrated to The Netherlands.
Abstract
Background
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are characterized by complex pathophysiology, phenotypic heterogeneity and disease ...progression. Patients with IBD show distinct shifts in circulating inflammatory proteins, which may be suggestive of biological mechanisms behind clinical disease progression. Thus far, proteomics studies in IBD have primarily focused on changes in the plasma proteome at pre- and post-diagnostic stages, as well as its genetic and phenotypic determinants. However, studies focusing on proteomic biomarkers for predicting the risk of disease progression are lacking. Here we aimed to identify plasma proteomic biomarkers associated with disease progression in patients with IBD.
Methods
In this study, a total of 83 inflammation-related plasma proteins were quantified in a cohort of 452 patients with IBD (267 with CD, 185 with UC) who participated in the 1000IBD project and had available follow-up data. Proximity extension assay technology was leveraged to measure these proteins. Disease progression outcomes, including the development of intestinal stenosis, IBD-related surgical interventions, and extraintestinal manifestations (EIMs), were extracted from electronic health records. Logistic regression analyses and Cox proportional hazards regression models were used to investigate associations between plasma proteins and the risk of disease progression outcomes.
Results
During a median follow-up of 10.3 (interquartile range IQR 7.6-11.1) years, 63 (23.6%) patients with CD developed intestinal stenosis, 53 (19.9%) patients with CD and 14 (7.6%) patients with UC underwent IBD-related surgery, and 120 (44.9%) patients with CD and 45 (24.3%) patients with UC developed EIMs. On multivariable analysis, macrophage colony-stimulating factor-1 (CSF-1) was most strongly associated with the presence of stricturing disease (Montreal B2 phenotype) (odds ratio OR per doubling in protein level 4.5, 95%CI: 1.6-12.9, P=0.005) and with a shorter stenosis-free survival (hazard ratio HR per doubling 4.2, 95%CI: 1.5-11.6, P=0.006). Furthermore, interferon-gamma (IFN-γ) was most strongly associated with surgery in CD (OR per doubling 1.6, 95%CI: 1.2-2.2, P=0.003) and with shorter surgery-free survival in CD (HR per doubling 1.4, 95%CI: 1.2-1.7, P<0.001) in multivariable analysis.
Conclusion
This study highlights that disease progression in IBD is associated with elevated levels of specific inflammatory plasma proteins. Specifically, CSF-1 and IFN-γ show most promise as possible proteomic biomarkers for the future development of intestinal stenosis and the risk of surgical interventions in patients with CD, respectively.
AIM To determine the prevalence of work disability in inflammatory bowel disease(IBD), and to assess risk factors associated with work disability.METHODS For this retrospective cohort study, we ...retrieved clinical data from the Dutch IBD Biobank on July 2014, containing electronic patient records of 3388 IBD patients treated in the eight University Medical Centers in the Netherlands. Prevalence of work disability was assessed in 2794 IBD patients and compared with the general Dutch population. Multivariate analyses were performed for work disability(sick leave, partial and full disability) and long-term full work disability(> 80% work disability for > 2 years).RESULTS Prevalence of work disability was higher in Crohn’s disease(CD)(29%) and ulcerative colitis(UC)(19%) patients compared to the general Dutch population(7%). In all IBD patients, female sex, a lower education level, and extra-intestinal manifestations, were associated with work disability. In CD patients, an age > 40 years at diagnosis, disease duration > 15 years,smoking, surgical interventions, and anti-TNFα use were associated with work disability. In UC patients, an age > 55 years, and immunomodulator use were associated with work disability. In CD patients, a lower education level(OR = 1.62, 95%CI: 1.02-2.58), and in UC patients, disease complications(OR = 3.39, 95%CI: 1.09-10.58) were associated with long-term full work disability.CONCLUSION The prevalence of work disability in IBD patients is higher than in the general Dutch population. Early assessment of risk factors for work disability is necessary, as work disability is substantial among IBD patients.
AIM:To validate the Montreal classification system for Crohn’s disease(CD) and ulcerative colitis(UC) within the Netherlands.METHODS:A selection of 20 de-identified medical records with an ...appropriate representation of the inflammatory bowel disease(IBD) sub phenotypes were scored by 30 observers with different professions(gastroenterologist specialist in IBD,gastroenterologist in training and IBD-nurses) and experience level with IBD patient care.Patients were classified according to the Montreal classification.In addition,participants were asked to score extra-intestinal manifestations(EIM) and disease severity in CD based on their clinical judgment.The inter-observer agreement was calculated by percentages of correct answers(answers identical to the "expert evaluation") and Fleiss-kappa(k).Kappa cutoffs:< 0.4-poor; 0.41-0.6-moderate; 0.61-0.8-good; > 0.8 excellent.RESULTS:The inter-observer agreement was excellent for diagnosis(k = 0.96),perianal disease(k = 0.92) and disease location in CD(k = 0.82) and good for age of onset(k = 0.67),upper gastrointestinal disease(k = 0.62),disease behaviour in CD(k = 0.79) and disease extent in UC(k = 0.65).Disease severity in UC was scored poor(k = 0.23).The additional items resulted in a good inter-observer agreement for EIM(k = 0.68) and a moderate agreement for disease severity in CD(k = 0.44).Percentages of correct answers over all Montreal items give a good reflection of the inter-observer agreement(> 80%),except for disease severity(48%-74%).IBD-nurses were significantly worse in scoring upper gastrointestinal disease in CD compared to gastroenterologists(P = 0.008) and gastroenterologists in training(P = 0.040).Observers with less than 10 years of experience were significantly better at scoring UC severity than observers with 10-20 years(P = 0.003) and more than 20 years(P = 0.003) of experience with IBD patient care.Observers with 10-20 years of experience with IBD patient care were significantly better at scoring upper gastrointestinal disease in CD than observers with less than 10 years(P = 0.007) and more than 20 years(P = 0.007) of experience with IBD patient care.CONCLUSION:We found a good to excellent interobserver agreement for all Montreal items except for disease severity in UC(poor).
Real-life data on long-term effectiveness and safety of dupilumab in atopic dermatitis patients are limited.
To study 52-week effectiveness and safety of dupilumab in a prospective multicenter cohort ...of adult patients with treatment-refractory atopic dermatitis.
Patients treated with dupilumab and participating in the Dutch BioDay registry were included. Clinical effectiveness and safety were evaluated.
Two hundred ten atopic dermatitis patients were included. Mean percentage change in Eczema Area and Severity Index score after 16 weeks was –70.0% (standard deviation 33.2%) and further decreased to –76.6% (standard deviation 30.6%) by week 52. A greater than or equal to 75% improvement in the score was achieved by 59.9% of individuals by week 16 and by 70.3% by week 52. The most reported adverse effect was conjunctivitis (34%). Limited patients (17; 8.1%) discontinued dupilumab treatment.
Because of the lack of a control group and observational design, factors of bias may have been induced.
Treatment with dupilumab resulted in a rapid improvement in clinical outcome measures, and effectiveness further improved during the 52-week follow-up period.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are ...limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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