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Abstract
Introduction Inflammatory bowel diseases (IBD), encompassing Crohn’s disease and ulcerative colitis, are chronic, inflammatory diseases of the gastrointestinal tract. We have initiated a Danish population-based inception cohort study aiming to investigate the underlying mechanisms for the heterogeneous course of IBD, including need for, and response to, treatment.
Methods and analysis IBD Prognosis Study is a prospective, population-based inception cohort study of unselected, newly diagnosed adult, adolescent and paediatric patients with IBD within the uptake area of Hvidovre University Hospital and Herlev University Hospital, Denmark, which covers approximately 1 050 000 inhabitants (~20% of the Danish population). The diagnosis of IBD will be according to the Porto diagnostic criteria in paediatric and adolescent patients or the Copenhagen diagnostic criteria in adult patients. All patients will be followed prospectively with regular clinical examinations including ileocolonoscopies, MRI of the small intestine, validated patient-reported measures and objective examinations with intestinal ultrasound. In addition, intestinal biopsies from ileocolonoscopies, stool, rectal swabs, saliva samples, swabs of the oral cavity and blood samples will be collected systematically for the analysis of biomarkers, microbiome and genetic profiles. Environmental factors and quality of life will be assessed using questionnaires and, when available, automatic registration of purchase data. The occurrence and course of extraintestinal manifestations will be evaluated by rheumatologists, dermatologists and dentists, and assessed by MR cholangiopancreatography, MR of the spine and sacroiliac joints, ultrasonography of peripheral joints and entheses, clinical oral examination, as well as panoramic radiograph of the jaws. Fibroscans and dual-energy X-ray absorptiometry scans will be performed to monitor occurrence and course of chronic liver diseases, osteopenia and osteoporosis.
Ethics and dissemination This study has been approved by Ethics Committee of the Capital Region of Denmark (approval number: H-20065831). Study results will be disseminated through publication in international scientific journals and presentation at (inter)national conferences.
- Inflammatory bowel disease
- EPIDEMIOLOGY
- Adult gastroenterology
- Paediatric gastroenterology
- IMMUNOLOGY
- MOLECULAR BIOLOGY
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- Inflammatory bowel disease
- EPIDEMIOLOGY
- Adult gastroenterology
- Paediatric gastroenterology
- IMMUNOLOGY
- MOLECULAR BIOLOGY
Strengths and limitations of this study
The study is a prospective population-based inception cohort study of all newly diagnosed patients with inflammatory bowel diseases patients, both adult, adolescent and paediatric, within a well-described geographical area, ensuring the cohort represents the whole spectrum of disease presentation and course.
The longitudinal study design, with regular collection of biological material, will enable investigations of the underlying mechanisms of the heterogeneous courses of IBD.
In this study population, the occurrence and course of some of the most common subclinical and clinical extraintestinal rheumatological, dermatological, oral and hepatobiliary manifestations will be thoroughly described.
Although well described, the cohort is limited by its sample size when compared with existing prospective population-based cohorts.
Due to the nature of the study design, missing data and biological samples are expected in some patients.
Introduction
Inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory diseases of the gastrointestinal (GI) tract. The pathogenesis of CD and UC is not fully understood but is thought to be the result of a complex interplay between genetic and environmental factors, epithelial barrier defects and altered gut microbiota, resulting in chronic relapsing innate and adaptive immune responses.1 2 The incidence of IBD is increasing worldwide, and in Europe alone, more than 1.3 million people are affected.3 Denmark has one of the highest prevalence in the world, with 0.8% of its population diagnosed with IBD.4 The disease course of IBD is highly heterogeneous with some patients experiencing only mild inflammation and few symptoms, while others develop severe inflammation and complications.5 6 Prospective population-based studies have recently demonstrated that a significant proportion of patients experience disease progression within the first 5 years of their diagnosis that requires hospitalisation, IBD-related surgery, and advanced therapy.5 6 Patients diagnosed in childhood (20%), and specifically those with a very early onset of IBD, have more widespread disease, higher need for more aggressive treatment and have increased risk of cancer and mortality compared with patients diagnosed as adults.7
Furthermore, up to 50% of patients with IBD experience extraintestinal manifestations (EIMs) of IBD or immune-mediated inflammatory diseases (IMIDs) before or during the disease course of IBD.8–10 Most commonly, EIMs occur in the musculoskeletal, dermatological, hepatopancreatobiliary and ocular organ systems.11–13 Some EIMs, IMIDs (such as spondyloarthritis or psoriasis) and IBD share common inflammatory mechanisms14 and environmental factors15 that are associated with increased morbidity and mortality.16 17 In addition, oral health status (ie, presence/absence of periodontitis, caries, periapical lesions) including the composition of the oral microbiome has been frequently discussed in the last decade as potentially relevant factor for IBD development, severity and progression.18–24 Based on the results of a recent questionnaire-based, case–control study performed in Denmark a significant association between diagnosis and severity of IBD, periodontitis and tooth loss rate was confirmed.25 26 Exploration of the pathogenesis of EIMs, including their overlap with IBD, might help clarify whether EIMs are systemic manifestations directly related to the intestinal disruptions of IBD, or whether these clinical conditions represent an abnormal, genetically mediated immunological response to complex environmental stimuli. Such efforts could facilitate the identification of novel pathogenic pathways that can be targeted by individually tailored treatments.
Changes in the disease course of IBD are believed to be determined by factors within the first few years following diagnosis.27 Therefore, it is important to identify patients at an early stage who might later develop aggressive disease to offer these patients closer follow-up and individually tailored therapy.28 Currently, physicians rely on relatively poor predictors of the disease course of UC and CD when managing patients with these diseases. In UC, current predictors include young age at diagnosis and extensive disease, which have been shown to be associated with an increased risk of acute severe UC.29 Accordingly, specific phenotypic appearances of CD, including perianal and upper GI involvement, have been shown to be predictive of disabling disease.30 31 Second, environmental risk factors, such as smoking, are associated with increased risk of medical refractoriness in patients with CD.32 Third, intestinal ultrasonography (IUS), a non-invasive modality for the assessment of disease activity and complications, has shown potential in predicting therapeutic response and risk of surgery.33–35
Gut microbiomes may fluctuate with IBD activity, and cytokine profiles in patients with IBD likewise seem to change over time.36 37 Changes in these measures might therefore predict the disease course of IBD and the response to IBD medications.38 Similarly, interactions between host and gut microbiota might play a role in IBD pathogenesis and thus warrant further research in representative cohorts.39 For example, it has been very recently reported that the gut microbiome of patients with IBD—in contrast to the gut microbiome of IBD-free controls—is significantly more alike to the oral microbiome.40 41 Recent preclinical trials investigating different mechanisms of the potential interplay between periodontitis and IBD have quite consistently shown the potential devastating effect of the oral microbiome on IBD pathogenesis and course, and a potentially positive effect of periodontal treatment on gut microbiome.41 A prospective investigation of the changes over time in all biological and environmental exposure patterns is necessary to assess their interactions and associations with the disease course which might ultimately facilitate development and implementation of precision medicine in the care of patients with IBD.
Study aims
IBD Prognosis Study aims to establish a prospective population-based cohort with an organised biobank system, from the time of diagnosis and added to throughout follow-up in order to characterise and predict the individual disease courses and treatment responses in patients with IBD. The primary and secondary aims are listed in table 1.
Primary and secondary aims of the IBD Prognosis Study
Methods
Study design overview
The IBD Prognosis Study is a population-based inception cohort study of newly diagnosed paediatric, adolescent and adult patients with IBD according to current diagnostic criteria (ie, Porto diagnostic criteria42 or Copenhagen diagnostic criteria43 within the 2-year period between 1 May 2021 and 30 April 2023.42 43 Patients will be followed prospectively with regular clinical examinations, imaging assessments and collection of biological samples, as described below. While the study aims to follow all patients for 20 years after their diagnosis of IBD, samples for the biobank will be collected during the first 5 years of follow-up. The study will be conducted at the Department of Gastroenterology and Hepatology, Herlev University Hospital and at the Gastrounit and Department of Paediatrics, Hvidovre University Hospital. The Department of Paediatrics, Hvidovre University Hospital covers the paediatric uptake area of both Hospitals. Together, these two hospitals cover an uptake area of approximately 1 050 000 inhabitants in the Copenhagen area (~20% of the total Danish population).44 45 Based on the current incidence of IBD in Denmark, a total of 550 adult patients and 100 adolescent or paediatric patients is expected to be diagnosed with IBD throughout the inclusion period.4
Follow-up
Follow-up visits will be scheduled according to the study timelines presented in tables 2 and 3. Additional follow-ups will take place at the treating physician’s discretion in case of significant disease events, which are defined as IBD-related hospitalisation or disease progression necessitating intensification of treatment. The follow-up period is 20 years from diagnosis until 30 April 2043. During years 6–20, patients will only be followed through their medical records.
Study timeline for adult patients with inflammatory bowel diseases
Study timeline for paediatric and adolescent patients with inflammatory bowel diseases
Data collection and management
Tables 2 and 3 provide the timeline for adult and paediatric patients, respectively.
The study outcome definitions and measures are listed in table 4. At each visit, all IBD-related clinical data will be prospectively collected, including patient demographics, disease activity, phenotypical disease presentation, results of blood and stool samples, current medical therapy, surgery, hospitalisation and occurrence of cancers.
Study outcome measures and definitions
In addition, all medical adverse reactions will be recorded prospectively. During each follow-up time point, patients are systematically asked about any medical adverse events which are categorised according to the medical dictionary of regulatory activities (MedDRA) 18.1 (or newer) terminology (table 1). Severity of adverse events, which will be graded based on clinical examination, and its implications for clinical management will be monitored as well.
Study data will be collected and managed using electronic case report forms (eCRFs) in the Research Electronic Data Capture system.46
Imaging assessments
MR enterography will be performed in all patients at the time of diagnosis as part of their diagnostic workup. Additionally, patients with CD or an unclassified type of IBD will undergo MR enterography 12 months after diagnosis, and CD patients will also undergo it 5 years from diagnosis (tables 2 and 3). Results and images from any scheduled or unscheduled endoscopic assessments will be recorded. The images will be scored as specified in table 4. Paediatric patients younger than 16 with CD will receive an X-ray examination of the left hand and wrist to investigate growth impairment at the time of diagnosis, and repeatedly if indicated by their disease phenotype (table 3).
Intestinal ultrasound
The infrastructure of the IBD Prognosis Study will be used to conduct substudies of the use of IUS in assessing disease burden and of its use as an early detector of disease progression. As such, IUS is planned at diagnosis, and again at 3, 6 (if F-calprotectin is higher than 250 µg/g), and 12 months of follow-up, and annually thereafter. In case of IBD-related surgery, IUS will be performed preoperatively and as part of the postoperative assessment 6–12 months after surgery. Sonographic disease activity will be assessed in terms of bowel wall thickness, colour Doppler signal, inflammatory fat (i-fat) and bowel wall stratification. The IBUS-SAS score, which integrates these four items, will be calculated as well.47 Scans will be performed systematically of the entire bowel, including the sigmoid colon, descending colon, transverse colon, ascending colon, cecum, terminal ileum and the proximal small bowel. Image acquisition, grading of parameters and documentation will follow the recommendations by Novak et al.47 Additional details for the IUS substudies are described in online supplemental file 1.
Supplemental material
Patient-reported outcomes
As specified in table 5, validated patient-reported outcomes (PROs) of clinical disease activity, environmental factors, disability and health-related quality of life will be collected throughout the study.
Questionnaires and patient-reported outcomes
Supplemental material
Extra-intestinal assessments
MR cholangiopancreatography (MRCP) will be performed at the time of diagnosis and after 5 years in all adult patients with IBD to assess the occurrence and phenotype of co-occurring hepatobiliary diseases associated with IBD. An MRCP will only be performed in paediatric patients older than 6 years with two consecutive abnormal (more than two times the reference value) plasma alanine aminotransferase or Gamma-glutamyl transferase measurements. The imaging protocols are presented in online supplemental file 3.
Supplemental material
Adult patients recruited during the first year of study will be examined by experienced rheumatologists, including a systematic clinical evaluation, MR of the spine and sacroiliac joints, as well as ultrasonographic evaluation of peripheral joints and entheses at the time of diagnosis and repeated after 5 years. The patients will also have a systematic analysis for Human Leucocyte Antigen B27 (HLA-B27) positivity, and will be asked to answer several PROs relating to rheumatological EIMs (online supplemental file 2). In addition, The Toronto Axial Spondyloarthritis Questionnaire on IBD (TASQ-IBD),48 which is a validated screening tool for extra-intestinal musculoskeletal symptoms will, along with the first examination and newly occurring rheumatological symptoms after 1 year, determine whether a patient will be offered an additional assessment 1 year after the diagnosis of IBD.
All adult patients recruited during the second year of study will be examined by experienced dentists, including a systematic clinical evaluation at the time of diagnosis and again after 12, 24 and 60 months. In addition, patients will be asked general questions on dental visit patterns, treatment needs, oral hygiene habits and occurrence of oral lesions, as well as questions on oral health-related quality of life (OHIP-5). Questions previously recommended for self-reported surveillance of periodontitis will also be asked to calculate the Periodontal Screening Score.49 Panoramic radiographs of the jaws will be recorded at baseline and after 5 years. The type and amount of dental treatment performed will be extracted annually from the Danish Health Insurance Registry (SSSY register).
All adolescent and paediatric patients included during the 2-year inclusion period will be offered an assessment by a paediatric rheumatologist including a systematic clinical evaluation and systematic ultrasonographic assessment of peripheral joints and entheses at the time of the IBD diagnosis. Disease activity will be evaluated according to the Juvenile Arthritis Disease Score with the same frequency of examinations as adults.50 In addition, measurements of HLA-B27, antinuclear antibodies and rheumatoid factor will be performed in all adolescent and paediatric patients at the time of diagnosis of IBD. However, in contrast to adult patients, adolescent and paediatric patients will only receive an MR scan of the spine and sacroiliac joints at the diagnosis of IBD if it is considered clinically relevant.
Adolescent and paediatric patients recruited during the second year of study will not be examined by dentist; however, dental radiographs will be requested annually from the national paediatric dental system (‘Skoletandpleie’). Additionally, the number and type of periodontal treatments, fillings and endodontic treatments will be collected annually via the Danish Health Insurance Registry (SSSY register).
All patients who present dermatological manifestations will have these abnormalities photodocumented and evaluated by a dermatologist. If determined to be clinically relevant, the patient will be invited to a physical examination by a dermatologist, who will focus on IBD-associated EIMs and IMIDs, for example, hidradenitis suppurativa, pyoderma gangrenosum, erythema nodosum and psoriasis, which will be recorded in detail. Furthermore, all patients will undergo a regular screening by questionnaires for abscesses that could indicate hidradenitis suppurativa.51 In such cases, an experienced hospital dermatologist will make an assessment and any instances of hidradenitis suppurativa will be scored according to the recommended scoring indices (online supplemental file 2). When considering dermatological adverse events with difficulty in distinguishing these from new-onset distinct dermatological diseases, we will refer these patients to dermatologists as described above.
Finally, all adult, adolescent and paediatric patients are offered examination with a dual-energy X-ray scan at the time of diagnosis and after 5 years of follow-up to explore the occurrence and course of osteopenia and osteoporosis. Fibroscans are performed whenever patients present biochemical and clinical signs of chronic liver diseases.
Food purchase data
Adult patients are invited to participate in a substudy focusing on consumer data. Purchase data are to be automatically logged and collected throughout the study period using a mobile app, Storebox, which records all payment receipts made with credit cards, from participants using the digital receipt provider Storebox.52 The aim of the substudy is to assess the purchase behaviour and its association and interplay with the disease course of IBD. Currently, more than one million Danes use the digital receipts provider, which covers three out the six largest supermarket chains in Denmark. This method allows for in-depth and large-scale description of food-intake pattern over time, without the need for participants to invest their time in the sub study actively. Unfortunately, this method cannot distinguish food bought for the patients from those bought for offspring or partners.
Biological samples
Biological samples, including blood samples, rectal swabs, stool samples, saliva samples and swabs of the oral cavity, will be collected at the time of diagnosis and prospectively during each scheduled and unscheduled follow-up visit, as well as at the time of disease events in all participants. The biobanking of blood samples includes plasma, serum, buffy coat, PAXgene samples and whole blood samples.
At the time of diagnosis, four intestinal tissue biopsies (two snap-frozen and two held in RNAlater) or two intestinal tissue biopsies (one snap-frozen and one held in RNAlater) will be collected from five predefined intestinal segments, according to presence or absence of macroscopic inflammation, respectively. The five segments include the terminal ileum, cecum, transverse colon, sigmoid colon and rectum. Following diagnosis, two samples (one snap-frozen and one held in RNAlater) will be collected from each segment and will be handled as described in table 6. Additional biopsies will be collected from other segments in the presence of inflammation.
Biobank of the IBD prognosis study
Patient and public involvement statement
No patients were involved in formulating the research question or the outcome measures, nor in planning the study design.
Analysis plan for biological samples
Microbiota analysis and microbiota DNA sequencing
Stool and saliva samples will be analysed for microbiota, which will undergo 16S and 18S PCR (examining bacteria, fungi and parasites), Illumina sequencing and annotation of DNA sequences to the species level. These data will be analysed with in-house R-scripts or equivalent current standard platforms that will identify both quantitative and qualitative differences in microbiota between specific groups of patients.
Human metagenomic analysis
After removing the human sequences from the computer set by aligning the reads against the human reference genome, the remainder will then be compared with databases containing reads from previously identified pathogens and our own WGS database using the software MGmapper (https://cge.cbs.dtu.dk/services/MGmapper/) or the equivalent current standard analysis platforms. To confirm that the microorganisms we find can be identified in the metagenomics analyses, we will perform single-nucleotide polymorphism analysis of the corresponding sequences found in the microbiome.53
RNA and protein extraction and analysis in both adult and paediatric populations
Buffy coat, intestinal biopsies and saliva samples will be analysed using a multiomics approach. RNA will be extracted from the standard punch biopsies of the intestine collected in RNAlater. Biopsies will then be transferred to a lysis buffer, homogenised and total RNA extracted simultaneously with protein and DNA fractions.
Global gene expression is to be analysed by RNA sequencing (Illumina PE150 system, Illumina, San Diego, California, USA) or the available platform at the time of analysis. Furthermore, gene analysis will focus on genes related to IBD pathogenesis, EIM pathogenesis and pharmacodynamics and kinetics of IBD-related medicine. PCR analysis, Western blotting and immunohistochemistry will subsequently be used on the same subgroup of patients to confirm expression patterns of interest.
Live peripheral blood mononuclear cells derived from buffy coat from blood samples will be archived in a subset of the patients and handled in order to perform single-cell characterisation, including single-cell sequencing and multiparameter cytometry, to characterise the composition and activation status of innate and adaptive cell populations.
For the assessment of proteome profiles, the isolated protein fraction will be investigated with antibody-based multiplex analyses detecting proteins related to inflammation, barrier function, tissue degeneration, regeneration and fibrosis.
Blood samples will be centrifuged to obtain plasma and stored at −80°C until needed for characterisation of preselected plasma proteins using inflammation assays.
Finally, metabolomics will be applied for the analysis of gut microbial metabolism as well as metabolic changes in patients with IBD using proton nuclear MR (1H-NMR) spectroscopy or mass spectrometry (MS).
Statistical analysis
Statistics will be computed using IBM SPSS software V.28.0.1 or R V.4.1.0 or newer. Descriptive analysis of the baseline characteristics of the overall population and by gender will be conducted. Continuous variables will be presented as mean±SD or median with IQRs and counting data will be presented as number and percentage (n, %). Comparison of groups will be conducted using t-test or Wilcoxon rank-sum test based on the type of distribution of data and homogeneity of variance. χ2 test or Fisher’s exact probability method will be used for counting data as appropriate.
The incidence rate of UC and CD and their disease events, as previously defined, will be estimated as the number of new cases of UC/CD or events divided by the total person-time at risk. The person-time at risk for each individual will be estimated as the time each participant remains free of events during the 20 years follow-up period. Survival analysis will be conducted using Kaplan-Meier curves and Cox proportional hazards method to calculate HRs with 95% CIs. In addition, multiple linear and logistical regression analysis will be used to evaluate the association between outcomes and potential risk factors. All models will be adjusted for potential confounding factors. In these regression analyses, missing data will be handled by the multiple imputation method. Participants lost to follow-up will be treated as right-censored data. A two-sided significance level of 0.05 will be used for all primary and secondary analyses unless stated otherwise.
Comparison of adult and paediatric data is not preprotocolled but might be conducted based on the findings.
Ethics and dissemination
The protocol has been approved by the Ethics Committee of the Capital Region of Denmark (H-20065831) and the Danish Data Protection Agency (P-2020-1065). The study will be conducted in accordance with the ethical principles outlined in the current version of the Declaration of Helsinki and all applicable local regulatory requirements. Study results will be published according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
MA and GRM are joint first authors.
Twitter @runewilkens
MA and GRM contributed equally.
Contributors MA and GRM: Participated in designing and planning all parts of the study, and drafting the manuscript. JB, JBS, FB, AVW: Participated in conception and designing and planning all parts of the study, and conducted a critical review of the manuscript. RW, KT, TB, JTB, JI: Participated in designing and planning the intestinal ultrasound programme and conducted a critical review of the manuscript. MØ, NV, CW, LT, VF, HASI: Participated in designing and planning the rheumatological programme, and conducted a critical review of the manuscript. ABJ, FKJ, SBH, HRS, YJWN, JMM, HST: Participated in designing and planning the magnetic resonance programme and conducted a critical review of the manuscript. SFT, YY, EAB: Participated in designing and planning the dermatological programme and conducted a critical review of the manuscript. CJ, MD-R, SJ: Participated in designing and planning the paediatric programme and conducted a critical review of the manuscript. FTM: Participated in designing and planning the purchase data programme and conducted a critical review of the manuscript. KB and AS: participated in designing and planning the odontological programme, and conducted a critical review of the manuscript. All authors have approved the final version of it for publication, including the author list.
Funding This study is investigator-initiated and is funded by Novo Nordisk Fonden A/S with an unrestricted grant. The collection of purchase data will be funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 874 662. HRS holds a 5-year professorship in precision medicine at the Faculty of Health Sciences and Medicine, University of Copenhagen which is sponsored by the Lundbeck Foundation (Grant No. R186-2015-2138). The maintenance of the paediatric subpopulation is sponsored by Louis Hansen Fonden.
Competing interests HRS: HRS has received honoraria as speaker from Sanofi Genzyme, Denmark and Novartis, Denmark, as consultant from Sanofi Genzyme, Denmark, Lophora, Denmark, and Lundbeck AS, Denmark, and as editor-in-chief (Neuroimage Clinical) and senior editor (NeuroImage) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany and from Gyldendal Publishers, Copenhagen, Denmark. JBS: Has received unrestricted research grants from Janssen and Takeda and is national coordinator of clinical trials from Boerhinger Ingelheim and Eli Lilly. JB: Personal fees from AbbVie, Janssen-Cilag, Celgene, Samsung Bioepis, and Pfizer; grants and personal fees from Takeda, MSD, and Tillots Pharma; grants from Novo Nordisk Foundation and Bristol Meyers Squibb.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.