Inflammatory Bowel Diseases

1. Background to the disease and the proposed project

The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases of the gastrointestinal tract. Inflammation can be debilitating with symptoms including severe abdominal pain, diarrhea, and weight loss, and has important social consequences. The exact pathogenesis is unknown, but the current hypothesis is that of an exaggerated mucosal immune response to the gut microbiota in a genetically susceptible host (Khor B, ea 2011). Both in CD and UC, a dysbiosis of the intestinal microbiota has been described (Joossens M, ea 2011 ; Machiels K, ea 2013). Recent advances in the understanding of human genetics, alongside technological advances, have revealed over 160 genetic loci associated with IBD, which have provided great insight into disease pathogenesis and implicated some unsuspected pathways (Jostins L, ea 2012).

The clinical course of IBD is very heterogeneous: while up to 50% of patients with UC and ca 30% with CD will have a relatively indolent disease course without the need for immunosuppression or surgery, up to 20% of UC patients require colectomy for either medically refractory disease or complications of long-standing inflammation, and over 50% of CD patients require surgery within 10 years of diagnosis.  The introduction of anti-TNF therapies 15 years ago has revolutionized clinical management with an ability to alter the natural history of IBD. In current practice, anti-TNF agents are initiated based on European and national guidelines (active inflammation despite failure of more conventional drugs). In addition, there is substantial heterogeneity in a patient’s individual response to therapy, with 10-15% of patients not responding to anti-TNF therapy and 40% of patients losing response over time.

2. Primary aim of the multicentric project

Partners :

  • UZ Brussel – Prof. Dr. Fazia Mana
  • UZ Gent – Prof. Dr. Martine Devos
  • CHU Liège – Prof. Dr. Eduourd Louis
  • Hôpital  Erasme – Prof. Dr. Denis Franchimont
  • UCL – Prof. Dr. Olivier Dewit
  • UZ Leuven – Prof. Dr. Severine Vermeire

The clinical course of IBD is very heterogeneous with differences in disease location and disease severity, which has important implications with respect to – often costly – treatment options. In addition, there is substantial heterogeneity in a patient’s individual response to therapy, and in potential adverse events to the drug. Therefore the ability to reliably identify those patients at greater risk of severe disease and who may potentially benefit from early aggressive therapeutic interventions is of major concern. Earlier research tried to link several clinical, serological and genetic parameters with severe disease behavior and prediction of response to therapies, but such studies have generally been limited, both by power, and in the scope of data available, and have lacked consistent replication.

The general aims of this project are to find the mechanisms and factors influencing a disabling disease course and response to therapy, and to translate them into clinically useful recommendations.

To do this, we will first develop two models based on the existing biobanks available at the different CRCs involved (retrospective samples) : one to predict a patients’ individual disease course, and another to predict an individual’s response to therapy. More specifically, clinical, serological, and genetic data will be combined to design a matrix analogous to the reported matrix for prediction of response to therapy in ankylosing spondylitis, and the widely accepted SCORE tables to predict cardiovascular risk.
Second, we will start the collection of a prospective cohort at the different IBD centers/CRCs, and to allow for multiple contributing factors, we will collect clinical information, DNA, serum, fecal samples, and tissue biopsies (prospective samples). The collected data will be combined to validate and improve the predictive model from the retrospective study. The most reliable strategy to investigate and predict a disabling disease course or response to therapy is to study a longitudinally collected prospective cohort, and to take into account the multifactorial etiology of the disease.

The included patients need to be newly diagnosed with IBD, and naïve to any treatment related to the disease. At the time of inclusion, demographic and clinical information needs to be documented. At different set time points different samples will be obtained. The aim is to get at least five years of follow-up for all included patients. Whenever there is an important change in the disease behavior or treatment policy, these samples also need to be collected. Considering the incidence of IBD and the numbers of centers involved it is estimated that at least 250  patients will be included per year. The (clinical) information and availability of samples will be stored in a centralized database; stakeholders will have access to the data related to this project. The minimal dataset will be made available for the ICT backbone of the CMI.  The CRC Leuven will provide operational support.