Scientific Abstract

Proposal No.  IBD-0016
Principal Investigator:  Paul J. Rutgeerts, M.D., Ph.D.
Applicant Institution:  Katholieke Universiteit Leuven (Belgium)
Project Title: Study on genetic, immunological and serological predictors of response to anti-TNFα treatment in Crohn's disease
Award Period:  December 1, 2002 – November 30, 2003

Crohn’s disease (CD) is a chronic disorder of the GI tract, involving most frequently the small and large intestine.  Symptoms include diarrhea, malabsorption and malnutrition and complications such as intestinal obstructions, fistula formation and bowel perforation and often require hospital admissions and surgery.  The prevalence of CD is estimated at 1.5/1000 in Western Europe and North America and importantly a marked increased incidence has been observed over the past couple of decades.  While the exact cause of CD remains elusive, our current notions have focused on abnormal T Helper-1 pro-inflammatory immune response in response to an external (microbial) trigger in a genetically predisposed individual.

The repertoire of medications used for the treatment of CD includes aminosalicylates, corticosteroids, immunosuppressive drugs and antibiotics.  However, treatment refractoriness is seen in approximately 30 to 40% of patients.  The therapeutic heterogeneity remains a problem in IBD.  Fortunately, the management of CD has recently entered a new era with the introduction of targeted biological agents.  In this regard, the monoclonal antibody to Tumor Necrosis Factor-alpha (TNFa, infliximab) represents a significant advance in the treatment of CD.  In patients with refractory luminal CD or CD complicated by fistulas, response rates of approximately 70% are achieved with infliximab and >30% of patients enter remission.  Despite these therapeutic successes, we are confronted with a subgroup of 30% of patients who are non-responders.  The reasons for this remain to be defined.

Polymorphisms in the TNF gene have been examined but do not shed light on defining responders and non-responders.  Genes involved in the apoptotic pathway which are responsible for maintaining the balance of cell production and cell loss in the intestinal mucosa (Fas, DAD1, MMP14, NFκBIA, IKK, IκB) are likely candidates, but have not been studied so far.  Also, cytokine profiles, reflective of the Th1/Th2 balance remain incompletely understood.  Besides the genetic and immunological markers, a number of (auto) antibodies (ASCA and PAB) have been examined in CD and other novel (auto) antibodies are currently under investigation:  a bacterial sequence from Pseudomonas fluorescens (I2), antibodies directed against the porin C of Eschericia coli (OmpC), and the glycoprotein YKL-40 (gp39).  However, the clinical value of these antibodies (including in predicting response to treatments) awaits definition.

To this end, the present proposal will focus on identifying predictors of response incorporating the above-defined parameters.  The identification of predictors of response or failure to a particular treatment is important for various reasons.  It can enable physicians to clearly define patients likely to benefit from a drug in advance.  It can also prevent patients from undergoing unnecessary treatment, it can lead to a more cost-effective therapeutic management by reserving these (mostly expensive) treatments only for those patients who will benefit and finally, it may help to understand the underlying reasons for response or failure to treatment.  Eventually, the identification of predictors to anti-TNF treatment in Crohn’s disease may also lead to direct implications in other diseases where infliximab is being used (rheumatoid arthritis, psoriasis, spondylarthropathy).

This study furthermore underscores the importance of using a multifactorial approach since three important fields (genetic, immunological and serological) will be covered in this proposal, which will allow for the determination of the interactions among these disciplines.  These types of interactions are likely to play a major role in the pathogenesis of Crohn’s disease.