Lay Summary

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

Crohn’s disease (CD) occurs especially in young adolescents between 15-25 years.  Both the small and large bowels are affected and symptoms include diarrhea, blood loss, and weight loss.  In Western Europe and North America, around 1.5-2 people out of 1,000 are affected with the disease and these numbers have increased over the past couple of decades.

The management of CD has recently entered a new era with the introduction of infliximab.  Infliximab is an antibody to tumor necrosis factor-alpha (TNFα, an inflammatory protein produced in IBD) and represents a significant advance in the treatment of CD.  In patients not responding to more conventional treatments for CD, or in patients with CD complicated by fistulas, positive response rates of approximately 70% are achieved with Infliximab.  Despite these therapeutic successes, we are confronted with a subgroup of 30% or more of patients who are non-responders.  The reasons for this lack of response need to be defined and understood.

Variants or so-called polymorphisms in the TNF gene have been examined, but do not shed light on defining who will benefit from the drug and who will not.  Other genes involved in maintaining a normal pro-inflammatory and anti-inflammatory balance in the human body are likely candidates, but have not been studied so far.  Besides the genetic and immunological markers, a number of (auto) antibodies have been examined in CD and other novel antibodies are currently under investigation (a sequence from the bacteria Pseudomonas fluorescens, antibodies directed against the cell-wall of the bacteria Eschericia coli).  However, the clinical value of these antibodies (including predicting response to treatments) awaits definition.

We will identify predictors of response to infliximab.  The identification will enable physicians to clearly define patients likely to benefit from a drug.  It can also prevent patients from undergoing unnecessary treatment, and could lead to a more cost-effective therapeutic management by reserving the most expensive treatments only for those patients who are likely to benefit.  The identification of predictors to anti-TNF treatment in CD may also lead to a better understanding of the cause of CD and its prevention or therapy.