Biological Therapies in Inflammatory Bowel Disease: Top-down or Bottom-up?

Bas Oldenburg; Daan Hommes

Disclosures

Curr Opin Gastroenterol. 2007;23(4):395-399. 

In This Article

Biologicals

The introduction of infliximab has resulted in a considerable change of IBD treatment paradigms, most notably in Crohn's disease. In the preantitumour necrosis factor (TNF) era, therapeutic options for Crohn's disease patients who were unresponsive to conventional treatment were limited, and most patients were facing surgery. Infliximab, however, has changed this perspective. In therapy-refractory patients this drug has been shown to be effective for active Crohn's disease with rapid onset of mucosal healing, to display steroid-sparing properties, to induce (partial) closure of perianal fistulas,[23,25,26] and to maintain remission in Crohn's disease patients who have responded to infliximab induction therapy when administered on an 8-week basis. Evidence that infliximab has efficacy in patients with moderate to severe ulcerative colitis has recently been published.[27,28] The proportion of patients with a remission, who were on steroids and who had mucosal healing after 30 and 54 weeks was significantly higher in patients receiving infliximab compared to placebo.

Two other anti-TNF compounds, adalimumab and certolizumab, have been shown to have clinical efficacy in patients with moderate to severe Crohn's disease and will be commercially available shortly.[29*,30*,31] Although data on long-term follow up and maintenance therapy in Crohn's disease are presently not available, it can be expected that all anti-TNF drugs have an overall comparable efficacy as has been shown in rheumatoid arthritis (RA).[32] The small differences in absolute benefit (i.e. the percentage difference between effectiveness of treatment in patients receiving an anti-TNF drug versus placebo in different controlled trials) in Crohn's disease, ranging from 20 to 32%, underscore this assumption.[33] Thus, the choice of a specific anti-TNF agent in the clinical setting should be dictated by the route of administration, side effect profiles and practical considerations.

A growing number of new biological agents are under investigation, varying from monoclonal antibodies to antisense mRNA products, peptides and vaccines. The highest response rates in Crohn's disease have been found after administration of the selective adhesion molecule-inhibiting agent natalizumab, which targets α4-integrins,[34] antiinterleukin (IL)-12 antibodies[35] and anti-IL-6 receptor monoclonal antibodies.[36] In ulcerative colitis the most promising results were reported in trials with visilizumab, an anti-CD3 antibody[37] and an antibody against the α4β7 integrin.[38] From most of those studies it can be deduced that biologics are effective in only a subpopulation of patients. In the ENACT I and the Huzaf trial (natalizumab and fontolizumab, respectively), for instance, C-reactive protein-positive patients were found to perform better. Regarding this particular parameter, however, it cannot be ruled out that it does not distinguish a specific subgroup, but simply identifies disease activity better than the widely used CDAI. This results in a more pronounced difference between active drug and placebo through a lower response in the placebo group instead of a higher response in the active drug users. For now, positioning of these new biologicals in the therapeutic pyramid has to await additional data from studies with longer follow up and the identification of parameters which may predict the natural course or response to specific compounds.

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