Biological therapy in the management of recent-onset Crohn's disease: why, when and how?

Crohn's disease is a chronic inflammatory bowel disease that may involve any part of the gastrointestinal tract. Conventional therapy consists of corticosteroids, azathioprine or methotrexate, but the clinical management of Crohn's disease is significantly hampered by adverse effects. With the introduction of biological agents (such as infliximab), the goals of therapy have advanced, including induction of remission with bowel healing as well as reduction in the rate of complications, surgeries and mortality. Current therapy for moderate to severe Crohn's disease is based on 'step-up' algorithms, which initiate treatment with corticosteroids followed by immunomodulatory agents, and defer therapy with biological agents until patients become refractory to conventional therapeutics. Recently, it has been shown that induction therapy with infliximab and azathioprine in recent-onset Crohn's disease (i.e. 'top-down' approach) is superior to current step-up algorithms to induce clinical remission. The underlying molecular mechanisms responsible for these differences in clinical outcome remain to be defined. Experimental studies have demonstrated that corticosteroids are able to induce impaired apoptosis of immune cells, including T cells and dendritic cells, resulting in loss of tolerance and subsequent autoimmunity. Further research will have to determine whether corticosteroid therapy augments the mechanism of loss of tolerance in Crohn's disease, which could complicate future clinical management.