What next after infliximab?

The use of infliximab (Remicade) has revolutionized the care of Crohn's disease (CD) patients who have proved refractory to standard treatment. The use of infliximab is very well tolerated in the majority of patients but in a small subset of patients may lead to the production of antibodies (termed "antibodies to infliximab"-ATI). The production of these antibodies has been associated with the development of both acute and delayed infusion reactions, although even in patients who develop ATIs, these reactions are relatively uncommon. Nonetheless, these reactions may occasionally be severe enough to lead to intolerance to infliximab. Another group of patients, after initially having excellent responses to infliximab, experience an attenuated response or loss of response over time. What is the cause of this loss of efficacy? ATIs may play a role in some patients but other potential reasons for this phenomenon have provoked much debate. The importance of other cytokines after TNF-alpha has been neutralized may be relevant as (this has been shown to be the case in rheumatoid arthritis (RA) is the idea of beneficial autoimmunity production to TNF-alpha. (Wildbaum G, Nahir MA, Karin N. Beneficial autoimmunity to proinflammatory mediators restrains the consequences of self-destructive immunity. Immunity 2003;19:679-88.) It has been shown that during the course of an autoimmune condition, the immune system mounts a beneficial autoantibody response to proinflammatory mediators. This response counteracts, to a certain degree, the autoimmune pathology. This natural counteraction has been illustrated in animal models of autoimmunity, and there has been evidence demonstrated that this occurs in human RA. Whether this occurs in Crohn's is unknown; infliximab is a chimeric monoclonal antibody containing an approximately 25% murine region. It had been hoped that the development of humanized or fully human monoclonal antibodies would provide therapeutic antibodies that did not induce an immune response. While this has unfortunately not proven to be the case-these products still have significant immunogenicity-these products do present an alternative therapy when infliximab cannot be used. In light of this, adalimumab (Humira) a human monoclonal antibody used for treating rheumatologic conditions has been investigated as an alternate treatment for patients with CD who after initially responding to infliximab experience intolerance or loss of efficacy. Is this a viable alternative?