Abstract
TNF antagonists have revolutionized the treatment of IBD. Nevertheless, between 30 and 45% of patients discontinue infliximab and other TNF antagonists over a 2- to 6-year period due to nonresponse, loss of response, or adverse events. Accordingly, the need for novel therapies grows each year. Recent studies have demonstrated the promise of new drugs with distinct modes of action for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). These include agents targeting leukocyte trafficking, therapies directed against IL-12/23 and Janus kinases (JAK), and antibodies against the classic inflammatory cytokine, IL-6. The anti-α4-integrin antibody, natalizumab, was the first effective antitrafficking agent for CD; however, its use has been greatly limited by the risk of progressive multifocal leukoencephalopathy. Therefore, second-generation antitrafficking agents have focused on restricting leukocyte blockade to the intestine through mechanisms interfering with α4β7-integrin and its interaction with mucosal addressin cellular adhesion molecule 1. IL-23 is a cytokine central to the adaptive immune responses that characterize IBD. Ustekinumab, targeting the p40 subunit of IL-12 and IL-23, and the oral JAK inhibitor tofacitinib have proven to be effective in phase 2 trials in CD and UC, respectively. In addition, antibodies targeting the proinflammatory cytokine IL-6 are being studied in CD. Each of the approaches described have promise as well as limitations, so it is likely that the search for novel agents in IBD will continue.
