Therapeutic Targets in Inflammatory Bowel Disease: Current and Future

IBD ETIOLOGY AND PATHOGENESIS Infl ammatory bowel disease (IBD) is a collection of disorders characterized by idiopathic infl ammation of the gastrointestinal tract. Although primarily classifi ed as either ulcerative colitis (UC) or Crohn’s disease (CD), the presentation of IBD can vary in terms of clinical symptoms, including location of disease involvement, disease severity, age at diagnosis, and presence of extraintestinal manifestations. Th e etiology of IBD is not fully understood but is likely infl uenced by numerous factors such as genetic predisposition, environmental factors, like the microbiota, and social behaviors, including smoking and diet. Th ese factors are thought to mediate subsequent epigenetic and immunological changes that contribute to the heterogeneity in the pathogenesis leading to disease. Figure 1 outlines major pathways thought to drive disease pathogenesis and corresponding drug targets. Recent drug failures in IBD, particularly anti-interleukin 17 (anti-IL17) in CD and anti-IL13 in UC, together with the mediocre performance of therapies that target anti-IL12p40, anti-IL23p19, and mucosal addressin cell adhesion molecule (MadCAM), highlight our fundamental lack of understanding of the impact of pathogenic heterogeneity in the treatment of IBD. Serological, genetic, and mucosal markers can defi ne diff erent clinical subphenotypes within CD and UC, thus implicating diverse biological pathways/mechanisms driving disease within these groups. For example, high levels of anti-neutrophil cytoplasmic antibodies are not only associated with a subpopulation of UC patients ( 1 ), but are also associated with nonresponse to antitumor necrosis factor (anti-TNF) therapy ( 2 ). Antibodies to Saccharomyces cerevisiae are more likely associated with severe disease in CD, defi ned by fi brostenotic and internal perforating disease, resulting in the need for small-bowel surgery ( 3 ). Genetic studies fi nd certain risk loci confer susceptibility to particular subphenotypes of both CD and UC ( 4,5 ), and predictive modeling based on a combination of phenotype, serologic, and genetic variables can identify patients who are likely to have a faster progression to surgery ( 6 ) and are nonresponsive to anti-TNF ( 7 ). Th ese studies not only emphasize the disease diversity in IBD but also defi ne a process of patient stratifi cation that could mitigate the diffi culties in treating disease driven by such variable pathogenic mechanisms. Disease heterogeneity is likely to be a major contributing factor to the frustration of successful drug development and new innovative therapies in recent years. Th ere has been a veritable drought in drug approvals between 1998 and 2014, with vedolizumab, a monoclonal antibody specifi c for α 4 β 7 integrin, being the most recent non-TNF-targeted drug approved for moderate-to-severe UC and CD ( 8 ). Although many new investigational drugs have reached Therapeutic Targets in Infl ammatory Bowel Disease: Current and Future