When it comes to treating ulcerative colitis, it’s a jungle out there. This is because the gut is the largest and most complex immune environment in the human body. To successfully treat intestinal tract disorders, therapeutic agents must be delivered at the right time, in the right amount, to the right location.
Tackling this issue head-on at the upcoming American College of Gastroenterology Annual Scientific Meeting, October 31 to November 2 in Washington, DC, is Scott Plevy, MD. His symposium, “Controversies in the Management of Ulcerative Colitis,” will invite participants to explore several key issues. For instance, does all dysplasia mandate colectomy? Which is the best indicator of therapeutic success—mucosal healing, or clinical endpoints? What treatment is most effective for patients with severe colitis—cyclosporine, infliximab, or surgery? Cyclosporine A, for instance, works by inhibiting the function of T cells—the same cells needed for defense against infectious pathogens. So treatment with this agent raises safety concerns for patients who are already compromised.
Dr. Plevy is Associate Professor of Medicine in the division of gastroenterology and hepatology at the University of North Carolina School of Medicine in Chapel Hill. His research is directed at exploring how interactions between the immune system and the environment create the “perfect storm” that culminates in inflammatory bowel diseases. One of the central environmental factors undergoing scrutiny in Dr. Plevy’s lab is enteric microbial flora; several studies are underway to determine how bacteria activate innate immune responses and pro-inflammatory pathways in the mucosal system. Discovering ways to inhibit these mechanisms and pathways should open the door to new and better treatments for IBD and ulcerative colitis.
In a recent paper,1 Dr. Plevy discussed several of the factors that have made it so difficult to find a truly effective treatment for IBD. One issue is the preponderance of animal, rather than human, studies. “Ultimately, identification of therapeutic targets requires a better understanding of why tumor necrosis factor (TNF) inhibitors are effective in patients with IBD and interleukin (IL)-10 is not. If a rational immunologic model for IBD pathogenesis exists, it must be tested in patients, [not just animals],” he and coauthor Stephan Targan wrote.1
Safety is another obstacle in the quest for effective treatment. The biologic agent natalizumab, for instance, works by blocking an integrin subunit which, in turn, prevents inflammatory cells from leaving the blood vessels and entering sites of inflammation such as the GI tract and brain. Although natalizumab is approved by the FDA, scattered reports of multifocal progressive encephalopathy in a small group of patients treated for a year caused it to fall out of favor.
Dr. Plevy cites the development of biologic agents that target specific defects associated with IBD, rather than blanket immunosuppression, as a goal of future therapy. An important innovation would be to find a way to deliver potent therapeutics directly to the intestinal tract. Taking this to the next level, Dr. Plevy noted “The challenge is to determine which molecules and populations of cells are the best therapeutic targets for different subgroups of patients, based on their genetic and biologic factors.”1 This would herald the era of customized therapy, rather than the “one size fits all” model currently in use. And if Dr. Plevy has anything to say about it, his the footprints and those of his team will be among the first on that landscape.
1. Plevy SE, Targan SR. Future therapeutic approaches for inflammatory bowel diseases. Gastroenterology. 2011;140:1838-1846.