Ulcerative colitis (UC) is a chronic inflammatory disease involving all or a portion of the colon. Currently, there are few effective medical therapies for UC. Furthermore, because of the potential toxicity of the currently available agents, there is a great need for alternative therapies to treat patients with UC refractory to therapy with 5-ASA agents. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors whose activities are regulated by high affinity binding of small lipophilic ligands such as steroid hormones. A new class of diabetic drugs, the thiazolidinediones, has been developed to bind to the gamma (g) subtype of the PPARs. Colonic epithelial cells express high levels of PPARg protein and have the ability to produce inflammatory cytokines that may contribute to the inflammatory process in UC. We have previously demonstrated that PPARg ligands significantly attenuate cytokine gene expression related to the inflammatory cascade in colon cancer cell lines. Furthermore, we and others have demonstrated that thiazolidinedione ligands for PPARg markedly reduce colonic inflammation in murine models of ulcerative colitis. In addition, we have shown in a pilot study that more than 50% of patients with mild to moderately active UC despite therapy with 5-ASA agents (and corticosteroids or imunomodulator medications for most patients) experienced improved symptoms within 12 weeks of therapy with rosiglitazone 4 mg twice daily. As such, we believe that PPARg may represent a novel target for modulating colonic inflammation in UC. The proposed study is a multi-center, double-blind, randomized controlled trial of rosiglitazone versus placebo for mild to moderately active ulcerative colitis refractory to standard therapy with oral 5-ASA agents. 176 subjects will be randomized to rosiglitazone 4mg bid or placebo for 12 weeks of therapy. The primary outcome will be improvement in disease activity as measured by the Disease Activity Index first described by Sutherland. Secondary outcomes will include clinical remission and quality of life. We will use the techniques of immunohistochemistry to detect expression of PPARg receptors in human colon tissue. We will also use the technique of immunohistochemistry to examine the change in NF-KB activation prior to and following therapy with either placebo or rosiglitazone. Specifically, we will compare expression of p65 and phosphorylated IKB-alpha, in colonic tissue prior to and following exposure to rosiglitazone and placebo. If our hypothesis is correct, this study will serve to establish that ligands for PPARg possess biological activity necessary to modulate the inflammatory response in the intact human colon.
| Lewis, James D; Chuai, Shaokun; Nessel, Lisa et al. (2008) Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis 14:1660-6 |
| Lewis, James D; Lichtenstein, Gary R; Deren, Julius J et al. (2008) Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology 134:688-95 |
