Biologics in Ulcerative Colitis

The underlying pathophysiology of CD differs slightly from that of UC. Hence, an effective treatment for one disease may not be effective for the other. The pathogenesis of UC is not well understood, but the large bowel epithelium appears to play an important proinflam-matory role. In UC, the large bowel mucosal epithelial cells secrete large amounts of chemokines, such as IL-9 and gro-a, which recruit activated neutrophils into the mucosal compartment (van Deventer 2003). Whereas CD is predominately a type 1 helper immunologically mediated disease, Th2 response appears to perpetuate the inflammation in the mucosa of patients with UC (Rutgeerts 2002).

Biologic agents approved or under evaluation for UC are included in Table 12.1. Based on the positive results from the ACT I and ACT II studies (Rutgeerts et al. 2005), infliximab was approved for by the US Food and Drug Administration for reducing the signs and symptoms, achieving clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active UC who have had an inadequate response to conventional therapy (Remicade prescribing information, 2006). Infliximab may also be efficacious as rescue therapy in severe colitis to avoid colectomy (Jarnerot et al. 2005). Preliminary results using IFN- (Nikolaus et al. 2003; Musch et al. 2002) appear promising and the agent is currently undergoing phase 2 studies in UC. Anti-a4|37 (MLN-02) has been investigated in UC as well as CD. In a short-term study, MLN02 was more effective than placebo for the induction of clinical and endoscopic remission in patients with active UC (Feagan et al. 2005). The anti-intercellular adhesion molecule 1 antisense oligonucleotide, alicaforsen, has generally proven ineffective in CD; however, inadequate dosing may have been an issue. In UC, alicaforsen enema has shown clear short- and long-term benefit in left-sided UC and may have potential in chronic pouchitis (Miner et al. 2004; van Deventer et al. 2004). In phase 2 trials, 59 % of the 22 patients taking 240 mg/day of alicaforsen reported a response, with 77% of those still responding by the end of the 6-month study. Patients with moderate UC experienced a greater response than those with mild disease (http://ibscrohns.about.com/od/prescrip-tiondrugs/a/ibdpipe_2.htm). Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype. It induces apoptosis in activated T cells and causes profound lymphopenia after infusion. Initial reports have demonstrated at least some efficacy in UC (Dignass et al. 2004). Visilizumab is in phase 2-3 studies in UC in patients with intravenous steroid-refractory UC. Table 12.2 includes the status of clinical trials of agents investigated for UC.

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