Infliximab for ulcerative colitis induction of remission and maintenance therapy.

Infliximab (Remicade, Centocor) was the first novel compound for inflammatory bowel disease to be introduced in 50 years. Early experience with the agent in Crohn's disease (CD) taught the medical and pharmaceutical communities important lessons regarding biologic therapies. Data from a study of single-dose therapy were so compelling that patients and families lobbied for fast-track approval from the US Food and Drug Administration (FDA). This was granted with a caveat requiring a safety registry. In the months following approval, clinicians realized that patients required further management after the initial treatment; they continued to infuse infliximab with little guidance regarding maintenance therapy other than insurers' policies. In order to define the role of infliximab in maintenance, the ACCENT I and II trials were conducted, the results of which satisfied the FDA regulatory requirements and led to an official maintenance indication for both fistulizing and ordinary intestinal CD, as well as a standardized maintenance dosing regimen of 5 mg/kg, every 8 weeks. While this was happening, infliximab was also in trials and was being used off-label for ulcerative colitis (UC) in the United States and Europe. Many of these uses were in patients assigned the diagnosis of indeterminate colitis, with the idea that these were cases of CD manifested as colitis. Other clinicians simply felt that infliximab would work in UC and wanted to try it. The published success rates for the various experiences of infliximab in UC ranged anywhere from 33% to 88%, and a randomized controlled trial was clearly required to determine the true efficacy. Having learned the lessons of infliximab in CD, the ACT I and ACT II trials were designed to test infliximab in UC patients for both induction and maintenance of remission using the same dosing regimen. Several hundred patients who had been failed by either steroid therapy, 5-aminosalicylate (5-ASA) therapy, or a combination of the two, were enrolled in these trials, and it was shown that the regimen that worked well in CD provided similar efficacy in UC. With the completion of FDA review of these data in October 2006, the FDA officially approved infliximab for the induction and long-term maintenance of remission in UC. This is very good news, particularly for hard-to-man-age, moderately active UC or the “working wounded.” Before infliximab, there were not many options for patients experiencing 5–10 stools daily who, despite regular treatment and frequent follow-up, were not improving. For these patients, it was difficult to justify hospital admission for intravenous cyclosporine therapy or for colectomy. Infliximab now provides another option, and with the FDA's approval, the battles to get this regimen approved by insurers have disappeared. Thus far with regard to infliximab, the efficacy studies and clinical experience of effectiveness have been entirely congruent. In CD, patients have a decrease in hospitalizations and fewer surgeries for their CD when maintained on regular infusions of infliximab. It is reasonable to have optimism that this will also hold true in UC. Will infliximab decrease the risk of colon cancer in patients with UC? Again, cautious optimism is in order. Despite some controversy, most clinicians agree that the degree of disease activity on biopsy is a marker of risk of dysplasia and progression to colorectal cancer. In this regard, even in asymptomatic patients, treatment may be able to provide further protection. This may be from specific chemoprotective effects from 5-ASA but may be direct cause and effect by controlling mucosal inflammation. It is reasonable to speculate that effective biologic therapy will decrease the risk of colon cancer, but it will be quite a while before useful data are available. Typically, a patient with pancolitis develops a substantial risk of colon cancer after 8 to 10 years of active disease. Dysplasia is generally an exclusion factor for clinical trials. This means that the detailed data available for subjects from trials may not tell us much in the short term. It will be many years before we have direct evidence of cancer prevention. Progression of dysplasia or other markers may give surrogate information, but until we have long-term data, patients will continue to require surveillance as advised in published guidelines.