Infliximab Use in Luminal Crohn's Disease

Infliximab has been available in the United States and Europe for more than 6 years, and its use has revolutionized the care of patients who have CD. It is used effectively for both the induction and maintenance of remission in patients who have CD and is efficacious in patients who have steroid-dependent/refractory CD and those who have fistulizing CD. Clinical trials and practice have shown infliximab to be safe, effective, and generally well tolerated. The ACCENT I and ACCENT II trials defined the best dosing and schedule regimens for its administration. With up to 30% of patients not responding to infliximab therapy, much attention has been devoted to identifying risk factors that could allow optimization of response rates. Parsi and colleagues and Arnott and colleagues demonstrated that nonsmoking and the concurrent use of immunomodulators are predictors of response to infliximab. Research has also focused on identifying biologic and immunologic markers that may correlate with response to infliximab. To date, N0D2/CARD15, anti-Saccharomyces cerevisiae antibody (ASCA), and antineutrophil cytoplasmic antibody (ANCA) have not been shown to be predictive of outcome with infliximab treatment for CD. Gene polymorphisms also are being studies with the hope that knowing the patient's genotype may help predict the course or severity of the disease, including the presence of extraintestinal manifestations, response to treatments, and susceptibility to toxicities. No single variable, however, has been consistently demonstrated to be a predictor of response to infliximab. The formation of ATIs in a small number of patients creates a clinical dilemma. ATIs have been associated with an attenuated response or loss of response to the medication over time and the development of both acute and delayed infusion reactions that occasionally are severe enough to lead to discontinuation of the medication. In such patients physicians are often left to ponder what therapy to try next. Adalimumab, a fully human monoclonal antibody used for treating rheumatologic conditions, has been investigated as an alternate treatment for patients who have CD who, after initially responding to infliximab, experience intolerance or loss of efficacy. Two studies have examined the use of adalimumab in patients who have active CD who had lost response to or developed intolerance to infliximab. In both these studies adalimumab was well tolerated and seemed to be a clinically beneficial option for such patients. Confirmation of these findings with ongoing randomized, double-blind, placebo-controlled trials is needed, however. The limits of conventional treatment for CD can be seen as a positive evolutionary force favoring the development and use of advanced therapies. The acceptance of antimetabolites began with data published a quarter-century ago and became robust in the past 5 to 10 years. Biologic therapy has become the standard of care at a far faster rate. The success seen with infliximab has broadened the acceptance of biologic therapy among professional peers, patients, and pharmaceutical developers. The lessons learned in the years since infliximab's arrival show the importance of long-term data in revealing important toxicities and best practices for maintenance. Tempered by this experience, the short cycle from concept to drug production possible with biologic therapies should bring even more advanced treatments to patients quickly while investigators work to find a cure.