Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease

BACKGROUND: Treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. We evaluated the clinical significance of these antibodies in patients with Crohn's disease. METHODS: In a cohort of 125 consecutive patients with Crohn's disease who were treated with infliximab infusions, we evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion. RESULTS: A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61 percent of patients. The presence of concentrations of 8.0 microg per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 microg per milliliter; P<0.001) and a higher risk of infusion reactions (relative risk, 2.40; 95 percent confidence interval, 1.65 to 3.66; P<0.001). Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median, 1.2 vs. 14.1 microg per milliliter; P<0.001). Patients who had infusion reactions had a median duration of clinical response of 38.5 days, as compared with 65 days among patients who did not have an infusion reaction (P<0.001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab (P<0.001) and high concentrations of infliximab four weeks after an infusion (P<0.001). CONCLUSIONS: The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response.