Original Article
Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease

https://doi.org/10.1016/S1542-3565(04)00238-1Get rights and content

Abstract

Background & Aims: The effect of different treatment regimens on antibody responses to infliximab and their clinical significance was examined by using data from ACCENT I. Methods: Patients with Crohn’s disease (n = 573) received 5 mg/kg infliximab (week 0) and then were randomly assigned to blinded infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (group I), 5 mg/kg infliximab (group II), or 5 mg/kg infliximab at weeks 2 and 6, followed by 10 mg/kg thereafter (group III). At week 14 or later, patients losing response could cross over to episodic infliximab treatment increased by 5 mg/kg. Samples for antibody determination were collected before the first infusion and at weeks 14, 22, 54, 62, 72, and, if applicable, before and after crossover. Results: Through week 72, antibodies to infliximab were detected in 30%, 10%, and 7% of groups I, II, and III, respectively (P < 0.0001). Patients receiving immunomodulators had a lower incidence of antibodies compared with patients receiving infliximab alone (10% and 18%, respectively; P = 0.02). Antibodies were associated with a 12% absolute increase in infusion reactions but no increase in serious infusion reactions or serum sickness—like reactions. In the overall population, similar proportions of antibody-positive and antibody-negative patients achieved clinical response (64% and 62%, respectively; P = NS) or clinical remission (41% and 39%, respectively; P = NS) at week 54. Notably, 86% of patients responded to retreatment, and 63% were in clinical response at week 54; however, fewer antibody-positive group I patients attained clinical remission (31%) compared with those who were antibody negative (37%) or antibody inconclusive (54%) (P = NS). Conclusions: Reduced antibody formation and greater clinical benefit were observed with an induction regimen followed by maintenance treatment compared with a single dose followed by episodic retreatment in Crohn’s disease patients treated with infliximab.

Section snippets

Patients

ACCENT I was a multicenter (55 sites), randomized, double-blinded trial of patients with moderate-to-severe Crohn’s disease (defined in part by disease of at least 3 months’ duration and a Crohn’s Disease Activity Index (CDAI)17 score between 220 and 400). Patients receiving 5-aminosalicylates, corticosteroids, or azathioprine/6-mercaptopurine (6-MP) were eligible, as described previously.16 All study procedures were carried out in accordance with ethical standards of the institutional review

Baseline characteristics and study treatment

All patients (n = 580) enrolled in ACCENT I began treatment with 5 mg/kg infliximab at week 0. At week 2, 573 patients were randomly assigned to 1 of the 3 treatment strategies, all of which included the opportunity for patients losing response at week 14 or later to cross over to episodic infliximab treatment (Figure 1). The baseline characteristics of this study population, including baseline use of immunomodulating agents, were similar across the treatment groups (Table 1). As shown in

Discussion

Monoclonal antibodies are unique proteins selected to recognize a specific biological target. All exogenous proteins, including monoclonal antibodies, are potentially immunogenic when therapeutically administered. Because of difficulties in measuring and standardizing the detection of immune responses with biologic agents, comparison of immunogenicity across products is discouraged by the United States Food and Drug Administration.19 The appropriate evaluation to determine the relative

Acknowledgements

The authors thank K.Patel for programming and statistical support and M.Perate for excellent editorial support.

Supported by Centocor, Inc. Dr. Hanauer is a consultant and lecturer, and does clinical research, for Centocor. Dr. Mayer owns Johnson & Johnson stock. Dr. Rutgeerts received research grants and consulting fees from Centocor. All of the authors employed by Centocor, Inc., own Johnson & Johnson stock.

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