Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease  Stephen B Hanauer, Carrie L Wagner, Mohan Bala, Lloyd Mayer, Suzanne Travers, Robert H Diamond, Allan Olson, Warren Bao, Paul Rutgeerts  Clinical Gastroenterology and Hepatology  Volume 2, Issue 7, Pages 542-553 (July 2004) DOI: 10.1016/S1542-3565(04)00238-1

Figure 1 ACCENT I study design. Of the 580 patients enrolled into the trial, 573 received an initial infusion of 5 mg/kg infliximab at week 0. At week 2, patients were stratified by response status and randomly assigned to 1 of 3 treatment strategy groups (placebo or group I, 5 mg/kg maintenance or group II, 10 mg/kg maintenance or group III). Patients were allocated to a treatment group using an adaptive stratified design, with strata of investigation site and duration of continuous exposure to corticosteroids (≤1 year, >1 year, no corticosteroids and no other Crohn’s disease medications, no corticosteroids but other Crohn’s disease medications). Patients receiving corticosteroids maintained a stable dose until week 6, after which a defined tapering schedule was started if the patient’s condition had improved. At week 14 or later, patients who responded to infliximab therapy but then worsened were eligible to cross over to active episodic treatment with infliximab 5, 10, and 15 mg/kg for patients originally assigned to groups I, II, and III, respectively. Worsening was defined by (1) an increase in the CDAI of at least 70 points from the qualifying score with a total score of at least 175 and an increase in the CDAI of 25% or more from the qualifying value, or (2) the introduction of a new treatment or an increase in the dose of an existing treatment for active Crohn’s disease. The final dose was administered at week 46, the final clinical assessment was performed at week 54, and the final analysis for antibodies to infliximab was at week 72. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)

Figure 2 Incidence of antibodies to infliximab over time. The proportion of antibody-positive patients assessed independently at each visit through week 72 is shown in (A) by antibody to infliximab status through week 72. All patients were assessed before treatment, at weeks 14, 22, 54, and 72, and before and after crossover. The cumulative count of antibody-positive patients through week 72 is shown in (B). Weeks 14, 22, 54, and 72 are shown in boxes to indicate the visits at which all patients were assessed for antibodies to infliximab. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)

Figure 3 Incidence of antibodies to infliximab in the presence and absence of concomitant immunomodulator use according to treatment group. The P values were calculated by using the χ2 test comparing the proportion of patients who were positive for antibodies to infliximab by whether they were receiving concomitant immunomodulators (6-MP, azathioprine, or methotrexate) at baseline. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)

Figure 4 Infusion reaction and clinical efficacy data by antibody to infliximab status among patients with evaluable samples. The proportions of all patients with any infusion reaction or serious infusion reaction through week 54 are shown in (A) by antibody to infliximab status through week 72. In (B), clinical response was defined as a reduction in the CDAI of ≥70 points and ≥25% from baseline, and remission was defined as a CDAI score <150. P values were first calculated by using the χ2 test across all 3 antibody categories (positive, negative, and inconclusive). If a significant difference (P < 0.05) was observed across the 3 antibody categories, then a further comparison of 2 antibody subgroups was conducted. Statistical significance was not tested for serious infusion reactions because of the limited number of events observed. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)

Figure 5 Mean changes in serum infliximab concentrations (A) and CDAI (B) 2 weeks after the baseline (week 0) infusion and first crossover (episodic) infusion in group I patients with known antibody to infliximab status at week 14 and who were subsequently retreated. Data are shown for group I patients who were antibody positive (n = 14), antibody negative (n = 59), or inconclusive (n = 17) at week 14. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)

Figure 6 Clinical response and remission at week 54 in group I patients with known antibody to infliximab status at week 14 who were subsequently retreated. Available efficacy data at week 54 are shown for group I patients who were antibody positive (n = 9), antibody negative (n = 44), or inconclusive (n = 11) at week 14. P values were first calculated by using the χ2 test across all 3 antibody categories (positive, negative, and inconclusive), and the results are shown above the bars in the graph. Clinical Gastroenterology and Hepatology 2004 2, 542-553DOI: (10.1016/S1542-3565(04)00238-1)