P449 Anti-drug Antibodies Inhibit Neutralization of TNF-alpha in Infliximab Treated Patients with Inflammatory Bowel Disease (IBD)
A. Eser*1, H. Vogelsang1, S. Reinisch2, G. Novacek1, C. Dejaco1, L. Kazemi-Shirazi1, C. Primas1, C. Lichtenberger1, S. Brehovsky1, S. Singh3, A. Jain3, W. Reinisch2
1Medical University of Vienna, Dept. for Gastroenterology and Hepatology, Vienna, Austria, 2McMaster University, Department of Internal Medicine, Hamilton, Canada, 3Prometheus Laboratories, Department of Research and Development, San Diego, United States
Infliximab (IFX) trough levels (TL) as well as c-max levels have been positively associated with its efficacy and negatively with IFX immunogenicity in patients with IBD. Clearance of IFX is increased in the presence of anti-drug antibodies (ADA). However, to what extent ADAs impact the binding and neutralization of soluble TNF-alpha in vivo remains largely unknown. In this study we assessed the relationship between IFX-, ADA- and TNF-alpha levels at a mid-infusion visit and at trough in patients with IBD on maintenance therapy.
Serum samples from 90 consecutive patients with IBD (Crohn's disease: n=66, ulcerative colitis: n=24) on IFX maintenance therapy were obtained at mid-infusion visits and at trough. IFX and ADA were measured by a homogeneous mobility shift assay from Prometheus, which allows detection of ADA in the presence of IFX. Serum TNF-alpha was measured by a Collaborative Enzyme Enhanced immuno-Reactive (CEER) Assay.
Patients had received a median number of 11 IFX infusions (range 3 - 71) with a median dose of 5.5 mg/kg (4.1- 10.9 mg/kg) before study entry. ADAs were detected in 18 pts at mid-infusion and in 21 pts at trough. In ADA positive pts median serum concentration of IFX was significantly lower than in ADA negative pts both at mid-infusion and at trough. Inversely, significantly higher serum concentrations of TNF-alpha were detectable in ADA positive pts at both visits (see Table1). At trough the TNF-alpha/IFX ratio was significantly higher in ADA positive patients (give data) than in those without ADA (give data, p<0.0001). No difference was seen in TNF-alpha levels when segregated by IFX serum levels alone.Interestingly, 3/10 (30%) ADA negative pts at mid-infusion with an IFX concentration below 8 µg/ml turned ADA positive at trough versus 1/36(3%) pts with an IFX concentration above or equal 8 µg/ml.
ADA detected in patients with IBD on IFX maintenance therapy impairs neutralization of soluble TNF-alpha and is associated with lower serum concentrations of IFX and higher levels of TNF-alpha both at mid-infusion and at trough. Our finding favours a strategy of a pre-emptive dose optimization in ADA positive patients due to insufficient control of inflammation.