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P470 Changes in serum through levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn's disease

C. Steenholdt*1, K. Bendtzen2, J. Brynskov1, O.Ø. Thomsen1, L.K. Munck3, L.A. Christensen4, G. Pedersen5, J. Kjeldsen6, M.A. Ainsworth1

1Herlev Hospital, Dept of Gastroenterology, Herlev, Denmark, 2Rigshospitalet, University Hospital of Copenhagen, Institute for Inflammation Research, Copenhagen, Denmark, 3Køge Hospital, Dept. of Medical Gastroenterology, Køge, Denmark, 4Aarhus Hospital, Dept. of Hepatology and Gastroenterology V, Aarhus, Denmark, 5Hvidovre Hospital, Dept. of Gastroenterology, Hvidovre, Denmark, 6Odense Hospital, Dept. of Medical Gastroenterology S, Odense, Denmark

Background

It is recommended to intensify the infliximab (IFX) regimen in case of inadequate treatment effect in patients with Crohn's disease. IFX trough concentrations and formation of anti-IFX antibodies (Abs) are associated with clinical efficacy of IFX, but these parameters are subject to change over time. This study therefore explored if changes in IFX and anti-IFX antibodies (Abs) during IFX intensification applied at treatment failure associated with clinical outcomes.

Methods

This was a post hoc analysis of a randomized controlled trial which had included 69 Crohn's disease patients with symptomatic IFX treatment failure defined as CDAI ≥220 or ≥1 draining perianal fistula.(1) The current study included 42 patients (35 luminal, 4 fistulizing, 3 both) who had received an intensified IFX regimen with infusions of 5 mg/kg every 4 weeks throughout the 12-week study period. Trough serum IFX and anti-IFX Abs were measured by homogeneous mobility shift binding assay (HMSA) (2) and functional cell-based reporter gene assay (RGA) (3) at treatment failure and end of trial.

Results

After 12 weeks of intensified IFX regimen, 21 patients (50%) had regained clinical response. While IFX levels at manifestation of treatment failure were comparable between responders and non-responders at week 12, the overall increase in IFX during treatment intensification was significantly higher among the responders (RGA: 8.8 μg/ml vs. 3.0, p=0.035; HMSA: 9.9 μg/ml vs. 4.7, p=0.040). Furthermore, ROC analysis of change in IFX trough levels during IFX intensification differentiated patients by clinical outcome: AUCROCRGA 0.75 [0.53-0.97], p=0.035; AUCROCHMSA 0.74 [0.53-0.95], p=0.042. All responders exhibited IFX increase ≥2.6 μg/ml (sensitivity 100%, specificity 50%). Anti-IFX Abs were detected at time of IFX treatment failure in 13 patients (32%) by HMSA, and in 6 (15%) patients by RGA (all of which were positive by HMSA). Anti-IFX Abs detected by HMSA were often non-functional (62% had simultaneous IFX detection) and generally became undetectable during IFX intensification (89%). However, even functional anti-IFX Abs detected by RGA became undetectable (100%).

Conclusion

Increased IFX exposure during treatment intensification associates with improved clinical outcomes indicating underlying pharmacokinetic issues in a subgroup of patients. However, non-pharmacokinetic mechanisms of treatment failure are also common and other biologic agents than TNF-inhibitors should be considered here. Anti-IFX Abs become undetectable during treatment intensification and seems of limited prognostic value in this situation.

(1) Steenholdt et al. Gut (2014)

(2) Wang et al. J Immunol Methods (2012)