566 Infliximab Concentration and Clinical Outcome in Patients With Ulcerative Colitis
2012
Background: Infliximab (IFX), a chimeric mouse/human IgG1 monoclonal antibody against tumor necrosis factor alpha is successfully used in the treatment of Crohn's disease and ulcerative colitis. Despite its beneficial effect, IFX can provoke an immunogenic response which can lead to loss of response to the drug. It is generally believed that, once elicited, an antibody response to a certain protein cannot be overcome. We hypothesised that in patients who elicit only low levels of antibodies to infliximab (ATI), these may disappear with dose optimisation and that patients may recapture response. Methods: In this retrospective analysis in 52 IFX-treated patients a total of 693 serum samples (average of 13.3 samples per patient) were analysed. Patients were selected based on ATIs detected on at least one time point during follow up with an in-house developed ELISA. All consecutive samples were then analysed for IFX trough levels (TLI; expressed in μg/ml; cut-off value: 0.91 μg/ ml) and ATIs (expressed in U/ml; cut-off value 7.95 U/ml) using a fluid phase mobility shift assay (Prometheus Laboratories, San Diego US). Treatment decisions to optimise and stop therapy were made on clinical grounds and CRP, without knowledge of ATI or TLI. Results: Patients developed ATIs after a median of 16 weeks (IQR 8-39) following initiation of IFX and after a median of 5 (IQR 3-7) infusions. In 14 (27%) patients ATIs disappeared over time whereas in 38 (73%) patients ATIs persisted. There was no difference in time to ATI onset between patients with transient or sustained ATIs. Patients with transient ATIs had significantly lower ATI levels (median 18.7 U/ml; IQR 10.6-31.5) compared to patients with sustained ATIs (median 22.1 U/ml; IQR 14.0-45.7; p<0.01; Mann-Whitney U test). Patients with sustained ATIs had a two-fold higher risk (RR 2.1; 95%CI 0.9-4.6; p<0.05) to suffer an acute infusion reaction compared to patients with transient ATIs. Concomitant immunomodulator (IMM) use was associated with lower ATI levels (median ATI level with IMM: 8.8 U/ml versus 15.5 U/ml without IMM; p<0.01; Mann-Whitney U test). In 8/14 patients (57%) ATIs disappeared following dose optimisation and in the other 6 patients (43%), ATIs disappeared spontaneously. Patients with sustained ATIs more often discontinued IFX treatment due to loss of response and/or hypersensitivity reactions compared to patients with transient ATIs (68% versus 14 % respectively; p<0.001; Fisher's Exact test). Conclusion: Antibodies to infliximabmay be transient and can disappear after dose optimisation. Sustained high levels of ATIs lead however to permanent loss of response. When low or undetectable TLI are detected, knowledge of ATIs is therefore important as low titre ATIs can be overcome mostly with dose optimisation and high titre ATIs lead to a higher risk of adverse events and necessitate treatment stop.
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