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The effectiviness of concomitant immunosuppressive therapy to suppress formation of antibodies to infliximab in crohn's disease
  1. Severine Vermeire (severine.vermeire{at}uz.kuleuven.ac.be)
  1. University Hospital Gasthuisberg, Belgium
    1. Maja Noman (maja.noman{at}uz.kuleuven.ac.be)
    1. University Hospital Gasthuisberg, Belgium
      1. Gert van Assche (gert.vanassche{at}uz.kuleuven.ac.be)
      1. University Hospital Leuven, Belgium
        1. Filip Baert (fbaert{at}hhr.be)
        1. Heilig Hart ziekenhuis Roeselare, Belgium
          1. Geert D'Haens (geert.dhaens{at}imelda.be)
          1. University Hospital Gasthuisberg, Belgium
            1. Paul J Rutgeerts (paul.rutgeerts{at}uz.kuleuven.ac.be)
            1. University Hospital Gasthuisberg, Belgium

              Abstract

              Introduction: Episodic infliximab (IFX) treatment is associated with the formation of antibodies to IFX (ATI) in the majority of patients which can lead to infusion reactions and a shorter duration of response. Concomitant immunosuppression (IS) reduces the risk of ATI formation.

              Aims & Methods: To investigate which of the IS, ie methotrexate (MTX) or azathioprine (AZA) is most effective at reducing the risk of ATI formation, we prospectively studied a multicenter cohort of 174 Crohn's disease patients treated with IFX in an on demand schedule. Three groups were studied: no immunosuppressives (n=59), concomitant MTX (n=50), concomitant AZA (n=65). ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories (San Diego) before, and 4 weeks after each infusion.

              Results: ATI were detected in 55% (96/174) of all patients. The concomitant use of immunosuppressive therapy (AZA or MTX) was associated with a lower incidence of ATI (53/115; 46%) compared to patients not on concomitant immunosuppression (43/59; 73%; p<0.001). The rate of ATI was not different for the MTX group (44%) compared with the AZA group (48%). Patients not taking immunosuppressive therapy had lower IFX levels (median 2.42μg/ml IQR 1-10.8, max 21μg/ml) 4 weeks after any follow-up infusion than patients on concomitant immunosuppressive therapy (median 6.45μg/ml IQR 3-11.6; max 21μg/ml) (p=0.065) but there was no difference between MTX or AZA. In patients who developed significant ATIs >8μg/ml during follow-up, the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower already in comparison with patients who did not develop ATI on follow-up or had inconclusive ATIs.

              Conclusion: Concomitant immunosuppression reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX. There is no difference between methotrexate and azathioprine in reducing these risks. ATI profoundly influences the pharmacokinetics of IFX. The formation of ATI >8μg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.

              • Crohn's disease
              • immunogenicity
              • immunosuppression
              • infliximab

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              • Determination of ATI and infliximab levels were performed by Prometheus Laboratories (San Diego, CA)

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