INFLAMMATORY BOWEL DISEASE

Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease

Severine Vermeire¹, Maja Noman¹, Gert Van Assche¹, Filip Baert², Geert D’Haens², Paul Rutgeerts¹

¹ Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
² Heilig Hart Ziekenhuis, Roeselare, Belgium
³ Imelda Ziekenhuis, Bonheiden, Belgium

Correspondence to:
Dr P Rutgeerts
Department of Internal Medicine, UZ Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium; paul.rutgeerts{at}uz.kuleuven.ac.be

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

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

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

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

Abbreviations: ACCENT, A Crohn’s disease Clinical study Evaluating infliximab in a New long-term Treatment; ATIs, antibodies to infliximab; AZA, azathioprine; ELISA, enzyme-linked immunosorbent assay; IFX, infliximab; IQR, interquartile range; IS, immunosuppressives; MTX, methotrexate; PBMC, peripheral blood mononuclear cell; PPV, positive predictive value; RA, rheumatoid arthritis

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