Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease
Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease
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DOI：
10.1136/gut.2006.099978
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发表时间：
2007-09-01
期刊：
影响因子：
24.5
通讯作者：
Rutgeerts, Paul
中科院分区：
文献类型：
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作者：
Vermeire, Severine;Noman, Maja;Rutgeerts, Paul
背景：在大多数患者中，间歇性英夫利昔单抗（IFX）治疗与IFX抗体（ATIs）的形成有关，这可能导致输注反应和较短的反应持续时间。同时使用免疫抑制剂（IS）可降低ATI形成的风险。目的和方法：为了研究哪种IS（即甲氨蝶呤（MTX）或硫唑嘌呤（AZA））在降低ATI形成风险方面最有效，对174名克罗恩病患者进行了多中心队列研究，这些患者按需接受IFX治疗。研究三组：无IS (n = 59)，合并MTX （n = 50）和合并AZA （n = 65）。在每次输注前和输注后4周，在普罗米修斯实验室采用盲法测量ATI和IFX浓度。结果：55%（96/174）的患者检出ATIs。与未同时使用IS治疗的患者（43/59;73%;p < 0.001）相比，同时使用IS治疗（AZA或MTX）与较低的ATIs发生率（53/115;46%）相关。MTX组（44%）与AZA组（48%）的ATIs发生率没有差异。未接受IS治疗的患者在任何随访输注后4周的IFX水平（中位数2.42 μ g/ml（四分位数范围（IQR） 1 - 10.8），最大21 μ g/ml）低于同时接受IS治疗的患者(中位数6.45 μ g/ml (IQR 3 - 11.6)，最大21 μ g/ml；p = 0.065)，但MTX与AZA之间无差异。在随访期间发生明显ATIs的患者中，首次输注后4周的IFX水平被回顾性发现显著低于随访中未发生ATIs或不确定ATIs的患者。结论：联合IS治疗可减少IFX治疗相关ATI的形成，改善IFX的药代动力学。MTX和AZA在降低这些风险方面没有区别。ATI对IFX的药代动力学影响深远。在第一次给药后4周，ATIs的形成与血清IFX水平降低有关。
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 mu g/ml (interquartile range (IQR) 1 - 10.8), maximum 21 mu g/ml) 4 weeks after any follow-up infusion than patients taking concomitant IS therapy (median 6.45 mu g/ml (IQR 3 - 11.6), maximum 21 mu g/ml; p = 0.065), but there was no difference between MTX or AZA. In patients who developed significant ATIs >8 mu g/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 mu g/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.