Antibodies Against Infliximab Are Associated with De Novo Development of Antibodies to Adalimumab and Therapeutic Failure in Infliximab-to-Adalimumab Switchers with IBD
Antibodies Against Infliximab Are Associated with De Novo Development of Antibodies to Adalimumab and Therapeutic Failure in Infliximab-to-Adalimumab Switchers with IBD
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DOI：
10.1097/mib.0000000000000138
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发表时间：
2014-10-01
影响因子：
4.9
通讯作者：
Steenholdt, Casper
中科院分区：
文献类型：
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作者：
Frederiksen, Madeline Therese;Ainsworth, Mark Andrew;Steenholdt, Casper
背景：相当大比例的炎症性肠病(IBD)患者从英夫利昔单抗(IFX)改为阿达利单抗(ADL)。我们调查了IFX的免疫原性是否影响免疫原性和以后ADL治疗的临床结果。方法：单中心队列研究，包括所有IBD患者，检测IFX或ADL的抗体。结果：187例接受IFX一线抗肿瘤坏死因子治疗的患者进行了抗IFX抗体的检测。大约有一半(49%)呈阳性。检测到的抗IFX抗体具有功能，以低于检测下限的中位数IFX浓度(四分位数范围为0.0001-0.0mU g/mL)来判断，而抗IFx抗体阴性患者的中位数为3.8mU g/mL(IQR1.3-7.9mU g/mL)，但与ADL没有交叉反应。对57例接受ADL治疗的患者进行了抗ADL抗体检测。12例(21%)检测呈阳性。既往有抗IFX抗体史的患者更容易产生抗ADL抗体(33%)，而没有发展史的患者(0%)：优势比估计为11，P=0.04。抗ADL抗体也是有功能的，因为在所有抗ADL抗体阳性的患者中检测不到ADL，而在抗ADL抗体阴性的患者中，ADL的中位数为8.3µg/mL(IQR5.0-11.0)，P<；0.0001。抗ADL抗体的存在增加了继发性ADL治疗失败的风险，OR28(3-248)，P<；0.001。ADL谷值与ADL维持治疗的疗效相关：AUCROC 0.77(0.62~0.93)，P<；0.01。结论：抗IFX抗体转换者易发生从头开始的抗ADL抗体，可能导致治疗失败。需要评估抗IFX抗体阳性转换者的ADL免疫原性，以确保在治疗反应不充分的情况下进行最佳干预，并避免不适当的ADL强化方案。
Background: A notable proportion of patients with inflammatory bowel disease (IBD) are switched from infliximab (IFX) to adalimumab (ADL). We investigated if immunogenicity of IFX influenced immunogenicity and clinical outcomes of later ADL therapy.Methods: Single-center cohort study including all patients with IBD assessed for antibodies (Abs) against IFX or ADL.Results: Anti-IFX Abs were evaluated in 187 patients treated with IFX as first line anti-TNF agent. Approximately, half (49%) were positive. Detected anti-IFX Abs had functional capacity as judged by a median IFX concentration below limit of detection (interquartile range, 0.0-0.0 mu g/mL) versus 3.8 mu g/mL (IQR, 1.3-7.9) in anti-IFX Ab-negative patients, P < 0.0001; but did not cross-react with ADL. Anti-ADL Abs were assessed in 57 ADL-treated patients. Twelve (21%) tested positive. Patients with previous anti-IFX Ab development were significantly more prone to develop anti-ADL Abs (33%) than those without (0%): odds ratio estimated 11, P = 0.04. The anti-ADL Abs were also functional because ADL was undetectable in all anti-ADL Ab-positive patients versus median 8.3 mu g/mL (IQR 5.0-11.0) in anti-ADL-negative patients, P < 0.0001. The presence of anti-ADL Abs increased the risk of secondary ADL treatment failure with OR 28 (3-248), P < 0.001. ADL trough levels, irrespectively of anti-ADL Ab status, associated with efficacy of ADL maintenance therapy: AUCROC 0.77 (0.62-0.93), P < 0.01.Conclusions: Switchers with anti-IFX Abs are prone to develop de novo anti-ADL Abs, which may result in therapeutic failure. Assessment of ADL immunogenicity in anti-IFX Ab-positive switchers is required to ensure optimal interventions at inadequate treatment responses and to avoid inappropriate ADL intensification regimens.