Amsterdam University Medical Center, Amsterdam, The Netherlands.
Alimentiv Inc, London, ON, Canada.
BioDrugs. 2021 Nov;35(6):715-733. doi: 10.1007/s40259-021-00507-5. Epub 2021 Nov 19.
Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment.
MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated.
Data from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44-0.62), adalimumab (RR 0.31; 95% CI 0.14-0.69), golimumab (RR 0.29; 95% CI 0.10-0.83), certolizumab pegol (RR 0.30; 95% CI 0.14-0.67) and natalizumab (RR 0.20; 95% CI 0.11-0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75; 95% CI 0.61-0.91) and higher rates of infusion reactions (RR 2.36; 95% CI 1.85-3.01).
Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.
免疫原性与形成抗药物抗体（ADA）是生物制剂治疗炎症性肠病（IBD）失败的重要原因。我们的目的是评估 ADA 的发生率、免疫调节剂联合治疗对 ADA 的影响以及 ADA 对生物制剂治疗 IBD 的疗效和安全性的影响。
从建库至 2020 年 4 月，我们在 MEDLINE、Embase 和 Cochrane 对照试验中心注册库（CENTRAL）中检索了评估生物制剂免疫原性的试验。使用推荐评估、制定与评价分级（GRADE）评估证据的总体确定性。主要结局是 ADA 发生率。次要结局包括可检测 ADA 与不可检测 ADA 患者的疗效和安全性结局。对于二分类结局，计算汇总风险比（RR）和 95%置信区间（CI）。
对 68 项研究的数据进行了分析，其中 33 项研究（5850 例患者）纳入了荟萃分析。英夫利昔单抗、阿达木单抗、戈利木单抗、培塞利珠单抗、乌司奴单抗和那他珠单抗的生物单药治疗 ADA 发生率分别为 28.0%、7.5%、3.8%、10.9%、6.2%和 16.0%。英夫利昔单抗和阿达木单抗联合治疗 ADA 发生率分别为 8.4%和 5.0%。在所有生物制剂中，使用药物敏感 ADA 检测方法、更高剂量和/或更频繁使用时，ADA 发生率被低估。与生物单药治疗相比，联合治疗可显著降低英夫利昔单抗（RR 0.52；95%CI 0.44-0.62）、阿达木单抗（RR 0.31；95%CI 0.14-0.69）、戈利木单抗（RR 0.29；95%CI 0.10-0.83）、培塞利珠单抗（RR 0.30；95%CI 0.14-0.67）和那他珠单抗（RR 0.20；95%CI 0.11-0.39）的 ADA 发生率。ADA 对英夫利昔单抗的产生与较低的临床缓解率（RR 0.75；95%CI 0.61-0.91）和更高的输注反应率（RR 2.36；95%CI 1.85-3.01）相关。
ADA 检测分析方法的差异阻碍了 IBD 中不同生物制剂之间真实 ADA 发生率的比较。免疫调节剂联合治疗的应用似乎降低了大多数生物制剂的 ADA 阳性率。对于英夫利昔单抗，ADA 与药物疗效降低和不良反应增加有关。
