BACKGROUND AND AIMS 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

中文翻译：

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炎症性肠病中针对生物制剂的抗药抗体形成：系统评价和荟萃分析。

背景和目的 生物制剂抗药抗体 (ADA) 形成的免疫原性是炎症性肠病 (IBD) 治疗失败的一个重要原因。我们的目的是评估 ADA 率、免疫调节剂联合治疗对 ADA 的影响以及 ADA 对 IBD 生物制剂疗效和安全性的影响。方法 MEDLINE、Embase 和 Cochrane 对照试验中央登记册 (CENTRAL) 从开始到 2020 年 4 月搜索了评估免疫原性的生物制剂试验。使用建议、评估、开发和评价的分级 (GRADE) 评估证据的总体确定性。主要结果是 ADA 率。次要结果包括可检测与不可检测 ADA 患者的疗效和安全性结果。对于二分结果，计算合并风险比 (RR) 和 95% 置信区间 (CI)。结果 对来自 68 项研究的数据进行了分析，33 项研究（5850 名患者）被纳入荟萃分析。生物单一疗法的合并 ADA 率为英夫利昔单抗 28.0%、阿达木单抗 7.5%、戈利木单抗 3.8%、赛妥珠单抗 10.9%、优特克单抗 6.2% 和那他珠单抗 16.0%。对于组合疗法和单一疗法，维多珠单抗的汇总 ADA 率为 8.4%，etrolizumab 为 5.0%。在所有生物制品中，由于使用药物敏感的 ADA 检测和更高的剂量和/或频率，ADA 率被低估了。接受英夫利昔单抗（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）联合治疗的患者的 ADA 率显着降低, certolizumab pegol (RR 0.30; 95% CI 0.14-0. 67) 和那他珠单抗 (RR 0.20; 95% CI 0.11-0. 39)。英夫利昔单抗的 ADA 与较低的临床反应率（RR 0.75；95% CI 0.61-0.91）和较高的输液反应率（RR 2.36；95% CI 1.85-3.01）相关。结论 检测 ADA 的分析方法的差异阻碍了 IBD 中生物制剂真实 ADA 率的比较。使用免疫调节剂联合治疗似乎可以降低大多数生物制剂的 ADA 阳性率。对于英夫利昔单抗，ADA 与药物疗效降低和不良事件增加有关。使用免疫调节剂联合治疗似乎可以降低大多数生物制剂的 ADA 阳性率。对于英夫利昔单抗，ADA 与药物疗效降低和不良事件增加有关。使用免疫调节剂联合治疗似乎可以降低大多数生物制剂的 ADA 阳性率。对于英夫利昔单抗，ADA 与药物疗效降低和不良事件增加有关。