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

背景和目标

对生物制剂形成抗药抗体 (ADA) 的免疫原性是炎症性肠病 (IBD) 治疗失败的重要原因。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 的有效性和安全性的影响。

方法

从开始到 2020 年 4 月，MEDLINE、Embase 和 Cochrane 对照试验中央注册中心 (CENTRAL) 都被搜索了评估免疫原性的生物制剂试验。使用推荐、评估、发展和评估分级 (GRADE) 评估证据的整体确定性。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。对于二分类结果，计算了汇总风险比 (RR) 和 95% 置信区间 (CI)。

结果

分析了 68 项研究的数据，荟萃分析中包括 33 项研究（5850 名患者）。生物单一疗法的汇总 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%。对于联合治疗和单药治疗，vedolizumab 的汇总 ADA 率为 8.4%，etrolizumab 为 5.0%。在所有生物制剂中，由于使用药物敏感的 ADA 检测和更高的剂量和/或频率，ADA 发生率被低估了。在接受英夫利昔单抗（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 0.10–0.8）联合治疗的患者中，ADA 发生率显着降低。 , 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)。

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。对于大多数生物制剂，使用免疫调节剂联合治疗似乎可以降低 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。