DataSheet1_Safety of biological therapy in patients with rheumatoid arthritis in administrative health databases: A systematic review and meta-analysis.docx

Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the synovial fluid of joints, tendons, and some extra-articular sites. Biologic agents have been highly effective and are comparable in reducing RA symptoms, slowing disease progression, and improving physical function; however, concerns have been raised about the risks of several potential adverse effects. Thus, this study aimed to assess the safety of biological therapy in patients with rheumatoid arthritis in observational studies using administrative health databases.
Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science were searched from inception to 21 October 2021. The analysis was divided into five groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus csDMARDs; bDMARDs versus csDMARDs; abatacept versus bDMARDs; and TNFi versus Janus kinase inhibitors (JAKi). The adverse events were cancer, cardiovascular events, infection, herpes zoster, tuberculosis, and death. The methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. A random-effects model estimated risk ratios with 95% confidence intervals.
Results: Thirty-one studies were eligible for inclusion in the present systematic review, published from 2014 to 2021. A total of 1,039,398 RA patients were assessed. The 31 studies evaluated eleven different biological drugs. No significant differences were found regarding safety between TNFi versus non-TNFi (RR 1.08; 95% CI 0.92–1.28; p < 0.01; I2 = 93.0%), TNFi versus csDMARDs (RR 0.91; 95% CI 0.75–1.10; p < 0.01; I2 = 87.0%), bDMARDs versus csDMARDs (RR 0.99; 95% CI 0.82–1.20; p < 0.01; I2 = 93.0%), abatacept versus bDMARDs (RR 0.80; 95% CI 0.54–1.18; p < 0.01; I2 = 90.0%), and TNFi versus JAKi (RR 3.54; 95% CI 0.30–42.09; p = 0.01; I2 = 81.0%). In the subgroup analysis, among studies comparing abatacept to TNFi, a lower risk of cardiovascular events was associated with abatacept (RR 0.37; 95% CI 0.24–0.55).
Conclusion: Our results do not suggest an increased risk of adverse events associated with biological therapy in treating RA patients, indicating a lower risk of cardiovascular events with abatacept than TNFi. However, these findings must be interpreted with caution given the limitations of this study and the low/very low certainty of the evidence.
Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?, identifier [CRD42020190838].

背景：类风湿关节炎（Rheumatoid arthritis, RA）是一种累及关节滑膜液、肌腱及部分关节外部位的全身性炎症性疾病。生物制剂（Biologic agents）在缓解RA症状、延缓疾病进展及改善躯体功能方面疗效显著，应用价值可与其他疗法媲美，但多项潜在不良反应风险引发了学界担忧。因此，本研究旨在通过行政健康数据库开展观察性研究，评估RA患者接受生物治疗的安全性。
方法：本研究检索了PubMed、Embase、Lilacs、Ovid、Scopus及Web of Science数据库，检索时限为建库至2021年10月21日。分析分为五组对照：肿瘤坏死因子抑制剂（Tumor necrosis factor inhibitors, TNFi） vs 非TNFi；TNFi vs 传统合成改善病情抗风湿药（conventional synthetic Disease-Modifying Antirheumatic Drugs, csDMARDs）；生物制剂改善病情抗风湿药（biologic Disease-Modifying Antirheumatic Drugs, bDMARDs） vs csDMARDs；阿巴西普（abatacept） vs bDMARDs；TNFi vs Janus激酶抑制剂（Janus kinase inhibitors, JAKi）。本次研究关注的不良事件包括恶性肿瘤、心血管事件、感染、带状疱疹、肺结核及死亡。采用纽卡斯尔-渥太华量表（Newcastle-Ottawa Scale, NOS）评估纳入研究的方法学质量，通过随机效应模型计算风险比（risk ratio, RR）及95%置信区间（confidence interval, CI）。
结果：本系统评价共纳入31项2014年至2021年发表的符合标准的研究，共计评估1039398例RA患者，上述31项研究共涉及11种不同的生物制剂。各组安全性结局均未发现显著差异：TNFi vs 非TNFi（RR=1.08；95%CI：0.92~1.28；P<0.01；I²=93.0%）、TNFi vs csDMARDs（RR=0.91；95%CI：0.75~1.10；P<0.01；I²=87.0%）、bDMARDs vs csDMARDs（RR=0.99；95%CI：0.82~1.20；P<0.01；I²=93.0%）、阿巴西普vs bDMARDs（RR=0.80；95%CI：0.54~1.18；P<0.01；I²=90.0%）以及TNFi vs JAKi（RR=3.54；95%CI：0.30~42.09；P=0.01；I²=81.0%）。亚组分析显示，在对比阿巴西普与TNFi的研究中，阿巴西普可降低心血管事件发生风险（RR=0.37；95%CI：0.24~0.55）。
结论：本研究结果显示，RA患者接受生物治疗并未增加不良事件发生风险，且阿巴西普较TNFi的心血管事件风险更低。但鉴于本研究存在一定局限性，且证据质量为低或极低等级，对本研究结果的解读需谨慎。
系统评价注册信息：系统评价注册链接：https://www.crd.york.ac.uk/prospero/display_record.php?，注册号：[CRD42020190838]。