小分子 JAK 抑制剂治疗类风湿关节炎的感染风险的系统评价和荟萃分析。
A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis.
机构信息
Centre for Rheumatic Disease, Kings College London.
Psychology Department, Institute of Psychiatry, Kings College London, London, UK.
出版信息
Rheumatology (Oxford). 2019 Oct 1;58(10):1755-1766. doi: 10.1093/rheumatology/kez087.
OBJECTIVES
To evaluate the risk of serious infection (SI) and herpes zoster (HZ) in rheumatoid arthritis patients receiving JAK inhibitors.
METHODS
We conducted a systematic literature review and meta-analysis of phase II and III randomized controlled trials of tofacitinib (5 mg bid), baricitinib (4 mg od) and upadacitinib (15 mg od). Patient-exposure years were calculated. A per-protocol analysis was applied, incorporating follow-up time from patients randomized to placebo who cross into the treatment arm. Pooled incidence rates per 100 person-years of SI and HZ were calculated. Incidence rate ratios (IRRs) of drug vs placebo were compared using a meta-synthesis approach.
RESULTS
Twenty-one studies were included in the meta-analysis; 11 tofacitinib (5888 patients), six baricitinib (3520 patients) and four upadacitinib studies (1736 patients). For SI, the incidence rates were 1.97 (95% CI: 1.41, 2.68), 3.16 (95% CI: 2.07, 4.63) and 3.02 (95% CI: 0.98, 7.04), respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI: 0.60, 2.45), 0.80 (95% CI: 0.46, 1.38) and 1.14 (95% CI: 0.24, 5.43), respectively. For HZ, the incidence rates were 2.51 (95% CI: 1.87, 3.30), 3.16 (95% CI: 2.07, 4.63) and 2.41 (95% CI: 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI: 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI: 0.66, 2.88) and 0.78 (95% CI: 0.19, 3.22), respectively. Indicator opportunistic infections excluding HZ were too rare to provide meaningful incidence rates.
CONCLUSION
The absolute SI rates were low. However across the JAK inhibitors, the incidence of HZ is higher than expected for the population (3.23 per 100 patient-years). While the risk was numerically greatest with baricitinib, indirect comparisons between the drugs did not demonstrate any significant difference in risk.
SYSTEMATIC REVIEW REGISTRATION NUMBER
Prospero 2017 CRD4201707879.
目的
评估类风湿关节炎患者接受 JAK 抑制剂治疗后发生严重感染（SI）和带状疱疹（HZ）的风险。
方法
我们对托法替布（5mg bid）、巴瑞替尼（4mg od）和乌帕替尼（15mg od）的 II 期和 III 期随机对照试验进行了系统文献回顾和荟萃分析。计算了患者暴露年数。采用方案预设分析，纳入从随机分配至安慰剂后交叉至治疗组的患者的随访时间。计算每 100 人年 SI 和 HZ 的发生率。采用综合合成方法比较药物与安慰剂的发病率比值比（IRR）。
结果
荟萃分析纳入 21 项研究；11 项托法替布（5888 例患者）、6 项巴瑞替尼（3520 例患者）和 4 项乌帕替尼研究（1736 例患者）。SI 的发生率分别为 1.97（95%CI：1.41，2.68）、3.16（95%CI：2.07，4.63）和 3.02（95%CI：0.98，7.04）。与安慰剂相比，治疗组的 IRR 无统计学意义：1.22（95%CI：0.60，2.45）、0.80（95%CI：0.46，1.38）和 1.14（95%CI：0.24，5.43）。HZ 的发生率分别为 2.51（95%CI：1.87，3.30）、3.16（95%CI：2.07，4.63）和 2.41（95%CI：0.66，6.18）。与安慰剂相比，巴瑞替尼治疗的 HZ 的 IRR 为 2.86（95%CI：1.26，6.50）。托法替布和乌帕替尼的 IRR 无统计学意义：1.38（95%CI：0.66，2.88）和 0.78（95%CI：0.19，3.22）。排除 HZ 的机会性感染的发生率太低，无法提供有意义的发病率。
结论
绝对 SI 发生率较低。然而，在 JAK 抑制剂中，HZ 的发生率高于预期（每 100 患者年 3.23 例）。虽然巴瑞替尼的风险最大，但药物之间的间接比较并未显示出任何显著的风险差异。
系统评价注册号
PROSPERO 2017 CRD4201707879。
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