Division of Rheumatology Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Seongnam-si Kyeongki-do, Seongnam, Korea.
Division of Rheumatology Department of Internal Medicine, Seoul National University Bundang Hospital, 166 Gumiro Bundang-gu Seongnam-si Kyeongki-do, Seongnam, Korea; Division of Rheumatology Department of Internal Medicine, Seoul National University College of Medicine, Seongnam, Korea.
Semin Arthritis Rheum. 2022 Aug;55:152019. doi: 10.1016/j.semarthrit.2022.152019. Epub 2022 Apr 28.
To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX).
Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi.
Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results.
In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.
本研究旨在比较来氟米特与 TNF 抑制剂（TNFi）、他克莫司与 TNFi 治疗甲氨蝶呤（MTX）背景下类风湿关节炎（RA）患者的感染风险。
本研究使用韩国国家健康保险服务数据库，对接受 TNFi、来氟米特或他克莫司治疗的 RA 患者进行了队列研究。主要结局是任何严重感染，定义为严重细菌、机会性和带状疱疹感染的复合终点。次要结局是主要结局的各个组成部分。采用倾向评分精细分层（PSS）和加权法调整混杂因素。采用 Cox 比例风险模型比较来氟米特与 TNFi、他克莫司与 TNFi，估计风险比（HR）及其 95%置信区间（CI）。
在 72516 例接受 MTX 治疗的 RA 患者中，我们确定了 3336 例 TNFi 起始治疗者、11122 例来氟米特起始治疗者和 5136 例他克莫司起始治疗者。在倾向评分加权后，2 个研究队列分别包括 10992 例来氟米特起始治疗者（与 1623 例 TNFi 起始治疗者匹配）和 5126 例他克莫司起始治疗者（与 2521 例 TNFi 起始治疗者匹配）。每 100 人年带状疱疹感染发生率（3.70-4.27）是严重细菌感染（1.12-1.36）的 3 倍以上，但机会性感染相对少见（0.11-0.23）。比较来氟米特与 TNFi，PSS 加权后的 HR[95%CI]为 1.03[0.89-1.22]，比较他克莫司与 TNFi，PSS 加权后的 HR[95%CI]为 0.91[0.77-1.08]。次要结局分析结果一致。
在这项全国性队列研究中，我们未发现 MTX 背景下 RA 患者中，来氟米特与 TNFi 相比，以及他克莫司与 TNFi 相比，严重感染（即严重细菌、机会性和带状疱疹感染）风险存在显著差异。
