Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment
Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment
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DOI：
10.3899/jrheum.171361
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Winthrop, Kevin L.
中科院分区：
文献类型：
--
作者：
Smolen, Josef S.;Genovese, Mark C.;Winthrop, Kevin L.
Objective. Baricitinib是一种口服，每日一次选择性Janus激酶（JAK 1/JAK 2）抑制剂，用于中度至重度活动性类风湿关节炎（RA）成人。我们使用综合数据库[8项III/II/Ib期试验，1项长期扩展（LTE）]评估了baricitinib在288周（截至2016年9月1日）内的安全性特征。“所有bari-RA”组包括接受任何baricitinib剂量的患者。安慰剂比较是基于6项研究（4 mg和安慰剂组，直至第24周）（“安慰剂-4 mg”数据集）。剂量反应评估基于4项2 mg和4 mg研究，包括LTE数据（“2 mg-4 mg-延长”）。不常见事件描述使用非对照全巴里RA。结果。有3492例患者接受了baricitinib治疗，总暴露患者年（PY）为6637（中位2.1年，最长5.5年）。在死亡率、导致停药的不良事件、恶性肿瘤、主要心血管不良事件（MACE）或严重感染方面，4 mg与安慰剂或4 mg与2 mg之间没有差异。与安慰剂相比，4 mg组感染（包括带状疱疹）的发生率显著更高。4 mg组报告了深静脉血栓形成/肺栓塞，但安慰剂组未报告[全巴里-RA发生率（IR）0.5/100 PY]; IR在剂量间无差异（分别为0.5 vs 0.6/100 PY，2 mg vs 4 mg）或与已发表的RA发生率相比无差异。全巴里RA组有6例淋巴瘤（IR 0.09/100 PY）、3例胃肠道穿孔（0.05/100 PY）、10例结核病（均在流行地区; 0.15/100 PY）和22例全因死亡（0.33/100 PY）。恶性肿瘤的IR（0.8/100 PY）和MACE（0.5/100 PY）较低，且不随时间延长而增加。在这项对暴露长达5.5年的中重度活动性RA患者的综合分析中，baricitinib在已证实疗效的背景下具有可接受的安全性特征。试验注册号：clinicaltrials.gov上的NCT 01185353、NCT 00902486、NCT 01469013、NCT 01710358、NCT 01721044、NCT 01721057、NCT 01711359和NCT 01885078。
Objective. Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib's safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)].Methods. The "all-bari-RA" group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 ("placebo-4 mg" dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data ("2 mg-4 mg-extended"). The uncommon events description used the non-controlled all-bari-RA.Results. There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure.Conclusion. In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.