From the Division of Rheumatology, Department of Medicine, Medical University of Vienna, Vienna, Austria; Division of Immunology and Rheumatology, Stanford University Medical Center, Palo Alto, California, USA; Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan; Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana, USA; Lilly Research Laboratories, Eli Lilly and Co., Kobe, Japan; Oregon Health Sciences University, Portland, Oregon, USA.
J.S. Smolen, MD, Division of Rheumatology, Department of Medicine, Medical University of Vienna; M.C. Genovese, MD, Division of Immunology and Rheumatology, Stanford University Medical Center; T. Takeuchi, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Keio University; D.L. Hyslop, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; W. Macias, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Rooney, MD, Lilly Research Laboratories, Eli Lilly and Co., USA; L. Chen, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., USA; C.L. Dickson, BS Pharm, Lilly Research Laboratories, Eli Lilly and Co., USA; J. Riddle Camp, BA, Lilly Research Laboratories, Eli Lilly and Co., USA; T.E. Cardillo, MSN, Lilly Research Laboratories, Eli Lilly and Co., USA; T. Ishii, MD, PhD, Lilly Research Laboratories, Eli Lilly and Co., Japan; K.L. Winthrop, MD, MPH, Oregon Health Sciences University.
J Rheumatol. 2019 Jan;46(1):7-18. doi: 10.3899/jrheum.171361. Epub 2018 Sep 15.
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)].
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.
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.
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.
巴利昔替尼是一种每日一次口服的选择性 Janus 激酶（JAK1/JAK2）抑制剂，用于治疗中重度活跃性类风湿关节炎（RA）的成人患者。我们通过一个综合数据库（8 项 III/II/Ib 期研究，1 项长期扩展研究）评估了巴利昔替尼的安全性概况，截至 2016 年 9 月 1 日。
“所有巴利昔替尼-RA 组”包括接受任何巴利昔替尼剂量的患者。基于接受 4 毫克巴利昔替尼和安慰剂至 24 周的 6 项研究（“安慰剂-4 毫克”数据集）进行安慰剂比较。基于包括长期扩展数据的 4 项 2 毫克和 4 毫克研究进行剂量反应评估（“2 毫克-4 毫克扩展”）。使用非对照所有巴利昔替尼-RA 描述罕见事件。
有 3492 名患者接受了巴利昔替尼治疗，共 6637 人年（中位数 2.1 年，最长 5.5 年）。与安慰剂相比，4 毫克组与 4 毫克组或 2 毫克组相比，死亡率、导致药物停药的不良事件、恶性肿瘤、主要不良心血管事件（MACE）或严重感染的发生率无差异。与安慰剂相比，4 毫克组的感染（包括带状疱疹）更为频繁。深静脉血栓形成/肺栓塞在 4 毫克组报告，但不在安慰剂组报告[所有巴利昔替尼-RA 发生率（IR）为 0.5/100 人年]；剂量间（4 毫克与 0.5 比 0.6/100 人年，2 毫克与 4 毫克）或与已发表的 RA 发生率相比，IR 无差异。所有巴利昔替尼-RA 中有 6 例淋巴瘤（IR 为 0.09/100 人年）、3 例胃肠道穿孔（IR 为 0.05/100 人年）、10 例结核病（均在流行地区；IR 为 0.15/100 人年）和 22 例全因死亡（IR 为 0.33/100 人年）。恶性肿瘤（0.8/100 人年）和 MACE（0.5/100 人年）的发生率较低，且随着暴露时间的延长而没有增加。
在这项接受中重度活跃性 RA 治疗且暴露时间长达 5.5 年的患者的综合分析中，巴利昔替尼在疗效得到证实的情况下具有可接受的安全性。临床试验注册编号：NCT01185353、NCT00902486、NCT01469013、NCT01710358、NCT01721044、NCT01721057、NCT01711359 和 NCT01885078，在 clinicaltrials.gov 上。
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