专家共识
ENGLISH ABSTRACT
Janus激酶抑制剂治疗风湿免疫病的中国专家共识(2024版)
张卓莉
赵岩
代表中华医学会风湿病学分会
中国初级卫生保健基金会风湿免疫专委会
Janus激酶抑制剂治疗风湿免疫病中国专家共识小组
作者及单位信息
·
DOI: 10.3760/cma.j.cn141217-20240522-00164
Chinese expert consensus on the use of Janus kinase inhibitor for the treatment of rheumatic and immunological diseases (2024)
Zhang Zhuoli
Zhao Yan
on behalf of Chinese Rheumatology Association
Committee for Rheumatologists and Immunologists of Chinese Primary Health Care Foundation
Chinese Expert Consensus Group on JAK Inhibitor Therapy for Rheumatic and Immune Diseases
Authors Info & Affiliations
Zhang Zhuoli
Department of Rheumatology and Immunology, Peking University First Hospital, Beijing 100034, China
Zhao Yan
Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Beijing 100730, China
on behalf of Chinese Rheumatology Association
Committee for Rheumatologists and Immunologists of Chinese Primary Health Care Foundation
Chinese Expert Consensus Group on JAK Inhibitor Therapy for Rheumatic and Immune Diseases
·
DOI: 10.3760/cma.j.cn141217-20240522-00164
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摘要

近年来,Janus激酶(JAK)抑制剂在治疗风湿免疫病中得到广泛应用,其疗效和安全性日益明确。为规范JAK抑制剂的临床应用管理,特别是针对托法替布、巴瑞替尼和乌帕替尼这3种在中国获批的JAK抑制剂在风湿免疫病治疗中的应用,本共识依据国内外循证证据提出了具体的建议和指导,涵盖了使用方法、适用人群、联合用药、特殊人群和超适应证使用、不良反应管理等方面,旨在为临床医生在使用JAK抑制剂时提供参考依据。

Janus激酶抑制剂;风湿性疾病;治疗;共识
引用本文

张卓莉,赵岩. Janus激酶抑制剂治疗风湿免疫病的中国专家共识(2024版)[J]. 中华风湿病学杂志,2024,28(07):433-444.

DOI:10.3760/cma.j.cn141217-20240522-00164

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风湿免疫病的诊疗在过去20年间有了突飞猛进的发展,尤其是小分子靶向改善病情抗风湿药(targeted synthetic disease modifying anti-rheumatic drugs,tsDMARD)的上市进一步提高了类风湿关节炎(rheumatoid arthritis,RA)、银屑病关节炎(psoriatic arthritis,PsA)和强直性脊柱炎(ankylosing spondyli-tis,AS)等多种风湿免疫病的疗效,显著改善了患者预后。Janus激酶(JAK)抑制剂是当下最主要的靶向合成改善病情抗风湿药(tsDMARD),通过抑制Janus激酶阻断细胞因子转导通路从而治疗多种风湿免疫病。目前已知JAK有4个亚型:JAK1、JAK2、JAK3和Tyk2,对应不同信号通路 [ 1 ](见 图1 )。
JAK家族与相关细胞因子

注:βc:β链;IL:白细胞介素;GM-CSF:粒细胞-巨噬细胞集落刺激因子;gp130:糖蛋白130;IFN:干扰素;γc:γ链;JAK:Janus激酶;LIF:白血病抑制因子;OSM:抑瘤素M;TYK:酪氨酸激酶

截止2023年12月31日,经查询国家药品监督管理局官方网站,在国内一共获批7款JAK抑制剂;其中托法替布、巴瑞替尼、乌帕替尼获批风湿免疫病的适应证,另外托法替布有普通片和缓释片2个剂型,药代动力学指标见 表1 。JAK抑制剂总体上包括泛JAK抑制剂和选择性JAK抑制剂,上市时间更长的JAK抑制剂在安全性方面的研究数据相对更多更充分。另外,有多家国内药厂通过药物一致性评价,与原研参比药生物学等效;我国一项原创性临床研究已经证实国产与原研托法替布的临床疗效和安全性相当,且成本效益更好 [ 2 ]
药物 剂型 吸收 分布 代谢与排泄
托法替布 普通片 生物利用度:74%,T max约1 h(0.5~1 h) 高脂饮食合用 b:AUC无变化,C max 降低32% 表观分布容积:87 L 血浆蛋白结合率:40% 70%原型经肝脏代谢,30%原型经肾脏排泄 代谢:主要经CYP3A4,少数经CYP2C19 半衰期:3 h
  缓释片 a 生物利用度:74%,T max约4 h(3~4 h) 高脂饮食合用 b:AUC无变化,C max 增加27%,T max延长约1 h 表观分布容积:87 L 血浆蛋白结合率:40% 70%原型经肝脏代谢,30%原型经肾脏排泄 代谢:主要经CYP3A4,少数经CYP2C19 半衰期:约6~8 h
巴瑞替尼 普通片 生物利用度:79%,T max约1 h(0.5~3 h) 与食物合用 b:AUC下降14%,C max下降18%,T max延长0.5 h 表观分布容积:50 L 血浆蛋白结合率:50% 10%原型经肝脏代谢,69%原型经尿液,15%原型经粪便排泄 代谢:主要经CYP3A4 半衰期:12~16 h
乌帕替尼 缓释片 生物利用度:76%,T max:2~4 h 高脂饮食合用 b:AUC增加29%,C max增加39% 表观分布容积:224 L 血浆蛋白结合率:52% 约21%被代谢,24%原型经尿液,38%原型经粪便排泄 代谢:主要经CYP3A4,少数经CYP2D6 半衰期:8~14 h
治疗风湿免疫病的JAK抑制剂体内药代动力学特点

注: a11 mg每日1次缓释片与5 mg每日2次普通片AUC与C max相当; b与食物/高脂饮食合用对AUC与C max的影响无临床意义;JAK:Janus激酶;T max:达峰时间;C max:药物的峰值浓度;AUC:曲线下面积;CYP3A4:细胞色素P450 3A4酶;CYP2C19:细胞色素P450 2C19酶;CYP2D6:细胞色素P450 2D6酶

由于JAK抑制剂的机制与疗效日益明确,口服给药,使用便利,不存在免疫原性,在国内经济性出众,JAK抑制剂在众多领域的临床应用爆发式增长,但规范JAK抑制剂的临床应用仍需要专业知识和用药技巧。为使广大医生充分了解药物特性和循证依据,优化用药方案,改善患者预后,中华医学会风湿病学分会联合中国初级卫生保健基金会风湿免疫专委会共识专家组共同编写了本共识。
本共识将聚焦在中国获批的3种JAK抑制剂在风湿免疫病中的应用。同时在本共识撰写过程中,国内外还有多款JAK抑制剂药物处于研发和临床研究阶段,最终审评审批结果未知,此次共识撰写不录入。
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张卓莉,Email: mocdef.6ab21gnahz.ilouhz
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赵岩,Email: mocdef.nabuyila2002hcmup_nayoahz
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国际实践指南注册与透明化平台(PREPARE-2023CN1001)
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