Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, No.1 Shuaifuyuan, Beijing, 100730, China.
Clin Rev Allergy Immunol. 2020 Dec;59(3):334-351. doi: 10.1007/s12016-020-08786-6.
The dysregulation of the JAK-STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous JAK inhibitors are currently being tested in phase II and III trials for the treatment of various autoimmune inflammatory diseases. In this narrative review, we elucidate the involvement of the JAK-STAT signaling pathway in the pathogenesis of connective tissue diseases (CTDs). We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren's syndrome, and vasculitis, based on laboratory and clinical research findings. JAK inhibitors have great potential for the treatment of various CTDs by reducing multiple cytokine production and suppressing inflammation, with the advantages of rapid onset in an oral formulation and decreased corticosteroid dependence and the associated adverse events, especially in refractory cases. We also highlight the safety of novel JAK inhibitors, which can cause opportunistic infections, especially viral infections. Being a very recent therapeutic option, information regarding the safety of JAK inhibitors during pregnancy and for pediatric use is limited. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs.
JAK-STAT 通路的失调与各种免疫紊乱有关。有 4 种 JAK 抑制剂已被批准用于类风湿关节炎（RA），目前有许多 JAK 抑制剂正在进行 II 期和 III 期临床试验，以治疗各种自身免疫性炎症性疾病。在这篇叙述性综述中，我们阐明了 JAK-STAT 信号通路在结缔组织疾病（CTD）发病机制中的作用。我们还讨论了第一代和第二代 JAK 抑制剂（托法替尼、巴瑞替尼、芦可替尼、培非替尼、菲戈替尼、乌帕替尼、索西替尼、依鲁替尼、地瑞努替布、R333 和 pf-06651600）在包括 RA、系统性红斑狼疮、皮肌炎、系统性硬化症、干燥综合征和血管炎在内的 CTD 中的疗效，这些疗效基于实验室和临床研究结果。JAK 抑制剂通过减少多种细胞因子的产生和抑制炎症，具有口服制剂起效迅速、减少皮质类固醇依赖和相关不良反应的优势，特别是在难治性病例中，具有治疗各种 CTD 的巨大潜力。我们还强调了新型 JAK 抑制剂的安全性，这些抑制剂可能会引起机会性感染，特别是病毒感染。作为一种非常新的治疗选择，关于 JAK 抑制剂在怀孕期间和儿科使用的安全性信息有限。然而，建议在孕妇和哺乳期妇女中避免使用 JAK 抑制剂。需要更多的临床数据，特别是关于高选择性抑制剂的数据，以判断 JAK 抑制在 CTD 中的疗效和安全性。
