Pathogenetic insights from the treatment of rheumatoid arthritis
Pathogenetic insights from the treatment of rheumatoid arthritis
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DOI：
10.1016/s0140-6736(17)31472-1
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发表时间：
2017-06-10
期刊：
影响因子：
168.9
通讯作者：
Schett, Georg
中科院分区：
文献类型：
--
作者：
McInnes, Iain B.;Schett, Georg
类风湿性关节炎是一种慢性自身免疫性疾病，会导致进行性关节损害、功能丧失和共病。在过去的二十年里，有效的生物制品和小分子激酶抑制剂的发展极大地改善了临床结果。正如对发病机制的了解在很大程度上导致了药物的开发，对这些特定免疫靶向药物的作用模式研究也揭示了哪些免疫途径推动了关节炎症和相关的共病。细胞因子抑制物在肿瘤坏死因子a和白介素6的疾病发病机制中起关键作用，也可能对粒细胞-巨噬细胞集落刺激因子起关键作用。最近，Janus Kinase(JAK)抑制剂的临床试验表明，通过JAK/STAT信号通路发出信号的细胞因子受体对疾病非常重要，告知其他细胞因子(如干扰素)的致病功能。最后，共刺激阻断和B细胞耗竭在临床上的成功应用揭示了获得性免疫反应及其引发的下游事件直接参与了滑膜炎症。综上所述，很明显，了解特定免疫干预的效果可以阐明最终的分子或细胞节点，这些节点对于维持复杂的炎症网络至关重要，这些网络为类风湿性关节炎等疾病提供了辅助服务。
Rheumatoid arthritis is a chronic autoimmune disease that causes progressive articular damage, functional loss, and comorbidity. The development of effective biologics and small-molecule kinase inhibitors in the past two decades has substantially improved clinical outcomes. Just as understanding of pathogenesis has led in large part to the development of drugs, so have mode-of-action studies of these specific immune-targeted agents revealed which immune pathways drive articular inflammation and related comorbidities. Cytokine inhibitors have definitively proven a critical role for tumour necrosis factor a and interleukin 6 in disease pathogenesis and possibly also for granulocyte-macrophage colony-stimulating factor. More recently, clinical trials with Janus kinase (JAK) inhibitors have shown that cytokine receptors that signal through the JAK/STAT signalling pathway are important for disease, informing the pathogenetic function of additional cytokines (such as the interferons). Finally, successful use of costimulatory blockade and B-cell depletion in the clinic has revealed that the adaptive immune response and the downstream events initiated by these cells participate directly in synovial inflammation. Taken together, it becomes apparent that understanding the effects of specific immune interventions can elucidate definitive molecular or cellular nodes that are essential to maintain complex inflammatory networks that subserve diseases like rheumatoid arthritis.