Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK.
Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany; Universitätsklinikum Erlangen, Erlangen, Germany.
Lancet. 2017 Jun 10;389(10086):2328-2337. doi: 10.1016/S0140-6736(17)31472-1.
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 α 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.
类风湿关节炎是一种慢性自身免疫性疾病，可导致进行性关节损伤、功能丧失和合并症。在过去二十年中，有效的生物制剂和小分子激酶抑制剂的发展极大地改善了临床结果。正如对发病机制的理解在很大程度上导致了药物的发展一样，对这些特定免疫靶向药物的作用机制的研究也揭示了哪些免疫途径驱动关节炎症和相关合并症。细胞因子抑制剂已明确证明肿瘤坏死因子 α 和白细胞介素 6 在疾病发病机制中以及可能在粒细胞-巨噬细胞集落刺激因子中具有关键作用。最近，Janus 激酶（JAK）抑制剂的临床试验表明，通过 JAK/STAT 信号通路信号传导的细胞因子受体对于疾病很重要，这为其他细胞因子（如干扰素）的致病功能提供了信息。最后，在临床上成功使用共刺激阻断和 B 细胞耗竭表明，适应性免疫反应以及这些细胞引发的下游事件直接参与滑膜炎症。综上所述，很明显，了解特定免疫干预的效果可以阐明维持类风湿关节炎等疾病复杂炎症网络所必需的明确的分子或细胞节点。
