Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNF alpha, chemokines, and growth factors are expressed in diseased joints. The rationale that TNF alpha played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNF alpha antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNF alpha antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3. Randomized, placebo-controlled, multi-center clinical trials of human TNF alpha inhibitors have demonstrated their consistent and remarkable efficacy in controlling signs and symptoms, with a favorable safety profile, in approximately two thirds of patients for up to 2 years, and their ability to retard joint damage. Infliximab (a mAB), and etanercept (a sTNF-R-Fc fusion protein) have been approved by regulatory authorities in the United States and Europe for treating RA, and they represent a significant new addition to available therapeutic options.

中文翻译：

---

类风湿关节炎的抗TNFα疗法：我们学到了什么？

类风湿关节炎（RA）是一种全身性疾病，其特征在于关节滑膜中的慢性炎症反应，并与软骨变性和近关节骨侵蚀有关。在患病的关节中表达了许多促炎细胞因子，包括TNFα，趋化因子和生长因子。TNFα在调节这些分子中发挥重要作用的基本原理及其病理生理潜力，最初是由以下证明提供的：将抗TNFα抗体添加到患病关节来源的代表性细胞的体外培养物中会抑制自发产生IL-1和其他促炎细胞因子的作用 将抗TNFα抗体或sTNFR融合蛋白全身性给药至RA的小鼠模型显示出抗炎和关节保护作用。临床研究中，通过静脉注射英夫利昔单抗（一种嵌合的抗TNFα单克隆抗体（mAB））阻断了RA患者的TNFα活性，这提供了TNF调节IL-6，IL-8，MCP-1和VEGF的产生，免疫和炎性细胞进入关节的募集，血管生成以及基质金属蛋白酶-1和-3的血药浓度降低。人类TNFα抑制剂的随机，安慰剂对照，多中心临床试验表明，它们在控制症状和体征方面具有一致且显着的疗效，并具有良好的安全性，在大约三分之二的患者中使用了长达2年的时间，并且具有这种能力延缓关节损伤。英夫利昔单抗（mAB），