Small molecule inhibitors of TNF in rheumatoid arthritis: elucidation of the target and mechanism of action

风湿性关节炎是一种关节疾病，会导致疼痛、残疾和生活质量下降。它是一种常见疾病，影响全世界约1：100的人。血液中的细胞进入关节，引发炎症，导致僵硬和肿胀，最终导致不可逆的关节损伤和残疾。据估计，40%的患者在确诊后5年内无法工作。类风湿性关节炎无法治愈，目前的治疗方法通常是有毒的，或者NHS对它们的使用受到成本的限制。由于制造成本高，英国只有10%的患者接受了这种领先的治疗方法。此外，这些疗法有许多副作用，并非所有患者都对治疗有反应。因此，有一个重要的医疗需求，开发新的更实惠的治疗方法，副作用更少。我们最近发现了一个可能的联系之间的toll样受体（蛋白质的细胞，通常被身体用来感知感染和组织损伤）和炎症发现在类风湿性关节炎患者的关节。在这项工作中，我们发现了可以控制这些受体的化学物质。当在从接受关节置换手术的类风湿患者中取出的关节组织中进行测试时，我们注意到这些化学物质也可以减少与该疾病相关的组织中的炎症。要将这些化学物质开发成可用于临床的药物，我们首先需要确切了解它们的工作原理。为了做到这一点，我们将进行类似于钓鱼的实验。这些化学物质将被用作诱饵，以拉出它们在人体细胞中相互作用的目标。然后将详细研究这些靶点，以帮助我们了解它们如何控制Toll样受体和炎症。这将为将来开发类风湿性关节炎的新疗法提供重要信息。

Rheumatoid arthritis is a disease of the joints that causes pain, disability and a reduced quality of life. It is a common disease that affects approximately 1:100 people worldwide. Cells from the blood move into the joints where they trigger inflammation causing stiffness and swelling, which eventually leads to irreversible joint damage and disability. Estimates suggest that 40% of patients are unable to work within 5 years of diagnosis. There is no cure for rheumatoid arthritis and current therapies are often toxic or their use by the NHS is limited by the cost. One of the leading therapies is only given to 10% of patients in the UK due to the high cost of manufacture. In addition, these therapies have many side effects and not all patients respond to treatment. Thus, there is an important medical need for the development of new more affordable therapies with fewer side effects.We have recently identified a possible link between toll-like receptors (proteins on cells that are normally used by the body to sense infections and tissue damage) and the inflammation found in the joints of rheumatoid arthritis patients. During this work we discovered chemicals that could control these receptors. When tested in joint tissue removed from rheumatoid patients having joint replacement surgery, we noticed that these chemicals could also reduce the inflammation in this tissue that is associated with the disease. To develop these chemicals into a drug that can be used in the clinic we first need to understand exactly how they work. To do this we will perform experiments that are comparable to going fishing. The chemicals will be used as bait to pull out the targets that they interact with in human cells. These targets will then be studied in detail to help us understand how they control toll-like receptors and inflammation. This will provide important information that is needed for the development of new therapies for rheumatoid arthritis in the future.