A rational approach to the use of combination biologic therapy in rheumatoid arthritis

TNF拮抗剂是一类用于治疗类风湿性关节炎和其他自身免疫性疾病的新药。这些药物通过阻断一种称为TNF的细胞因子的活性来发挥作用，该细胞因子在疾病过程中起着重要作用。使用类风湿性关节炎的小鼠模型，我们最近发现TNF阻断的一个意想不到的后果是另一种细胞因子IL-17的产生增加，这也有助于疾病的过程。因此，抗TNF治疗的有益作用被IL-17产生增加的有害作用抵消。在此基础上，我们预测TNF拮抗剂和IL-17拮抗剂的组合将具有增强的治疗效果，并且我们已经使用关节炎小鼠模型获得了初步证据，表明情况确实如此。在这个建议中，我们将首先确定TNF拮抗剂增加类风湿性关节炎和其他自身免疫性疾病患者的IL-17水平。接下来，我们将在小鼠中验证使用TNF拮抗剂和IL-17拮抗剂的联合治疗的概念。这将为开展类风湿性关节炎联合治疗的临床试验提供科学依据。最后，我们将寻求确定有兴趣在患者中测试联合治疗概念的工业合作伙伴。这项研究将有助于建立一种新的治疗方法，这种方法将改善现有疗法的长期疗效。

TNF antagonists are a new class of drugs that are used to treat rheumatoid arthritis and other autoimmune diseases. These drugs act by blocking the activity of a cytokine, known as TNF, that plays an important role in the disease process. Using a mouse model of rheumatoid arthritis, we have recently discovered that one of the unexpected consequences of TNF blockade is the increased production of another cytokine, IL-17, that also contributes to the disease process. Hence, the beneficial effects of anti-TNF therapy are offset by the deleterious effects of increased IL-17 production. On this basis we would predict that a combination of a TNF antagonist and an IL-17 antagonist would have an enhanced therapeutic effect and we have obtained preliminary evidence using a mouse model of arthritis to suggest that this is the case. In this proposal we will first establish that TNF antagonists increase IL-17 levels in patients with rheumatoid arthritis and other autoimmune diseases. Next, we will validate the concept of combination therapy using a TNF antagonist and an IL-17 antagonist in mice. This will provide the scientific rationale for conducting clinical trials of combination therapy in rheumatoid arthritis. Finally, we will seek to identify industrial partners interested in testing the concept of combination therapy in patients. This study will help to establish a novel approach to treatment that will have improved long-term efficacy over existing therapies.