A rational approach to the use of combination biologic therapy in rheumatoid arthritis
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
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.
Technical Summary
TNF antagonists represent a major breakthrough in the treatment of a number of autoimmune and inflammatory diseases but there are serious obstacles to their more general use, including high cost and lack of durable therapeutic effect.
Using a mouse model of rheumatoid arthritis, we have recently discovered that one of the unexpected consequences of TNF blockade is the increased expression of IL-17, a potent pro-inflammatory cytokine. Thus, the beneficial effects of anti-TNF therapy are offset by the deleterious effects of increased IL-17 production. In addition, we have preliminary evidence in mice that anti-TNF and anti-IL-17 act synergistically to suppress arthritis and induce disease remission. In this proposal we will first establish that TNF blockade upregulates the IL-17 pathway in patients with rheumatoid arthritis and other autoimmune diseases. Next, we will confirm the ability of anti-TNF and anti-IL-17 to act synergistically in mice and establish the optimal form of combination therapy for use in human therapy. This will provide the scientific rationale for conducting clinical trials of combination biologic therapy in rheumatoid arthritis. The potential benefit of this study will be to establish a novel therapeutic approach which has improved long-term efficacy over existing therapies and which will increase the numbers of patients that can be treated effectively by TNF antagonists.
Using a mouse model of rheumatoid arthritis, we have recently discovered that one of the unexpected consequences of TNF blockade is the increased expression of IL-17, a potent pro-inflammatory cytokine. Thus, the beneficial effects of anti-TNF therapy are offset by the deleterious effects of increased IL-17 production. In addition, we have preliminary evidence in mice that anti-TNF and anti-IL-17 act synergistically to suppress arthritis and induce disease remission. In this proposal we will first establish that TNF blockade upregulates the IL-17 pathway in patients with rheumatoid arthritis and other autoimmune diseases. Next, we will confirm the ability of anti-TNF and anti-IL-17 to act synergistically in mice and establish the optimal form of combination therapy for use in human therapy. This will provide the scientific rationale for conducting clinical trials of combination biologic therapy in rheumatoid arthritis. The potential benefit of this study will be to establish a novel therapeutic approach which has improved long-term efficacy over existing therapies and which will increase the numbers of patients that can be treated effectively by TNF antagonists.
