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

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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.