Rheumatoid arthritis affects about 1% of all populations, women two to three times more often than men. This translates to a total of 5 million rheumatoid arthritis sufferers in the major pharmaceutical markets. The market for agents used to treat rheumatoid arthritis totaled $1.6 billion in 2000. At present, treatments of this disease are based on symptomatic therapies such as NSAIDs (including the new COX-2 inhibitors), gold-containing compounds and corticosteroids. The current trend however is to move towards disease-modifying anti-rheumatic drugs (DMARDs). Inhibitors of angiogenesis offer one exciting approach. Other approaches include the use of immunosuppressants. Examples of this therapeutic class include methotrexate, azathioprine and cyclosporine although side effect profiles are driving the industry towards more specific modulators of cytokines. Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. In our previous edition of TherapeuticAdvances we focussed on Toyama’s T-614 (iguratimod). T-614 suppresses the production of IL-1, IL-6, IL-8 and TNF and is in phase III development for the treatment of rheumatoid arthritis as a result of its ability to slow bone destruction and as shown more recently, to stimulates osteoblastic differentiation. Here we focus on advances in the development of IL-8 receptor antagonists. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. GlaxoSmithKline researchers have recently investigated the effects of a potent and selective nonpeptide antagonist of human CXCR2 in models of arthritis. In acute models, oral administration of the antagonist reduced synovial fluid neutrophils, monocytes, and lymphocytes. In the more robust LPS- and OVA-induced chronic arthritis models, the antagonist reduced synovial fluid levels of TNF-alpha, IL-8, PGE2, leukotriene B4, and leukotriene C4. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils, suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease. Only a few CXCR2 receptor antagonists are in development however these data offer good proof of concept to support further development of this therapeutic class. 

Entry date January, 2003

Adapted from Podolin et al, J Immunol 2002 Dec 1;169(11):6435-44 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.