Biogen Idec (CAMBRIDGE, Mass.) announced studies published in the August 15, 2006 issue of the providing evidence that TWEAK (TNF-like weak inducer of apoptosis), a TNF family member, is a novel arthritogenic mediator that contributes to joint tissue inflammation, angiogenesis, and destruction, and may inhibit endogenous repair. Data are presented providing support for TWEAK blockade as a novel therapeutic approach for the treatment of rheumatoid arthritis (RA) and perhaps for other autoimmune diseases as well.

Initially described in 1997 by Biogen Idec and University of Geneva researchers, TWEAK is expressed by activated macrophages, promotes angiogenesis, induces the production of proinflammatory cytokines and chemokines by synoviocytes obtained from RA and advanced osteoarthritis (OA) patient tissue, potentiates the proinflammatory response to TNF and IL-1Beta in normal fibroblasts, and induces the formation of osteoclasts. The receptor for TWEAK, fibroblast growth factor-inducible gene 14 (Fn14/TWEAK-R), is known to be highly up-regulated in tissues subject to injury, regeneration, and inflammatory processes. The current findings provide evidence that activation of the TWEAK/Fn14 inflammation pathway may play an important role in the disease process that causes RA and that TWEAK blockade may provide a new approach to developing RA (and OA) treatments. In the collagen-induced arthritis (CIA) mouse model for RA: (1) the serum TWEAK level was dramatically elevated and anti-TWEAK-neutralizing monoclonal antibody significantly ameliorates the clinical manifestations of CIA, and (2) TWEAK blockade reduced serum levels of a panel of arthritogenic mediators including MMM-9, MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), and diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Using in vitro models, TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis from mesenchymal stem cells and osteoblastogenesis from progenitor cells.

"Despite considerable progress, many rheumatoid arthritis patients do not adequately respond to current treatments, indicating that other pathways are involved in this complex disease," said Timothy Zheng, PhD, Senior Scientist, Molecular Discovery, at Biogen Idec. "Our investigative research suggests that TWEAK contributes to the disease through multiple mechanisms, and inhibiting the TWEAK pathway may represent a new set of opportunities for treatment."

Biogen Idec is examining the role of the TWEAK/Fn14 pathway in several autoimmune diseases, and whether TWEAK might underlie TNF blockade failure in certain autoimmune disease patient populations.

—A. Techman