New compounds offer promising alternatives for future therapy -- Advances in RA: The next generation of therapies
Byline: NIMESH A. DAYAL, MD and ERIC M. RUDERMAN, MD
ABSTRACT: The tumor necrosis factor a (TNF-a) antagonists have been shown to be effective in patients with rheumatoid arthritis (RA). New biologic therapies in development offer promising alternatives. In a study of humanized antibody to human interleukin-6 receptor in refractory RA, treatment led to a reduction in disease activity. Abatacept was found to be effective in a separate trial of patients who had active RA despite having received therapy with methotrexate (MTX) or TNF-alpha antagonists. Rituximab in combination with MTX has a promising risk/benefit ratio. Future approaches to RA treatment include TNF family proteins, TNF-related apoptosis-inducing ligand, and small molecular inhibitors of intracellular signaling. None is likely to supplant MTX and the TNF-alpha antagonists as the standard of care in the near future. (J Musculoskel Med. 2006;23:337-346)
This is the eighth in a special series of articles on early diagnosis and aggressive management of rheumatoid arthritis.
The clinical and commercial success of the tumor necrosis factor a (TNF-alpha) antagonists etanercept, infliximab, and adalimumab for the management of rheumatoid arthritis (RA) has not gone unnoticed, by the medical community or the pharmaceutical industry. The biologic agents that are currently available, particularly the TNF-alpha antagonists, have been shown to be very effective.1,2 Now a new generation of biologic therapies recently available and on the horizon offer physicians and patients promising alternatives.
These newer biologic agents include other compounds that affect cytokine activity and those that inhibit cellular activation and inflammatory gene transcription by other means. Developing therapies include antibodies, soluble receptors, and recombinant versions of naturally occurring antagonists, as well as small molecules that specifically inhibit intracellular, cell-cell, and cell-matrix interactions that drive the inflammatory process. Future progress in the treatment of patients with RA may include use of combinations of existing and future biologic agents and conventional therapies aimed at improving response rates without increasing adverse effects.
In this article, we review the current clinical data on biologic agents recently approved and those that may be available for clinical use in the near future. We also discuss other compounds that may have potential for future RA therapy.
TARGETING THE CYTOKINE NETWORK
The rheumatoid joint is characterized by the presence of an inflamed and overgrown synovial membrane, the pannus. Many types of inflammatory cells may be identified within this hypertrophic, hyperplastic synovial tissue, including macrophages, T lymphocytes, plasma cells, dendritic cells, and fibroblasts. These cells communicate through a complex network of cytokines; in active disease, there appears to be an imbalance between proinflammatory and anti-inflammatory cytokines and other cytokine antagonists. A full review of the cytokine network involved in RA3 is beyond the scope of this article.
Compounds that control the cytokine network that may be available in the near future include humanized antibody to human interleukin (IL)-6 receptor (tocilizumab), a monoclonal antibody directed against the IL-6 receptor. Recently approved compounds include rituximab, a chimeric monoclonal antibody directed against the B cell-specific surface protein CD 20, and abatacept (CTLA4-Ig), a...
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