Arthritides - Monoclonal Antibodies in Anti inflammatory Therapy

ARTHRITIDES

Of all the autoimmune arthritides, RA is the most prevalent, affecting at least 1% of the general popula-tion in the United States. If not treated aggressively early in the course of disease RA can result in irreversible joint destruction, severe functional im-pairment and lead to a need for joint replacement surgery (Olsen and Stein, 2004). Although early intervention with steroids and DMARDs have helped demonstrate that the inflammatory course of RA can be interrupted and delayed, these therapies are not without significant side effects, and are not sufficient for many patients. For patients with safety issues or inadequate clinical efficacy with DMARDs, there are now many newer targeted options for treating RA including, anakinra (Kineret ), infliximab (Remicade ), etanercept (Enbrel ), adalimumab (Humira ), abatacept (Orencia ), and rituximab (Rituxan ) (Genovese, 2005).

The controlled clinical trials evaluating these agents in RA typically measure clinical efficacy over a 6 to 12 month period using a composite outcome like the one developed by and named after the American College of Rheumatology (ACR). For example, an ACR20 describes a 20 percent improvement from baseline on therapy in the number of tender and swollen joints plus a similar improvement in a composite of at least 3 out of 5 of the following: pain, patient’s self global assessment, physician’s global assessment, disability and a lab estimate of inflamma-tion (erythrocyte sedimentation rate or C-reactive protein). A 50% or 70% improvement are termed ACR50 and ACR70, respectively. If a trial reports an ACR20 of 30% on active drug and 5% on placebo, that means the 30% of the patients receiving the active drug had a 20% improvement in the outcomes (as noted above) compared to only 5% of the patients receiving placebo. Product inserts also refer to“disease-modification,” which is assessed in RA as a slowing in radiographic worsening of joint disease.

TNF-a is now recognized as a central inflam-matory cytokine involved in endothelial permeability, upregulation of adhesion molecules and subsequent influx of leukocytes, activation of myeloid, granulo-cytic and lymphoid cell populations, induction of acute phase reactants from the liver and of proteolytic enzymes in tissues including cartilage and synovium. In addition both soluble and transmembrane forms of TNF-a are ubiquitous parts of cell death signaling pathways. Of the three approved anti-TNF therapies, one (etanercept) is a receptor-Fc fusion protein, whereas the other two (infliximab and adalimumab) are IgG₁ monoclonal antibodies. Although they have broadly similar efficacy and safety profiles in RA, there are significant differences in the three anti-TNF agents including their dosing characteristics, which are quite distinct (Furst et al., 2006).