ANTI-TUMOR NECROSIS FACTOR-α MONOCLONAL ANTIBODY THERAPY FOR RHEUMATOID ARTHRITIS
Section snippets
Background
TNF was named for its ability to induce necrosis when injected into certain tumors. Although the initial observation of this effect was made in the 1890s, almost all of what is known about TNF has been discovered over the past 2 decades. Soon after it was cloned in 1984, TNF was found to be identical to another molecule that had been called “cachectin”; it was also found to be approximately 30% homologous to the molecule known as “lymphotoxin” (LT).50 Genes encoding both TNF-α (cachectin) and
Antibodies/Trial Designs
A number of studies have evaluated anti-TNF-α mAb therapy in RA (Table 1).15, 16, 17, 31, 32, 41, 55, 56 Most of the studies published to date have used cA2. cA2 is a chimeric mAb that consists of the variable regions of a murine anti-TNF-α mAb engrafted onto a human IgG1κ molecule. The resulting construct is approximately two-thirds human. cA2 has a high affinity for trimeric TNF-α (Kd ∼ 100p M) and has been shown to effectively inhibit TNF-α in numerous in vitro systems.19 After steady state
FUTURE DIRECTIONS
There are many exciting avenues that should allow refinement and optimization in the use of anti-TNF-α mAbs in RA. One potentially relevant area will be the definition of subsets of patients for whom this type of therapy is most efficacious. In animal studies, it has been shown that different therapies may be more or less effective at different stages of arthritis.29 In RA also, it has been suggested that patients may be heterogeneous in their clinical presentations as well as their response to
CONCLUSION
Treatment of RA patients with an anti-TNF-α mAb has proven to be extremely effective. Rigorous studies have proven the utility and acceptability of these agents. Additional studies have begun to define the optimal treatment paradigms for the use of anti-TNF-α mAb, including combination therapy. In the near future, these powerful agents may be introduced into the therapeutic armamentarium for RA. This should afford tangible and substantial clinical benefit to some of the patients suffering from
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Incidence and nature of infectious disease in patients treated with anti-TNF agents
2009, Autoimmunity ReviewsCitation Excerpt :As described earlier, TNF-α plays a crucial role in host defense, particularly in macrophage activation and granuloma formation. TNF-α inhibitor agents induces macrophage dysfunction and makes persons prone to opportunistic infections [97,145–159]; particular attention should be given to those infections whose containment depends on these immune processes such as non-tuberculous mycobacteria (as discussed above) [160], histoplasmosis, coccidiomycosis, and listeriosis [34,91,157,158,160–165]. Although the incidence of opportunistic infections is low, one study using data from the British registry found that the rate of intracellular infections among patients with RA treated with TNF-α inhibitor agents was 200 per 100,000 persons, a value significantly higher than in similar patients treated with DMARDs [34,91,106,132].
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Address reprint requests to Arthur F. Kavanaugh, MD, The University of Texas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235–8577, e-mail:[email protected]
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University of Texas, Southwestern Medical School; and the Veterans Administration North Texas Health Care System, Dallas, Texas