ANTI-TUMOR NECROSIS FACTOR-α MONOCLONAL ANTIBODY THERAPY FOR RHEUMATOID ARTHRITIS

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Over the past few decades, the immunopathogenesis of rheumatoid arthritis (RA) has become more clearly defined.26, 35, 62 The initiation of this progressive, systemic inflammatory disorder probably results from the appropriate exposure of a genetically susceptible host to some unidentified etiologic antigen. The propagation and sustenance of inflammation reflect an active, ongoing, immunologically driven process.26, 35, 62 Several components of the immune response are intimately involved in the pathogenesis of RA (Fig. 1). Changes in the vasculature occur early in the disease course and facilitate its propagation. Such changes include angiogenesis and alteration of the endothelium into an activated, “high endothelial venule” phenotype. Recirculating CD4+ T lymphocytes, particularly those with a “memory” phenotype, accrue in the synovium utilizing specific adhesion molecules. T cells play a central role in initiating and orchestrating the autoimmune response.35 Resident synovial cells such as fibroblasts, macrophages, dendritic cells, mast cells, endothelial cells, and B cells all are crucial to facets of rheumatoid inflammation.22, 26, 35, 62 Interactions among these various cells result in the liberation of various mediators, such as cytokines, prostaglandins, and many others. These soluble mediators produce local tissue damage and cause many of the signs and symptoms of disease. In addition, some mediators, particularly cytokines, also exert prominent effects on cells. This facilitates the propagation of the chronic immunologic response that underlies rheumatoid inflammation.

Cytokines are small peptide molecules that are often released from cells upon activation and that bind specific receptors. They can serve numerous functions.18, 37, 39 Regarding function, cytokines may exhibit pleiotropy (i.e., one cytokine can mediate diverse functions), redundancy (i.e., several cytokines may mediate the same activity), or antagonism (i.e., the effects of one cytokine may inhibit those of another cytokine). Although cytokines may be spoken of individually, in vivo they function in complex networks or cascades. The overall outcome may reflect the balance between proinflammatory factors (e.g., inflammatory cytokines) and anti-inflammatory factors (e.g., soluble forms of cytokine receptors, cytokines with anti-inflammatory function) that are present in the local milieu.18, 37, 39

In RA, there is substantial evidence that cytokines, particularly proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), subserve a crucial role in disease propagation and expression.18, 22, 26, 35, 37, 39, 62 These cytokines may be particularly attractive therapeutic targets in RA.3, 19, 21 A number of recent trials have used varied methods to modulate the function of these important cytokines. This article focuses on the progress that has been made using monoclonal antibodies (mAb) directed against TNF-α in patients with RA.

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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      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

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