TNF has been implicated in the pathogenesis of many chronic autoimmune and inflammatory diseases, in particular rheumatoid arthritis (RA), psoriatic arthritis (PsA), psoriasis, ankylosing spondylitis (AS), and Crohn's disease. Among its diverse pathologic effects, TNF triggers the production of collagenases and other proinflammatory cytokines such as interleukin (IL)-1, IL-6, and granulocyte-macrophage colony stimulating factor (Brenner et al. 1989; Lee and Kavanaugh 2005); stimulates the expression of endothelial adhesion molecules (e.g., endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular cell adhesion molecule-1), attracting leukocytes into affected joints; upregulates matrix metalloproteinase synthesis by synovial macrophages, fibroblasts, osteo-clasts, and chondrocytes; and inhibits proteoglycan synthesis in cartilage (Weinblatt et al. 2003). High concentrations of TNF are found in the synovial fluid of patients with RA (Saxne et al. 1988) and PsA (Partsch et al. 1997); in psoriatic lesions of patients with psoriasis (Ritchlin et al. 1998); in the joints of patients with AS (Braun et al. 1995); and in the stool, mucosa, and blood of patients with Crohn's disease (Braegger et al. 1992; Murch et al. 1991, 1993). In animal models of inflammatory arthritis, TNF has been shown to accelerate disease activity, and anti-TNF antibodies have been shown to decrease disease activity (Cooper et al. 1992; Williams et al. 1992).
Adalimumab is highly specific and does not bind to or inhibit other forms of TNF, such as lymphotoxin-a (LTa, previously called TNF-|3). Upon binding to TNF, adalimumab neutralizes the biologic activities of this cytokine by blocking its interaction with the TNF-RI/II cell surface receptors and modulating biologic responses that are induced or regulated by TNF (Fig. 3.2) (Salfeld et al. 1998; Lee and Kavanaugh 2005). Adalimumab also binds to and neutralizes the cell membrane-associated form of TNF, which may play a role in disease (Georgopoulos et al. 1996).
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