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ABSTRACT: The cause of rheumatoid arthritis (RA) is unknown; however, extensive research has yielded great insight into its pathogenesis. Lymphocytes play a significant role, but a lesser role in the perpetuation of late disease. The rheumatoid synovium is composed primarily of fibroblasts and monocytes that produce inflammatory cytokines, of which interleukin-1 and tumor necrosis factor are of key importance. Potential regulatory mechanisms balancing the effects of these cytokines are inadequate to prevent joint damage and subsequent disability. These cytokines seem responsible for stimulating destructive processes in the joint via induction of prostaglandins, angiogenesis, chemokines, adhesion molecules, osteoclastogenesis, and matrix metalloproteinases. This review discusses recent research findings in the immunopathogenesis of RA with respect to potential targets for therapy.
The American Journal of the Medical Sciences 05/2002; 323(4):171-80. · 1.39 Impact Factor
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ABSTRACT: The elucidation of inducible cyclooxygenase (Cox-2) dependent inflammatory pathways led to the development of specific Cox-2 inhibitors, the coxibs. These agents include the currently available celecoxib and rofecoxib and such second-generation agents as parecoxib, valdecoxib, and etoricoxib. The therapeutic advantage of coxibs is founded primarily in their lack of significant gastrointestinal (GI) side effects. Clinical trials have demonstrated the efficacy of coxibs to be completely comparable with traditional nonsteroidal anti-inflammatory drugs (NSAIDs), and pharmacoeconomics suggest favorable cost/benefit ratios with these agents compared with traditional NSAIDs, related to their reduced GI complication profiles and lower indirect costs associated with disability. Although several clinical questions remain (eg, use with low-dose aspirin, risk of thrombosis, myocardial infarction, edema, and hypertension), the emergence and clinical utility of coxibs is likely to continue on the basis of their efficacy and relative GI safety advantage. Although newer, more specific Cox-2 inhibitors may alter the choice, it is likely that this class of anti-inflammatories will become (if they have not already) the drugs of first choice in the treatment of acute pain, chronic pain, and most rheumatic conditions in the 21st century. In addition to the treatment of rheumatic conditions, it is possible that coxibs will also be of clinical utility in protection against malignant transformation and Alzheimer disease.
The American Journal of the Medical Sciences 05/2002; 323(4):181-9. · 1.39 Impact Factor
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ABSTRACT: The recent elucidation of pathogenic processes involving tumor necrosis factor alpha and interleukin-1beta in the pathogenesis and persistence of rheumatoid arthritis led to the development of biological modifier agents that have had significant impact on disease severity and progression. These agents--etanercept, infliximab, and anakinra--produce a dramatic reduction in RA disease activity with relatively low toxicity compared with currently available disease-modifying antirheumatic drugs. The main prohibition to their broader utilization is cost. The success of these agents underscores the investigative approaches to the pathogenesis of RA and the appropriate design of pharmaceutical agents to target specific proinflammatory molecules.
The American Journal of the Medical Sciences 05/2002; 323(4):197-205. · 1.39 Impact Factor
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ABSTRACT: Interleukin-2 (IL-2) plays an important role in adaptive immune responses. These responses differ between females and males and may be due to the sex steroid estrogen. In this investigation we show that estrogen suppresses IL-2 production from activated peripheral blood T cells and CD4+ T cell lines at the transcriptional level. Suppression of IL-2 occurred at short term, high 17-β-estradiol concentrations as well as longer term lower 17-β-estradiol concentrations. In CD4+ Jurkat T cells, suppression of IL-2 was associated with decreased nuclear binding of two important IL-2 promoter transcription factors: NFκB and AP-1. The decreased nuclear binding of NFκB occurred in the setting of estrogen-induced increases in IκBα protein levels, an important inhibitor of NFκB nuclear translocation. 17-β-Estradiol was also shown to inhibit IL-2 receptor (IL-2R) expression in activated peripheral blood T cells. Estrogen-induced suppression of IL-2 and its receptor may have many ramifications for our understanding of immune and autoimmune sexual dichotomies, immune responses during pregnancy, and potential therapeutic intervention with hormone agonists and antagonists.
Cytokine.
