Novel strategies for the therapy of rheumatoid arthritis (1997)

T management of rheumatoid arthritis (RA) presents a major challenge to the medical community. The physical and psychological sequelae of this chronic inflammatory arthropathy not only diminish the quality of life, but also reduce life expectancy. Furthermore, the high prevalence of the disease, combined with the costs associated with treatment, disability and loss of productivity, raise substantive socio-economic issues. As the pathoaetiology of the disease remains unknown, therapy, of necessity, is symptomatic and mainly addresses pain and disability while attempting to slow the progress of the disease. Conventional therapies, including corticosteroids, non-steroidal antiinflammatory drugs (NSAIDs) and slow-acting antirheumatic drugs (SAARDs), have been established, in part, empirically and, in part, in response to the apparently autoimmune features of RA. In general, conventional pharmacotherapy has yielded disappointing results and the side-effects may even contribute to the higher mortality of patients with RA compared to the general population. In the past few years, efforts have been made to formulate new therapeutic concepts based on the growing understanding of the pathophysiology of RA, which is summarized in the following. RA is a chronic, systemic, inflammatory disease that leads to progressive destruction of the joints. Histopathologically, the affected joints are characterized by a highly hyperplastic synovium that is infiltrated with inflammatory cells such as monocytes, and lymphocytes, the latter often concentrated within follicle-like aggregates. Infiltration of the synovium occurs through multiple blood vessels created through the process of neoangiogenesis. These newly created blood vessels have been found to express specific adhesion molecules on the endothelium that guide inflammatory cells to the site of inflammation and enhance their transition across the endothelium, or lymphocyte trafficking. The main feature of RA that distinguishes it from other arthropathies, such as osteoarthritis, however, is the adhesion of the synovium and subsequent invasion into cartilage and bone. This process is mediated by ‘transformed appearing’ fibroblasts. Although the term ‘transformation’ commonly refers to malignant cells, the term ‘transformed appearing’ does not imply uncontrolled proliferation because RA synovial cells do not reveal an increased rate of proliferation [1], but in this context describes a state of metabolic cellular activation associated with a transformed-appearing cellular phenotype. The mechanisms of the activation of rheumatoid synovial fibroblasts with respect to the overexpression of proto-oncogenes and factors that influence the balance between proliferation and apoptosis are the subject of ongoing research [2]. Invasion and destruction of articular cartilage and bone are due to enzymatic degradation of their matrices, which consist of a variety of structural proteins, such as collagens and proteoglycans, that confer the different biomechanical properties of these tissues. Synovial fibroblasts and chondrocytes produce both matrix-degrading proteases, including metalloproteases and cysteine proteases, and their inhibitors. In disease states, this physiological balance is disturbed by a relative overproduction of proteases; a process which can be induced experimentally by proinflammatory cytokines, such as tumour necrosis factor alpha (TNF-a) and interleukin-1 (IL-1). All of these pathophysiological features of RA represent potential targets for therapies. Interestingly, the growing body of knowledge concerning the pathophysiology of RA has shed light on the actions of some conventional therapies. Cyclophosphamide and steroids, for example, affect apoptosis, whereas steroids may reduce cytokine synthesis. It is hoped that the development of strategies designed to pinpoint specific pathophysiological targets will result in more effective and specific therapies. Strategies might include, for example, the prevention of further infiltration of inflammatory cells by either interference with leucocyte trafficking through inhibition of neoangiogenesis or inhibition of expression of adhesion molecules. The number and activity of inflammatory cells that have already infiltrated the synovium might be reduced cytotoxically, by the administration of anti-inflammatory cytokines, or neutralization of anti-inflammatory cytokines with antibodies or soluble antigen receptors. Developments in monoclonal antibody technology rendered the targeting of specific cell types and molecules feasible almost a decade ago [3,4]. Early studies using this technology were driven by the traditional paradigm that T cells are the main instigators of RA and were focused on the depletion of Submitted 5 August 1996; accepted 7 August 1996.