RA is a common human disease with a prevalence of about 1 percent in most parts of the world . The clinical presentation can vary in terms of severity and the age of onset, although the peak occurs between the fifth and sixth decades of life. Patients display painful, stiff, and swollen joints, generally presenting with a symmetrical polyarthritis, predominantly involving the small joints of the hands and wrists, as well as the metatarsophalangeal joints, ankles, knees, and cervical spine. Periarticular structures, such as bursae and tendon sheaths, are commonly inflamed. Nonarticular features may also be seen in RA, including inflammatory nodules, vasculitis, and pericarditis, together with involvement of the lungs and nervous system. The mortality of patients with severe RA is equivalent to that of individuals with triple vessel coronary artery disease. After 2 years, joint erosions are seen in most patients, and the majority of patients become clinically disabled within 20 years. In the UK, around 387,000 adults have RA, equivalent to 0.81 percent of the adult population, and there are approximately 12,000 new cases each year. Surveys indicate that more than 9 million working days were lost because of RA in 1999-2000 in Great Britain, representing £833 million lost production. Indeed, in a recent study, RA patients of working age were found to be 32 times more likely to stop work on health grounds than matched controls. RA thus imposes a significant social and economic burden, due to loss of earnings and medical expenses, apart from adversely affecting quality of life.
In spite of many years of intensive investigation, the cause of RA remains unknown, although current thinking favors the concept of a multifactorial disease, in which contributory genetic factors combine with environmental and possibly infectious influences to initiate disease. The association between RA and genetic elements encoded within the HLA-DR region supports the importance of T cells in disease pathogenesis. More than 80 percent of Caucasian RA patients express HLA-DR1 or HLA-DR4 subtypes. The primary site of inflammation is the synovial lining of the closed spaces of articular joints, which increases greatly in mass and becomes infiltrated by blood-derived cells of lympho-hematopoietic origin, including T cells, B cells, and macrophages. The lymphocytes infiltrating the synovium are predominantly CD4+ T cells, with high expression of memory CD45R0 antigens and activation markers such as HLA-DR and CD69. A feature of the synovium in RA is an altered density of sublining capillaries and postcapillary venules. Subsequently, the synovium becomes locally invasive at the synovial interface with cartilage and bone. Progressive destruction of cartilage and bone eventually combines to produce deformities and functional deterioration and profound disability in the long term.
Over the past two decades, our understanding of the pathogenesis of RA has increased considerably, based on a range of studies using human tissue and animal models of disease. Of relevance to this review, the importance of the microvasculature in RA has become increasingly apparent, and this is discussed in subsequent sections.
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