Pathogenesis of joint damage in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by the appearance of progressive joint damage that may be identified only months after the onset of symptom s. Early cartilage and bone erosion is associated with the accumulation of several cell populations in the synovial membrane (SM) and the formation of a proliferating pannus. The synovial sublining layer contains several cell populations including macrophages, T and B lymphocytes, dendritic cells, a nd polymorphonuclear leukocytes. The Lining layer contains large numbers of macrophages and fibroblast-like synoviocytes. The interface between pannus and cartilage is occupied predominantly by activated macrophage population s and synoviocytes capable of secreting destructive proteases in abundance. We have observed that macrophages aggregate preferentially adjacent to the cartilage-pannus junction (CPJ) and express differentiation phenotypes tha t are absent from the Lining layer macrophages of more remote SM. Moreover, in a prospective study, the number of SM macrophages correlated with the d egree of joint damage occurring over one year. Similar results were obtaine d when SM biopsy samples were analyzed and correlated with clinical and rad iological changes occurring over 6 years. Macrophages and synoviocytes at t he CPJ express matrix metalloproteinase and cathepsin mRNA from the earlies t stage of RA. The mechanisms involved in the secretion of tissue degrading enzymes by macrophages and synoviocytes are undergoing further investigati on and preliminary results suggest that different regulation pathways may e xist.