From patients with arthralgia, pre-RA and recently diagnosed RA: what is the current status of understanding RA pathogenesis?

Abstract

It is believed that therapy for rheumatoid arthritis (RA) is the most effective and beneficial within a short time frame around RA diagnosis. This insight has caused a shift from research in patients with established RA to patients at risk of developing RA and recently diagnosed patients. It is important for improvement of RA therapy to understand when and what changes occur in patients developing RA. This is true for both seropositive and seronegative patients. Activation of the immune system as presented by autoantibodies, increased cytokine and chemokine production, and alterations within several immune cells occur during RA development. In this review we describe RA pathogenesis with a focus on knowledge obtained from patients with arthralgia, pre-RA and recently diagnosed RA. Connections are proposed between altered immune cells, cytokines and chemokines, and events like synovial hyperplasia, pain and bone damage.

Figure 1

Schematic overview of different immune processes in blood during the development of RA. Upper left: CD56^dim NK cells are capable of killing autoimmune cells like B cells and CD8 T cells. RF immune complexes bind to the FcγRIIIa receptor on NK cells causing apoptosis and thereby reduce CD56^dim NK cell number. Cytokines like IL-5 exert their influence on B cells resulting in more immunoglobulin secretion. MIG attracts CD8 T cells via the CXCR3 receptor to lymph nodes where these cells become short-lived effector cells. B cells migrate out of the bloodstream. IL-13 prevents synovial fibroblasts from apoptosis induced by NO. Synovial hyperplasia will develop. Upper right: Levels of autoantibodies have risen, epitope spreading has occurred, and antibody modifications like glycosylation, sialylation and galactosylation are altered. CD56^dim NK cell number is still reduced and start to dysfunction by lowered IFNγ production. Reduction of IFNγ results in skewing towards Th17 cell differentiation. Th17 cells and Th17 subpopulations migrate from blood under the influence of MIG, MIP-1α and MCP-1. Neutrophils are activated and recruited from blood via MIP-1α. Lower left: The cytokines IL-8 and IL-13 are altered in the blood of patients with seronegative arthralgia. IL-8 could induce pain by binding to receptors on nociceptor sensory neurons. IL-13 prevents synovial fibroblasts from apoptosis induced by NO. Synovial hyperplasia will develop. Lower right: Increased IL-10 and decreased Rantes and eotaxin are detected. CD56^bright NK cell number is increased. These cells are capable of secreting proinflammatory cytokines like IL-13. Any type of arrow displayed within the figure are suggested links between antibodies, immune cells and cytokines or chemokines. The indicated cytokines and chemokines are not necessarily secreted by the depicted immune cells. IFNγ, interferon gamma; IL, interleukin; RA, rheumatoid arthritis; RF, rheumatoid factor.