The pathophysiology of RA is complex and appears to involve multiple mechanisms1–4
The pathophysiology of RA involves aspects of both innate and adaptive immunity, which may occur in a parallel fashion.1
Activation of the innate immune response with ubiquitously expressed autologous antigens probably occurs early in RA and may serve as a key pathogenic mechanism that initiates synovial inflammation.1,5
Several autoantibody systems are implicated, including:
Rheumatoid factor (RF) – produced by synovial B-cells1,2
Anti-cyclic citrunillated peptide (CCP) antibodies; potentially a more specific indicator of RA than RF3
Activation of the innate immune response is likely to activate the adaptive immune system, through the presentation of autoantigens via MHC molecules to T cells.
Activated T cells in the synovium stimulate monocytes, macrophages and synovial fibroblasts to produce pro-inflammatory cytokines, for example, interleukin (IL)-1, IL-6, IL-15, IL-18, tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor4–6
These inflammatory responses are implicated in:
Driving continued immune cell recruitment to the joint and synovium1
Stimulating B cells to produce immunoglobulins, including RF1,4
Inducing expression of adhesion molecules, which further promote recruitment of activated immune cells1
Driving expression of degradative enzymes, thereby initiating joint destruction1,4
Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003; 423:356–361.
Ates A, et al. Effects of rheumatoid factor isotypes on disease activity and severity in patients with rheumatoid arthritis: a comparative study. Clin Rheumatol 2007; 26:538–545.
Silveira IG, et al. Anti-CCP antibodies have more diagnostic impact than rheumatoid factor (RF) in a population tested for RF. Clin Rheumatol 2007; 26:1883–1889.
Choy EH & Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344:907–916.
Smolen JS, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007; 370:1861–1874.
Heinrich PC, et al. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334 (Pt 2):297–314.