Rheumatoid Arthritis: Background
Rheumatoid arthritis (RA) is a chronic, progressive and disabling inflammatory disease characterized by joint destructive process associated with synovial proliferation and secretion of high levels of proinflammatory mediators including cytokines, metalloproteases and growth factors.
RA is usually characterized by symmetric inflammatory polyarthritis and affects approximately 0.5–1% of the general population worldwide.[1] Like for other rheumatic diseases, the pathophysiology of RA is not yet fully understood. One potential synthesis of the data available on pathogenesis suggests that the innate immunity activation and a favorable genetic background are the basis of the induction phase that gets the joint ready for the subsequent coming of inflammatory and immune cells.[2,3] The proinflammatory mediators released act on different cell populations including lymphocytes, neutrophils, endothelial cells, synoviocytes, osteoclasts and chondrocytes by inducing the maintenance of a Th1 inflammation with angiogenesis and chemotaxis.[4] The relative abundance of Th1 cells and cytokines suggests that the synovium resembles a Th1-like delayed-type hypersensitivity reaction. Th2 cytokines and cellular responses that normally suppress Th1 activation are nearly absent, suggesting the possibility that the lack of T-cell activation along the Th2 pathway in RA contributes to disease perpetuation. Several studies indicate that a particular type of T cell, Treg cells (thymus-derived natural regulatory T cells), and in particular the subset characterized by the production of IL-17 called Th17 cells, may play an important role in the pathogenesis of RA. The circulating Th17 and Th17/Th1 cell frequencies are different in patients with early or established RA, and active or inactive disease.[5]
Among the released inflammatory mediators IL-1β, TNF-α and IL-6 are the pivotal cytokines in the physiopathology of the synovial inflammation that activate several cell types, including lymphocytes, neutrophils, endothelial cells, osteoclasts, chondrocytes and synoviocytes, and upregulate a number of pathways linked to the inflammation. Bone erosions are subsequently caused by osteoclasts, whereas cartilage dissolution results from proteolytic enzymes produced by synoviocytes in the pannus or synovial fluid neutrophils.[2]
It is well reported that immunoreactivity can be identified before clinical disease and manifested by the production of rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA) that contributes to erosiveness and severity.[6–8]
Genes play a key role in susceptibility to RA and disease severity. Class II MHC genes, especially genes containing a specific five-amino acid sequence in the hypervariable region of HLA-DR4, are the most prominent genetic association. Newly defined genetic associations, including polymorphisms in the PTPN22 and PADI 4 genes, and many cytokine promoter polymorphisms, population-specific genes and other undefined genes are reported as genetic markers of diagnosis and prognosis.[2,6,9]
It has been recognized that early therapeutic intervention improves clinical outcomes and reduces the accrual of joint damage and disability. The optimized use of old therapies and the availability of new drugs have dramatically enhanced the success of RA management.[10] Recently, a joint working group from the ACR and the European League Against Rheumatism (EULAR) revised the old criteria set and developed a new approach to classifying RA.[11,12] The work, which was among patients newly presenting with undifferentiated inflammatory synovitis, focused on identifying factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease, that is to say RA. In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (score range: 0–5), serologic abnormality (score range: 0–3), elevated acute-phase response (score range: 0–1) and symptom duration (two levels; range: 0–1). These new criteria focus on findings that facilitate earlier recognition of RA and outcome prediction.
Int J Clin Rheumatol. 2013;8(1):13-25. © 2013 Future Medicine Ltd.
