Aetiology

The aetiology of rheumatoid arthritis (RA) is unknown. Some studies have, however, pointed to possible causative factors.

Genetic factors

Family history confers a two- to fourfold increased risk for RA in first-degree relatives.[17]​ The presence of a major histocompatibility complex class II allele human leukocyte antigen (HLA), DRw4, is more common in patients with RA. These HLA alleles code for a shared amino acid sequence that has been named the shared epitope, which may be involved in the pathogenesis of RA.[18]

A role for polymorphisms of genes in both the innate and adaptive immune system have been demonstrated to increase the risk of RA, some of these include:[19][20][21][22][23][24][25]

  • PTPN22

  • T-cell subsets, for example, Tph cells

  • macrophage subsets, including MERTK-, MerTK+, CX3CR1+ tissue-resident macrophages

  • IL-6 promoter polymorphism (-174 G>C, -572 G>C, and -597 G>A) in Asian populations

In susceptible people, the interaction of genes and environment may result in a loss of tolerance of self-proteins that contain a citrulline residue.[26]

Environmental factors

Smoking and overweight/obesity have been associated with an increased risk of RA.​[10]

Smoking is associated with the production of rheumatoid factor and anti-CCP antibodies, which are both specific and sensitive antibodies that increase the risk of developing RA.[27] The increased risk of RA for people who smoke is dependent on the amount smoked per day combined with number of years they smoked.[10][11][12][13]​​​ A gene-environment interaction between heavy smoking and HLA-DRB1 has been demonstrated in patients with HLA-SE seropositive RA risk.[28][29]

Excess body mass index is associated with an increase in inflammatory markers and chronic low grade inflammation, and may be associated with an increased risk of autoimmune diseases including RA.[30][31]​​​

​​​Infection

An infection as a triggering factor for RA in genetically susceptible individuals has been proposed, but no specific infectious agent has been identified.[32]

Pathophysiology

The synovitis, swelling, and joint damage which characterise active RA are the result of complex autoimmune and inflammatory processes that involve components of both the innate and adaptive immune systems.[26]​ Inflamed synovium is central to the pathogenesis of RA. The synovium shows increased angiogenesis, cellular hyperplasia, influx of inflammatory cells, changes in the expression of cell surface adhesion molecules, and many cytokines.[1] The synovial lining becomes hyperplastic, with infiltration of the sublining with mononuclear cells including T cells, B cells, macrophages, and plasma cells. This formation of locally invasive synovial tissue is characteristic and it is involved in causing the erosions seen in RA.[26]

Cytokines affect all phases of the inflammatory process, and tumour necrosis factor (TNF), interleukin 1, and interleukin 6 seem to be the most abundant in the joint. Both TNF and interleukins promote proliferation, metalloproteinase expression, adhesion molecule expression, and further secretion of other cytokines.[33]​ High levels of metalloproteinase activity are thought to contribute to joint destruction. The proliferation of new blood vessels provides for the hypertrophic synovium. This very inflammatory setting, when not treated, leads to the eventual destruction of the involved joint.

Sclerostin, a regulator of bone metabolism and vascular calcification involved in regulating the Wnt/β-catenin signaling pathway, has been shown to be involved in the pathogenesis of RA.[34][35] Evidence from one systematic review suggests that people with RA have a higher level of circulating sclerostin compared with people without RA.​[35]

Pentraxin-3 (PTX-3) has been demonstrated to be involved in acute and chronic inflammation and in innate immunity.[36][37] Compared with healthy controls, circulating PTX-3 levels are significantly higher in people with RA.[38]​​

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