TOPIC 165. RHEUMATOID ARTHRITIS
Definition. Rheumatoid arthritis (RA) is a chronic, systemic, immune-mediated inflammatory disease characterised by persistent, usually symmetric inflammatory synovitis. It primarily affects peripheral synovial joints and can cause cartilage destruction, marginal bone erosions, deformity and extra-articular disease.
Aetiology and risk factors
Genetic susceptibility: HLA-DRB1 alleles carrying the shared epitope are strongly associated with seropositive RA. Other immune-regulatory genes, including PTPN22, contribute to susceptibility.
Environmental factors: cigarette smoking is an important risk factor, particularly in genetically susceptible individuals. Silica exposure and some periodontal/mucosal inflammatory exposures have also been associated.
Sex and hormones: RA is more common in women; hormonal and sex-related immune factors may influence risk, but no single hormonal cause explains the disease.
Other influences: age, family history, mucosal microbiome and epigenetic factors may contribute. RA is multifactorial; no single trigger is necessary or sufficient.
Immunopathogenesis – from loss of tolerance to synovitis
A. Loss of immune tolerance and autoantibody formation
- In susceptible individuals, environmental and mucosal factors can promote post-translational modification of proteins, particularly citrullination (conversion of arginine residues to citrulline by peptidyl-arginine deiminase enzymes).
- Citrullinated proteins may be recognised as autoantigens. In genetically susceptible people, antigen presentation through particular HLA-DRB1 molecules facilitates activation of autoreactive CD4+ T cells.
- Activated T cells provide help to B cells. B cells differentiate into plasma cells and produce autoantibodies, especially anti-citrullinated protein antibodies (ACPA/anti-CCP) and rheumatoid factor (RF).
- RF is commonly an IgM antibody directed against the Fc portion of IgG. ACPA and RF can form immune complexes, activate complement and amplify inflammation.
- Autoantibodies may be detectable years before clinically apparent arthritis. However, not every patient is seropositive, and a positive antibody alone does not establish the diagnosis.
B. Synovial inflammation
- CD4+ T cells, B cells, plasma cells, macrophages and dendritic cells accumulate in the synovium. Synovial lining cells proliferate and the synovium becomes hyperplastic.
- Macrophages and activated synovial fibroblasts release pro-inflammatory cytokines, particularly TNF-α, IL-1 and IL-6. IL-17 from Th17 cells and other mediators also contribute.
- These cytokines promote endothelial activation, increased vascular permeability, leukocyte recruitment and further activation of synovial fibroblasts and macrophages.
- The synovium becomes oedematous, hypervascular and infiltrated by inflammatory cells. Chronic inflammation may produce lymphoid aggregates or germinal-centre-like structures.
C. Pannus formation and joint destruction
Pannus is thick, proliferative, inflamed synovial granulation tissue that grows over and invades the articular cartilage and adjacent bone.
- Activated fibroblast-like synoviocytes produce matrix metalloproteinases (MMPs) and other proteolytic enzymes, degrading cartilage extracellular matrix.