Rheumatoid Arthritis

Etiology

Smoking is now a well-known environmental trigger of RA initiation . Genetic contribution is estimated at around 50 to 60%. The strongest predisposing gene variants are found in the human leukocyte antigen (HLA) genes, accounting for 30 to 50% of overall genetic susceptibility to RA. Multiple RA risk alleles within the HLA-DRB1 gene share a conserved amino acid sequence. The presence of one HLA SE allele confers an odds ratio to develop RA around 4, and the presence of two SE copies increases the odds ratio to approximately 11. Additionally, the incidence of RA is higher in female compared to male, with an incidence ratio of about 2:1 to 3:1.

Role of autoantibodies in RA

• Binding to Fc receptors forming immune complexes

In RA, rheumatoid factor (RF) may induce the formation of immune complexes at the sites of synovial inflammation, ensuing the activation of complement and leukocyte infiltration that may contribute to the perpetuation of local inflammatory responses and amplification of RF production in the synovium. Immune complexes containing ACPA and citrullinated fibrinogen can stimulate TNF secretion via stimulation of Fcγ receptors on macrophages. The effector functions of the ACPA immune complexes can be modified by the presence of RF-IgM or RF-IgA, which boosts the Fcγ receptor-mediated immune response and increases complement activation.

Fig. 3 The pathogenetic role of the rheumatoid factor

• Neutrophil Extracellular Traps (NETs) formation

The augmented generation of neutrophil extracellular traps (NETs) is another manner in which ACPA and/or RF antibodies could affect disease development or persistence. Amplified citrullinated autoantigen exposure via NETosis might be involved in promoting autoantibody generation and production in predisposed hosts. Moreover, NETs can trigger inflammatory responses in synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules.

• Osteoclast activation

Seropositive RA is associated with increased damage to joints. ACPA may directly affect osteoclasts and thereby lead to the formation of bone erosions. ACPA have been reported to bind to the osteoclast surface and enhance differentiation of osteoclast precursors in vitro and in vivo. Adoptive transfer of ACPA has also led to increased bone resorption in mice models.  There is also a hypothesis that ACPA is directly linked to formation of bone erosions via IL-8 induction.

Major targets in RA

• Rheumatoid factor, RF

RF is useful in predicting the development of RA, as the detection of IgM, IgA, and IgG of RF may predate disease onset by years. High titers of RF have been associated with worse prognosis, more aggressive articular disease, increased disease activity, reduced rates of remission, higher prevalence of extra-articular manifestations, and increased morbidity and mortality, especially when in combination with ACPA.

• Cyclic citrullinated peptide, CCP

Citrullinated peptides are generated in response to a posttranslational modification mediated by PAD enzymes. Multiple antibody isotypes including IgG, IgA, and IgM directed against these citrullinated peptides are detected in RA. The Fc region of anti-citrullinated protein antibodies (ACPA) has a lower level of galactosylation and sialylation that can drive osteoclastogenesis in vitro and in vivo through altered FcγR signaling. Moreover, RA patients with low levels of ACPA-IgG Fc sialylation had lower bone volumes and trabecula numbers.

• Mutated citrullinated vimentin, MCV

Antibodies to mutated citrullinated vimentin (MCV) is a protein that is released in the synovial microenvironment and has been identified as a potential autoantigen in RA. Elevated levels of MCV antibodies in the blood are often associated with RA and has been identified as a potential diagnostic tool for RA.