Etiology and pathogenesis of Rheumatoid Arthritis

What is the etiology and pathogenesis of Rheumatoid Arthritis?

The exact cause of RA remains unknown, but it is likely multifactorial, with genetic (human leucocyte antigen [HLA] genes and others) and environmental factors (smoking, silica, and others) playing important roles. Autoantibodies (RF, ACPAs) can be found in the blood several years before the development of joint inflammation during a phase of RA development called “preclinical RA.” Preclinical RA suggests that the initiating events in RA may occur outside of the joints. These initiating events may take place at mucosal surfaces, and involve a complex interaction between the genes and environment, and the innate and adaptive immune systems. Over time, systemic autoimmunity can transition to clinical symptoms and joint inflammation at which time an individual may meet classification criteria for RA.

Genetic factors: The major histocompatibility complex (MHC) region coding for certain HLA-DR genes accounts for a large proportion of the known genetic risk for RA. The susceptibility to RA is mainly associated with the third hypervariable region of DRβ chains from amino acids 70 to 74 (referred to as the shared epitope; so named because this unique amino acid sequence can be found on numerous DR4 and DR1 alleles that are enriched in RA populations). In addition, over 100 genetic loci outside the MHC have been associated with an increased risk of developing RA; each of these increases the odds ratio of developing RA by only 1.2–2-fold, although this varies among ethnicities. Polymorphisms of PTPN22, TRAF1-C5, STAT4, TNFAIP3, and PADI4 are well established. Epigenetic factors (histone modification, DNA methylation) are also likely to be important.

In addition to population-based genetic studies, twin studies show that the concordance rate for RA is 12% to 15% in monozygotic twins and 2% to 3% in fraternal twins. This is in comparison with the rate of RA in the general population of ∼1% and suggests that familial factors (genetics and/or shared environmental risk) account for a substantial portion of an individual’s susceptibility to RA. It is important to keep in mind that 80% to 90% of all RA is sporadic, that is, occurring in individuals with no family history of RA.

Environmental factors: Smoking is the best characterized environmental risk factor for RA. It is more strongly associated with ACPA-positive (1.9-fold) compared with ACPA-negative (1.3-fold) RA. Cigarette exposure in the setting of two shared epitope alleles can increase the odds ratio for ACPA-positive RA by 21-fold. The smoking-associated risk of RA is dose-dependent (2-fold for >20 pack years) and persists for 10 to 20 years after a person quits smoking. Other inhaled factors (e.g., silica dust, air pollution) have also been associated with RA. While the exact role that they may play in the development of RA is uncertain, bacteria in the microbiomes of mucosal sites (e.g., mouth, lung, gut) may also contribute to RA development. For example, Porphyromonos gingivalis (an organism associated with periodontitis) can express peptidylarginine deiminase (PAD) enzymes that can citrullinate resident proteins through the posttranslational modification of arginine to citrulline. Additionally, Prevotella copri is expanded in the stool of patients with RA and is thought to be associated with specific immune responses in these patients. Viruses (Epstein–Barr virus [EBV], parvovirus B19) have been associated with RA as well. The exact role of microbial organisms in the initiation and propagation of RA-related autoimmunity is unknown, and this remains an active area of research.

Autoantibodies: Multiple autoantibody systems are implicated in RA pathogenesis, including RF and antibodies to modified protein antigens (AMPAs). AMPAs include antibodies to citrullinated and carbamylated (homocitrulline) proteins. These neoantigens cause a heightened immune response when presented to the immune system by HLA-DR molecules containing the shared epitope. ACPAs and anticarbamylated antibodies can bind citrullinated and carbamylated proteins locally or form immune complexes that can deposit in the tissue, thereby directly playing a role in disease pathogenesis.

Initiation of clinical disease: The mechanism of initiation of clinical synovitis is unknown. It is hypothesized that ACPAs could target citrullinated proteins in the joint. In addition, certain immune complexes that include ACPAs and RF can deposit in synovial postcapillary venules inciting inflammation through complement activation. Tissue inflammation can increase vascular permeability with the influx of more inflammatory cells (e.g., neutrophils, CD8 T cells) and antibodies (including ACPAs). Inflammation can upregulate PAD enzymes and myeloperoxidase causing citrullination and carbamylation, respectively, of synovial proteins and cartilage proteins. Binding of ACPAs, especially to citrullinated vimentin, can lead to osteoclastogenesis, chondrocyte damage, and release of degraded collagen and proteoglycan neoepitopes from cartilage. In addition, neutrophils can release neutrophil extracellular traps that can drive local inflammation.

Perpetuation of clinical disease: RA is thought to be perpetuated by activation of the adaptive immune system, with the innate immune system and self-antigens acting as a persistent adjuvant. For example, neoepitopes created by synovial inflammation and cartilage injury can be taken up by an influx of dendritic cells into the synovium. Dendritic cells from a genetically predisposed host will more efficiently present the neoantigens to T lymphocytes in the synovial tissue and draining lymph nodes. Epitope spreading may occur, with a break in tolerance and an immune response directed toward native antigens. T-cells, macrophages, synovial fibroblasts, and B cells may be activated in different combinations to produce proinflammatory cytokines that perpetuate chronic synovitis and tissue destruction. Activation of local osteoclasts can facilitate development of bony erosions.

Prevention of clinical disease: Smoking cessation is the only modifiable risk factor demonstrated to reduce RA risk. In addition, clinical trials are underway in the United States and Europe to determine whether intervention with immune modulating therapies can prevent the onset of joint disease in individuals who are at a high risk of developing RA in the future.


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