ETIOLOGY AND GENETICS

The specific underlying cause of RA (i.e., triggers in the susceptible host) is unknown. As for most autoimmune diseases, RA is thought to result from a complex interaction of genetic and environmental factors. RA may consist of multiple environmental stimuli leading to a common clinical presentation. There is not a known single mechanism of initiation or perpetuation. Various environmental triggers such as smoking, obesity, silica exposure, mineral oil, and organic solvents have been associated with the development of RA. Smoking has the most impact, particularly on CCP antibody–positive disease; CCP-positive disease has a more distinct presentation and epidemiology than CCP-negative disease.

An individual’s genetic profile also plays a critical role in the susceptibility to and severity of RA. Supporting a genetic component, studies have revealed a 9% to 15% concordance in monozygotic twins that is approximately four times greater than the rate in dizygotic twins. RA is a polygenetic disease with over 100 susceptibility loci reported. The genes with the greatest impact lie in the class II major histocompatibility (MHC) locus, accounting for approximately 60% of the genetic risk for RA. A specific sequence on the HLA-DR haplotype involved in antigen recognition is called the shared epitope, which is strongly associated with severe RA and extra-articular manifestations. Multiple mutations in various alleles can then cause changes in the peptide binding grove leading to decreased self-tolerance. Although important, the shared epitope does not fully explain RA because it also occurs in only 25% to 35% of the white population whereas the chance of developing RA in shared-epitope carriers is only 1 in 25 (4%). Non-MHC and HLA genetic associations primarily involve pathways within CD4+ T cells and pathways affecting T- and B-cell interactions, cellular proliferation, and cytokine signaling pathways.

The interplay between environmental and genetic factors is most clearly seen with the increased risk of RA associated with smoking and the MHC class II loci. The exact association between the two is unclear, but research has shown that the bacteria in periodontal and mucosal lung disease, which are increased with smoking, can promote citrullination of bacteria leading to antibodies against multiple different citrullinated peptides. Anti-CCP antibodies are associated with aggressive disease.

For a deeper discussion of these topics, please see Chapter 248, “Rheumatoid Arthritis,” in Goldman-Cecil Medicine, 26th Edition.