What are the possible root causes of Rheumatoid Arthritis (RA)?

From the Guidelines

Rheumatoid arthritis (RA) is likely caused by a complex interplay of genetic predisposition, environmental triggers, and immune system dysfunction, with the strongest genetic risk factor being the HLA-DRB1 gene, particularly the "shared epitope" alleles, as identified in a 2021 study published in the Annals of the Rheumatic Diseases 1. The root causes of RA can be broken down into several key factors, including:

• Genetic predisposition: The HLA-DRB1 gene, particularly the "shared epitope" alleles, increases the risk of RA by 5-10 times, as noted in a 2021 study 1.
• Environmental triggers: Smoking, certain infections like Epstein-Barr virus or Porphyromonas gingivalis, and lung exposures to silica dust or other irritants may trigger RA, especially in genetically susceptible individuals, as discussed in a 2021 study 1.
• Immune system dysfunction: The production of autoantibodies like rheumatoid factor and anti-citrullinated protein antibodies (ACPAs) often occurs years before symptoms appear, targeting modified proteins in the joints and leading to synovial inflammation, joint damage, and systemic inflammation, as explained in a 2021 study 1.
• Hormonal factors: Women are 2-3 times more likely to develop RA than men, with pregnancy sometimes temporarily improving symptoms, suggesting a role for hormonal factors in the development of RA, as noted in a 2021 study 1.
• Other potential contributing factors: Obesity and gut microbiome imbalances may also contribute to the inflammatory environment that promotes RA development, as discussed in a 2021 study 1. It is essential to understand these root causes to explain why early treatment targeting the immune system can effectively control the disease and prevent joint damage, as emphasized in a 2021 study 1. Some key populations at risk of RA include:
• First-degree relatives (FDRs) of people with RA, who may be feasibly identified from the general population and are being studied to understand the pathobiology of RA and the influence of specific risk factors on disease progression, as discussed in a 2021 study 1.
• Indigenous North Americans, who exhibit high RA prevalence rates, predominantly seropositive, severe disease, familial clustering of cases, and unfavorable disease outcomes, as noted in a 2021 study 1.
• Individuals with asymptomatic at-risk conditions, such as serum ACPA and/or other autoantibodies, who should be assessed for core and emerging risk factors, as recommended in a 2021 study 1.

From the Research

Possible Root Causes of Rheumatoid Arthritis (RA)

The possible root causes of Rheumatoid Arthritis (RA) can be categorized into genetic and environmental factors.

• Genetic Factors:
  • HLA-DRB1 is considered the main RA gene, but it only accounts for part of the familial risk for RA 2.
  • Other genes such as TNFR2, PADI4, SLC22A4, RUNX1, and PTPN22 have been associated with RA susceptibility 2.
  • The "shared epitope" genetic factor has been strongly associated with an increased risk for RA 3.
• Environmental Factors:
  • Smoking is the best-known environmental risk factor for RA and interacts with HLA-DR shared epitope genes to result in a high risk of RA 4.
  • Inhaled pollutants, nutritional habits, infectious, hormonal, and reproductive factors may also play a role in RA development 5.
  • Exposure to tobacco smoke has been associated with an increased risk for RA 3.
  • Mucosal inflammation and microbial factors are also considered contributors to the development of RA 3.
• Hormonal Factors:
  • Hormonal factors, such as female sex, have been associated with an increased risk for RA 3.
  • Reproductive factors may also play a role in RA development 5.
• Other Factors:
  • A family history of RA is a strong risk factor for the disease 3.
  • The identification of a "preclinical" period of RA, characterized by local or systemic autoimmunity, suggests that risk factors for RA are acting long prior to first clinical evidence of the disease 3.