Rheumatoid arthritis (RA) is a chronic autoimmune disease where the immune system mistakenly attacks the lining of the joints, causing inflammation, pain, and eventual erosion of bone and cartilage. While the precise sequence of events that initiates RA is not fully understood, research points to a complex interaction between a person’s genetic background and various external influences. Certain factors increase an individual’s susceptibility to developing this condition, often years before symptoms appear. Understanding these risk factors is a primary step in identifying individuals who may benefit from early monitoring and preventative strategies.
Demographic and Inherited Predispositions
Inherent biological characteristics play a defining role in the likelihood of developing rheumatoid arthritis. Sex is one of the most established risk factors, with women being two to three times more likely to develop RA than men. This discrepancy points to a strong influence of hormonal and reproductive factors. The risk of onset typically increases substantially between the ages of 40 and 60.
Genetic predisposition is another inherent factor that significantly affects risk, though it does not guarantee the disease will develop. The strongest genetic association lies with the Human Leukocyte Antigen (HLA) genes, particularly the HLA-DRB1 alleles. These genes produce proteins that help the immune system distinguish between the body’s own cells and foreign invaders. Certain variations of HLA-DRB1, often called the “shared epitope,” can increase the risk of developing RA by five to ten times, especially for the anti-citrullinated protein antibody (ACPA) positive form.
The presence of these HLA-DRB1 alleles is not sufficient to cause RA on its own. This genetic susceptibility must interact with environmental factors to trigger the autoimmune cascade. This interplay highlights why a family history of RA increases baseline risk, as close relatives are more likely to share these genetic markers. Despite the strong genetic link, known genetic variants currently only account for a fraction of the total familial risk.
Modifiable Lifestyle Factors
Individual habits and physical state represent risk factors that can be altered to reduce the likelihood of developing RA. Cigarette smoking is the most significant modifiable environmental risk factor, increasing both the risk and the severity of the disease. Smoking is particularly linked to the development of the more severe, seropositive form of RA where anti-citrullinated protein antibodies (ACPA) are present.
The biological mechanism involves toxic compounds in smoke creating an inflammatory environment, particularly in the lungs. This environment promotes a process called citrullination, where certain proteins are chemically modified. The immune system then incorrectly identifies these modified proteins as foreign, leading to the production of ACPA autoantibodies that target the body’s own tissues. Quitting smoking can gradually reduce this heightened risk, though the risk level may take several years to drop significantly.
Excess body weight is another factor that can be managed to mitigate risk. Obesity is associated with an increased incidence of RA, particularly in women. Adipose tissue (body fat) is metabolically active and secretes numerous pro-inflammatory molecules called adipokines. This excess tissue contributes to systemic, low-grade inflammation, which can promote the onset of RA in susceptible individuals.
Specific Biological and Environmental Exposures
Specific biological events and external environmental exposures can contribute to RA risk. Female reproductive factors, distinct from the general sex difference, modulate risk, suggesting a role for fluctuating hormone levels. For example, experiencing early menopause (before the age of 45) is associated with an increased risk of developing RA.
An increased number of pregnancies may influence risk, with women who have given birth to four or more children showing a higher incidence. Women who have had a hysterectomy or oophorectomy also face a higher risk, further supporting the influence of reproductive hormones on immune system function. These hormonal shifts appear to affect immune tolerance, which is the body’s ability to avoid attacking its own tissues.
Exposure to certain infectious agents and imbalances in the body’s natural microbial populations are also implicated in the development of RA. Periodontal disease, a gum infection caused by bacteria such as Porphyromonas gingivalis, has been linked to increased risk. This bacterium produces enzymes that facilitate the same citrullination process that occurs in the lungs of smokers, potentially triggering the production of anti-citrullinated protein antibodies.
Specific occupational and environmental irritants also pose a risk. Exposure to crystalline silica dust, which occurs in occupations such as mining, construction, and rock drilling, is an established environmental risk factor. This exposure is primarily linked to the ACPA-positive form of RA and may lead to a chronic inflammatory response in the lungs that initiates the autoimmune process.