Risk Factors for Rheumatoid Arthritis

The cause of RA is not completely understood but likely involves an interaction of multiple factors.¹³ These factors can be broadly described as hereditary, environmental, and genetic.¹⁴

As mentioned earlier, two different subsets of RA have been identified based on whether or not patients test positive for autoantibodies.¹² These different subsets are termed seropositive and seronegative RA.¹² (The prefix “sero” implies that they are determined by studying the blood.)³ Seropositive and seronegative RA may have different causes—factors that are associated with seropositive RA may not be associated with seronegative RA.¹² 

Individuals with a family history of RA are 3 to 5 times more likely to develop RA.¹⁴ This is likely due to both genetic and environmental factors shared by individuals in the same family.¹⁴ 

Heredity is an independent risk factor for RA, because the genetic and environmental factors that explain RA are not completely understood.¹⁴ 

A number of environmental and lifestyle factors have been associated with an increased risk of RA. Of these, smoking is the risk factor with the most supporting evidence, and has been found to be a risk factor specific to seropositive RA.1^3,14,15 Other factors include silica dust exposure, body mass index, low alcohol intake, dietary factors, parity (ie, having given birth),³ and socioeconomic status.¹⁴

In addition, there are other factors that have been hypothesised to contribute to the onset of RA due to their interaction with the immune system.¹³ These include certain infections, periodontal disease (ie, gum disease), and the bacterial environment within the gastrointestinal tract.¹³ 

Many genes have been associated with an increased risk of RA.¹⁶ Most notable are genes of the human leucocyte antigen (HLA) complex that provide instructions for cell-surface molecules important for immune system functioning.^3,16,17 Certain HLA gene variants may predispose a patient to aberrant immune activation and regulation.¹⁶ These HLA gene variants have been associated with a doubled risk of seropositive RA.^14,15

Genetic risk factors may further increase risk of RA when combined with environmental risk factors. For example, smoking has been found to increase the risk of RA more for individuals with certain HLA gene variants.¹³

3 - Stedman’s medical dictionary for the health profession and nursing: Baltimore Maryland: Lippincott Williams & Wilkins. Illustrated 5th ed. 2005.
12 - Malmstrӧm V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 2017; 17(1):60-75. doi:10.1038/nri.2016.124.
13 - McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011; 365(23):2205-2219.
14 - Jiang X, Frisell T, Askling J, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheum. 2015; 67(2):352-362.
15 - Klareskog L, Stolt P, Lundberg K, et al; and the Epidemiological Investigation of Rheumatoid Arthritis Study Group. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006; 54(1):38-46.
16 - McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017; 389:2328-2337.
17 - Hickey MJ, Valenzuela NM, Reed EF. Alloantibody generation and effector function following sensitization to human leukocyte antigen. Front Immunol. 2016; 7:30. doi:10.3389/fimmu.2016.00030.