As a group, environmental and other non-genetic factors are thought to account for roughly 40% of the risk for developing RA, with genetics accounting for the remaining 60%. When we talk about the role that the environment plays in causing or contributing to the development of a disease, we mean several things. Our environment refers to where we live and what substances or organisms we come in contact with, including bacteria, viruses, dust, and pollutants.1
There can be some overlap between environmental factors and other non-genetic factors, such as lifestyle and diet and certain socioeconomic factors. In another section, non-genetic risk factors such as lifestyle (diet, for example), medical interventions, and constitutional factors, including hormonal levels and obesity, are discussed.
Risk factors and auto-antibodies
In RA, the immune system malfunctions and turns against the body’s own healthy joint tissue. As part of the autoimmune response in RA, the immune system develops auto-antibodies against healthy tissue, similar to the way the normal immune response develops antibodies against foreign organisms (such as viruses) that invade the body. Recent research has shown that RA can be divided into subtypes according to the auto-antibodies that are found in RA joint tissue. These subtypes are referred to as ACPA-positive and ACPA-negative RA. ACPA is short for anti-citrullinated protein/peptide antibody, which refers to a particular kind of antibody designed to attack proteins that have undergone a process called citrullination in response to inflammation.2
It turns out that the influence of genetic and environmental risk for RA differ dramatically according to whether a patient is ACPA-positive (ACPA is detected) or ACPA-negative (ACPA is not detected). For instance, the environmental risk factor of smoking is mainly a risk factor only for patients who are ACPA-positive. Interestingly, ACPA-positive patients usually test positive as well for rheumatoid factor (RF), a chemical that is often found in the joints of patients with RA.3
What is the evidence supporting environmental risk factors?
Conducting a study that measures the impact of environmental exposures on the risk of developing a disease like RA that may result from a combination of genetic, environmental, and other risk factors can be difficult. Therefore, there are relatively few well designed studies examining environmental factors.
Smoking is the most well-established environmental risk factor (it may also be considered a lifestyle risk factor) for development of RA. There have been a number of epidemiologic studies showing that smoking increases the risk of developing RA. One such study was conducted in the UK and looked at 13 pairs of identical (monozygotic) twins. For each twin pair, one twin was a smoker and one was not, and one had RA and one did not. (Remember, identical twins share the exact same genetic material, so some factor other than genetics would have to explain the development of RA.) It turned out that in 12 out of 13 pairs, the smoker was also the twin that had RA. Other types of studies confirmed these results and have established smoking as a factor that increases risk for RA.3
While there is strong evidence linking smoking and increased risk for RA, it was only recently that smoking was shown to be only a risk factor for RA patients who are ACPA-positive (as well as RF-positive). Additionally, the risk is highest for patients who have certain inherited mutations in the gene HLA DRB1. Among people who are ACPA-positive, the risk for developing RA is 10 to 40 times greater in those with certain mutations in HLA DRB1 compared with those without those mutations.3
The question of whether second-hand smoking increases risk is, as of yet, still unanswered.3
Silica dust exposure
Another well established environmental risk factor for RA is silica dust (stone dust), a kind of exposure that mainly affects people in the mining industry. Again, like smoking this risk factor appears to mainly affect those with ACPA-positive RA.3
Mineral oils and other immune system activators
Mineral oils, including distillates of petroleum, are among a broad range of compounds (known as adjuvants) with the ability to activate the immune system (this means to trigger an immune response). Interestingly, in laboratory experiments these compounds have been shown to induce inflammatory arthritis in rodents. In one study, high levels of occupational exposure to hydraulic oil was shown to be associated with increased risk of developing RA. However, few other systematic studies have examined exposure to mineral oils and other similar compounds and risk of RA.3
Although there has been much interest in the idea that some sort of infection (either viral or bacterial) might play a role in triggering RA, to date there is little evidence to support this theory. One possibility is that infections may play a similar role as the range of petroleum compounds that activate the immune system.3
To date, the virus with the strongest association with risk for developing RA is the Epstein-Barr virus (EBV), a member of the herpesvirus family which is one of the most common viruses in humans. In the US, most adults (between the ages of 35 and 40 years) have been infected with EBV at some point in their lives. Studies linking EBV with RA have found high levels of the virus in lymphocytes that circulate in the body. Additionally, EBV has been found in synovial fluid of patients with RA.4
Other micro-organisms with possible association with risk for RA include parvovirus B19, Mycoplasma pneumoniae, Proteus, Bartonella, Chlamydia, Porphyromonas gingivalis, and Borrelia burgdorferi. However, most of these associations have been made on results from small studies that have not been widely reproduced4