When genetic factors, such as the shared epitope alleles of human leukocyte antigen (HLA-SE), which is associated with three times the RA risk, are combined with environmental triggers, the probability of that person later developing RA skyrockets.5 For example, someone with two HLA-SE alleles who also smokes has a 21-fold higher chance of developing anti-citrullinated protein antibody-positive (ACPA-positive) disease.6 Other environmental factors, including periodontal disease, obesity, lower socioeconomic status and exposure to silica dust in the air, are also associated with higher RA risk, but some people have these factors and never progress to autoimmunity, the authors say. So we can’t yet say that modifying certain habits will make a difference when it comes to developing RA, says Prof. Emery.
‘The evidence that changing avoidable risk factors prevents progression to the various stages of disease is still awaited.’ —Professor Paul Emery
“The evidence that changing avoidable risk factors prevents progression to the various stages of disease is still awaited. It is common sense to advise on cessation of smoking and improving dental care, as they have other benefits.”
Localized Autoimmunity
What may propel an individual from genetic and environmental risks to that important third phase, systemic autoimmunity? Localized autoimmunity that starts at mucosal surfaces, such as the mouth, lung or gut, may tell us which patients may be most likely to move ahead on the spectrum, says Prof. Emery. Events on those mucosal surfaces may trigger the ACPA responses that play a role in RA development.
For example, the bacterium involved in periodontal disease, Porphyromonas gingivalis, may set in motion a chain of events that causes citrullinated antigens to be produced in the mouth, causing an ACPA response.7 There is a strong association between periodontal disease and RA in ACPA-positive patients, and anti-cyclic citrullinated peptide (anti-CCP) antibodies have been found in the saliva of people with RA.8,9
The lung is another site where autoimmunity may begin. Smoking is associated with citrullination in the lung mucosal surfaces in people with ACPA-positive RA, and that process may produce antigens that lead to first local, then systemic, autoimmunity, say Ms. Mankia and Prof. Emery.10 Whether they smoke or not, patients with ACPA-positive, early RA may have abnormal changes in their lungs that can be spotted on high-resolution computed tomography (HRCT) imaging scans.11
Similarly, the gut may also be an important place to look for signs of localized autoimmunity. An imbalance of bacteria in the gut can disrupt the normal balance of T cells and lead to autoimmunity.12 New, untreated RA patients show higher levels of Lactobacillus and Prevotella copri in their guts.13,14 We do not yet know if gut dysbiosis triggers autoimmunity or is the result of it, the authors add.