2015 ACR/ARHP Annual Meeting: RA Pathogenesis and Prevention

Evidence is now strongly pointing to the lung as a primary site of origin of RA, said Dr. Holers, prompting a new experimental focus on a potential mucosal-initiation etiology in the pathogenesis of early RA. Such evidence includes data showing an association between persons at risk of or with early RA and environmental exposures (e.g., to smoking, silica, airborne particulate matter), the presence of immunoglobulin A (IgA) autoantibodies, pulmonary abnormalities on high-resolution computed tomography (HRCT), local production of ACPA in the lung, expansion of IgA producing plasmablasts in at-risk individuals, periodonitits and mucosal dysbiosis.

Still not fully understood, he said, is the transition from this pre-clinical early stage of disease to synovitis of which environmental and genetic factors could play a role. A major question needing an answer is at what specific point do environmental factors, such as smoking exposure or omega-3 fatty acids intake, play a role in disease development. “We need prospective, natural history studies to understand how this entire process occurs,” he said, along with better knowledge of how genetic factors influence this process.

Moving Toward Prevention

Along with providing better targeted therapeutics, underlying this research is the primary aim of preventing RA. “The field is moving toward prevention,” said Dr. Holers, adding that in the future rheumatologists may be able to detect patients at risk of RA or with the very earliest warning signs of disease by, for example, sputum testing that may reveal early pathophysiologic changes as described above.

Table 3: Prevention Strategies
Key: CCP, cyclic citrullinated peptide; RF, rheumatoid factor; ULN, upper limit of normal
Notes: *Prevention of Clinically Manifest Rheumatoid Arthritis by B Cell Directed Therapy in the Earliest Phase of the Disease
**Arthritis Prevention in the Pre-Clinical Phase of RA with Abatacept
***Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis

To that end, a number of RA prevention approaches are under investigation (see Table 3).

Also under consideration is general population screening for either single or multiple diseases based on the rationale of the prevalence of autoimmune disease (about 8% of the population) and the highly specific and unique autoantibodies that can be detected prior to the clinical onset of autoimmune disease.

Epidemiological findings suggest that smoking, contraceptive use & omega-3 fatty acids have an effect on pre-clinical autoimmunity. Unlike these factors, the effects of pollution & development of RA comorbidities do not appear until later in the disease process when initial signs & symptoms of RA appear.

According to Dr. Holers, one strategy for implementing screening would be to first test it in a pilot population (e.g., families with children or people with high-risk genotypes). He also said that an effort to accelerate development of array-based screening across immune diseases is ongoing within studies funded by the National Institutes of Health.