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The Lung in Pre-RA

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Rheumatoid arthritis (RA) causes joint inflammation and joint damage. RA affects approximately 1% of the population, which is more than 1 million people in the US and more than 23 million people across the world. RA can cause joint pain, disability, and early death. There is no cure for RA. That is why research is needed to understand what causes RA so that better treatments can be designed to stop this damaging disease.


In RA, the immune system displays abnormalities and dysregulation several years before the onset of any joint inflammation. Our research team studies the ‘pre-clinical’ phase of RA or ‘pre-RA,’ which is the time during RA development before joint inflammation begins. If we can better understand what causes the pre-clinical phase of RA and what drives the transition from pre-RA to joint disease, we can identify new ways to prevent development of the damaging joint disease of RA.


The Mucosal Origins Hypothesis outlines how RA begins at a mucosal site. There are several mucosal sites where the immune system and environment interact and could therefore be sites where inflammation and autoimmunity in RA are initially triggered. Our research team focuses on the lung, and we use a procedure called induced sputum collection to easily and safely measure the biology of the lungs in people. We have made several important contributions over the past 10 years in this area. Our research findings were the first to identify an increased prevalence of inflammatory airway abnormalities on CT imaging of the lung in people with pre-clinical RA-associated autoimmunity. We were the first to identify that a portion of individuals in the pre-clinical phase of RA generate RA-related autoantibodies in the lung, including anti-citrullinated protein antibodies (ACPA), anti-peptidylarginine deiminase antibodies (anti-PAD4), and rheumatoid factor (RF). We have also made the novel finding that ACPA production in the lung strongly correlates with neutrophil extracellular traps (NETs) in individuals who have a high risk of developing RA. Overall, our team’s work has been a major factor to advance the understanding of the earliest steps of RA development by demonstrating that early inflammation and autoimmunity in RA occur outside of the joints, and in the lungs in many people. Following our studies, the field has begun to intensively study mucosal biology, in the lung and at other mucosal sites, as a key player in development and progression of the pre-clinical period of RA.


Our ongoing work in this area continues to strengthen the connection between the lung and the development of RA. We are currently studying the utility of antibodies in sputum to predict which individuals with pre-clinical RA will transition to joint disease. We also have ongoing studies that evaluate different cell types in the lung to better understand what aspects of the immune system have become dysregulated in the lung and contribute to the development of RA. Ultimately, we hope to develop novel lung-targeted prevention strategies that abrogate RA at the site of initial immune dysregulation.

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