Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease resulting from the complex interaction between genes and environment. In a large majority of patients this interaction leads to formation of disease-specific anti-citrullinated proteins antibodies (ACPA). Systemic autoimmunity may be triggered at mucosal sites (such as the lungs) long before the first signs of inflammation are starting in the joints. According to this model, smoking (and others environmental triggers) induces subclinical inflammation in the lungs, leading to increased local citrullination and formation of ACPA in genetically susceptible individuals. Lung changes on high-resolution computer tomography are present in both early-untreated ACPA positive RA and ACPA positive individuals at risk for but not yet having disease. Further, signs of subclinical inflammation and immune activation with germinal centers formation and ACPA enrichment is present in early untreated RA. Shared citrullinated targets have been described in the lungs and joints of patients with RA and more recent data unravels novel mechanisms showing how this extra-articular triggered autoimmunity progresses to joint-specific inflammation. Beside an initiating role, the lung might also be a secondary target for antibodies, especially in longstanding seropositive RA.