Radiographic airway abnormalities in untreated early rheumatoid arthritis are associated with peripheral neutrophil activation

Abstract

Background: The role of the lung for the initiation and progression of rheumatoid arthritis (RA) is still unclear. Up to 10% of RA patients develop severe treatment resistant lung disease. Understanding early disease mechanisms is of great importance. The objective of this study was to determine whether there is an association between peripheral neutrophil phenotypes and presence of pulmonary abnormalities (PA) on chest high-resolution computed tomography (HRCT) in untreated early RA (ueRA). Methods: Clinical data and blood were collected, and HRCT performed at diagnosis on 30 consecutive anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive ueRA patients. HRCTs were evaluated for the presence and extent of RA-associated parenchymal, airway and/or pleural abnormalities. Expression of phenotype markers on neutrophils were determined by flow cytometry. Levels of calprotectin, ACPA and RF were measured using immunoassays. Results: The frequency of having any PA was 60%. Airway abnormalities were present in 50%, parenchymal nodules in 43% and interstitial lung abnormalities (ILA) in 10%. Unsupervised multivariate factor analysis showed clustering of any PA with neutrophil activation, parameters of inflammation and RF titres. In univariate analysis, the patients with PA displayed significantly increased CD11b and decreased CD62L expression on neutrophils (1.2-fold, p = 0.014; 0.8-fold, p = 0.012) indicating activation, and significantly increased RF IgM titre and CRP (5.7-fold, p = 0.0025; 2.3-fold, p = 0.0035) as compared to no PA. Titres of RF, but not ACPA, correlated with expression of the neutrophil activation marker CD11b. A stratified analysis demonstrated that airway involvement was the PA subtype with the strongest association with neutrophil activation. Conclusion: We report a strong association between radiographic airway findings and activation of circulating neutrophils in early RA supporting a role of innate immunity and the lung in disease onset. Our results also indicate different contributions of RF and ACPA in the RA pathogenesis.