Background We have previously demonstrated that smoking induces citrullination in the lungs of healthy smokers and we know that ACPA develops in RA patients many years before disease onset.
Objectives In this study we aimed to investigate the hypothesis that lung changes in association with smoking and ACPA might be a primary rather than a secondary extra articular manifestation in RA.
Methods 103 RA patients with symptom duration less than 1 year at the time of diagnosis and naive to DMARD treatment were included in the RA cohort. A second non-RA cohort matched for age, smoking status and gender (n=43) was investigated with an identical protocol. X-ray, (high resolution computer tomography (HRCT) and dynamic spirometry were performed in both cohorts. HRCT changes were defined as presence of infiltrates, fibrosis, emphysema and bronchiectasis. Bronchoscopy was performed in a subgroup of RA patients (n=21) and BAL samples as well as mucosal large bronchial biopsies were retrieved. ELISA was used to detect local production of IgA and IgG ACPA in the BAL fluid. Mass spectrometry was used for identification of citrullinated epitopes in 6 of the lung biopsies and additional 8 synovial RA biopsies. immunohistocehmsitry was performed for detection peptydilamino deiminase (PAD) enzymes in the lungs biopseis. Contingency tables and chi-square test as well as a generalized linear model were used for analysis of the clinical data. Man-Whitney test was used to analyze differences in immunohistochemistry double blind semi-quantitative scores between independent groups.
Results 44% of the RA patients had identifiable HRCT changes as compared with only 23% in the healthy non-RA controls. ACPA presence but not smoking status was associated with HRCT changes. A majority of serum ACPA positive RA patients subjected to lung bronchoscopy had detectable levels of ACPA in the BAL fluids. Mass spectometry identified 5 proteins in the synovium (in total 8 sites) and 4 in the lungs (in total 6 sites) containing citrullinated residues. Two vimentin derived citrullinated peptides were present in a majority of both synovial and lung biopsies with slightly higher citrullinated/unmodified peptides ratios in the smokers as compared to non-smokers (median ratio of 0.03 in smokers and 0.02 in non smokers for one of the peptides and a median ratio of 4.5 in the smokers and 0.04 in the non smokers for the second vimentin peptide). Immunohistochemistry demonstrated a significant increase in expression of both PAD2 and PAD4 in the lungs of current smokers independent of the ACPA status. Results on citrullinated protein expression are pending.
Conclusions We demonstrate that HRCT abnormalities, shared citrullinated epitopes with the joints as well as local production of ACPA are present in the in RA lungs already at disease onset. We propose that site-specific extra articular changes (such as in the lungs) are the intitiating event of the specific immune response in ACPA positive RA.
Disclosure of Interest None Declared
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