Objective. It has been suggested that immunologic events in the lungs may be involved in triggering immunity, in particular production of anti-citrullinated protein antibodies (ACPAs) during early phases of rheumatoid arthritis (RA). The aim of this study was to investigate the structural and immunologic features of the lungs in incident cases of early RA in relation to ACPA presence and smoking status. Results. HRCT imaging revealed that 63% of ACPA-positive RA patients had parenchymal lung abnormalities, compared with only 37% of ACPA-negative RA patients and 30% of healthy controls (each P < 0.05). These significant differences remained after adjustment for smoking status. Airway changes detected by HRCT were more frequent in RA patients than in healthy controls (66% versus 42%; P < 0.05), but there was no difference between ACPA-positive and ACPAnegative RA patients. Immunohistochemical studies of the bronchial tissue showed increased staining for citrullinated proteins in ACPA-positive RA patients compared with ACPA-negative RA patients (P < 0.05). ACPA levels were relatively higher in the BAL fluid as compared with the sera of ACPA-positive RA patients, suggesting that there is local production of ACPAs in the lungs of these patients.Conclusion. The presence of ACPAs is associated with parenchymal lung abnormalities, site-specific citrullination, and antibody enrichment in the lungs early in the development of ACPA-positive RA.

Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.

Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.

Signs of immune cell accumulation and activation are present both in the bronchial tissue and in BAL of untreated patients with early RA without concomitant lung disease, strengthening the role of the lung compartment as an important player in ACPA-positive RA.

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BackgroundRheumatoid arthritis (RA)-associated anticitrullinated protein/peptide antibodies (ACPA) might originate at mucosal sites such as the lungs. We aimed to examine the relationship between the ACPA repertoire and lung abnormalities on high-resolution CT (HRCT) in patients with earlyuntreated RA.Methods106 patients with newly diagnosed untreated RA were examined with HRCT of the lungs. Blood samples were analysed for presence of rheumatoid factor (RF) and ACPA using either a CCP2 detection kit or an immunochip containing 10 different citrullinated peptides. Association between HRCT findings and the antibody repertoire was assessed by logistic regression analysis.ResultsThe number (%) of patients with HRCT abnormalities was 58 (54.7%) for parenchymal abnormalities and 68 (64.2%) for airway abnormalities. CCP2 IgG, RF IgA and antibodies against citrullinated fibrinogen were associated with the presence of parenchymal lung abnormalities. Interestingly, a high number of ACPA fine specificities gave a high risk of having parenchymal lung abnormalities at the time of RA diagnosis. No significant signals were identified between ACPA specificities and risk for airway abnormalities.ConclusionsThe presence of RF and ACPAs (especially against citrullinated fibrinogen peptides) as well as high number of ACPAs fine specificities are associated with parenchymal lung abnormalities in patients with early, untreated RA. This provides further support for an important pathogenic link between the lung and systemic autoimmunity, contributing to RA development.

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BackgroundThe authors have previously demonstrated that smoking induces citrullination in the lungs of healthy smokers and they know that anticitrullinated protein antibodies (ACPA) develop in rheumatoid arthritis (RA) patients many years before disease onset. It was hypothesised that shared citrullinated targets are present in the lungs and joints of RA affected individuals and sought to investigate this by full-proteome analysis of synovial and lung biopsies of RA patients. Material and methods Proteins were extracted from synovial (n=7, fi ve females and two males, median age 58, 66.7% ACPA positive) and lung (n=6, four females and two males, median age 63, 66.7% ACPA positive) biopsies of RA patients. Synovial biopsies were obtained at the time of open surgery from patients with long-standing RA (mean disease duration 24 years). Large bronchi biopsies were obtained by bronchoscopy from patients with newly diagnosed RA (three smokers and three non-smokers) with symptom duration less than 1 year. The proteins were reduced, alkylated and digested with Lys-C, separated by reverse-phase nanofl ow-chromatography and analysed by LTQ-Velos-Orbitrap using multiple fragmentation methods. The data were searched against the human International Protein Index database using the Mascot search engine and all citrullinated peptides were manually verifi ed. The degree of modifi cation was quantifi ed manually. The fi nal results were expressed as ratios of citrullinated versus nonmodifi ed peptides. Results Over 3300 peptides and 500 proteins were identifi ed in the different samples. The overall protein profi les varied between patients. Five of the identifi ed proteins in the synovium (in total eight sites) and four in the lungs (in total four sites) contained citrullinated residues. Two vimentin derived citrullinated peptides were present in a majority of synovial and lung biopsies with slightly higher citrullinated/unmodifi ed peptides ratios in smokers 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). While non-