Association of fine specificity and repertoire expansion of anticitrullinated peptide antibodies with rheumatoid arthritis associated interstitial lung disease

Abstract

Background Interstitial lung disease (ILD) is associated with high morbidity and mortality in rheumatoid arthritis (RA). Citrullinated proteins are observed in RA lung tissues; however, the association of specific anticitrullinated peptide antibodies (ACPA) with ILD in RA is unknown. Methods RA patients underwent multidetector CT (MDCT) of the chest, from which ILD features and a semiquantitative ILD Score (ILDS; range 0–32) were assessed. Anti-CCP (CCP2) and levels of a panel of antibodies against 17 citrullinated and four noncitrullinated peptides were assessed from concurrent serum samples using a custom Bio-Plex bead array. High level ACPA was defined as ≥the group 75th percentile. Results Among the 177 RA patients studied, median levels of CCP2 and all specific ACPAs were 46–273% higher among RA patients with versus those without ILD (all p values <0.05), and higher levels correlated with higher ILDS. In contrast, levels of non-citrullinated protein antibodies were not higher in those with ILD. RA patients had a median of 2 high level ACPA reactivities (range 0–16), with each high level ACPA associated, on average, with a 0.10 unit higher ILDS (p=0.001). This association remained significant after adjusting for characteristics associated with ILD (age, gender, current and former smoking, Disease Activity Score for 28 joints, current prednisone and leflunomide use). More high level ACPA were observed in those with versus without pulmonary function restriction or impaired diffusion. Conclusions Our findings of a broader ACPA repertoire in RA ILD suggest a possible role for ACPA in the pathogenesis of ILD.

Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease

“…As reported by other investigators, in our cohort, smoking was associated with a UIP pattern on HRCT. GILES et al [21] demonstrated that, compared with non-smokers, smokers with rheumatoid arthritis had higher numbers of circulating anti-citrullinated protein antibodies and were more likely to have a UIP pattern on HRCT. In most of our multivariate models, smoking conferred a poorer prognosis.…”

Smoking and interstitial lung diseases

“…It is established that in smokers with rheumatoid arthritis there are citrullinated peptides in the bronchoalveolar lavage fluid cells, which are not present in nonsmokers [41]. Two recent studies revealed higher levels of specific ACPAs in RA-ILD patients than in patients with rheumatoid arthritis without ILD [42,43], and there was also an association with a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) [43]. These findings may be indicative of an important role for smoking and citrullination in the development of ILD related to rheumatoid arthritis and provide new diagnostic tools concerning lung involvement [38,44].…”

Detection of Rheumatoid Arthritis–Interstitial Lung Disease Is Enhanced by Serum Biomarkers

“…Importantly, several independent IPF biomarker studies suggest that peripheral blood biomarkers are most effective when used in conjunction with clinical risk factors (23,28). In addition, it is important to note that multiple independent studies have shown that select autoantibodies (high-titer rheumatoid factor [RF] [17,18,32] and anticyclic citrullinated peptide [CCP] antibodies [17,18,[33][34][35]) are specifically associated with the presence of ILD in patients with RA and therefore could further enhance the value of clinical risk factors.…”