Autoantibodies against citrullinated and native proteins and prediction of rheumatoid arthritis-associated interstitial lung disease: a nested case–control study

Background: Rheumatoid arthritis-associated interstitial lung disease (ILD) is one of the leading causes of premature death among patients with rheumatoid arthritis. Improving prediction of rheumatoid arthritis-associated ILD is crucial to allow for earlier diagnosis and treatment. We aimed to identify fine-specificity anti-citrullinated protein antibodies (ACPAs) associated with incident rheumatoid arthritis-associated ILD. Methods: In this nested case–control study within the prospective Brigham Rheumatoid Arthritis Sequential Study (BRASS), we matched cases of incident rheumatoid arthritis-associated ILD diagnosed between March 1, 2003, and April 14, 2016, to control patients with rheumatoid arthritis without ILD on the following characteristics: time of blood collection, age, sex, rheumatoid arthritis duration, and rheumatoid factor status. We measured ACPA and anti-native protein antibodies using a multiplex assay on stored serum collected before onset of rheumatoid arthritis-associated ILD. We used logistic regression models to calculate odds ratios (ORs) with 95% CIs for rheumatoid arthritis-associated ILD, adjusting for prospectively collected covariates. We estimated the optimism-corrected area under the curves (AUCs) using internal validation. We used model coefficients to generate a risk score for rheumatoid arthritis-associated ILD. Findings: We identified 84 incident rheumatoid arthritis-associated ILD cases (mean age 67 [SD 10] years, 65 [77%] female and 19 [23%] male, 76 [90%] White) and 233 rheumatoid arthritis controls without ILD (mean age 66 [11] years, 186 [80%] female and 47 [20%] male, 219 [94%] White). We identified six fine-specificity antibodies that were associated with rheumatoid arthritis-associated ILD. The antibody isotypes and targeted proteins were IgA2 to citrullinated histone 4 (adjusted OR 0·08 [95% CI 0·03–0·22] per log-transformed unit), IgA2 to citrullinated histone 2A (4·03 [2·03–8·00]), IgG to cyclic citrullinated filaggrin (3·47 [1·71–7·01]), IgA2 to native cyclic histone 2A (5·52 [2·38–12·78]), IgA2 to native histone 2A (4·60 [2·18–9·74]), and IgG to native cyclic filaggrin (2·53 [1·47–4·34]). These six antibodies predicted the risk of rheumatoid arthritis-associated ILD better than did all clinical factors combined (optimism-corrected AUC 0·84 versus 0·73). We developed a risk score for rheumatoid arthritis-associated ILD by combining these antibodies with clinical factors (smoking, disease activity, glucocorticoid use, and obesity). At 50% predicted probability of developing rheumatoid arthritis-associated ILD, the risk scores both without (2·6) and with (5·9) antibody biomarkers achieved a specificity of 93% or higher for rheumatoid arthritis-associated ILD. Interpretation: Specific ACPAs and anti-native protein antibodies improve prediction of rheumatoid arthritis-associated ILD. These findings implicate synovial protein antibodies in the pathogenesis of rheumatoid arthritis-associated ILD and, once validated in external studies, suggest that these antibodies might have clinical utility in predicting the development of ILD in patients with rheumatoid arthritis. Funding: US National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases.