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.