This nested case-control study within the Brigham RA Sequential Study matched incident RA-ILD cases to RA-noILD controls on time of blood collection, age, sex, RA duration, and
rheumatoid factor status. A multiplex assay measured ACPA and anti-native
protein antibodies from stored serum prior to RA-ILD onset. Logistic regression models calculated odds ratios (OR) with 95% confidence intervals (CI) for RA-ILD, adjusting for prospectively-collected covariates. We estimated optimism-corrected area under the curves (AUC) using internal validation. Model coefficients generated a risk score for RA-ILD.
Findings: We analyzed 84 incident RA-ILD cases (mean age 67 years, 77% female, 90% White) and 233 RA-noILD controls (mean age 66 years, 80% female, 94% White). We identified six fine specificity
antibodies that were associated with RA-ILD. The antibody isotypes and targeted
proteins were:
IgA2 to citrullinated
histone 4 (OR 0.08 per log-transformed unit, 95% CI 0.03-0.22),
IgA2 to citrullinated
histone 2A (OR 4.03, 95% CI 2.03-8.00),
IgG to cyclic citrullinated
filaggrin (OR 3.47, 95% CI 1.71-7.01),
IgA2 to native cyclic
histone 2A (OR 5.52, 95% CI 2.38-12.78),
IgA2 to native
histone 2A (OR 4.60, 95% CI 2.18-9.74), and
IgG to native cyclic
filaggrin (OR 2.53, 95% CI 1.47-4.34). These six
antibodies predicted RA-ILD risk better than all clinical factors combined (optimism-corrected AUC=0·84 versus 0·73). We developed a risk score for RA-ILD combining these
antibodies with the clinical factors (smoking, disease activity,
glucocorticoid use,
obesity). At 50% predicted RA-ILD probability, the risk scores both without (score=2·6) and with (score=5·9)
biomarkers achieved specificity ≥93% for RA-ILD.
Interpretation: Specific ACPA and anti-native
protein antibodies improve RA-ILD prediction. These findings implicate synovial
protein antibodies in the pathogenesis of RA-ILD and suggest clinical utility in predicting RA-ILD once validated in external studies.
Funding: National Institutes of Health.