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

Abstract

Background: To identify fine specificity anti-citrullinated protein antibodies (ACPA) associated with incident rheumatoid arthritis-associated interstitial lung disease (RA-ILD).

Methods: 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.

Figure 1.. Receiver operating characteristic curves for incident RA-ILD risk among 84 cases and 233 RA-noILD controls in BRASS, adding novel biomarkers and MUC5B to clinical factors

ROC = receiver operating characteristic, RA = rheumatoid arthritis. Area under curve is noted in parentheses next to each model name. Demographic = age, race and ethnicity, education; Lifestyle = BMI, smoking pack-years; RA factors = RA duration, RF, anti-CCP, bone erosion, rheumatoid nodules, methotrexate use, glucocorticoid use, biologic DMARD use, DAS28-CRP, MDHAQ; Clinical factors combined = demographic + lifestyle + RA factors; Novel biomarkers = H4 33–48 cit 39 (IgA2), H2A/a-2 1–20 cit (IgA2), Filaggrin 48–65 cit2 cyclic (IgG), H2A/a 1–20 cyclic (IgA2), H2A/a-2 1–20 (IgA2), Filaggrin 48–65 cyclic (IgG)