Autoantibody seropositivity and risk for interstitial lung disease in a prospective male-predominant rheumatoid arthritis cohort of U.S. veterans

Jake G. Natalini, Joshua F. Baker, Namrata Singh, Tina D. Mahajan, Punyasha Roul, Geoffrey M. Thiele, Brian C. Sauer, Cheilonda R. Johnson, Steven M. Kawut, Ted R. Mikuls, Bryant R. England

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Rationale: Prior studies investigating associations of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) seropositivity with risk for rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) have mostly used cross-sectional or case-control designs. Objectives: To determine whether combined autoantibody seropositivity and higher individual autoantibody concentrations were associated with increased risk for RA-ILD in a prospective RA cohort. Methods: Within the Veterans Affairs Rheumatoid Arthritis prospective registry, we performed a cross-sectional study of prevalent ILD and a retrospective cohort study of incident ILD (diagnosed after at least 12 mo of longitudinal follow-up). We used logistic and Cox regression methods to determine whether combined RF/ACPA seropositivity and higher autoantibody concentrations were independently associated with greater risk for prevalent and incident ILD, respectively. Results: Among 2,328 participants (median age 64 yr, 89.3% male), 100 (4.3%) subjects had prevalent ILD at enrollment. During 14,281 patient-years of follow-up, 83 (3.7%) of the remaining 2,228 were subsequently diagnosed with incident ILD (5.8 cases per 1,000 person-years). Patients with combined RF/ACPA seropositivity had a higher probability of prevalent ILD compared with seronegative subjects (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.24-6.78). RF titers demonstrated a monotonic association with prevalent ILD (OR, 2.69; 95% CI, 1.11-6.51 for low-positive [15-45 IU/ml] titers; OR, 3.40; 95% CI, 1.61-7.18 for high-positive [.45 IU/ml] titers; P for trend 0.01). Patients with high-positive (.15 U/ml) ACPA titers were also at higher risk for prevalent ILD (OR, 1.91; 95% CI, 1.04-3.49) compared with ACPA-negative subjects. Combined RF/ACPA seropositivity was not associated with increased risk for incident ILD, nor were high- or low-positive RF or ACPA titers. In a piecewise linear spline model, however, RF titers greater than 90 IU/ml independently correlated with increased risk for incident ILD (hazard ratio, 1.68, 95% CI, 1.02-2.77). Conclusions: Combined RF/ACPA seropositivity and individual autoantibody concentrations were strongly associated with prevalent but not incident RA-ILD. Only patients with RF concentrations.90 IU/ml were observed to be at higher risk of incident RA-ILD.

Original languageEnglish (US)
Pages (from-to)598-605
Number of pages8
JournalAnnals of the American Thoracic Society
Issue number4
StatePublished - Apr 2021


  • Anti-citrullinated protein antibodies
  • Rheumatoid arthritis-associated interstitial lung disease
  • Rheumatoid factor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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