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Original article
Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis
  1. Elana J Bernstein1,
  2. R Graham Barr1,2,
  3. John H M Austin3,
  4. Steven M Kawut4,
  5. Ganesh Raghu5,
  6. Jessica L Sell1,
  7. Eric A Hoffman6,
  8. John D Newell Jr6,
  9. Jubal R Watts Jr7,
  10. P Hrudaya Nath7,
  11. Sushil K Sonavane7,
  12. Joan M Bathon1,
  13. Darcy S Majka8,
  14. David J Lederer1,2
  1. 1Department of Medicine, Columbia University Medical Center, New York, New York, USA
  2. 2Department of Epidemiology, Columbia University Medical Center, New York, New York, USA
  3. 3Department of Radiology, Columbia University Medical Center, New York, New York, USA
  4. 4Department of Medicine and Center for Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  5. 5Department of Medicine, University of Washington, Seattle, Washington, USA
  6. 6Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
  7. 7Department of Radiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
  8. 8Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
  1. Correspondence to Dr David J Lederer, Departments of Medicine and Epidemiology (in Pediatrics), Columbia University Medical Center, 161 Fort Washington Ave, Room 3-321A, New York, NY 10032, USA; davidlederer{at}


Background Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults.

Methods We measured serum rheumatoid factor (RF) and anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between −600 and −250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking.

Results In adjusted models, HAA increased by 0.49% (95% CI 0.11% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected.

Conclusions RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.

  • Connective tissue disease associated lung disease
  • Rheumatoid lung disease
  • Interstitial Fibrosis
  • Clinical Epidemiology
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  • DSM and DJL contributed equally.

  • Twitter Follow David Lederer at @davidlederer

  • Twitter Rheumatoid arthritis-related autoantibodies are associated with subclinical interstitial lung disease.

  • Contributors Substantial contributions to the conception or design of the work; or the acquisition, analysis or interpretation of data for the work: EJB, RGB, JHMA, SMK, GR, JLS, EAH, JDN, JRW, PHN, SKS, JMB, DSM, DJL. Drafting the work or revising it critically for important intellectual content: EJB, RGB, JHMA, SMK, GR, JLS, EAH, JDN, JRW, PHN, SKS, JMB, DSM, DJL. Final approval of the version submitted for publication: EJB, RGB, JHMA, SMK, GR, JLS, EAH, JDN, JRW, PHN, SKS, JMB, DSM, DJL. Accountability for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: EJB, RGB, JHMA, SMK, GR, JLS, EAH, JDN, JRW, PHN, SKS, JMB, DSM, DJL.

  • Funding This research was supported by contracts N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164 and N01-HC-95165 from the NHLBI and by grants UL1-TR-000040 and UL1-TR-001079 from NCRR. The MESA Lung Study is funded by R01-HL077612, RC1-HL100543 and R01-HL093081 from the NHLBI. The MESA Lung Fibrosis Study is funded by R01-HL103676 from the NHLBI and in part by a grant from the Pulmonary Fibrosis Foundation. The MESA Autoimmunity Study is funded by R01-HL104047 from the NHLBI and in part by an Arthritis Foundation Arthritis Investigator Award.

  • Competing interests DJL has received consulting fees from Genentech/Roche, Boehringer-Ingelheim, Gilead, Pharmakea, Veracyte, Patara Pharmaceuticals, Degge Group and the France Foundation related to IPF; Columbia University has received funding for clinical trials in IPF from Boehringer-Ingelheim, Gilead, Bayer, Global Blood Therapeutics and Fibrogen; Columbia University has received funding from the Pulmonary Fibrosis Foundation for DJL's consulting services; DJL has received fees for serving as a Deputy Editor for the Annals of the American Thoracic Society and as a Statistical Editor for Thorax. EAH is a founder and shareholder in VIDA Diagnostics. JDN is a consultant for VIDA Diagnostics and GSK; he is also a patent holder with and has stock options in VIDA Diagnostics. JRW is a member of the IPF Rally Educational Advisory Board and has received honoraria and travel expenses from the IPF Rally Educational Advisory Board.

  • Ethics approval MESA was approved by the Institutional Review Board for each participating study site.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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