title: Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers.
abstract: BACKGROUND
  Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized.
  
  
  OBJECTIVE
  To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD.
  
  
  METHODS
  Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR.
  
  
  RESULTS
  A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD.
  
  
  CONCLUSIONS
  Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Doyle
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Avignat S
authors.initials: AS
authors.lastname: Patel
authors.affiliation: 2 Center for Pulmonary Functional Imaging.|3 Department of Radiology.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Hatabu
authors.affiliation: 2 Center for Pulmonary Functional Imaging.|3 Department of Radiology.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Nishino
authors.affiliation: 4 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Guodong
authors.initials: G
authors.lastname: Wu
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Osorio
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Golzarri
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andres
authors.initials: A
authors.lastname: Traslosheros
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarah G
authors.initials: SG
authors.lastname: Chu
authors.affiliation: 5 Division of Rheumatology, Immunology and Allergy, and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Frits
authors.affiliation: 5 Division of Rheumatology, Immunology and Allergy, and.
authors.forename: Christine K
authors.initials: CK
authors.lastname: Iannaccone
authors.affiliation: 6 Division of Rheumatology and Clinical Immunology and.
authors.forename: Diane
authors.initials: D
authors.lastname: Koontz
authors.affiliation: 7 Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Carl
authors.initials: C
authors.lastname: Fuhrman
authors.affiliation: 5 Division of Rheumatology, Immunology and Allergy, and.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Souheil Y
authors.initials: SY
authors.lastname: El-Chemaly
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: George R
authors.initials: GR
authors.lastname: Washko
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|8 Channing Laboratory, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Gary M
authors.initials: GM
authors.lastname: Hunninghake
authors.affiliation: 9 Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, New York; and.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: 5 Division of Rheumatology, Immunology and Allergy, and.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Dellaripa
authors.affiliation: 6 Division of Rheumatology and Clinical Immunology and.
authors.forename: Chester V
authors.initials: CV
authors.lastname: Oddis
authors.affiliation: 5 Division of Rheumatology, Immunology and Allergy, and.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Shadick
authors.affiliation: 10 Division of Rheumatology, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Ascherman
authors.affiliation: 1 Pulmonary and Critical Care Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.|4 Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
mesh_terms: D000367:Age Factors; D000368:Aged; D019540:Area Under Curve; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000150:complications*; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers / Q000097:blood; D018925:Chemokines / Q000097:blood; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000097:blood* / Q000150:complications / Q000175:diagnosis*; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000097:blood; D008875:Middle Aged; D011446:Prospective Studies; D037663:Pulmonary Surfactant-Associated Protein D / Q000097:blood; D012372:ROC Curve; D012307:Risk Factors; D012737:Sex Factors
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D018925:Chemokines; D037663:Pulmonary Surfactant-Associated Protein D; D020783:Matrix Metalloproteinase 7
keywords: biomarkers; interstitial lung disease; rheumatoid arthritis; risk prediction; subclinical
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