title: Association of cross-reactive antibodies targeting peptidyl-arginine deiminase 3 and 4 with rheumatoid arthritis-associated interstitial lung disease.
abstract: BACKGROUND
  A subset of rheumatoid arthritis (RA) patients have detectable antibodies directed against the peptidyl-arginine deiminase (PAD) enzyme isoforms 3 and 4. Anti-PAD3/4 cross-reactive antibodies (anti-PAD3/4XR) have been shown to lower the calcium threshold required for PAD4 activation, an effect potentially relevant to the pathogenesis of RA-associated interstitial lung disease (ILD).
  
  
  METHODS
  RA patients underwent multi-detector computed tomography (MDCT) of the chest with interpretation by a pulmonary radiologist for ILD features. A semi-quantitative ILD Score (range 0-32) was calculated. Concurrent serum samples were assessed for antibodies against PAD by immunoprecipitation with radiolabeled PAD3 and PAD4.
  
  
  RESULTS
  Among the 176 RA patients studied, any ILD was observed in 58 (33%) and anti-PAD3/4XR was detected in 19 (11%). The frequency of any ILD among those with anti-PAD3/4XR was 68% vs. 29% among those with no anti-PAD (crude OR = 5.39; p = 0.002) and vs. 27% among those with anti-PAD4 that was not cross-reactive with PAD3 (crude OR = 5.74; p = 0.001). Both associations were stronger after adjustment for relevant confounders (adjusted ORs = 7.22 and 6.61, respectively; both p-values<0.01). Among ever smokers with anti-PAD3/4XR, the adjusted frequency of any ILD was 93% vs. 17% for never smokers without the antibody (adjusted OR = 61.4; p = 0.001, p-value for the interaction of smoking with anti-PAD3/4XR<0.05).
  
  
  CONCLUSIONS
  The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. These findings may suggest etiopathologic mechanisms of RA-ILD, and their clinical utility for predicting ILD warrants additional study.
authors.affiliation: Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Jon T
authors.initials: JT
authors.lastname: Giles
authors.affiliation: Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Erika
authors.initials: E
authors.lastname: Darrah
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Sonye
authors.initials: S
authors.lastname: Danoff
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Cheilonda
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Felipe
authors.initials: F
authors.lastname: Andrade
authors.affiliation: Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Antony
authors.initials: A
authors.lastname: Rosen
authors.affiliation: Division of Rheumatology, Columbia University, College of Physicians and Surgeons, New York, New York, United States of America.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Bathon
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000150:complications* / Q000175:diagnosis / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000276:immunology*; D017563:Lung Diseases, Interstitial / Q000150:complications* / Q000175:diagnosis / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D063868:Patient Outcome Assessment; D011446:Prospective Studies; D000080063:Protein-Arginine Deiminase Type 3; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D012307:Risk Factors
chemical_list: D001323:Autoantibodies; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080063:Protein-Arginine Deiminase Type 3; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases