title: Anti-carbamylated protein antibodies are present prior to rheumatoid arthritis and are associated with its future diagnosis.
abstract: OBJECTIVE
  Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel.
  
  
  METHODS
  Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]. Positivity for all antibodies was determined as ≥ 2 SD of log-transformed means from controls. Relationships between autoantibodies and future RA were assessed in prediagnosis serum for all RA cases compared to controls using sensitivity, specificity, and logistic regression. Differences in diagnostic accuracy between antibody combinations were assessed using comparisons of area under the curves (AUC).
  
  
  RESULTS
  Anti-CarP-FCS was 26% sensitive and 95% specific for future RA, whereas anti-CarP-Fib was 16% sensitive and 95% specific for future RA. Anti-CarP-FCS positivity was associated with future RA, while anti-CarP-Fib trended toward association. The antibody combination of anti-CCP2 and/or ≥ 2 RF (RF-Neph and/or RF-isotypes) resulted in an AUC of 0.72 for future RA, where the AUC was 0.71 with the addition of anti-CarP-FCS to this prior combination.
  
  
  CONCLUSIONS
  Adding anti-CarP-FCS to antibody combinations did not improve AUC. However, anti-CarP-FCS was associated with future onset of RA, and was present in prediagnosis serum in ∼10% of RA cases negative for anti-CCP2 but positive for RF.
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Gan
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Leendert A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: M Kristen
authors.initials: MK
authors.lastname: Demoruelle
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Kolfenbach
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Zerbe
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Deane
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Jess D
authors.initials: JD
authors.lastname: Edison
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: William R
authors.initials: WR
authors.lastname: Gilliland
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: From the Colorado School of Public Health; Division of Rheumatology, University of Colorado Aurora, Colorado; Walter Reed National Military Medical Center, Bethesda, Maryland, USA; and the Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.R.W. Gan, MPH; G.O. Zerbe, PhD; J.M. Norris, PhD, Colorado School of Public Health; L.A. Trouw, PhD; J. Shi; R.E.M. Toes, PhD; T.W.J. Huizinga, MD; Department of Rheumatology, Leiden University Medical Center; M.K. Demoruelle, MD; J.R. Kolfenbach, MD; K.D. Deane, MD; V.M. Holers, MD, Division of Rheumatology, University of Colorado; J.D. Edison, MD; W.R. Gilliland, MD, Walter Reed National Military Medical Center. Michael.Holers@ucdenver.edu.
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology; D012217:Rheumatoid Factor / Q000097:blood; D012680:Sensitivity and Specificity
chemical_list: D001323:Autoantibodies; D007136:Immunoglobulins; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D012217:Rheumatoid Factor
keywords: AUTOANTIBODIES; EPIDEMIOLOGY; RHEUMATOID ARTHRITIS