title: Role of Anti-Carbamylated Protein Antibodies Compared to Anti-Citrullinated Protein Antibodies in Indigenous North Americans With Rheumatoid Arthritis, Their First-Degree Relatives, and Healthy Controls.
abstract: Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies, including seropositivity for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs). In addition, antibodies to carbamylated proteins (anti-CarP) are present in patients with RA and are associated with joint damage. This study was undertaken to assess the presence of anti-CarP antibodies in indigenous North Americans (First Nations [FN] populations) with RA compared to their at-risk first-degree relatives (FDRs) and healthy controls.
  
  
  
  Anti-CarP IgG and ACPAs (specifically, anti-cyclic citrullinated peptide [anti-CCP] antibodies) were measured by enzyme-linked immunosorbent assay in the sera of FN patients with RA (n = 95), their unaffected FDRs (n = 109), and healthy FN controls (n = 85). Antibodies to additional citrullinated peptides were measured using a multiplex ACPA array, and the number of peptides recognized was reported as an ACPA score. Groups were compared using the chi-square test and Mann-Whitney U test. Associations between RA and seropositivity for RF, ACPAs, and anti-CarP antibodies were determined by logistic regression.
  
  
  
  Anti-CarP antibodies were more frequent in FN patients with RA (44.3%) compared to FDRs (18.3%) and FN controls (4.7%) (both P < 0.0001 versus RA). Moreover, anti-CarP antibodies were more frequent in FDRs than in FN controls (P = 0.008). The ACPA score was higher in anti-CCP-positive FN patients with RA than in anti-CCP-positive FN FDRs (median score 7 [interquartile range (IQR) 7] versus median score 1 [IQR 4]; P = 0.04). The association with RA was strongest when all 3 autoantibodies (RF, anti-CCP, and anti-CarP) were present in the patients' serum (odds ratio 194, 95% confidence interval 23-1,609, P < 0.0001).
  
  
  
  Anti-CarP antibodies are prevalent in FN patients with RA and also more common in their at-risk FDRs compared to healthy controls. The results indicate an association of RF, ACPAs, and anti-CarP with RA that is strongest when all 3 autoantibodies are present. These findings may provide new insights into the evolution of autoimmunity in preclinical RA.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Koppejan
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Trouw
authors.affiliation: Stanford University School of Medicine, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
authors.forename: J
authors.initials: J
authors.lastname: Sokolove
authors.affiliation: Stanford University School of Medicine, Stanford, California, and VA Palo Alto Health Care System, Palo Alto, California.
authors.forename: L J
authors.initials: LJ
authors.lastname: Lahey
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: T J W
authors.initials: TJ
authors.lastname: Huizinga
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: I A
authors.initials: IA
authors.lastname: Smolik
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: D B
authors.initials: DB
authors.lastname: Robinson
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: H S
authors.identifier: 0000-0002-0796-4422
authors.initials: HS
authors.lastname: El-Gabalawy
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: R E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: C A
authors.initials: CA
authors.lastname: Hitchon
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000502:physiology*; D002956:Citrulline / Q000031:analogs & derivatives* / Q000276:immunology; D005260:Female; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D012217:Rheumatoid Factor / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; C001352:homocitrulline; D002956:Citrulline; D012217:Rheumatoid Factor