title: Associations of antibodies against citrullinated peptides with human leukocyte antigen-shared epitope and smoking prior to the development of rheumatoid arthritis.
abstract: BACKGROUND
  It has previously been shown that an increased number of antibodies against citrullinated peptides/proteins (ACPA) predate the onset of rheumatoid arthritis (RA). Over time antibody positivity expands, involving more specific responses when approaching the onset of symptoms. We investigated the impact of human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking on the development of ACPA, as well as in combination with ACPA during the state of quiescent autoimmunity (before the onset of symptoms), on the development of RA.
  
  
  METHODS
  Blood samples donated to the Medical Biobank of Northern Sweden from individuals prior to the onset of symptoms of RA (n=370) and after onset (n=203) and from population-based controls (n=585) were used. Antibodies against 10 citrullinated peptides, fibrinogen (Fibα561-583, α580-600, ß62-81a, ß62-81b, ß36-52), vimentin (Vim2-17, 60-75), filaggrin (CCP-1/Fil307-324), α-enolase (CEP-1/Eno5-21), collagen type II (citC1359-369), and anti-cyclic citrullinated peptide (CCP)2 antibodies were analysed.
  
  
  RESULTS
  HLA-SE-positive individuals were more frequently positive for ACPA compared with HLA-SE-negative individuals prior to the onset of symptoms of RA, particularly for antibodies against CEP-1 and Fibß62-81a (72). Smoking was associated with antibodies against Vim2-17 and citC1359-369. HLA-SE and smoking showed increasing association to the presence of the antibodies closer to disease onset. The highest odds ratio (OR) for development of RA was for the combination of HLA-SE alleles and ACPA positivity, especially for antibodies against Fibß62-81b, CCP-1/Fil307-324, and Fibβ36-52. A gene-environment additive interaction between smoking and HLA-SE alleles for the risk of disease development was found, with the highest OR for individuals positive for antibodies against Fibβ36-52, CEP-1, and Fibα580-600.
  
  
  CONCLUSIONS
  The relationships between antibodies against the different ACPA specificities, HLA-SE, and smoking showed a variable pattern in individuals prior to the onset of RA. The combination of smoking and HLA-SE alleles was significantly associated with the development of some of the antibody specificities closer to onset of symptoms, and these associations remained significant at diagnosis. An additive gene-environment interaction was found for several of the antibodies for the development of RA.
authors.affiliation: Institution of Public Health and Clinical Medicine/Rheumatolgy, Umeå University, SE-90185, Umeå, Sweden. heidi.kokkonen@umu.se.
authors.forename: Heidi
authors.initials: H
authors.lastname: Kokkonen
authors.affiliation: Institution of Public Health and Clinical Medicine/Rheumatolgy, Umeå University, SE-90185, Umeå, Sweden. mikael.brink@medicin.umu.se.
authors.forename: Mikael
authors.initials: M
authors.lastname: Brink
authors.affiliation: Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden. monika.hansson@ki.se.
authors.forename: Monika
authors.initials: M
authors.lastname: Hansson
authors.affiliation: Institution of Public Health and Clinical Medicine/Rheumatolgy, Umeå University, SE-90185, Umeå, Sweden. ewa.lassen@vll.se.
authors.forename: Ewa
authors.initials: E
authors.lastname: Lassen
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. linda.mathsson-alm@thermofisher.com.|Thermo Fisher Scientific, Uppsala, Sweden. linda.mathsson-alm@thermofisher.com.
authors.forename: Linda
authors.initials: L
authors.lastname: Mathsson-Alm
authors.affiliation: Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden. rikard.holmdahl@ki.se.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. johan.ronnelid@igp.uu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.affiliation: Rheumatology Unit, Karolinska University Hospital, Stockholm, Sweden. lars.klareskog@ki.se.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Institution of Public Health and Clinical Medicine/Rheumatolgy, Umeå University, SE-90185, Umeå, Sweden. solbritt.rantapaa.dahlqvist@umu.se.
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D005260:Female; D000091344:Filaggrin Proteins; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D012189:Retrospective Studies; D012907:Smoking / Q000009:adverse effects / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D006680:HLA Antigens; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide