title: Protective effect of HLA-DRB1*13 alleles during specific phases in the development of ACPA-positive RA.
abstract: OBJECTIVE
  Human leucocyte antigen (HLA)-DRB1*13 alleles are associated with protection from anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). It is, however, unknown at which phase of disease development (seroconversion, ACPA maturation, disease onset or outcome) these alleles are most important. We therefore examined the effect of HLA-DRB1*13 on: ACPA presence (systemic autoimmunity associated with RA) in individuals with and without RA, on ACPA characteristics and on clinical outcome measures.
  
  
  METHODS
  The effect of HLA-DRB1*13 on ACPA presence in subjects with or without RA (non-RA) was assessed in the Swedish twin registry (n=10 748). ACPA characteristics were studied in patients with ACPA-positive RA from the Swedish Epidemiological Investigation of RA (EIRA, n=1224) and the Dutch Leiden Early Arthritis Clinic (EAC, n=441). Disease activity at inclusion and disease outcome (disease-modifying antirheumatic drugs (DMARD)-free sustained remission and radiographic progression) was assessed in patients with RA from the EAC.
  
  
  RESULTS
  HLA-DRB1*13 is associated with protection from ACPA-positive RA (prevalence 16% vs 28% in ACPA-negative non-RA), but not with significant protection from ACPA in individuals without RA (prevalence: 22%, p value 0.09). HLA-DRB1*13 is associated with lower ACPA-levels (EIRA: 447 U/ml versus 691 U/ml, p value= 0.0002) and decreased citrullinated epitope recognition (EIRA: p<0.0001). No association between HLA-DRB1*13 and disease activity or outcome was found.
  
  
  CONCLUSIONS
  These data indicate that HLA-DRB1*13 mainly affects the onset of ACPA-positive RA in ACPA-positive non-RA individuals. In RA, HLA-DRB1*13 influences ACPA characteristics but not the disease course. This implies that therapeutic strategies aimed at emulating the HLA-DBR1*13 protective effect may be most effective in ACPA-positive healthy individuals at risk for RA.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Jurgen
authors.initials: J
authors.lastname: van Heemst
authors.affiliation: Department of Rheumatology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aase H
authors.initials: AH
authors.lastname: Hensvold
authors.affiliation: Department of Epidemiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Xia
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Hanna
authors.initials: H
authors.lastname: van Steenbergen
authors.affiliation: Department of Rheumatology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Annette
authors.initials: A
authors.lastname: van der Helm-van Mil
authors.affiliation: Department of Rheumatology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.affiliation: Department of Rheumatology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: van der Woude
mesh_terms: D000328:Adult; D000483:Alleles; D000906:Antibodies / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D004200:Diseases in Twins / Q000097:blood* / Q000235:genetics / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000097:blood* / Q000235:genetics; D006801:Humans; D008297:Male; D010456:Peptides, Cyclic / Q000097:blood / Q000276:immunology; D065840:Protective Factors; D012042:Registries
chemical_list: D000906:Antibodies; D000939:Epitopes; D059811:HLA-DRB1 Chains; C506473:HLA-DRB1*13 antigen; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide
keywords: Ant-CCP; Autoantibodies; Early Rheumatoid Arthritis; Gene Polymorphism; Rheumatoid Arthritis