title: Differences in the Spectrum of Anti-Citrullinated Protein Antibody Fine Specificities Between Malaysian and Swedish Patients With Rheumatoid Arthritis: Implications for Disease Pathogenesis.
abstract: Antibodies to the citrullinated protein antigens (ACPAs) are important in the diagnosis and pathogenesis of rheumatoid arthritis (RA). However, the prevalence of ACPAs with different fine specificities in different populations is unclear. This study sought to examine the fine specificity of the antibody responses toward citrullinated proteins in RA patients from Malaysia, an area where genetic and environmental determinants of RA are different from those in more frequently studied cohorts of Caucasian subjects.
  
  
  
  A multiplex analytic microarray system was used to analyze the occurrence of antibodies to 10 different citrullinated peptides (filaggrin [fil307-324], vimentin [Vim2-17, Vim60-75], fibrinogen [Fibα563-583, Fibα580-600, Fibβ36-52, Fibβ62-81a, Fibβ62-81b], enolase [Eno5-21], and type II collagen [CitCII355-378]) in serum samples from 4,089 RA patients (1,231 Malaysian and 2,858 Swedish) and 827 healthy control subjects (249 Malaysian and 578 Swedish). The positive reaction threshold for each peptide was set separately for each population based on a specificity of 98%.
  
  
  
  Distinct differences in the frequencies of 5 ACPA fine specificities (Vim60-75, Vim2-17, Fibβ62-81b, Eno5-21, and CitCII355-378) were found between the Malaysian and Swedish RA populations, despite a nearly identical percentage of patients in each population who were positive for anti-cyclic citrullinated peptide 2 antibodies. In Malaysian RA patients compared with Swedish RA patients, the frequencies of antibodies to Vim60-75 (54% versus 44%, corrected P [Pcorr] = 1.06 × 10-8) and CitCII355-378 (17% versus 13%, Pcorr= 0.02) were significantly higher, while the frequencies of antibodies to Vim2-17 (25% versus 32%, Pcorr= 1.91 × 10-4), Fibβ62-81b (15% versus 30%, Pcorr= 2.47 × 10-22), and Eno5-21 (23% versus 50%, Pcorr= 3.64 × 10-57) were significantly lower.
  
  
  
  Serum ACPA fine specificities differ between RA patients in different populations, although the total proportions of individuals positive for ACPAs are similar. Differing patterns of ACPA fine specificity could be attributed to variations in genetic and/or environmental factors.
authors.affiliation: Institute for Medical Research, Kuala Lumpur, Malaysia, and Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Chun Lai
authors.initials: CL
authors.lastname: Too
authors.affiliation: Ministry of Health, Putrajaya, Malaysia.
authors.forename: Shahnaz
authors.initials: S
authors.lastname: Murad
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Hansson
authors.affiliation: Uppsala University and Thermo Fisher Scientific, Uppsala, Sweden.
authors.forename: Linda Mathsson
authors.initials: LM
authors.lastname: Alm
authors.affiliation: Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Jasbir Singh
authors.initials: JS
authors.lastname: Dhaliwal
authors.affiliation: Karolinska Institutet, Stockholm, Sweden, and Southern Medical University, Guangzhou, China.
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: Karolinska Institutet and Center for Occupational and Environmental Medicine, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.affiliation: Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.affiliation: Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D013548:Sweden; D055815:Young Adult
chemical_list: D001323:Autoantibodies; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide