title: Association of HLA alleles and clinical features in patients with synovitis of recent onset.
abstract: OBJECTIVE
  To determine how HLA alleles are associated with the clinical disease patterns of patients with synovitis of recent onset.
  
  
  METHODS
  The HLA alleles A, B, C, DRbeta1, and DQbeta1 were determined in a cohort of 211 patients (mean age 42 years, 64% female, 79% white) with recent-onset synovitis in 1 or more peripheral joints. At a mean disease duration of 33 weeks, 98 patients (46%) met the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), 38 (18%) met the European Spondylarthropathy Study Group criteria for spondylarthropathy (SpA), and 75 (36%) were classified as having undifferentiated arthropathy (UA). Controls were racially matched healthy individuals (n = 244).
  
  
  RESULTS
  Shared epitope (SE) alleles were significantly more common in rheumatoid factor-positive (RF+) patients fulfilling the ACR RA criteria than in other patients with early arthritis (65% versus 35%; P < 0.001). In addition, the RA patients had by far the highest frequency of radiographic erosions (52% and 39% in RF+ and RF- RA, respectively, versus 3% and 9% in SpA and UA patients, respectively; P < 0.0001). The presence of SE alleles was a particularly strong predictor of early erosions in the RF- RA patients (odds ratio [OR] 6.8, 95% confidence interval [95% CI] 1.2-45). The presence of 2 SE alleles or an associated DQbeta1*0301 (DQ7) or DQbeta1*0302 (DQ8) allele appeared to modestly increase the risk of early erosions, although these DQ alleles were in strong linkage disequilibrium with DRbeta1*0401, both in the patient and in the control populations. B27 was linked with the presence of SE alleles in the patients, including those patients fulfilling the RA criteria, but not in the controls (12% versus 3%; P < 0.001). Enthesitis was present in 23 (11%) of 211 patients, was highly associated with B27 (OR 4.2, 95% CI 1.5-11.5), and surprisingly, was not a feature specific only to the SpA group. The B8-DR3 haplotype was significantly increased in the patient subgroups compared with controls (17% versus 7%; P < 0.01), although the clinical significance of this association is unclear.
  
  
  CONCLUSIONS
  This study of HLA associations in a diverse cohort of early synovitis patients emphasizes the complex degree of genetic interaction between alleles at several major histocompatibility complex loci, which regulates clinical phenotypes. In particular, SE and B27, while predisposing patients to characteristic clinical syndromes, had an unexpected degree of association in this cohort, perhaps explaining the overlap in clinical features in many patients.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: El-Gabalawy
authors.forename: R
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: D
authors.initials: D
authors.lastname: Smith
authors.forename: T
authors.initials: T
authors.lastname: Arayssi
authors.forename: S
authors.initials: S
authors.lastname: Bale
authors.forename: P
authors.initials: P
authors.lastname: Gulko
authors.forename: C
authors.initials: C
authors.lastname: Yarboro
authors.forename: R L
authors.initials: RL
authors.lastname: Wilder
authors.forename: J H
authors.initials: JH
authors.lastname: Klippel
authors.forename: H R
authors.initials: HR
authors.lastname: Schumacher
mesh_terms: D000328:Adult; D000483:Alleles; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy; D015331:Cohort Studies; D005260:Female; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D012217:Rheumatoid Factor / Q000097:blood; D013585:Synovitis / Q000235:genetics* / Q000276:immunology*
chemical_list: D018501:Antirheumatic Agents; D006680:HLA Antigens; D012217:Rheumatoid Factor