title: Interpretation of an Extended Autoantibody Profile in a Well-Characterized Australian Systemic Sclerosis (Scleroderma) Cohort Using Principal Components Analysis.
abstract: OBJECTIVE
  To determine the relationships between systemic sclerosis (SSc)-related autoantibodies, as well as their clinical associations, in a well-characterized Australian patient cohort.
  
  
  METHODS
  Serum from 505 Australian SSc patients were analyzed with a commercial line immunoassay (EuroLine; Euroimmun) for autoantibodies to centromere proteins CENP-A and CENP-B, RNA polymerase III (RNAP III; epitopes 11 and 155), the 90-kd nucleolar protein NOR-90, fibrillarin, Th/To, PM/Scl-75, PM/Scl-100, Ku, topoisomerase I (topo I), tripartite motif-containing protein 21/Ro 52, and platelet-derived growth factor receptor. Patient subgroups were identified by hierarchical clustering of the first 2 dimensions of a principal components analysis of quantitative autoantibody scores. Results were compared with detailed clinical data.
  
  
  RESULTS
  A total of 449 of the 505 patients were positive for at least 1 autoantibody by immunoblotting. Heatmap visualization of autoantibody scores, along with principal components analysis clustering, demonstrated strong, mutually exclusive relationships between CENP, RNAP III, and topo I. Five patient clusters were identified: CENP, RNAP III strong, RNAP III weak, topo I, and other. Clinical features associated with CENP, RNAP III, and topo I were consistent with previously published reports concerning limited cutaneous and diffuse cutaneous SSc. A novel finding was the statistical separation of RNAP III into 2 clusters. Patients in the RNAP III strong cluster had an increased risk of gastric antral vascular ectasia, but a lower risk of esophageal dysmotility. Patients in the other cluster were more likely to be male and to have a history of smoking and a history of malignancy, but were less likely to have telangiectasia, Raynaud's phenomenon, and joint contractures.
  
  
  CONCLUSIONS
  Five major autoantibody clusters with specific clinical and serologic associations were identified in Australian SSc patients. Subclassification and disease stratification using autoantibodies may have clinical utility, particularly in early disease.
authors.affiliation: Flinders University, Bedford Park, South Australia, and Commonwealth Scientific and Industrial Research Organization (CSIRO), Adelaide, South Australia, Australia.
authors.forename: K A
authors.initials: KA
authors.lastname: Patterson
authors.affiliation: Flinders University and Flinders Medical Centre, Bedford Park, South Australia, and SA Pathology, Adelaide, South Australia, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Roberts-Thomson
authors.affiliation: Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Lester
authors.affiliation: Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Tan
authors.affiliation: Flinders Medical Centre, Bedford Park, South Australia, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Hakendorf
authors.affiliation: University of Adelaide, Adelaide, South Australia, and Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Rischmueller
authors.affiliation: Menzies Institute for Medical Research, Hobart, Tasmania, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Zochling
authors.affiliation: Monash Health and Monash University, Melbourne, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Sahhar
authors.affiliation: University of Queensland, Brisbane, Queensland, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Nash
authors.affiliation: Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Roddy
authors.affiliation: University of Adelaide, Adelaide, South Australia, and Queen Elizabeth Hospital, Woodville, South Australia, Australia.
authors.forename: C
authors.initials: C
authors.lastname: Hill
authors.affiliation: University of Melbourne and St. Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Nikpour
authors.affiliation: St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: W
authors.initials: W
authors.lastname: Stevens
authors.affiliation: University of Adelaide and Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: S M
authors.initials: SM
authors.lastname: Proudman
authors.affiliation: Flinders University and Flinders Medical Centre, Bedford Park, South Australia, and Repatriation General Hospital, Daw Park, South Australia, Australia.
authors.forename: J G
authors.initials: JG
authors.lastname: Walker
mesh_terms: D000368:Aged; D034961:Antigens, Nuclear / Q000276:immunology; D001315:Australia; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D000076247:Centromere Protein A; D051936:Centromere Protein B / Q000276:immunology; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology; D015331:Cohort Studies; D003286:Contracture / Q000209:etiology / Q000276:immunology; D004264:DNA Topoisomerases, Type I / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D015154:Esophageal Motility Disorders / Q000209:etiology / Q000276:immunology; D005095:Exoribonucleases / Q000276:immunology; D063326:Exosome Multienzyme Ribonuclease Complex / Q000276:immunology; D005260:Female; D020252:Gastric Antral Vascular Ectasia / Q000209:etiology / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000453:epidemiology; D035463:Pol1 Transcription Initiation Complex Proteins / Q000276:immunology; D025341:Principal Component Analysis; D012320:RNA Polymerase III / Q000276:immunology; D016601:RNA-Binding Proteins / Q000276:immunology; D011928:Raynaud Disease / Q000209:etiology / Q000276:immunology; D017479:Receptors, Platelet-Derived Growth Factor / Q000276:immunology; D012261:Ribonucleoproteins / Q000276:immunology; D012595:Scleroderma, Systemic / Q000150:complications / Q000453:epidemiology / Q000276:immunology*; D012737:Sex Factors; D012907:Smoking / Q000453:epidemiology; D013684:Telangiectasis / Q000209:etiology / Q000276:immunology; D000099207:SS-A Antigen
chemical_list: D034961:Antigens, Nuclear; D001323:Autoantibodies; D001324:Autoantigens; D000076247:Centromere Protein A; D051936:Centromere Protein B; D002868:Chromosomal Proteins, Non-Histone; D004264:DNA Topoisomerases, Type I; D004268:DNA-Binding Proteins; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; D000072200:Ku Autoantigen; D035463:Pol1 Transcription Initiation Complex Proteins; D012320:RNA Polymerase III; D016601:RNA-Binding Proteins; D017479:Receptors, Platelet-Derived Growth Factor; D012261:Ribonucleoproteins; D000099207:SS-A Antigen; C000619700:CENPA protein, human; C497926:CENPB protein, human; C571398:EXOSC9 protein, human; C047458:fibrillarin; C063844:transcription factor UBF; C077044:EXOSC10 protein, human; C000606509:Xrcc6 protein, human