title: Role of class II human leucocyte antigens in the progression from early to definite systemic sclerosis.
abstract: OBJECTIVE
  HLAs have been extensively associated with SSc susceptibility but their role in the progression of the disease is poorly understood. In 2013 the ACR and European League Against Rheumatism (EULAR) jointly defined criteria for the classification of SSc that allow the early identification of definite SSc patients. In this study we investigated the role of HLA class II antigens in the progression from early to definite SSc.
  
  
  METHODS
  One hundred and fifty-eight subjects with early SSc according to LeRoy and Medsger criteria and no other manifestation indicative of definite SSc at referral were considered. All the patients underwent high-resolution HLA class II typing and the appraisal of definite SSc was retrospectively conducted in a prospective manner. Lifetime analysis was conducted to gauge the effect of genetic and clinical characteristics on progression of the disease.
  
  
  RESULTS
  The median estimated time to progression was 45 months from referral; the 5 and 10 year estimates of progression were 59.8% and 80%, respectively. ACAs were associated with a reduced risk of progression [median survival 55 vs 23 months for ACA-positive vs ACA-negative patients, P = 0.035; hazard ratio (HR) 0.67 (95% CI 0.458, 0.979)]. HLA alleles within the HLA DQ5-DR1 haplotype [HLA-DRB1*0101-HLA-DQA1*0101(4)-HLA-DQB1*0501] reduced the risk of progression of the disease [median survival 108 vs 44 months for DQ5-DR1 carriers vs DQ5-DR1 non-carriers; HR 0.388 (CI 0.211, 0.712), P = 0.001, corrected P = 0.014]. In multivariate models, the effect of genetics was found to be independent of ACA positivity or other baseline factors; additive risks were observed when the DQ5-DR1 haplotype and ACA were jointly considered.
  
  
  CONCLUSIONS
  HLA class II alleles within the HLA DQ5-DR1 haplotype are associated with lower rates of progression from early to definite SSc.
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Vigone
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Santaniello
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Marchini
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Montanelli
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Caronni
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Severino
authors.affiliation: Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. lorberimm@hotmail.com.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beretta
mesh_terms: D000328:Adult; D000483:Alleles; D018450:Disease Progression; D005260:Female; D006681:HLA-D Antigens / Q000235:genetics* / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology; D059848:HLA-DQ alpha-Chains / Q000235:genetics / Q000276:immunology; D059866:HLA-DQ beta-Chains / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000276:immunology
chemical_list: D006681:HLA-D Antigens; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C410042:HLA-DQ5 antigen; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II
keywords: classification criteria; human leucocyte antigens; systemic sclerosis