title: Autoantibodies against Endothelin 1 Type A Receptor Are Strong Predictors of Digital Ulcers in Systemic Sclerosis.
abstract: OBJECTIVE
  To determine the predictive value of functional autoantibodies against vascular receptors for the development of ischemic digital ulcers (DU) in patients with systemic sclerosis (SSc).
  
  
  METHODS
  Angiotensin II Type 1 receptor (AT1R) and endothelin 1 Type A receptor (ETAR) autoantibodies were measured at baseline in a prospective cohort of 90 patients with SSc together with 5 validated angiogenic markers. The primary outcome was the occurrence of at least 1 new ischemic DU during the 5-year followup.
  
  
  RESULTS
  Twenty-four patients developed at least 1 new DU during the followup period. Univariate Cox analysis revealed that concentrations above the median value of anti-AT1R and anti-ETAR antibodies were predictive of the occurrence of ischemic DU (HR 2.85, 95% CI 1.19-6.84 and HR 3.39, 95% CI 1.35-8.50, respectively). A first multivariate Cox analysis including functional autoantibodies and clinical predictors of new DU confirmed anti-ETAR autoantibodies as independent predictors of the occurrence of new ischemic DU (HR 3.15, 95% CI 1.22-8.13) together with a history of DU at baseline. In a second model implemented with angiogenic markers, anti-ETAR autoantibodies remained an independent predictor of the occurrence of new ischemic DU (HR 9.59, 95% CI 1.75-52.64) together with the presence at baseline of active DU or history of DU.
  
  
  CONCLUSIONS
  Anti-ETAR autoantibodies can be used together with the presence of current or past DU to identify patients with SSc who are at risk for the development of subsequent DU. These autoantibodies may allow for earlier management and therapeutic intervention.
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute. jerome.avouac@cch.aphp.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Riemekasten
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meune
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute.
authors.forename: André
authors.initials: A
authors.lastname: Kahan
authors.affiliation: From the Paris Descartes University, Sorbonne Paris Cité, Rheumatology A Department, Cochin Hospital; Paris Descartes University, Institut National de la Santé Et de la Recherche Médicale, Unité 1016 (INSERM U1016), and Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104 (CNRS UMR8104), Cochin Institute; Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, Bobigny, France and Unité Mixte de Recherche 942 (UMR 942), Paris, France; Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine, Berlin, Germany.J. Avouac, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; G. Riemekasten, MD, PhD, Department of Rheumatology, Clinical Immunology, and German Rheumatism Research Centre, a Leibniz institute, Charité-University Medicine; C. Meune, MD, PhD, Paris 13 University, University Hospital of Paris-Seine-Saint-Denis, Cardiology Department, and UMR 942; B. Ruiz, Assistant Ingenior, Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute; A. Kahan, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital; Y. Allanore, MD, PhD, Paris Descartes University, Sorbonne Paris Cité, Rheumatology A department, Cochin Hospital, and Paris Descartes University, INSERM U1016, and CNRS UMR8104, Cochin Institute.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D017677:Age Distribution; D000368:Aged; D000704:Analysis of Variance; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005385:Fingers / Q000098:blood supply*; D005602:France; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D044022:Receptor, Endothelin A / Q000276:immunology / Q000378:metabolism*; D018570:Risk Assessment; D012595:Scleroderma, Systemic / Q000097:blood / Q000453:epidemiology* / Q000276:immunology*; D012720:Severity of Illness Index; D017678:Sex Distribution; D012883:Skin Ulcer / Q000097:blood / Q000453:epidemiology* / Q000503:physiopathology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D044022:Receptor, Endothelin A
keywords: AUTOANTIBODIES; BIOMARKER; DIGITAL ULCERS; SYSTEMIC SCLEROSIS