title: Anti-A2 and anti-A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A.
abstract: BACKGROUND
  Hemophilia A (HA) is a congenital bleeding disorder resulting from factor VIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision.
  
  
  OBJECTIVE
  To identify predictive markers of ITI efficacy.
  
  
  METHODS
  The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n = 7] and ITI failure [n = 8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis).
  
  
  RESULTS
  Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P < 0.018). ROC analysis showed that anti-A1 and anti-A2 Abs were the best at discriminating between outcome groups (area under the ROC curve of > 0.875).
  
  
  CONCLUSIONS
  Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA.
authors.affiliation: UMR3145 CNRS/BioRad, SysDiag, Montpellier, France.
authors.forename: P
authors.initials: P
authors.lastname: Lapalud
authors.forename: C
authors.initials: C
authors.lastname: Rothschild
authors.forename: E
authors.initials: E
authors.lastname: Mathieu-Dupas
authors.forename: J
authors.initials: J
authors.lastname: Balicchi
authors.forename: Y
authors.initials: Y
authors.lastname: Gruel
authors.forename: D
authors.initials: D
authors.lastname: Laune
authors.forename: F
authors.initials: F
authors.lastname: Molina
authors.forename: J F
authors.initials: JF
authors.lastname: Schved
authors.forename: C
authors.initials: C
authors.lastname: Granier
authors.forename: G
authors.initials: G
authors.lastname: Lavigne-Lissalde
mesh_terms: D019540:Area Under Curve; D001323:Autoantibodies / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003029:Coagulants / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D000939:Epitopes; D005169:Factor VIII / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use*; D005602:France; D006467:Hemophilia A / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood*; D007167:Immunotherapy / Q000379:methods*; D007223:Infant; D011237:Predictive Value of Tests; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D003029:Coagulants; D000939:Epitopes; D007074:Immunoglobulin G; C078147:F8 protein, human; D005169:Factor VIII
keywords: blood coagulation factor inhibitors; factor VIII; fluoroimmunoassay; hemophilia A; immune tolerance