title: High rate of spontaneous inhibitor clearance during the long term observation study of a single cohort of 524 haemophilia A patients not undergoing immunotolerance.
abstract: BACKGROUND
  The natural history of inhibitors in patients with haemophilia A not undergoing immune tolerance induction (ITI) is largely unknown. A recent randomized controlled trial suggests that the higher the FVIII dose used for ITI, the faster the clearance and the lower the rate of bleeding, without any difference in the rate of tolerance. We aimed at assessing the rate of spontaneous inhibitor clearance in a large cohort of patients not undergoing ITI.
  
  
  METHODS
  A retrospective analysis of anti-FVIII inhibitors of long-term registry data in a single centre cohort of 524 haemophilia A patients considered for synovectomy was performed. Patients were tested for inhibitors before and 15 days after any and each surgical episode and thereafter did not undergo immune tolerance at any time.
  
  
  RESULTS
  The cumulative incidence of inhibitors overall was 34% (180 out of 524) with the highest percentage of 39% (168 out of 434) in severe patients which represented 83% of the cohort. Among the 180 inhibitor patients: 63 had permanent inhibitors; 70 fulfilled current criteria for transient inhibitors but a third category of 47 additional patients cleared the alloantibody spontaneously in >6 months. At logistic regression, both the inhibitor titre and the gene mutation were shown to predict time to clearance.
  
  
  CONCLUSIONS
  Spontaneous clearance of inhibitors over variable time in the absence of ITI treatment was found in up to 2/3 of the cases.
authors.affiliation: Transfusion Service, Hemophilia and Regional Blood Disease Centre, Castelfranco Veneto Hospital, ULSS 8 Regione Veneto, Treviso, Italy. giuseppe.tagariello@ulssasolo.ven.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tagariello
authors.forename: Alfonso
authors.initials: A
authors.lastname: Iorio
authors.forename: Davide
authors.initials: D
authors.lastname: Matino
authors.forename: Donata
authors.initials: D
authors.lastname: Belvini
authors.forename: Roberta
authors.initials: R
authors.lastname: Salviato
authors.forename: Roberto
authors.initials: R
authors.lastname: Sartori
authors.forename: Paolo
authors.initials: P
authors.lastname: Radossi
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: C078147:F8 protein, human; D005169:Factor VIII