title: Prevalence and epitope specificity of non-neutralising antibodies in a large cohort of haemophilia A patients without inhibitors.
abstract: Antibodies (inhibitors and non-neutralising antibodies [NNA]) directed against factor VIII (FVIII) remain the main iatrogenic complication in haemophilia A (HA) patients. Inhibitors reduce FVIII pro-coagulant properties, whereas NNA are directed against non-functional epitopes. NNA are poorly studied and their prevalence, epitope specificity and physiopathology inadequately defined. The aim of this study was first to evaluate NNA prevalence in a French retrospective multicentric series of 210 patients without inhibitors, then to determine their epitope specificity (against the heavy chain [HC] or the light chain [LC] of FVIII) and particularly to assess the prevalence of anti-B domain NNA using specifically designed x-MAP assays. NNA occurred in 18.1% of patients (38/210) and their prevalence was not influenced by the severity of the disease. Among the 38 patients with NNA, 73.7% had anti-FVIII Abs against the HC, 13.2% against the LC and 13.2% had anti-FVIII Abs against both chains. There is thus a clear immuno-dominance of the HC of FVIII in the epitope profile of NNA, whatever the severity of HA. The proportion of NNA that recognised the B domain was 18.4% (n=7/38). A multivariate analysis did not highlight differences in NNA occurrence between patients treated with recombinant FVIII or with plasma- derived FVIII (19.6% vs. 14.9%, p=0.53).
authors.affiliation: UMR 3145 SysDiag CNRS/Bio-Rad, 34184 Montpellier, France.
authors.forename: A
authors.initials: A
authors.lastname: Lebreton
authors.forename: P
authors.initials: P
authors.lastname: Lapalud
authors.forename: H
authors.initials: H
authors.lastname: Chambost
authors.forename: C
authors.initials: C
authors.lastname: Biron-Andréani
authors.forename: P-E
authors.initials: PE
authors.lastname: Morange
authors.forename: C
authors.initials: C
authors.lastname: Combescure
authors.forename: A
authors.initials: A
authors.lastname: Marquès-Verdier
authors.forename: C
authors.initials: C
authors.lastname: Berger
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: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D018604:Epitope Mapping; D000939:Epitopes / Q000378:metabolism*; D005169:Factor VIII / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005602:France; D006467:Hemophilia A / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism*; D007223:Infant; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D012189:Retrospective Studies
chemical_list: D000906:Antibodies; D000939:Epitopes; D016056:Immunodominant Epitopes; C078147:F8 protein, human; D005169:Factor VIII