title: Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome.
abstract: BACKGROUND
  Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT.
  
  
  METHODS
  Adult male and female patients on ERT for at least one year were included. Urinary Gb3 was measured by HPLC, plasma lysoGb3 by LC-ESI-MS/MS and AB with a neutralization assay.
  
  
  RESULTS
  Of the 59 patients evaluable patients, 0/30 females and 17/29 males developed anti-agalsidase antibodies (AB+). Only 3/17 males had transient (low) titers (tolerized). All AB+ patients developed antibodies during the first year of treatment. Change of agalsidase preparation (or dose) did not induce antibody formation. AB+ males had significant less decline in plasma lysoGb3 compared to AB- males (p = 0.04). Urinary Gb3 levels decreased markedly in AB- but remained comparable to baseline in AB+ males (p<0.01). (Lyso)Gb3 reduction in plasma and urine on ERT was correlated with LVmass reduction in females and development white matter lesions and stroke.
  
  
  CONCLUSIONS
  In male patients antibodies against aGal A remained present up to 10 years of ERT. The presence of these antibodies is associated with a less robust decrease in plasma lysoGb3 and a profound negative effect on urinary Gb3 reduction, which may reflect worse treatment outcome.
authors.affiliation: Department of Endocrinology and Metabolism, Division of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Rombach
authors.forename: Johannes M F G
authors.initials: JM
authors.lastname: Aerts
authors.forename: Ben J H M
authors.initials: BJ
authors.lastname: Poorthuis
authors.forename: Johanna E M
authors.initials: JE
authors.lastname: Groener
authors.forename: Wilma
authors.initials: W
authors.lastname: Donker-Koopman
authors.forename: Erik
authors.initials: E
authors.lastname: Hendriks
authors.forename: Mina
authors.initials: M
authors.lastname: Mirzaian
authors.forename: Sijmen
authors.initials: S
authors.lastname: Kuiper
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.forename: Gabor E
authors.initials: GE
authors.lastname: Linthorst
mesh_terms: D000328:Adult; D000906:Antibodies / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000097:blood / Q000188:drug therapy* / Q000276:immunology* / Q000652:urine; D005260:Female; D005915:Globosides / Q000652:urine*; D006017:Glycolipids / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009500:Neutralization Tests; D021241:Spectrometry, Mass, Electrospray Ionization; D013107:Sphingolipids / Q000097:blood*; D053719:Tandem Mass Spectrometry; D013995:Time; D016896:Treatment Outcome; D014281:Trihexosylceramides / Q000652:urine*; D000519:alpha-Galactosidase / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000906:Antibodies; D005915:Globosides; D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C514780:globotrihexosylceramide; C063288:globotriaosyl lysosphingolipid; D000519:alpha-Galactosidase