Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease.
Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-α or -β). Agalsidase inhibition was associated with higher lyso-globotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m(2); P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.
Department of Nephrology, Hypertension, and Rheumatology, Internal Medicine D, University Hospital Muenster, Muenster, Germany;
Malte
M
Lenders
Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Muenster, Muenster, Germany;
Jörg
J
Stypmann
Department of Neurology, University Hospital Muenster, Muenster, Germany; and.
Thomas
T
Duning
Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany.
Boris
B
Schmitz
Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany.
Stefan-Martin
SM
Brand
Department of Nephrology, Hypertension, and Rheumatology, Internal Medicine D, University Hospital Muenster, Muenster, Germany; Eva.Brand@ukmuenster.de.
Eva
E
Brand
D000328:Adult; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D017211:Treatment Failure; D000519:alpha-Galactosidase / Q000627:therapeutic use*
D000519:alpha-Galactosidase
Fabry disease; enzyme; glomerular filtration rate; left ventricular mass; replacement therapy