Clinical ResearchSerum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry DiseaseLenders, Malte*; Stypmann, Jörg†; Duning, Thomas‡; Schmitz, Boris§; Brand, Stefan-Martin§; Brand, Eva* Author Information *Department of Nephrology, Hypertension, and Rheumatology, Internal Medicine D, University Hospital Muenster, Muenster, Germany; †Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Muenster, Muenster, Germany; ‡Department of Neurology, University Hospital Muenster, Muenster, Germany; and §Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany Correspondence: Prof. Eva Brand, University Hospital Muenster, Internal Medicine D, Nephrology, Hypertension, and Rheumatology, Albert-Schweitzer-Campus 1, D-48149 Muenster, Germany. Email: [email protected] Received December 16, 2014 Accepted March 11, 2015 Journal of the American Society of Nephrology 27(1):p 256-264, January 2016. | DOI: 10.1681/ASN.2014121226 Buy Metrics Abstract 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 m2; 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. Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.