Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

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 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.

Keywords: Fabry disease; enzyme; glomerular filtration rate; left ventricular mass; replacement therapy.

Figure 1.

Measurements of serum-mediated ERT inhibition in Fabry patients. ERT inhibition in (A) men, (B) women, and (C) identification of ERT inhibition positive male patients with FD. The dotted line represents the cut-off value of 50% mean ERT inhibition. Error bars represent SEM. Values represent mean±SD. NS, not significant; ***P<0.001.

Figure 2.

Association of serum-mediated ERT inhibition with clinical parameters. ERT inhibition is associated with (A) increasing lyso-Gb3 levels, (B) increasing MSSI values, and (C) increasing creatinine values in men with FD under ERT.

Figure 3.

Forest plot of increased risks of ERTⁱ⁺ compared with ERT^i– men with FD.

Figure 4.

Longitudinal 5-year retrospective analysis of ERT inhibition negative (ERT^i–) and positive (ERTⁱ⁺) men. Filled circles represent ERT^i– patients, empty circles represent ERTⁱ⁺ patients.