Impact of Anti-drug Antibodies in Patients with Fabry Disease under Enzyme Replacement Therapy: Long-Term Outcomes

Neutralizing anti-drug antibodies (ADAs) against enzyme replacement therapy (ERT) in Fabry disease (FD) are associated with disease progression despite therapy in affected male patients. The aim of this study was to assess the long-term effects of ADAs on clinical outcomes. We analyzed the long-term outcomes of ADA-positive ( n = 24) and ADA-negative ( n = 28) male patients under agalsidase alfa or beta. The assessment included Fabry-associated clinical events (FACEs), determination of cardiac and renal function, evaluation of FD-related symptoms, and the analysis of plasma globotriaosylsphingosine (lyso-Gb 3 ) values. Median observation time was 10 years. ADA-positive and ADA-negative patients presented with comparable disease burden at baseline. Although there were no significant differences in the overall event rate of FACEs ( p = 0.114), ADA-positive patients had an increased risk of ischemic cardiac events, an increase in interventricular septum thickness in diastole (median difference 0.25 mm per year; 95% confidence interval [CI] 0.06–0.42; p = 0.0053), and a steeper decline in estimated glomerular filtration rate (eGFR) (median difference −0.39 ml/min/1.73 m 2 per year; 95% CI −2.40 to 0.25; p = 0.0554). Macroalbuminuria and high-risk patients according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines at baseline resulted in an accelerated yearly eGFR decline of −6.5 in ADA-positive patients ( p < 0.001) versus −2.1 ml/min/1.73 m 2 in ADA-negative patients ( p = 0.0177; comparison: p = 0.0079). The lyso-Gb 3 decrease was more pronounced in ADA-negative patients ( p = 0.0407). Compared to ADA-negative patients, ADA-positive male patients with FD show significantly worse clinical long-term outcomes under ERT. They should be classified as high-risk patients, undergo close monitoring, and receive intensive treatment. Immune tolerance induction to prevent ADAs might be considered to improve the therapeutic efficacy in future.