Abstract
Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.
Highlights
Fabry disease (FD; OMIM 301500) is a rare, X-linked, lysosomal storage disease caused by mutations in the alpha-galactosidase A (GLA) gene
The negative effect of inhibiting anti-drug antibodies (iADAs) on disease outcome was confirmed in classical male patients, as iADA positive patients had an accelerated renal decline compared to iADA negative patients [6]
Our large international Fabry cohort study identified the following variables to be associated with an increased risk of iADA development in male patients with classical FD: (1) having a nonsense or frameshift mutation. (2) starting treatment with agalsidase beta and (3) higher levels of the disease biomarker in plasma before start of treatment
Summary
Fabry disease (FD; OMIM 301500) is a rare, X-linked, lysosomal storage disease caused by mutations in the alpha-galactosidase A (GLA) gene. These included: the dose and frequency of administration [21], the origin and glycosylation of the product (e.g., in which cell line is the product produced) [22,23], the age of the recipient [21,24], mutation type (nonsense vs missense) [25] and the presence of residual native protein in the patient, referred to as cross- reactive immunologic material (CRIM) status [15,25] These factors may play a role in iADA formation in Fabry disease as well.
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