Occurrence of Infusion Associated Reactions and Antidrug Antibodies in Enzyme Replacement Therapy for Fabry Disease and the Effect of Preventive Measures.

Male patients with the classical phenotype of Fabry disease (FD) are at risk of developing inhibiting antidrug antibodies (iADAs) against recombinant α-galactosidase-A, administered in the form of enzyme replacement therapy (ERT). The presence of ADAs is linked to infusion-associated reactions (IARs) and reduced ERT effectiveness. This study evaluates the incidence of iADAs and IARs in ERT treated classical male FD patients, their interrelatedness and the effect of an adjusted ERT initiation protocol, aimed at inducing immune tolerance. In this monocenter cohort study, a retrospective analysis was performed to evaluate the occurrence of iADAs and IARs. Prospectively, a stepwise dose escalation ERT initiation protocol was evaluated in classical male FD patients with a calculated high risk of iADA formation and compared to the standard initiation protocol. Retrospectively (n = 52), the proportion of patients experiencing IARs was higher in patients that developed iADAs (20/27 seropositive patients, 0/19 seronegative, p < 0.001). Higher iADA titers were associated with persisting iADA titers (p = 0.004). Prospectively (n = 17), none of the patients in the intervention group (stepwise dose escalation) experienced IARs (0/8), compared to half of the patients in the control group (5/9, p = 0.029). The proportion of patients developing iADAs was not different between the two groups (respectively, 4/8 and 6/9, p = 0.52). To conclude, iADA development is associated with the occurrence of IARs. The stepwise dose escalation at ERT initiation used in the current study in a single cohort seems to prevent IARs in male patients with classical FD, but does not seem to prevent iADA development.