Impact of immunosuppressive therapy on therapy‐neutralizing antibodies in transplanted patients with Fabry disease

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Inhibitory antibodies towards enzyme replacement therapy (<jats:styled-content style="fixed-case">ERT</jats:styled-content>) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (<jats:styled-content style="fixed-case">FD</jats:styled-content>). However, little is known about the impact of immunosuppressive therapy on <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition in these patients with <jats:styled-content style="fixed-case">FD</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In this retrospective study, we investigated the effect of long‐term immunosuppression on <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition in male patients with <jats:styled-content style="fixed-case">FD</jats:styled-content> (<jats:italic>n</jats:italic> = 26) receiving immunosuppressive therapy due to kidney (<jats:italic>n</jats:italic> = 24) or heart (<jats:italic>n</jats:italic> = 2) transplantation.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>No <jats:styled-content style="fixed-case">ERT</jats:styled-content>‐naïve transplanted patient (<jats:italic>n</jats:italic> = 8) developed antibodies within follow‐up (80 ±72 months) after <jats:styled-content style="fixed-case">ERT</jats:styled-content> initiation. Seven (26.9%) patients were tested <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition positive prior to transplantation. No <jats:italic>de novo </jats:italic><jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition was observed after transplantation (<jats:italic>n</jats:italic> = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate‐mofetil/mycophenolate acid, <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition decreased after transplantation (<jats:italic>n</jats:italic> = 12; <jats:italic>P</jats:italic> = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re‐increase <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition (<jats:italic>n</jats:italic> = 4, median [range]: 16.6 [6.9; 36.9] %; <jats:italic>P</jats:italic> = 0.0972) over time. One <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition‐positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent <jats:italic>de novo </jats:italic><jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition in <jats:styled-content style="fixed-case">ERT</jats:styled-content>‐naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition in affected patients, but did not result in long‐term protection. Future studies are needed to establish <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition‐specific immunosuppressive protocols with long‐term modulating properties to warrant an improved disease course in <jats:styled-content style="fixed-case">ERT</jats:styled-content> inhibition‐positive males.</jats:p></jats:sec>