M Lenders1, D Oder2, A Nowak3, S Canaan-Kühl4, L Arash-Kaps5, C Drechsler2, B Schmitz6, P Nordbeck2, J B Hennermann5, C Kampmann5, S Reuter1, S-M Brand6, C Wanner2, E Brand1. 1. Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Muenster, Germany. 2. Department of Internal Medicine I, Divisions of Cardiology and Nephrology, Comprehensive Heart Failure Center (CHFC), Fabry Center for Interdisciplinary Therapy (FAZIT), University of Wuerzburg, Wuerzburg, Germany. 3. Department of Internal Medicine, University Hospital of Zurich and University of Zurich, Zurich, Switzerland. 4. Department of Medicine, Division of Nephrology, Campus Virchow-Klinikum, University Hospital Charité, Berlin, Germany. 5. Villa Metabolica, Department for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany. 6. Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany.
Abstract
BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.
BACKGROUND: Inhibitory antibodies towards enzyme replacement therapy (ERT) are associated with disease progression and poor outcome in affected male patients with lysosomal disorders such as Fabry disease (FD). However, little is known about the impact of immunosuppressive therapy on ERT inhibition in these patients with FD. METHODS: In this retrospective study, we investigated the effect of long-term immunosuppression on ERT inhibition in male patients with FD (n = 26) receiving immunosuppressive therapy due to kidney (n = 24) or heart (n = 2) transplantation. RESULTS: No ERT-naïve transplanted patient (n = 8) developed antibodies within follow-up (80 ±72 months) after ERT initiation. Seven (26.9%) patients were tested ERT inhibition positive prior to transplantation. No de novo ERT inhibition was observed after transplantation (n = 18). In patients treated with high dosages of immunosuppressive medication such as prednisolone, tacrolimus and mycophenolate-mofetil/mycophenolate acid, ERT inhibition decreased after transplantation (n = 12; P = 0.0160). Tapering of immunosuppression (especially prednisolone) seemed to re-increase ERT inhibition (n = 4, median [range]: 16.6 [6.9; 36.9] %; P = 0.0972) over time. One ERT inhibition-positive patient required interventions with steroid therapy and increased doses of tacrolimus, which also lowered ERT inhibition. CONCLUSION: We conclude that the immunosuppressive maintenance therapy after transplantations seems to be sufficient to prevent de novo ERT inhibition in ERT-naïve patients. Intensified high dosages of immunosuppressive drugs are associated with decreased antibody titres and decreased ERT inhibition in affected patients, but did not result in long-term protection. Future studies are needed to establish ERT inhibition-specific immunosuppressive protocols with long-term modulating properties to warrant an improved disease course in ERT inhibition-positive males.
Authors: Malte Lenders; Leon Paul Neußer; Michael Rudnicki; Peter Nordbeck; Sima Canaan-Kühl; Albina Nowak; Markus Cybulla; Boris Schmitz; Jan Lukas; Christoph Wanner; Stefan-Martin Brand; Eva Brand Journal: J Am Soc Nephrol Date: 2018-11-01 Impact factor: 10.121
Authors: Aizeddin A Mhanni; Christiane Auray-Blais; Michel Boutin; Alie Johnston; Kaye LeMoine; Jill Patterson; Johannes M F G Aerts; Michael L West; Cheryl Rockman-Greenberg Journal: Mol Genet Metab Rep Date: 2020-06-24
Authors: Jonas Müntze; Daniel Gensler; Octavian Maniuc; Dan Liu; Tereza Cairns; Daniel Oder; Kai Hu; Kristina Lorenz; Stefan Frantz; Christoph Wanner; Peter Nordbeck Journal: Clin Pharmacol Ther Date: 2019-01-13 Impact factor: 6.875
Authors: Sanne J van der Veen; Wytze J Vlietstra; Laura van Dussen; André B P van Kuilenburg; Marcel G W Dijkgraaf; Malte Lenders; Eva Brand; Christoph Wanner; Derralynn Hughes; Perry M Elliott; Carla E M Hollak; Mirjam Langeveld Journal: Int J Mol Sci Date: 2020-08-12 Impact factor: 5.923