TY  - JOUR
A1  - van der Veen, Sanne J.
A1  - Vlietstra, Wytze J.
A1  - van Dussen, Laura
A1  - van Kuilenburg, André B.P.
A1  - Dijkgraaf, Marcel G. W.
A1  - Lenders, Malte
A1  - Brand, Eva
A1  - Wanner, Christoph
A1  - Hughes, Derralynn
A1  - Elliott, Perry M.
A1  - Hollak, Carla E. M.
A1  - Langeveld, Mirjam
T1  - Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - Fabry disease
KW  - enzyme replacement therapy
KW  - anti-drug antibodies
KW  - prediction model
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285687
SN  - 1422-0067
VL  - 21
IS  - 16
ER  - 
TY  - JOUR
A1  - Lenders, Malte
A1  - Hennermann, Julia B.
A1  - Kurschat, Christine
A1  - Rolfs, Arndt
A1  - Canaan-Kühl, Sima
A1  - Sommer, Claudia
A1  - Üçeyler, Nurcan
A1  - Kampmann, Christoph
A1  - Karabul, Nesrin
A1  - Giese, Anne-Katrin
A1  - Duning, Thomas
A1  - Stypmann, Jörg
A1  - Krämer, Johannes
A1  - Weidemann, Frank
A1  - Brand, Stefan-Martin
A1  - Wanner, Christoph
A1  - Brand, Eva
T1  - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease
JF  - Orphanet Journal of Rare Diseases
N2  - Background
The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines.

Methods
Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed.

Results
Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels.

Conclusion
The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.
KW  - Fabry disease
KW  - females
KW  - lyso-Gb3
KW  - enzyme replacement therapy
KW  - guidelines
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543
VL  - 11
IS  - 88
ER  -