Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study
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To determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease.
Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data.
Consenting adults (N = 289) and children (N = 22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2 years respectively).
Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke.
We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p = 0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p < 0.001) and a small increase in eGFR in men and women without pre-treatment proteinuria (p = 0.01 and p < 0.001 respectively). The same analyses in children provided no statistically significant results. No associations between time on ERT and pain, risk of needing a hearing aid, or risk of stroke or TIAs, were found.
These data provide some further evidence on the long-term effectiveness of ERT in adults with Fabry disease, but evidence of effectiveness could not be demonstrated in children.
KeywordsProteinuria Enzyme Replacement Therapy Fabry Disease Leave Ventricular Mass Index Transient Ischaemic Attack
We thank study site personnel Marie Meehan, Andrea Hill, Debbie Hugh, Sarah West, Sandhya Maddukuri, Kate Blackler, Hannah Russon, Navneeta Reddy, Jennifer Hutchinson, Nike Aina and Noura Hamdi for their hard work in the recruitment of patients to this study, and in managing the patients’ data at each of the seven sites. We thank the late Ed Wraith, Robin Lachmann, Atul Mehta, Ashok Vellodi, Patrick Deegan, Tim Cox, Chris Hendriksz, Philip Lee, Uma Ramaswami, Simon Jones and Tanya Collin-Histed for their contribution to the design and conduct of the study. Thanks to Rob Anderson for his contribution to the design of the study and data collection forms, to Sheena Oxer and Louise Klinger for their contribution to the set-up and coordination of the study, and to Laura Cocking for her help in the design and the management of the databases throughout the study.
We are grateful to all members of the LSD patient support groups and the Trial Steering Committee. Finally, special thanks to the patients and their families who allowed us to collect information from their hospital records and gave their time to complete the questionnaires. We thank them for their invaluable contribution.
Compliance with ethics guidelines
Conflicts of interest
Lindsey Anderson, Katrina Wyatt, William Henley, Vasilis Nikolaou and Stuart Logan declare that they have no conflicts of interest.
Stephen Waldek is a member of the Fabry Registry Board and the Fabry Expert Group and has received funding for research, and honoraria for lectures and consultancy on research studies from Shire HGT and Genzyme. He has also received research grants from Biomarin, Synageva and Amicus.
Derralynn Hughes has received funding for research and travel to meetings, honoraria for lectures and consultancy projects or advisory boards from Shire HGT, Genzyme, Amicus, Actelion, and Biomarin. Consultancy and advisory board work is administered via UCL business and used in part to fund research.
Gregory M. Pastores has received funding for research and travel to meetings, honoraria for lectures and consultancy projects or advisory boards from Shire HGT, Genzyme, Amicus, Actelion, and Biomarin.
All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients before being included in the study.
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