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. 2017 Aug 1;12(8):e0182379.
doi: 10.1371/journal.pone.0182379. eCollection 2017.

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors

Maarten Arends  1 , Marieke Biegstraaten  1 , Derralynn A Hughes  2 , Atul Mehta  2 , Perry M Elliott  3 , Daniel Oder  4 , Oliver T Watkinson  3 , Frédéric M Vaz  5 , André B P van Kuilenburg  5 , Christoph Wanner  4 , Carla E M Hollak  1
Affiliations

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors

Maarten Arends et al. PLoS One. .

Abstract

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR <90 ml/min/1.73m2 to 4 at eGFR <30, compared to patients with an eGFR >90. In addition, men with classical disease and a baseline eGFR <60 ml/min/1.73m2 had a faster yearly decline (-2.0 ml/min/1.73m2) than those with a baseline eGFR of >60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

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Conflict of interest statement

Competing Interests: MA, OW, FV and AK have no competing interests to declare. CW has received honoraria for lecturing from Sanofi Genzyme (Cambridge, MA, United States) and a grant to the institution from Sanofi Genzyme and Shire (Dublin, Ireland). AM has received honoraria for consultancies and educational activities as well as research support from Shire, Sanofi Genzyme, Protalix/Pfizer (New York City, NY, United States), and Amicus. DO has received speakers honoraria from Sanofi Genzyme and travel assistance from Sanofi Genzyme and Shire. PE has received speaker fees from Shire and consultancy and speaker fees from Sanofi Genzyme, Pfizer and Gilead Sciences (Foster City, CA). DH has received honoraria for speaking and participating in advisory boards and support for research from Shire, Sanofi Genzyme, Amicus (Cranbury, NJ, United States), and Protalix (Carmiel, Israel). Also, DH has a consultancy arrangement through UCL Consultants (London, United Kingdom) to support, in part, laboratory research. MB and CH have in the past received travel support and educational/research grants from Sanofi Genzyme and Shire, in accordance with the Research Code of the Academic Medical Center. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Event free survival all patients treated with ERT combined.
Shaded areas represent the 95% CI. Crosses indicate censoring.
Fig 2
Fig 2. LysoGb3 in classical men.
LysoGb3 concentrations in nmol/l per individual patient.
Fig 3
Fig 3. Hazard ratios for different cut off points of eGFR at baseline.
Hazard ratios compared to a baseline eGFR of >90 ml/min/1.73m2, adjusted for age, sex and phenotype.
See this image and copyright information in PMC

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