Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain

Saskia M Rombach, Bouwien E Smid, Machtelt G Bouwman, Gabor E Linthorst, Marcel G W Dijkgraaf, Carla E M Hollak, Saskia M Rombach, Bouwien E Smid, Machtelt G Bouwman, Gabor E Linthorst, Marcel G W Dijkgraaf, Carla E M Hollak

Abstract

Background: Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.

Methods: Renal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.

Results: Of 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively).

Conclusions: Long term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.

Trial registration: ClinicalTrials.gov NCT00701415.

Figures

Figure 1
Figure 1
Overview of ERT and non-ERT cohort. A. The flow-chart shows the patients in the ERT cohort for the prospective analysis of renal function, left ventricular mass and cerebral white matter lesions; B. the flow-chart demonstrates all patients with complete medical records and the cohorts used for the analysis of the age to the first complication.
Figure 2
Figure 2
Developing a first complication. The curves show the percentage without a first complication during follow-up. The small vertical lines represent censored data (follow-up till the vertical line without development of a complication). A. Age at time of the first complication is depicted for the NH cohort and the ERT cohort. B. The time to the first complication is shown based on the median ERT duration for the ERT cohort only: patients receiving ERT more than 4.2 years (13M/16F, age at start of ERT 40.1 (15.9-71.5) years) or less than 4.2 years (14M/15F, age at start of ERT 41.2 (15.2-60.5 years)). Of note, in the analysis ERT duration was included as a continuous variable.

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