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

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.

SUBMITTER: Arends M

PROVIDER: S-EPMC5538714 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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

Arends Maarten M Biegstraaten Marieke M Hughes Derralynn A DA Mehta Atul A Elliott Perry M PM Oder Daniel D Watkinson Oliver T OT Vaz Frédéric M FM van Kuilenburg André B P ABP Wanner Christoph C Hollak Carla E M CEM

PloS one 20170801 8

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 ...[more]

PMID: 28763515

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Project description:This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the effects of enzyme replacement therapy with human alpha-galactosidase A. The study population comprised 20 patients (11 males, 9 females) aged 15-69 years (mean 39.7). Patients underwent a complete clinical and instrumental evaluation before starting and during enzyme replacement therapy. Median follow-up was 51.5 months (range 25-73). Nine patients (45%) complained of hearing symptoms (hearing loss, tinnitus); for six of them the onset and/or progression of the hearing loss were sudden. Vertigo or dizziness was reported by 6 patients (30%). Audiological evaluation showed a sensorineural hearing loss in 18 ears (45%; 10 in male patients, 8 in females). The hearing thresholds for 0.5, 1, 2 and 4 kHz frequencies ranged from 10 to 65 dB HL. Hearing loss was unilateral in 8 cases (40%; 4 in male patients, 4 in females). Also high frequency hearing loss for 4 and 8 kHz was evaluated. No signs of retro-cochlear lesions were observed by means of otoacoustic emissions and auditory brainstem response. Vestibular examinations showed a functional impairment in 7 ears (17.5%, all male patients). During enzyme replacement therapy the auditory function showed some degrees of worsening but no significant changes were observed at statistical analysis. In conclusion involvement of the inner ear is common in men and women with Fabry disease. In this study, a high incidence of cochlear hearing loss was found, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement showed a lower incidence and different pattern, thus suggesting that several patho-physiological mechanisms could play a role in determining inner ear damage in Fabry disease. Results obtained show that enzyme replacement therapy may stabilize hearing function; however, further studies on the physiopathology of the inner ear damage are needed.

Project description:Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no treatment, patients treated with agalsidase alfa demonstrated slower decline in renal function and slower progression of left ventricular hypertrophy. Treated male patients with baseline eGFR < 60 mL/min/1.73 m(2) had a mean (standard error of the mean [SEM]) annualized change in eGFR of - 2.86 (0.53) mL/min/1.73 m(2)/y compared with - 6.8 (1.5) in the published untreated cohort. The mean (SEM) rate of LVMI increase with treatment was 0.33 (0.10) g/m(2.7)/y in males and 0.48 (0.09) in females, compared with 4.07 (1.03) in untreated males and 2.31 (0.81) in untreated females. Morbidity occurred later in treated patients, with ~ 16% risk of a composite morbidity event (26% in males) after 24 months with ERT versus ~ 45% without treatment, with first events and deaths also occurring at older ages in patients administered ERT (e.g., estimated median survival in treated males was 77.5 years versus 60 years in untreated males). Findings from these retrospective comparisons of observational data and published literature support the long-term benefits of ERT with agalsidase alfa for Fabry disease in slowing the progression of renal impairment and cardiomyopathy. Treatment also appeared to delay the onset of morbidity and mortality. Interpretation of these findings should take into account that they are based on retrospective comparisons with previously published data.

Dataset Information

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

Publications

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

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