Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Objective

The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.

Methods

A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.

Results

During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients ( n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred ( n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min ⁻¹ per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain ( n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.

Conclusion

Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.

Related collections

Most cited references 19

Record: found
Abstract: found
Article: not found

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

R Schiffmann, J. B. Kopp, H Austin … (2001)

Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

0 comments Cited 218 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey.

P Elliott, A Linhart, R Giugliani … (2009)

Fabry disease is a rare X-linked lysosomal storage disorder characterised by severe multisystemic involvement that leads to major organ failure and premature death in affected men and women. Over the past 7 years, the Fabry Outcome Survey (FOS) has collected data on the natural history of Fabry disease, and the long-term efficacy and safety of enzyme-replacement therapy. This paper provides an update on the first analysis of FOS data. Baseline data on clinical manifestations and causes of death in a cohort of 1453 patients (699 male, 754 female) from 19 countries worldwide were analysed. Causes of death of affected relatives were analysed separately. The most frequently reported signs and symptoms of Fabry disease were neurological. Cardiac, ocular, gastrointestinal, dermatological, auditory and renal manifestations were also common. The principal causes of death among 181 affected relatives of patients in FOS (most of whom had died before 2001) were renal failure in males (42%) and cerebrovascular disease in females (25%). In contrast, of the 42 patients enrolled in FOS whose deaths were reported between 2001 and 2007, cardiac disease was the main cause of death in both male (34%) and female (57%) patients. These data suggest that the importance of renal disease as a cause of death in patients with Fabry disease is decreasing while the importance of cardiac disease is increasing. This pattern probably reflects improvements in the management of renal disease in patients with Fabry disease.

0 comments Cited 121 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

Stephen Waldek, Robert J Desnick, Marie McDonald … (2007)

Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement. To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease. Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial. 41 referral centers in 9 countries. 82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent. Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months). The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point. Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group. The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event. Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.

0 comments Cited 108 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Intern Med

Journal ID (iso-abbrev): J. Intern. Med

Journal ID (publisher-id): joim

Title: Journal of Internal Medicine

Publisher: BlackWell Publishing Ltd (Oxford, UK )

ISSN (Print): 0954-6820

ISSN (Electronic): 1365-2796

Publication date (Print): October 2013

Publication date (Electronic): 06 May 2013

Volume: 274

Issue: 4

Pages: 331-341

Affiliations

Department of Medicine, Divisions of Cardiology and Nephrology, University of Würzburg Würzburg, Germany

Comprehensive Heart Failure Center, University of Würzburg Würzburg, Germany

Institute of Radiology, University of Würzburg Würzburg, Germany

Department of Neurology, University of Würzburg Würzburg, Germany

Author notes

Correspondence: Frank Weidemann, Medizinische Klinik und Poliklinik I, Universitätsklinik Würzburg, Oberdürrbacherstr. 6, D-97080 Würzburg, Germany., (fax: +49 931 201639191; e-mail: weidemann_f@ 123456medizin.uniwuerzburg.de ).

[*]

The first two authors contributed equally.

Article

DOI: 10.1111/joim.12077

PMC ID: 4282332

PubMed ID: 23586858

SO-VID: 78057a1e-c206-4c47-a7b8-4df2e14742cc

License:

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date accepted : 16 April 2013

Comments

Comment on this article

scite_

206

187

Smart Citations

206

187

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Cited by 93

See all cited by

Most referenced authors 525

See all reference authors

Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications

Read this article at

Abstract

Objective

Methods

Results

Conclusion

Related collections

Chinese Journal of General Practice

Most cited references 19

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey.

Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 1,017

Cited by 93

Most referenced authors 525