A 15-Year Perspective of the Fabry Outcome Survey

Giugliani, Roberto; Niu, Dau-Ming; Ramaswami, Uma; West, Michael; Hughes, Derralynn; Kampmann, Christoph; Pintos-Morell, Guillem; Nicholls, Kathleen; Schenk, Jörn-Magnus; Beck, Michael

doi:10.1177/2326409816666298

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Journal of Inborn Errors of Metabolism and Screening

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Review • J. inborn errors metab. screen. 4 • 2016 • https://doi.org/10.1177/2326409816666298 copy

A 15-Year Perspective of the Fabry Outcome Survey

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agalα). Established in 2001, FOS provides long-term data on agalα safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demonstrated correlations between ocular changes and Fabry disease severity. These FOS data represent a rich resource with utility not only for description of natural history/therapeutic effects but also for exploratory hypothesis testing and generation of tools for diagnosis/management, with the potential to improve future patient outcomes.

Keywords
agalsidase alfa; enzyme replacement therapy; Fabry disease; Fabry Outcome Survey; outcomes

Milestone	Year(s)
Development and validation of FOS Mainz Severity Score Index	2004, 2006¹⁸18 Whybra, C, Kampmann, C, Krummenauer, F. The Mainz Severity Score Index: a new instrument for quantifying the Anderson–Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet. 2004;65(4):299–307.^,¹⁹19 Whybra, C, Bähner, F, Baron, K. Measurement of disease severity and progression in Fabry disease. In: Mehta, A, Beck, M, Sunder-Plassmann, G, eds. Fabry Disease: Perspectives From 5 Years of FOS. Oxford, UK: Oxford PharmaGenesis; 2006:315–322.
Define clinical manifestations in female and pediatric patients	2006²⁰20 Deegan, PB, Baehner, AF, Barba Romero, MA, Hughes, DA, Kampmann, C, Beck, M; European FOS Investigators . Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006;43(4):347–352.^,²¹21 Ramaswami, U, Whybra, C, Parini, R; FOS European Investigators. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr. 2006;95(1):86–92.
Confirm high prevalence of cardiac morbidity	2007²²22 Linhart, A, Kampmann, C, Zamorano, JL; European FOS Investigators . Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry Outcome Survey. Eur Heart J. 2007;28(10):1228–1235.
Report changes over time in cause of death in patients with Fabry disease	2009²³23 Mehta, A, Clarke, JT, Giugliani, R; FOS Investigators . Natural course of Fabry disease: changing pattern of causes of death in FOS–Fabry Outcome Survey. J Med Genet. 2009;46(8):548–552.
Establish and validate prognostic and severity scores for Fabry disease	2010, 2012²⁴24 Hughes, DA, Malmenäs, M, Deegan, PB; FOS Investigators . Fabry International Prognostic Index: a predictive severity score for Anderson-Fabry disease. J Med Genet. 2012;49(3):212–220.^,²⁵25 Hughes, DA, Ramaswami, U, Barba Romero, MÁ, Deegan, P; FOS Investigators . Age adjusting severity scores for Anderson-Fabry disease. Mol Genet Metab. 2010;101(2-3):219–227.
Establish incidence of Fabry disease variants and implications for clinical management	2014²⁶26 Liu, H-C, Lin, H-Y, Yang, C-F. Globotriaosylsphingosine (lyso-Gb3) might not be a reliable marker for monitoring the long-term therapeutic outcomes of enzyme replacement therapy for late-onset Fabry patients with the Chinese hotspot mutation (IVS4+919G>A). Orphanet J Rare Dis. 2014;9:111.
Provide long-term data for morbidity and mortality of patients with Fabry disease treated with agala for 5 years	2015²⁷27 Beck, M, Hughes, D, Kampmann, C; Fabry Outcome Survey Study Group. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: a Fabry Outcome Survey analysis. Mol Genet Metab Rep. 2015;3:21–27.
Describe correlations between ocular changes and Fabry disease severity	2015²⁸28 Pitz, S, Kalkum, G, Arash, L. Ocular signs correlate well with disease severity and genotype in Fabry disease. PLoS One. 2015;10(3):e0120814.

		ERT
Duration,
Analysis		years	n
Cardiac Manifestations				LVMI Change From Baseline, g/m^2.7
Treated Male Versus Female
Beck, Mol Genet Metab		5.2	Men, n = 71	0.33 (SEM: 0.10)
	Rep. 2015²⁷27 Beck, M, Hughes, D, Kampmann, C; Fabry Outcome Survey Study Group. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: a Fabry Outcome Survey analysis. Mol Genet Metab Rep. 2015;3:21–27.		Women, n = 93	0.48 (SEM: 0.09)
Hughes, Mol Genet Metab.		4	Men, n = 45	-2.5
	2011³⁷37 Hughes, DA, Barba Romero, MÁ, Hollak, CE, Giugliani, R, Deegan, PB. Response of women with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS—the Fabry Outcome Survey. Mol Genet Metab. 2011;103(3):207–214.		Women, n = 24	-7.3^a a P < .05 versus baseline.
Impact of Baseline LVH
Mehta, Lancet. 2009³3 Mehta, A, Beck, M, Elliott, P; Fabry Outcome Survey investigators. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet. 2009;374(9706):1986–1996.		5	With baseline LVH, n = 32	-7.3 (SD: I5.3)^a a P < .05 versus baseline.
			Without baseline LVH, n = 25	1.8 (SD: 10.1)
Beck, Mol Genet Metab		5.2	With baseline LVH	Men (n = 29), 0.19 (SEM: 0.16)
	Rep. 2015²⁷27 Beck, M, Hughes, D, Kampmann, C; Fabry Outcome Survey Study Group. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: a Fabry Outcome Survey analysis. Mol Genet Metab Rep. 2015;3:21–27.			Women (n = 45), 0.77 (SEM: 0.14)
			Without baseline LVH	Men (n = 42), 0.47 (SEM: 0.13)
				Women (n = 48), 0.19 (SEM: 0.11)
Hughes, Mol Genet Metab.		4	Women with baseline LVH, n = 12	-8.49^a a P < .05 versus baseline.
	2011³⁷37 Hughes, DA, Barba Romero, MÁ, Hollak, CE, Giugliani, R, Deegan, PB. Response of women with Fabry disease to enzyme replacement therapy: comparison with men, using data from FOS—the Fabry Outcome Survey. Mol Genet Metab. 2011;103(3):207–214.		Women without baseline LVH, n = 12	-0.67
Whybra, Genet Med.		4	Females with baseline LVMI >85 g/m^2.7, n = 9	-40.0^a a P < .05 versus baseline.
	2009⁴⁵45 Whybra, C, Miebach, E, Mengel, E. A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease. Genet Med. 2009;11(6):441–449.		Females with baseline LVMI >60-85 g/m^2.7, n = 9	-14.3^a a P < .05 versus baseline.
			Females with baseline LVMI >48-60 g/m^2.7, n = 8	-7.3^a a P < .05 versus baseline.
			Females with baseline LVMI <48 g/m^2.7, n = 11	-4.5^a a P < .05 versus baseline.
Kampmann, Orphanet J		10	With baseline LVH	Males (n = 15), -13.55^a a P < .05 versus baseline.
	Rare Dis. 2015⁴⁶46 Kampmann, C, Perrin, A, Beck, M. Effectiveness of agalsidase alfa enzyme replacement in Fabry disease: cardiac outcomes after 10 years’ treatment. Orphanet J Rare Dis. 2015;10:125.			Females (n = 16), NA^b b Value not given, but authors stated change from baseline was not significant at 10 years.
			Without baseline LVH	Males (n = 6), NA^b b Value not given, but authors stated change from baseline was not significant at 10 years.
				Females (n = 8), NA^b b Value not given, but authors stated change from baseline was not significant at 10 years.
				Mean eGFR Change From Baseline,
Renal Manifestations				mL/min/1.73 m²/year
Treated Male Versus Female
Feriozzi, Am J Nephrol.		3	Men, n = 115	-2.66 (SD: 5.07)^a a P < .05 versus baseline.
	2009⁴⁷47 Feriozzi, S, Schwarting, A, Sunder-Plassmann, G, West, M, Cybulla, M; International Fabry Outcome Survey Investigators . Agalsidase alfa slows the decline in renal function in patients with Fabry disease. Am J Nephrol. 2009;29(5):353–361.		Women, n = 50	-1.20 (SD: 3.28)^a a P < .05 versus baseline.
Mehta, Lancet. 2009³3 Mehta, A, Beck, M, Elliott, P; Fabry Outcome Survey investigators. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet. 2009;374(9706):1986–1996.		5	Men, n = 103	-3.17^a a P < .05 versus baseline.
			Women, n = 47	-0.89^a a P < .05 versus baseline.
Feriozzi, Clin J Am Soc		= 5	Men, n = 134	-2.2 (95% CI: -2.8 to - I.7)^a a P < .05 versus baseline.
	Nephrol. 2012⁴²42 Feriozzi, S, Torras, J, Cybulla, M, Nicholls, K, Sunder-Plassmann, G, West, M; FOS Investigators . The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin J Am Soc Nephrol. 2012;7(1):60–69.		Women, n = 74	-0.7 (95% CI: -1.4 to 0.0)
Impact of Comorbidity or Baseline eGFR
Beck, Mol Genet Metab		5.4	Baseline eGFR = 60 mL/min/1.73 m²	Men (n = 117), -1.68 (SEM: 0.19)
	Rep. 2015²⁷27 Beck, M, Hughes, D, Kampmann, C; Fabry Outcome Survey Study Group. Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: a Fabry Outcome Survey analysis. Mol Genet Metab Rep. 2015;3:21–27.			Women (n = III), -0.43 (SEM: 0.21)
			Baseline eGFR <60 mL/min/1.73 m²	Men (n = I8), -2.86 (SEM: 0.53)
				Women (n = 22), 0.36 (SEM: 0.42)
Feriozzi, Clin J Am Soc		=5	Hypertensive, n = 66	-2.4 (95% CI: -3.I to - I.7)^a a P < .05 versus baseline.
	Nephrol. 2012⁴²42 Feriozzi, S, Torras, J, Cybulla, M, Nicholls, K, Sunder-Plassmann, G, West, M; FOS Investigators . The effectiveness of long-term agalsidase alfa therapy in the treatment of Fabry nephropathy. Clin J Am Soc Nephrol. 2012;7(1):60–69.		Normotensive, n = 142	-I.2 (95% CI: - I.7 to -0.6)^a a P < .05 versus baseline.
			Baseline eGFR =90 mL/min/1.73 m²	Men (n = 87), -2.6 (95% CI: -3.I to -2.0)^a a P < .05 versus baseline.
				Women (n = I9), -1.4 (95% CI: -2.6 to -0.I)^a a P < .05 versus baseline.
			Baseline eGFR 30-59 mL/min/1.73 m²	Men (n = I5), -2.5 (95% CI: -3.9 to - I.I)^a a P < .05 versus baseline.
				Women (n = I2), -0.5 (95% CI: -2.0 to I.0)

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[1] Corresponding Author: Roberto Giugliani, MD, PhD, Medical Genetics Service HCPA, Dep Genet UFRGS, and INAGEMP, Porto Alegre, Brazil. Email: rgiugliani@hcpa.edu.br