GAUCHER DISEASE TYPE 1 IN THE SKELETON: REVIEW OF LATIN AMERICA

Camelo Júnior, José Simon; Dragosky, Marta; Drelichman, Guillermo

doi:10.1590/S1808-185120161504166050

Acessibilidade / Reportar erro

Brasil

Español English

sumário « anterior atual seguinte »

Sumário

Review Article • Coluna/Columna 15 (4) • Oct-Dec 2016 • https://doi.org/10.1590/S1808-185120161504166050 copy

GAUCHER DISEASE TYPE 1 IN THE SKELETON: REVIEW OF LATIN AMERICA

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Gaucher disease (GD) is the most prevalent lysosomal storage disease, and is characterized by the accumulation of glucosylceramide and glucosylsphingosine in tissues throughout the body. With the advent of enzyme replacement therapy, the prognosis for patients with GD has dramatically improved. Still, the skeletal manifestations associated with GD respond slowly to enzyme replacement therapy and are the most significant contributor of disease related patient morbidity. This review of bone manifestations in GD presents the most recent theories on its pathophysiology, and gives a systematic review of studies with Latin American patients that report the frequency of bone manifestations and the effects of enzyme replacement therapy on their treatment. We conclude by emphasizing the importance of early identification and proper management at appropriate dosage levels of enzyme replacement therapy to reduce the morbidity caused by GD.

Keywords:
Gaucher disease; Skeleton; Prevalence; Latin America.

Country	Study	Ages*	Range/median	Gender**	Splenectomy ***	Bone pain	Bone crisis	Bone changes	Erlenmeyer flask deformity	Osteopenia	Marrow infiltration	Infarction	Avascular necrosis	Fractures	Lytic lesions	Joint replacement	Growth retardation
Number of patients with bone manifestation/Total patients in cohort
ICGG Registry cohorts
Brazil	^{Sobreira, 2007}28. Sobreira E, Pires RF, Cizmarik M, Grabowski GA. Phenotypic and genotypic heterogeneity in Gaucher disease type 1: a comparison between Brazil and the rest of the world. Mol Genet Metab. 2007;90(1):81-6. (28)	A	-	MF	NS	45/78	14/87	-	26/53	-	-	-	5/53	4/53	9/53	-	-
		% in sample			0	58	16		49				9	8	17
Brazil	^{Sobreira, 2008}29. Sobreira EAP, Bruniera P. Avaliação de dois anos de tratamento da doença de Gaucher tipo 1 com terapia de reposição enzimática em pacientes do estado de São Paulo, Brasil. Rev Bras Hematol Hemoter. 2008;30(3):193-201. (29)	CA	1-55 yr 11.8	MF	S	44/90	-	-	-	-	-	-	-	-	-	-	-
		% in sample			24	49
Latin America¹	^{Drelichman, 2012}31. Drelichman G, Linares A, Villalobos J, Cabello JF, Kerstenetzky M, Kohan RM, et al. Gaucher disease in Latin America. A report from the Gaucher Disease International Registry and the Latin American Group for Gaucher disease. Med (Buenos Aires). 2012;72(4):273-82. (31)	CA	-	MF	S	228/475	60/462	9/39^#	119/190	128/183	127/151	52/159	40/165	14/129	55/163	-	-
		% in sample			7	48	13	23	63	70	84	33	24	11	34
Latin America²	Current study	CA	-	MF	S	204/448	51/436	-	111/149	-	105/130	42/135	39/141	11/118	48/151	-	-
		% in sample			21^Δ	46	12		74		81	31	28	9	32
All ages, splenectomy status, gender					46-58%		12-16%	23%	49-74%	70%	81-84%	31-33%	9-28%	8-11%	17-34%	-	-
Non Registry cohorts							12-16%	23%	49-74%	70%	81-84%	31-33%	9-28%	8-11%	17-34%	-	-
Brazil	^{Mendonça, 2001}32. Mendonça VF, de Paula M, Tereza M, Fernandes C, Boasquevisque EM. Manifestações esqueléticas da doença de Gaucher. Radiol Bras. 2001;34(3):151-4. (32)	CA	4-62 yr 28.9	MF	NS	-	-	-	30/32	32/32	-	-	9/32^##	3/32	9/32	13/32	-
	% in sample				0				94	100			28	9	28	40
	Subset			M	NS	-	-	-	13/14	14/14	-	-	3/14	1/14	7/14	7/14	-
	% in sample				0				93	100			21	7	50	50
	Subset			F	NS	-	-	-	17/18	18/18	-	-	3/18	2/18	2/18	6/18	-
	% in sample				0				94	100			17	11	11	33
Brazil	^{Oliveira, 2002}36. Oliveira MC, Oliveira BM, Queirós E, Viana MB. Clinical and nutritional aspects of Gaucher disease: prospective study of 13 children at a single center. J Pediatr (Rio J). 2002;78(6):517-22. (36)³	C	1-10 yr	MF	S	5/13	-	5/13	-	-	-	-	5/13	5/13	-	-	-
		% in sample			38	38		38					38	38
Argentina	^{Drelichman, 2007}30. Drelichman G, Ponce E, Basack N, Freigeiro D, Aversa L, Graciela E, et al. Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease. J Pediatr. 2007;151(2):197-201. (30)	C	1-12 yr	MF	NS	3/5	-	-	-	3/5	-	-	-	-	-	-	4/5
		% in sample			0	60				60							80
Brazil	^{Mota, 2007}33. Mota RM, Mankin H. Use of plain radiography to optimize skeletal outcomes in children with type 1 Gaucher disease in Brazil. J Pediatr Orthop. 2007;27(3):347-50. (33)	C	3-18 yr	MF	S	-	1/18	1/18	1/18	1/18	6/18	1/18	-	-	7/18	-	-
		% in sample			0.6		6	6	6	6	33	6			39
Brazil	^{Ferreira, 2008}34. Ferreira JS, Ferreira VL, Ferreira DC. Estudo da doença de Gaucher em Santa Catarina. Rev Bras Hematol Hemoter. 2008;30(1):5-11.⁴ (34)	CA	-	MF	NS	-	-	-	2/10	4/10	1/10	1/10	3/10	1/10	-	-	-
		% in sample			0				20	40	10	10	30	10
Brazil	Oi, 2013⁵ (35)	A	-	MF	NS	-	-	-	2/5	4/6	-	-	1/5	1/5	1/5	-	-
		% in sample			0				40	60			20	20	20
All ages, splenectomy status, gender				38-60%		6%	6-38%	6-94%	6-100%	10-33%		6-10%	17-38%	7-38%	11-39%	33-50%	80%

Study	Country	Sample	Study Objective	Affects on Bone Manifestations	Key point
Mota, 2007 (33)	Brazil	18 children	Patients were followed for up to 10 years (mean follow-up, 4 years and 4 months ± 3 years and 3 months). Bone changes were evaluated by plain radiographs in all patients.	Clinical and radiological improvement was noted in 13 (72%) of 18 patients; bone lesions worsened in 5 (28%) of 18 patients. Final ERT dose was statistically different between those who improved versus those who worsened (55 ± 10 U/kg vs. 29 ± 2 U/kg; P < 0.03).	Importance of ERT dose
^{Drelichman, 2007}30. Drelichman G, Ponce E, Basack N, Freigeiro D, Aversa L, Graciela E, et al. Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease. J Pediatr. 2007;151(2):197-201. (31)	Argentina	5 children	5 children had at least 1 year of ERT but therapy was discontinued for 1 to 3 years. These features were measured at baseline (immediately before initiating ERT), when ERT was withdrawn, when ERT was resumed, and at least 11 months after resuming ERT.	Before ERT was interrupted - no radiological skeletal manifestations were present. 4 of the children interrupted on ERT had serious bone manifestations requiring hospitalization, immobilization, and analgesics; after 9-11 months of ERT re-initiated the radiological manifestations continued to persist. Suggesting 4 out of the 5 children whose ERT was interrupted had sustained irreversible skeletal damage and resulting disability.	Implies prevention of bone problems with ERT in children and importance of continued use
Parisi, 2008 (62)	Argentina	9 adults	Evaluated bone composition in GD1 patients receiving imiglucerase in a mean dose of 53 ± 13 IU/kg/2weeks, during 4.9 ± 3.9 years and compared with 145 sex and age matched healthy individuals	GDI patients receiving the lower dose of ERT (<60 IU/kg/2weeks) presented lower BMD values than those receiving the higher dose (≥60 IU/kg/2weeks) (0.968 ± 0.032 vs. 1.088 ± 0.061 g/m2, respectively, p<0.001).	Importance of ERT dose
^{Sobreira, 2008}29. Sobreira EAP, Bruniera P. Avaliação de dois anos de tratamento da doença de Gaucher tipo 1 com terapia de reposição enzimática em pacientes do estado de São Paulo, Brasil. Rev Bras Hematol Hemoter. 2008;30(3):193-201. (29)	Brazil	41 children 71 patients	Evaluated individuals with GD1 at baseline and after 24 months of mean dosage of imiglucerase 35 UI/kg/2 weeks	From baseline to 18 months, the frequency in short stature was significantly reduced. Incidence of bone pain also progressively reduced from baseline to 18 months, reaching statistical significance as early as 6 months.	ERT improved growth and bone pain
Lukina, 2014 (63)	Multi-centered includes Argentina and Mexico	19 adults	Phase II Trial of Eliglustat - a substrate reduction therapy over 4 years in treatment naïve GD1 (18-56 yo)	Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: −1.6 ± 1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow was reduced or stable in 17/18 patients. There were no bone crises.	Improved lumbar spine T-score and BMI
Hughes, 2015 (64)	Multi-centered includes Argentina and Paraguay	57 patients	Long-term data from velaglucerase alfa phase III clinical trial in a single extension study (aged 3-62) Measures reported over 24 months (extension plus Phase 3)	Lumbar spine BMD Z-scores in adults improved by 24 months, no difference in mean Z-score changes in the femoral neck likely because most patients (>64%) at baseline were no more than 1 SD below peak bone density at the femoral neck, which is considered normal.	Improved on lumbar spine z-score measure, but not on others
Mistry, 2015 (65)	Multi-centered includes Colombia and Mexico	40 patients	Eliglustat (substrate reduction)-Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries.	Eliglustat treatment resulted in a statistically significant improvement in mean total BMB score and there was no change in the placebo treatment group, P = 0.002. Other markers of bone disease, including BMD, showed no significant change.	Improved BMB but not BMD
Cox, 2015 (66)	Multi-centered includes Argentina and Brazil	160 patients	Phase 3, randomized, open label, non-inferiority trial of 106 Eliglustat versus 54 imiglucerase; Average age 37.6 yrs (14.2)* and 37.5 yrs (14.9)*	Mean bone mineral density was in the normal range and maintained; mean bone marrow burden scores showed moderate infiltration of haemopoietic marrow and were also maintained	BMD and BMB were within the normal range and were maintained

Sociedade Brasileira de Coluna Al. Lorena, 1304 cj. 1406/1407, 01424-001 São Paulo, SP, Brasil, Tel.: (55 11) 3088-6616 - São Paulo - SP - Brazil
E-mail: coluna.columna@uol.com.br

Acompanhe os números deste periódico no seu leitor de RSS

[1] Correspondence: Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Puericultura e Pediatria. Av. Bandeirantes, 3900, Monte Alegre, Ribeirão Preto, SP, Brazil. 14049-900. jscamelo@fmrp.usp.br