Echocardiographic assessment of pulmonary hypertension in Gaucher's disease

Elstein, Deborah; Klutstein, Marc; Lahad, Amnon; Abrahamov, Ayala; Hadas‐Halpern, Irith; Zimran, Ari

doi:10.1016/s0140-6736(98)10194-0

Cited by 95 publications

(71 citation statements)

References 10 publications

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“…Echocardiography and PFTs, undertaken to rule out possible onset of pulmonary hypertension 13, 14, revealed no pathology or safety concerns throughout the observation period and mean values remained within the normal range for age, ethnicity, and height 15.…”

Section: Resultsmentioning

confidence: 87%

“…Although electrocardiography is clearly a universal safety measure, the choice of the other two measures was Gaucher‐specific. At the time of initiation of this trial, there was concern about the possibility of either primary‐like 13 or secondary 14 pulmonary hypertension among patients with GD who may have been respectively treated with imiglucerase 13 or insufficiently treated with imiglucerase 14. Beyond the very mild natural diminution because of age in PFTs 15, there was no clinical evidence of pulmonary hypertension following prolonged exposure to velaglucerase alfa.…”

Section: Discussionmentioning

confidence: 99%

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Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

et al. 2015

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Velaglucerase alfa is a human β‐glucocerebrosidase approved for Gaucher disease type 1 (GD1) treatment. This report summarizes the 7‐year experience of the now‐completed phase I/II and extension studies of adult GD1 patients who received velaglucerase alfa. Ten patients who completed the 9‐month, phase I/II study entered the extension trial TKT025EXT, of which eight completed this study. Doses were reduced after a cumulative treatment period of 15 to 18 months. Although all patients experienced ≥1 adverse event, no patient withdrew due to a drug‐related adverse event or required premedication. No patient developed anti‐drug antibodies, compliance remained high (median 98%), and seven of eight eligible patients transitioned to home infusions under supervision by healthcare professionals. Statistically significant improvements were observed for efficacy parameters: mean percentage changes from baseline (95% confidence intervals) were 18% (12%, 24%) for hemoglobin concentration, 115% (66%, 164%) for platelet counts, and −42% (−53%, −31%) and −78% (−94%, −62%) for liver and spleen volumes, respectively. Improvements were also observed for secondary endpoints chitotriosidase and CCL18 levels and exploratory endpoints (bone mineral density [BMD], bone marrow burden [BMB] scores). Normalization to near‐normalization of individuals' hemoglobin concentrations, platelet counts, liver volumes, and BMB scores was observed, and there were marked improvements in spleen volumes, biomarkers, and BMD. TKT025EXT represents the longest, prospective clinical trial for GD1 treatment to date and suggests that, despite dose reduction within 18 months of initiating therapy, velaglucerase alfa was generally well tolerated and was associated with marked improvement, including near normalization and/or normalization of key GD1 disease parameters. Am. J. Hematol. 90:577–583, 2015. © 2015 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

et al. 2015

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“…In the case of pulmonary hypertension in Gaucher disease, which is distinct from infiltrative lung disease, we have previously noted our concern that one sees a primary-like form of pulmonary hypertension in patients treated with enzyme replacement [19] in addition to the pulmonary hypertension that is secondary to severe Gaucher disease. The significant correlation between Ddimers and elevated TI gradients may suggest that pulmonary hypertension due to Gaucher disease is induced initially as microthrombi.…”

Section: Discussionmentioning

confidence: 99%

D‐dimer assay in Gaucher disease: Correlation with severity of bone and lung involvement

et al. 2003

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The D-dimer assay as a marker of cross-linked fibrin may also be an indicator of active microvascular thrombosis, even in patients without overt hypercoagulation. In type I Gaucher disease, there is tremendous phenotypic variability that cannot be ascribed solely to different genotypes. Thus, there are no predictive tests to ascertain patients at risk for bone involvement, such as avascular necrosis, or lung disease, particularly pulmonary hypertension, which are two of the major causes of morbidity in Gaucher disease and which are slow to respond to enzyme replacement therapy. Previous studies to correlate these parameters with thrombophilic profiles have not been conclusive. Levels of D-dimers were assayed and compared to the presence of avascular necrosis and abnormally elevated TI gradient among other variables, in 118 unselected adult patients (52 males) with Gaucher disease. Of these, 19 patients had very mild Gaucher disease (Severity Score Index, SSI < 5) and 23 had severe disease (SSI > 15); 29 had avascular necrosis; 37 were splenectomized (due to massive splenomegaly and hypersplenism). As an indirect measure of pulmonary hypertension, TI gradient was used: 90 patients had normal TI gradients (<25 mmHg), and 12 patients had abnormal TI gradients (>30 mmHg). There were significant correlations between D-dimers and avascular necrosis, splenectomy, and elevated TI gradient. Thus, the D-dimer assay may be potentially predictive of bone and lung involvement in Gaucher disease. Am. J. Hematol. 73:236-239, 2003.

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“…38 There are several bone and skeletal assessment scores, [39][40][41][42] in addition to actual bone densitometry 42,43 and bone marker 42 evaluations. Echocardiography 44 is recommended for follow-up of pulmonary hypertension. There are also specific tools for quality of life 45 assessment and cognitive function 46 which are optimal for clinical trials rather than routine evaluations.…”

Section: Enzyme Replacement Therapy (Ert): the Early Yearsmentioning

confidence: 99%

“…It has been suggested that there is a predisposition for PH in patients with type 1, especially in the presence of additional genetic factors and epigenetic modifiers. 74 Others have suggested a causal relationship 44 between PH and ERT, particularly among young splenectomized women, but this has been difficult to prove. Treatment withdrawal may be considered in these patients who evince primary-like PH and progressive increases in TI gradient (30 mmHg) with ERT during routine echocardiographic monitoring.…”

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confidence: 99%

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease

Elstein¹

2009

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Abstract:Most patients who suffer from symptomatic Gaucher disease will benefit from enzyme replacement therapy (ERT) with imiglucerase. The safety profile is excellent, only a small percentage of those exposed developing antibodies; similarly, very few patients require pre-medication for allergic reactions. Within 3 to 5 years of imiglucerase therapy, best documented at doses of 30 to 60 units/kg/infusion, hepatosplenomegaly can be expected to be reduced so that the liver volume will be maintained at 1 to 1.5 times normal (30% to 40% reduction from advent of ERT) and spleen volume to 2 to 8 times normal (50% to 60% reduction from advent of ERT). For anemic and thrombocytopenic patients, with 2 to 5 years of imiglucerase, hemoglobin levels are expected to be 11 g/dL for women and children and 12 g/dL for men; and platelet counts in patients with an intact spleen, depending on the baseline value, should approximately be doubled. Bone crises and bone pain but not irreversible skeletal damage will improve in most patients. Nonetheless, some features and some symptomatic patients apparently do not respond equally well and/or perhaps inadequately. The benefit for patients with the neuronopathic forms is primarily in improved visceral and hematological signs and symptoms. There are still several unresolved issues, the high per-unit cost being an important one, which have spurred the development of biosimilar enzymes as well as chaperone therapies currently in clinical trials.

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Echocardiographic assessment of pulmonary hypertension in Gaucher's disease

Cited by 95 publications

References 10 publications

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

Seven‐year safety and efficacy with velaglucerase alfa for treatment‐naïve adult patients with type 1 Gaucher disease

D‐dimer assay in Gaucher disease: Correlation with severity of bone and lung involvement

Review of the safety and efficacy of imiglucerase treatment of Gaucher disease

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