Letter concerning “Enzyme replacement therapy in a patient with Fabry disease and the development of IgE antibodies against agalsidase beta but not agalsidase alpha”, by Tanaka et al.

FWN – Publicaties zonder aanstelling Universiteit Leide

Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation

Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcome

Position statement on the role of healthcare professionals, patient organizations and industry in European Reference Networks

A call from the EU for the set-up of European Reference Networks (ERNs) is expected to be launched in the first quarter of 2016. ERNs are intended to improve the care for patients with low prevalent or rare diseases throughout the EU by, among other things, facilitating the pooling and exchange of experience and knowledge and the development of protocols and guidelines. In the past, for example where costly orphan drugs have been concerned, industry has played an important role in facilitating consensus meetings and publication of guidelines. The ERNs should provide a unique opportunity for healthcare professionals and patients to lead these activities in an independent way. However, currently costs for networking activities are not to be covered by EU funds and alternative sources of funding are being explored. There is growing concern that any involvement of the industry in the funding of ERNs and their core activities may create a risk of undue influence. To date, the European Commission has not been explicit in how industry will be engaged in ERNs. We believe that public funding and a conflict of interest policy are needed at the level of the ERNs, Centers of Expertise (CEs), healthcare professionals and patient organizations with the aim of maintaining scientific integrity and independence. Specific attention is needed where it concerns the development of clinical practice guidelines. A proposal for a conflict of interest policy is presented, which may support the development of a framework to facilitate collaboration, safeguard professional integrity and to establish and maintain public acceptability and trust among patients, their organizations and the general public

Cost-effectiveness of enzyme replacement therapy for Fabry disease

The cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care was evaluated in the Dutch cohort of patients with Fabry disease. Cost-effectiveness analysis was performed using a life-time state-transition model. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort consisting of males and females aged 5-78 years. Intervention with ERT (either agalsidase alfa or agalsidase beta) was compared to the standard medical care. The main outcome measures were years without end organ damage (renal, cardiac en cerebrovascular complications), quality adjusted life years (QALYs), and costs. Over a 70 year lifetime, an untreated Fabry patient will generate 55.0 years free of end-organ damage (53.5 years in males, 56.9 years in females) and 48.6 QALYs (47.8 in males, 49.7 in females). Starting ERT in a symptomatic patient increases the number of years free of end-organ damage by 1.5 year (1.6 in males, 1.3 in females), while the number of QALYs gained increases by a similar amount (1.7 in males, 1.4 in females). The costs of ERT starting in the symptomatic stage are between €9 - €10 million (£ 7.9 - £ 8.8 million, $13.0-$14.5 million) during a patient's lifetime. Consequently, the extra costs per additional year free of end-organ damage and the extra costs per additional QALY range from €5.5 - €7.5 million (£ 4.8 - £ 6.6 million, $8.0 -$ 10.8 million), undiscounted. In symptomatic patients with Fabry disease, ERT has limited effect on quality of life and progression to end organ damage. The pharmaco-economic evaluation shows that this modest effectiveness drives the costs per QALY and the costs per year free of end-organ damage to millions of euros. Differentiation of patients who may benefit from ERT should be improved to enhance cost-effectivenes

Screening for Fabry disease using whole blood spots fails to identify one-third of female carriers

Introduction. Recently, a method to analyse dried whole blood spots to diagnose Fabry disease (deficiency of the lysosomal enzyme alphaGal A) was described. However given its X-linked inheritance female Fabry patients can exhibit normal alphaGal A activities. This could lead to underestimation in screening females for Fabry disease using this method. Methods. aGal A activity was measured in dried whole blood spots of 21 females with documented Fabry disease. Results. Only 13/21 (67%) had reduced aGal A activities, concluding that one-third of female carriers would not be identified during screening. Additional determination of alphaGlucosidase activity (alphaGlu) and the construction of an alphaGal/alphaGlu ratio did not increase sensitivity of the assay. Conclusion. Assays using alphaGal activity for determination of Fabry disease in females have a high false-negative value. Screening for a-Gal A deficiency by means of whole blood spots should not be performed in a females. (C) 2004 Elsevier B.V. All rights reserve

Novel therapeutic targets for the treatment of Fabry disease

Fabry disease is an X-linked lysosomal storage disorder resulting from deficient activity of alpha-galactosidase A. The traditional concept that is used to explain the complications of the disease involves progressive accumulation of globotriaosylceramide in endothelial and smooth muscle cells, resulting in vascular damage. Clinically, progressive renal insufficiency, cardiac involvement and brain pathology evolves. Two pharmaceutical companies have developed enzyme replacement therapy in Fabry disease. Although the first clinical trials showed great promise, it is clear that long-term effects are not as robust as was anticipated. Stabilisation of renal function and decreases in cardiac hypertrophy has been observed, but some patients may experience progressive complications. As there are recent indications that serum components contribute to the pathophysiology of Fabry disease, fundamental studies are needed to unravel the precise role and identity of these factors. Combination of these basic studies with clinical follow up may ultimately reveal when the 'point of no return' is reached. Advanced renal insufficiency seems to be a clinical indicator of lack of response, but other signs and symptoms are probably related to adverse outcome. It is anticipated that in the future controlled studies in early symptomatic or presymptomatic patients will be required. In addition, alternative strategies such as substrate reduction or chaperone therapy, either alone or in combination with enzyme replacement therapy, should be explored. Because Fabry disease is rare, collaborative efforts should be undertaken and openness of data should be strived fo

Plasma thrombopoietin levels in patients with chronic renal failure

INTRODUCTION: Thrombopoietin (Tpo) is the most important regulator of thrombocytopoiesis. The main sites of Tpo production are the liver and the kidney produce Tpo. In the current study, the influence of renal failure on overall Tpo production was evaluated. MATERIALS AND METHODS: Tpo levels were measured in 23 patients on hemodialysis (HD) and 16 patients on chronic ambulatory peritoneal dialysis (CAPD). Plasma glycocalicin (GC) levels and platelet counts were measured as parameters of platelet mass and platelet turnover. RESULTS: Platelet counts were significantly lower in the HD group, both before 207+/-98 x 10(9)/l (P <0.001) and after hemodialysis 202+/-102 x 10(9)/l (P <0.001) when compared to healthy controls, 293+/-79 x 10(9)/l. No significant difference was found between platelet counts in patients on CAPD and healthy donors. Mean plasma Tpo levels of HD patients were higher both before 23+/-18 AU/ml (P <0.0001) and after dialysis 25+/-26 AU/ml (P <0.0001), as compared to Tpo levels in healthy controls (11+/-8 AU/ml). Patients on CAPD had significantly higher Tpo concentrations, 29+/-25 AU/ml than healthy controls (P <0.0001). There was no difference in Tpo level between the HD and CAPD group. No correlation was found between Tpo concentration and platelet count, hematocrit, creatinine or uremia levels. The GC concentration was significantly higher in HD patients and CAPD patients when compared to healthy controls. There was no correlation between GC and Tpo level or platelet count. CONCLUSION: These results confirm the increased platelet turnover in patients with chronic renal failure. Moreover this study shows that the kidney does not seem to play a major role in the overall Tpo production in the bod

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages

Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage. Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages. Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis. Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR > 60 ml/min/1.73 m(2), decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR  < 60 ml/min/1.73 m(2) had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT. ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry diseas