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Background Infantile Pompe disease is a rare metabolic disease. Patients generally do not survive the first year of life. Enzyme replacement therapy (ERT) has proven to have substantial effects on survival in infantile Pompe disease. However, the costs of therapy are very high. In this paper, we assess the cost-effectiveness of enzyme replacement therapy in infantile Pompe disease. Methods A patient simulation model was used to compare costs and effects of ERT with costs of effects of supportive therapy (ST). The model was filled with data on survival, quality of life and costs. For both arms of the model, data on survival were obtained from international literature. In addition, survival as observed among 20 classic-infantile Dutch patients, who all received ERT, was used. Quality of life was measured using the EQ-5D and assumed to be the same in both treatment groups. Costs included the costs of ERT (which depend on a child's weight), infusions, costs of other health care utilization, and informal care. A lifetime time horizon was used, with 6-month time cycles. Results Life expectancy was significantly longer in the ERT group than in the ST group. On average, ST receiving patients were modelled not to survive the first half year of life; whereas the life expectancy in the ERT patients was modelled to be almost 14 years. Lifetime incremental QALYs were 6.8. Incremental costs were estimated to be € 7.0 million, which primarily consisted of treatment costs (95%). The incremental costs per QALY were estimated to be € 1.0 million (range sensitivity analyses: € 0.3 million - € 1.3 million). The incremental cost per life year gained was estimated to be € 0.5 million. Conclusions The incremental costs per QALY ratio is far above the conventional threshold values. Results from univariate and probabilistic sensitivity analyses showed the robustness of the results. [ABSTRACT FROM AUTHOR]

Background: Governments have identified innovation in pharmaceuticals and medical technology as a priority for health policy. Although the contribution of medical care to health has been studied extensively in clinical settings, much less is known about its contribution to population health. We examine how innovations in the management of four circulatory disorders have influenced trends in cause-specific mortality at the population level. Methods: Based on literature reviews, we selected six medical innovations with proven effectiveness against hypertension, ischaemic heart disease, heart failure and cerebrovascular disease. We combined data on the timing of these innovations and cause-specific mortality trends (1970–2005) from seven European countries. We sought to identify associations between the introduction of innovations and favourable changes in mortality, using Joinpoint-models based on linear spline regression. Results: For both ischaemic heart disease and cerebrovascular disease, the timing of medical innovations was associated with improved mortality in four out of five countries and five out of seven countries, respectively, depending on the innovation. This suggests that innovation has impacted positively on mortality at the population level. For hypertension and heart failure, such associations could not be identified. Conclusion: Although improvements in cause-specific mortality coincide with the introduction of some innovations, this is not invariably true. This is likely to reflect the incremental effects of many interventions, the time taken for them to be adopted fully and the presence of contemporaneous changes in disease incidence. Research on the impact of medical innovations on population health is limited by unreliable data on their introduction. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported large socioeconomic inequalities in mortality from conditions amenable to medical intervention, but it is unclear whether these can be attributed to inequalities in access or quality of health care, or to confounding influences such as inequalities in background risk of diseases. We therefore studied whether inequalities in mortality from conditions amenable to medical intervention vary between countries in patterns which differ from those observed for other (non-amenable) causes of death. More specifically, we hypothesized that, as compared to non-amenable causes, inequalities in mortality from amenable causes are more strongly associated with inequalities in health care use and less strongly with inequalities in common risk factors for disease such as smoking. Methods: Cause-specific mortality data for people aged 30-74 years were obtained for 14 countries, and were analysed by calculating age-standardized mortality rates and relative risks comparing a lower with a higher educational group. Survey data on health care use and behavioural risk factors for people aged 30-74 years were obtained for 12 countries, and were analysed by calculating age-and sex-adjusted odds ratios comparing a low with a higher educational group. Patterns of association were explored by calculating correlation coefficients. Results: In most countries and for most amenable causes of death substantial inequalities in mortality were observed, but inequalities in mortality from amenable causes did not vary between countries in patterns that are different from those seen for inequalities in non-amenable mortality. As compared to non-amenable causes, inequalities in mortality from amenable causes are not more strongly associated with inequalities in health care use. Inequalities in mortality from amenable causes are also not less strongly associated with common risk factors such as smoking. Conclusions: We did not find evidence that inequalities in mortality from amenable conditions are related to inequalities in access or quality of health care. Further research is needed to find the causes of socio-economic inequalities in mortality from amenable conditions, and caution should be exercised in interpreting these inequalities as indicating health care deficiencies. [ABSTRACT FROM AUTHOR]

Background: Infantile Pompe disease is a rare metabolic disease. Patients generally do not survive the first year of life. Enzyme replacement therapy (ERT) has proven to have substantial effects on survival in infantile Pompe disease. However, the costs of therapy are very high. In this paper, we assess the cost-effectiveness of enzyme replacement therapy in infantile Pompe disease.Methods: A patient simulation model was used to compare costs and effects of ERT with costs of effects of supportive therapy (ST). The model was filled with data on survival, quality of life and costs. For both arms of the model, data on survival were obtained from international literature. In addition, survival as observed among 20 classic-infantile Dutch patients, who all received ERT, was used. Quality of life was measured using the EQ-5D and assumed to be the same in both treatment groups. Costs included the costs of ERT (which depend on a child's weight), infusions, costs of other health care utilization, and informal care. A lifetime time horizon was used, with 6-month time cycles.Results: Life expectancy was significantly longer in the ERT group than in the ST group. On average, ST receiving patients were modelled not to survive the first half year of life; whereas the life expectancy in the ERT patients was modelled to be almost 14 years. Lifetime incremental QALYs were 6.8. Incremental costs were estimated to be € 7.0 million, which primarily consisted of treatment costs (95%). The incremental costs per QALY were estimated to be € 1.0 million (range sensitivity analyses: € 0.3 million - € 1.3 million). The incremental cost per life year gained was estimated to be € 0.5 million.Conclusions: The incremental costs per QALY ratio is far above the conventional threshold values. Results from univariate and probabilistic sensitivity analyses showed the robustness of the results. [ABSTRACT FROM AUTHOR]

Background: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease. Methods: Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Cox's proportional hazards models were used for univariable and multivariable analyses. Results: Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87). Conclusion: This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients. [ABSTRACT FROM AUTHOR]

Aim: To examine the long-term consequences of glycogen storage in the central nervous system (CNS) for classic infantile Pompe disease using enzyme replacement therapy.Method: Using neuropsychological tests and brain magnetic resonance imaging (MRI), we prospectively assessed a cohort of 11 classic infantile Pompe patients aged up to 17 years.Results: From approximately age 2 years onwards, brain MRI showed involvement of the periventricular white matter and centrum semiovale. After 8 years of age, additional white-matter abnormalities occurred in the corpus callosum, internal and external capsule, and subcortical areas. From 11 years of age, white-matter abnormalities were also found in the brainstem. Although there seemed to be a characteristic pattern of involvement over time, there were considerable variations between patients, reflected by variations in neuropsychological development. Cognitive development ranged from stable and normal to declines that lead to intellectual disabilities.Interpretation: As treatment enables patients with classic infantile Pompe disease to reach adulthood, white-matter abnormalities are becoming increasingly evident, affecting the neuropsychological development. Therefore, we advise follow-up programs are expanded to capture CNS involvement in larger, international patient cohorts, to incorporate our findings in the counselling of parents before the start of treatment, and to include the brain as an additional target in the development of next-generation therapeutic strategies for classic infantile Pompe disease.What This Paper Adds: In our long-term survivors treated intravenously with enzyme replacement therapy, we found slowly progressive symmetric white-matter abnormalities. Cognitive development varied from stable and normal to declines towards intellectual disabilities. [ABSTRACT FROM AUTHOR]

Aim: Mucopolysaccharidosis type II (MPS II) is caused by variants in the iduronate-2-sulphatase gene (IDS). Patients can be either neuronopathic with intellectual disability, or non-neuronopathic. Few studies have reported on the IDS genotype-phenotype relationship and on the molecular effects involved. We addressed this in a cohort study of Dutch patients with MPS II.Method: Intellectual performance was assessed for school performance, behaviour, and intelligence. Urinary glycosaminoglycans were quantified by mass spectrometry. IDS variants were analysed in expression studies for enzymatic activity and processing by immunoblotting.Results: Six patients had a non-neuronopathic phenotype and 11 a neuronopathic phenotype, three of whom had epilepsy. Total deletion of IDS invariably resulted in the neuronopathic phenotype. Phenotypes of seven known IDS variants were consistent with the literature. Expression studies of nine variants were novel and showed impaired IDS enzymatic activity, aberrant intracellular processing, and elevated urinary excretion of heparan sulphate and dermatan sulphate irrespective of the MPS II phenotype.Interpretation: We speculate that very low or cell-type-specific IDS residual activity is sufficient to prevent the neuronal phenotype of MPS II. Whereas the molecular effects of IDS variants do not distinguish between MPS II phenotypes, the IDS genotype is a strong predictor. [ABSTRACT FROM AUTHOR]

Hip problems in Mucopolysaccharidosis type VI (MPS VI) lead to severe disability. Lack of data on the course of hip disease in MPS VI make decisions regarding necessity, timing and type of surgical intervention difficult. We therefore studied the development of hip pathology in MPS VI patients over time. Data were collected as part of a prospective follow-up study. Standardized supine AP pelvis and frog leg lateral radiographs of both hips were performed yearly or every 2 years. Image assessment was performed quantitatively (angle measurements) and qualitatively (hip morphology). Clinical burden of hip disease was evaluated by physical examination, six minute walking test (6MWT) and a questionnaire assessing pain, wheelchair-dependency and walking distance. A total of 157 pelvic radiographs of 14 ERT treated MPS VI patients were evaluated. Age at first image ranged from 2.0 to 21.1 years. Median follow up duration was 6.8 years. In all patients, even in the youngest, the acetabulum and os ilium were dysplastic. Coverage of the femoral head by the acetabulum improved over time, but remained insufficient. While the femoral head appeared normal in the radiographs at young age, the ossification pattern became abnormal in all patients over time. In all patients the distance covered in the 6MWT was reduced (median Z scores − 3.3). Twelve patients had a waddling gait. Four patients were partially wheelchair-dependent and ten patients had limitations in their maximum walking distance. In conclusion, clinically significant hip abnormalities develop in all MPS VI patients from very early in life, starting with deformities of the os ilium and acetabulum. Femoral head abnormalities occur later, most likely due to altered mechanical forces in combination with epiphyseal abnormalities due to glycosaminoglycan storage. The final shape and angle of the femoral head differs significantly between individual MPS VI patients and is difficult to predict. [ABSTRACT FROM AUTHOR]

Rationale, aims and objectives Differences in the performance of medical care may be due to variation in the introduction and diffusion of medical innovations. The objective of this paper is to compare seven European countries ( United Kingdom, the Netherlands, West Germany, France, Spain, Estonia and Sweden) with regard to the year of introduction of six specific pharmaceutical innovations (antiretroviral drugs, cimetidine, tamoxifen, cisplatin, oxalaplatin and cyclosporin) that may have had important population health impacts. Methods We collected information on introduction and further diffusion of drugs using searches in the national and international literature, and questionnaires to national informants. We combined various sources of information, both official years of registration and other indicators of introduction (clinical trials, guidelines, evaluation reports, sales statistics). Results and conclusions The total length of the period between first and last introduction varied between 8 years for antiretroviral drugs and 22 years for cisplatin. Introduction in Estonia was generally delayed until the 1990s. The average time lags were smallest in France (2.2 years), United Kingdom (2.8 years) and the Netherlands (3.5 years). Similar rank orders were seen for year of registration suggesting that introduction lags are not only explained by differences in the process of registration. We discuss possible reasons for these between-country differences and implications for the evaluation of medical care. [ABSTRACT FROM AUTHOR]

An abstract of the article "Impact of enzyme replacement therapy on survival in adults with Pompe disease" by Michelle Kruijshaar, Iris Plug, Ralph D'Agostino Sr., Marloes Hagemans, Arnold Reuser, Ans van der Ploeg and Deniz Güngör is presented.

Background: Pompe disease is a rare metabolic myopathy for which disease-specific enzyme replacement therapy (ERT) has been available since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients. However, no data on the effect of ERT on the survival of adult patients are currently available. The aim of this study was to assess the effect of ERT on survival in adult patients with Pompe disease.Methods: Data were collected as part of an international observational study conducted between 2002 and 2011, in which patients were followed on an annual basis. Time-dependent Cox's proportional hazards models were used for univariable and multivariable analyses.Results: Overall, 283 adult patients with a median age of 48 years (range, 19 to 81 years) were included in the study. Seventy-two percent of patients started ERT at some time during follow-up, and 28% never received ERT. During follow-up (median, 6 years; range, 0.04 to 9 years), 46 patients died, 28 (61%) of whom had never received ERT. After adjustment for age, sex, country of residence, and disease severity (based on wheelchair and ventilator use), ERT was positively associated with survival (hazard ratio, 0.41; 95% CI, 0.19 to 0.87).Conclusion: This prospective study was the first to demonstrate the positive effect of ERT on survival in adults with Pompe disease. Given the relatively recent registration of ERT for Pompe disease, these findings further support its beneficial impact in adult patients. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pompe disease is a hereditary metabolic myopathy, for which enzyme replacement therapy (ERT) has been available since 2006. We investigated whether ERT reduces fatigue in adult patients with Pompe disease. Methods: In this prospective international observational survey, we used the Fatigue Severity Scale (FSS) to measure fatigue. Repeated measures ANOVA was used to analyze the data over time. In a subgroup of patients, we also evaluated muscle strength using the Medical Research Council Scale, measured pulmonary function as Forced Vital Capacity, and assessed depression using the Hospital Anxiety and Depression Scale. Results: We followed 163 patients for a median period of 4years before ERT and for 3years during ERT. Before ERT, the mean FSS score remained stable at around 5.3 score points; during ERT, scores improved significantly by 0.13 score points per year (p<0.001). Fatigue decreased mainly in women, in older patients and in those with shorter disease duration. Patients' improvements in fatigue were moderately correlated with the effect of ERT on depression (r 0.55; CI 95% 0.07 to 0.70) but not with the effect of ERT on muscle strength or pulmonary function. Conclusions: Fatigue is a common and disabling problem in patients with early and advanced stages of Pompe disease. Our finding that ERT helps to reduce fatigue is therefore important for this patient population, irrespective of the mechanisms underlying this effect. [Copyright &y& Elsevier]

Abstract: Maroteaux–Lamy syndrome (mucopolysaccharidosis type VI, MPS VI) is a rare progressive metabolic disorder characterized by coarse facial features, hepatosplenomegaly, restrictive pulmonary function, cardiac abnormalities and stiff joints. The disease is caused by a deficiency of the lysosomal enzyme N-acetyl galactosamine 4-sulfatase which leads to glycosaminoglycan (GAG) storage in various tissues. It presents as a clinical spectrum with varying disease progressions and severities. While the phases I/II/III studies proved the effectiveness of enzyme-replacement therapy (ERT) with recombinant human arylsulfatase B, long-term data are still scarce. Over treatment periods ranging from 1.3 to 5.4years, this prospective open-label follow-up study in 11 Dutch mucopolysaccharidosis type VI patients (age 2–18years) showed that ERT had significant positive effects on cardiac-wall diameters (IVSd and LVMI), left and right shoulder flexions (p<0.001), liver size and spleen size (p<0.001), urinary GAG excretion (p<0.001), and the scales of quality of life (motor functioning and body functioning). ERT did not affect cardiac valve regurgitation or hearing function; HRQoL decreased slightly in two domains (‘anxiety’ and ‘negative emotions’), and patients with the rapid and slow progressive forms of the disease differed with regard to baseline GAG excretion and GAG decrease during treatment. In conclusion, ERT had an effect on several clinical parameters. This effect was established in an open cohort of young mucopolysaccharidosis type VI patients. [Copyright &y& Elsevier]

Background: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B). Methods: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome. in vitro Results: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase . in vitro Conclusions: The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy. [ABSTRACT FROM AUTHOR]

Background and study aims: There is widespread consensus on the need for better indicators of the effectiveness of healthcare. We carried out an analysis of the validity of amenable mortality as an indicator of the effectiveness of healthcare, focusing on the potential use in routine surveillance systems of between-country variations in rates of mortality. We assessed whether the introduction of specific healthcare innovations coincided with declines in mortality from potentially amenable causes in seven European countries. In this paper, we summarise the main results of this study and illustrate them for four conditions. Data and methods: We identified 14 conditions for which considerable declines in mortality have been observed and for which there is reasonable evidence in the literature of the effectiveness of healthcare interventions to lower mortality. We determined the time at which these interventions were introduced and assessed whether the innovations coincided with favourable changes in the mortality trends from these conditions, measured using Poisson linear spline regression. All the evidence was then presented to a Delphi panel. Main results: The timing of innovation and favourable change in mortality trends coincided for only a few conditions. Other reasons for mortality decline are likely to include diffusion and improved quality of interventions and in incidence of diseases and their risk factors, but there is insufficient evidence to differentiate these at present. For most conditions, a Delphi panel could not reach consensus on the role of current mortality levels as measures of effectiveness of healthcare. Discussion and conclusions: Improvements in healthcare probably lowered mortality from many of the conditions that we studied but occurred in a much more diffuse way than we assumed in the study design. Quantification of the contribution of healthcare to mortality requires adequate data on timing of innovation and trends in diffusion and quality and in incidence of disease, none of which are currently available. Given these gaps in knowledge, between-country differences in levels of mortality from amenable conditions should not be used for routine surveillance of healthcare performance. The timing and pace of mortality decline from amenable conditions may provide better indicators of healthcare performance. [ABSTRACT FROM AUTHOR]

An abstract of the article "Enzyme replacement therapy and fatigue in adults with Pompe disease" by Deniz Güngö, Juna de Vries, Esther Brusse, Michelle Kruijshaar, Linda van den Berg, Wim Hop, Arnold Reuser, Pieter van Doorn, Marloes Hagemans and Iris Plug is presented.

Background: Mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome; MPS VI) is an autosomal recessive lysosomal storage disorder in which deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B; ARSB) leads to the storage of glycosaminoglycans (GAGs) in connective tissue. The genotype-phenotype correlation has been addressed in several publications but the picture is not complete. Since 2007, enzyme-replacement therapy (ERT) has been available for patients with MPS VI in the Netherlands. The purpose of our study was to learn more about the genotype-phenotype correlations in MPS VI and the antibody response to ERT with galsulfase (recombinant human arylsulfatase B).Methods: We identified ARSB mutations in 12 patients and used site-directed mutagenesis to study their effect. Antibody levels to galsulfase were measured using ELISA and a semi-quantitative immunoprecipitation method. We assessed the in vitro inhibitory effect of antibodies on galsulfase uptake and their effect on clinical outcome.Results: Five patients had a rapidly progressive phenotype and seven a slowly progressive phenotype. In total 9 pathogenic mutations were identified including 4 novel mutations (N301K, V332G, A237D, and c.1142 + 2 T > C) together composing 8 pathogenic genotypes. Most mutations appeared not to affect the synthesis of ARSB (66 kD precursor), but to hamper its maturation (43 kD ARSB). Disease severity was correlated with urinary GAG excretion. All patients developed antibodies to galsulfase within 26 weeks of treatment. It was demonstrated that these antibodies can inhibit the uptake of galsulfase in vitro.Conclusions: The clinical phenotypes and the observed defects in the biosynthesis of ARSB show that some of the mutations that we identified are clearly more severe than others. Patients receiving galsulfase as enzyme-replacement therapy can develop antibodies towards the therapeutic protein. Though most titers are modest, they can exceed a level at which they potentially affect the clinical outcome of enzyme-replacement therapy. [ABSTRACT FROM AUTHOR]