Large variation in effects during 10 years of enzyme therapy in adults with Pompe disease.
ABSTRACT: OBJECTIVE:To determine the effects of 10 years of enzyme replacement therapy (ERT) in adult patients with Pompe disease, focusing on individual variability in treatment response. METHODS:In this prospective, multicenter cohort study, we studied 30 patients from the Netherlands and France who had started ERT during the only randomized placebo-controlled clinical trial with ERT in late-onset Pompe disease (NCT00158600) or its extension (NCT00455195) in 2005 to 2008. Main outcomes were walking ability (6-minute walk test [6MWT]), muscle strength (manual muscle testing using Medical Research Council [MRC] grading), and pulmonary function (forced vital capacity [FVC] in the upright and supine positions), assessed at 3- to 6-month intervals before and after the start of ERT. Data were analyzed with linear mixed-effects models for repeated measurements. RESULTS:Median follow-up duration on ERT was 9.8 years (interquartile range [IQR] 8.3-10.2 years). At the group level, baseline 6MWT was 49% of predicted (IQR 41%-60%) and had deteriorated by 22.2 percentage points (pp) at the 10-year treatment point (p < 0.001). Baseline FVC upright was 54% of predicted (IQR 47%-68%) and decreased by 11 pp over 10 years (p < 0.001). Effects of ERT on MRC sum score and FVC supine were similar. At the individual level, 93% of patients had initial benefit of ERT. Depending on the outcome measured, 35% to 63% of patients had a secondary decline after ?3 to 5 years. Still, at 10 years of ERT, 52% had equal or better 6MWT and/or FVC upright compared to baseline. CONCLUSIONS:The majority of patients with Pompe disease benefit from long-term ERT, but many patients experience some secondary decline after ?3 to 5 years. Individual variation, however, is considerable. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for the majority of adults with Pompe disease, long-term ERT positively affects, or slows deterioration in, muscle strength, walking ability, and/or pulmonary function.
Project description:BACKGROUND:Pompe disease is a rare, progressive metabolic myopathy. The aim of this study is to investigate the associations of physical outcomes with patient-reported outcome measures (PROMs) in late-onset Pompe disease. METHODS:We included 121 Dutch adult patients with Pompe disease. Physical outcomes comprised muscle strength (manual muscle testing using Medical Research Council [MRC] grading, hand-held dynamometry [HHD]), walking ability (6-min walk test [6MWT]), and pulmonary function (forced vital capacity [FVC] in upright and supine positions). PROMs comprised quality of life (Short Form 36 health survey [SF-36]), participation (Rotterdam Handicap Scale [RHS]) and daily-life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale). Analyses were cross-sectional: the time-point before, and closest to, start of Enzyme Replacement Therapy was chosen. Associations between PROMs and physical outcomes were investigated using linear regression models. RESULTS:RHS and R-PAct scores were better in patients with higher FVC supine and upright, HHD, MRC and 6MWT scores, accounting for the effect of sex, disease duration, use of wheelchair and ventilator support. While the SF-36 Physical Component Summary (PCS) was correlated positively with FVC upright, HHD, MRC and 6MWT scores, there was no significant relationship between the SF-36 Mental Component Summary (MCS) and any of the physical outcomes. CONCLUSIONS:Participation, daily-life activities, and the physical component of quality of life of adult Pompe patients are positively correlated to physical outcomes. This work serves as a first step towards assessing how changes over time in physical outcomes are related to changes in PROMs, and to define the minimal change in physical outcomes required to make an important difference for the patient.
Project description:BACKGROUND: Enzyme replacement therapy (ERT) in adults with Pompe disease, a progressive neuromuscular disorder, is of promising but variable efficacy. We investigated whether it alters the course of disease, and also identified potential prognostic factors. METHODS: Patients in this open-label single-center study were treated biweekly with 20 mg/kg alglucosidase alfa. Muscle strength, muscle function, and pulmonary function were assessed every 3-6 months and analyzed using repeated-measures ANOVA. RESULTS: Sixty-nine patients (median age 52.1 years) were followed for a median of 23 months. Muscle strength increased after start of ERT (manual muscle testing 1.4 percentage points per year (pp/y); hand-held dynamometry 4.0 pp/y; both p < 0.001). Forced vital capacity (FVC) remained stable when measured in upright, but declined in supine position (-1.1 pp/y; p = 0.03). Muscle function did not improve in all patients (quick motor function test 0.7 pp/y; p = 0.14), but increased significantly in wheelchair-independent patients and those with mild and moderate muscle weakness.Relative to the pre-treatment period (49 patients with 14 months pre-ERT and 22 months ERT median follow-up), ERT affected muscle strength positively (manual muscle testing +3.3 pp/y, p < 0.001 and hand-held dynamometry +7.9 pp/y, p < 0.001). Its effect on upright FVC was +1.8 pp/y (p = 0.08) and on supine FVC +0.8 (p = 0.38). Favorable prognostic factors were female gender for muscle strength, and younger age and better clinical status for supine FVC. CONCLUSIONS: We conclude that ERT positively alters the natural course of Pompe disease in adult patients; muscle strength increased and upright FVC stabilized. Functional outcome is probably best when ERT intervention is timely.
Project description:The majority of children and adults with Pompe disease in the population of European descent carry the leaky splicing GAA variant c.-32-13T>G (IVS1) in combination with a fully deleterious GAA variant on the second allele. The phenotypic spectrum of this patient group is exceptionally broad, with symptom onset ranging from early infancy to late adulthood. In addition, the response to enzyme replacement therapy (ERT) varies between patients. The insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) has been suggested to be a modifier of disease onset and/or response to ERT. Here, we have investigated the effect of the ACE I/D polymorphism in a relatively large cohort of 131 children and adults with Pompe disease, of whom 112 were followed during treatment with ERT for 5 years. We assessed the use of wheelchair and mechanical ventilation, muscle strength assessed via manual muscle testing and hand-held dynamometry (HHD), distance walked on the six-minute walk test (6MWT), forced vital capacity (FVC) in sitting and supine position and daily-life activities assessed by R-PAct. Cross sectional analysis at first visit showed no differences between the genotypes with respect to age at first symptoms, diagnosis, wheelchair use, or ventilator use. Also response to ERT over 5 years assessed by linear mixed model analyses showed no significant differences between ACE groups for any of the outcome measures. The patient cohort contained 24 families with 54 siblings. Differences in ACE genotype could neither explain inter nor intra familial differences. We conclude that the ACE I/D polymorphism does not explain the large variation in disease severity and response to ERT observed among Pompe patients with the same c.-32-13T>G GAA variant.
Project description:BACKGROUND:Late-onset Pompe disease (LOPD) is a rare, metabolic disease primarily affecting the musculoskeletal and respiratory systems. Forced vital capacity (FVC) is commonly used to measure pulmonary function; however, associations between FVC and other LOPD outcomes remain unclear. METHODS:A systematic literature review was conducted on November 2015, updated September 2016 and supplemented with clinical trial data from the sponsor. Outcomes included: 6-min walk test distance (6MWT), FVC, maximal inspiratory/expiratory pressure (MIP/MEP), Medical Research Council-skeletal muscle strength score (MRC), 36-item short-form survey-physical component score (SF-36), Rotterdam Handicap Scale (RHS), Fatigue Severity Scale (FSS) and survival. Individual patient data meta-analysis was used for cross-sectional analyses and longitudinal analyses to determine associations between percent of predicted FVC and LOPD measures and outcomes. RESULTS:Fifteen studies were selected. From cross-sectional analyses, FVC and MRC were most strongly associated. Specifically, patients with 10% higher FVC (a round number for illustrative purposes only) were associated with a 4.72% (95% confidence interval [CI]: 3.37, 6.07) higher MRC score, indicating a positive association. Similarly, slopes for the 6MWT and SF-36 relative to a 10% higher FVC were estimated at 33.2 meters (95% CI 24.0, 42.4) and 1.2% (95% CI 0.24, 2.16%), respectively. From longitudinal analyses, a 10% incremental increase in predicted FVC was associated with an average increase of 4.12% in MRC score (95% CI 1.29, 6.95), 35.6 m in the 6MWT (95% CI 19.9, 51.6), and 1.34% in SF-36 (95% CI 0.08, 2.60). There was insufficient data to conduct analyses for RHS, FSS and survival. CONCLUSIONS:FVC is positively associated with LOPD measures and outcomes across multiple domains. Additionally, longitudinal changes in FVC are positively associated with changes in the 6MWT, MRC and SF-36.
Project description:OBJECTIVES:Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic-infantile patients and in adults, little has been published on ERT in children with non-classic presentations. STUDY DESIGN:This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function (6-minute walk test, quick motor-function test (QMFT)), muscle strength (hand-held dynamometry; manual muscle testing), and lung function (FVC sitting and supine). For each outcome measure, we used linear mixed-effects models to calculate the difference at group level between the start of therapy and 7 years of ERT. Patients' individual responses over time were also evaluated. RESULTS:Eleven males and six females started ERT at ages between 1.1 and 16.4 years (median 11.9 years); 82% of them carried the common c.-32-13T > G GAA gene variant on one allele. At group level, distance walked increased by 7.4 percentage points (p < 0.001) and QMFT scores increased by 9.2 percentage points (p = 0.006). Muscle strength scores seemed to remain stable. Results on lung function were more variable. Patients' individual data show that the proportion of patients who stabilized or improved during treatment ranged between 56 and 69% for lung function outcomes and between 71 and 93% for muscle strength and muscle function outcomes. CONCLUSIONS:We report a positive effect of ERT in patients with childhood Pompe disease at group level. For some patients, new or personalized treatments should be considered.
Project description:Pompe disease/glycogen storage disease type II, is a rare, lysosomal storage disorder associated with progressive proximal myopathy, causing a gradual loss of muscular function and respiratory insufficiency. Studies of patients with late-onset Pompe disease have used endpoints such as the 6-minute walking test (6MWT) and forced vital capacity (FVC) to assess muscular and respiratory function during disease progression or treatment. However, the relevance of these markers to late-onset Pompe disease and the minimal clinically important difference (MCID) for these endpoints in late-onset Pompe disease have not yet been established. A literature search was carried out to identify studies reporting the MCID (absolute and relative) for the 6MWT and FVC in other diseases. The MCIDs determined in studies of chronic respiratory diseases were used to analyze the results of clinical studies of enzyme replacement therapy in late-onset Pompe disease. In 9 of the 10 late-onset Pompe disease studies reviewed, changes from baseline in the 6MWT were above or within the MCID established in respiratory diseases. Clinical improvement was perceived by patients in 6 of the 10 studies. In 6 of the 9 late-onset Pompe disease studies that reported FVC, the changes from baseline in percentage predicted FVC were above or within the MCID established in respiratory diseases and the difference was perceived as either an improvement or stabilization by patients. However, applying the 6MWT and FVC MCIDs from studies of chronic respiratory diseases to late-onset Pompe disease has several important limitations. Outcome measures in muscular dystrophies include composite measures of muscle function and gait, as well as Rasch-designed and validated tools to assess disease-related quality of life and activities of daily living. Given that the relevance to patients with late-onset Pompe disease of the 6MWT or FVC MCIDs established for chronic respiratory diseases is unclear, these measures should be evaluated specifically in late-onset Pompe disease and alternative outcome measures more specific to neuromuscular disease considered.
Project description:In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.
Project description:Introduction:Mucopolysaccharidosis (MPS) type IVA is a rare, autosomal recessive lysosomal storage disease causing substrate accumulation in various organs and tissues. MPS IVA is associated with both obstructive and restrictive airway disease, with the former often resulting in sleep disordered breathing (SDB). Respiratory failure is a primary cause of death in this condition. The aim of this study was to characterise and catalogue the long-term respiratory changes in patients with MPS IVA treated with, or without, enzyme replacement therapy (ERT). Methods:In this retrospective, longitudinal, repeated-measures cohort study, descriptive statistics and non-parametric correlation were performed for demographic, respiratory function and oximetry variables over a study period from January 2009 to December 2018. Composite clinical endpoints used in this study for evaluating pulmonary function included spirometry variables (FEV1, FEV1 [%Pred] FVC, FVC [%Pred] and FEV1/FVC), oximetry variables (median %Spo2, ODI 3%, mean nadir 3%, ODI 4%, mean nadir 4% and min dip SpO2 [%]) and 6MWT to assess functional exercise capacity and thus integrated cardiopulmonary function. Results:Sequential spirometry and oximetry values were collected from 16 patients, of which 13/16 were ERT treated. In general, during the study period there was a global reduction in static spirometry values in all subjects, as well as cardiorespiratory function as assessed by the 6MWT, with the decline being delayed in the ERT group. Oximetry changed to a minor degree over time in the ERT group, whereas it declined in the non-ERT group. FEV1, FVC [%predicted] and ODI 3% exhibited a strong, combined positive correlation (r 0.74-95% CI 0.61 to 0.83; p?<?.0001). Non-invasive ventilation (NIV) and adenotonsillectomy appeared more effective in the ERT group, either improving pulmonary function or attenuating deterioration. Conclusions:Whilst spirometry values showed a gradual decline across all groups, oximetry showed modest improvement in respiratory function. The amalgamation of FEV1, FVC [%predicted] and ODI 3% appeared predictive of changes in respiratory function in this study, suggestive as being composite endpoints for monitoring disease progression as well as guiding response to ERT in MPS IVA patients.
Project description:In neuromuscular disease, non-invasive ventilation (NIV) is indicated if sleep-disordered breathing (SDB) or significant respiratory muscle weakness (RMW) is present. We investigated immediate and long-term effects of NIV on sleep and nocturnal ventilation in patients with late-onset Pompe disease (LOPD).Polysomnography and transcutaneous capnometry were performed in 22 adult patients. If indicated, NIV was initiated the subsequent night and follow-up sleep studies were scheduled. Sleep quality and health-related quality of life (HRQoL) were self-assessed using standard questionnaires.Fourteen patients received enzyme replacement therapy (ERT), five patients were treatment-naÏve, and three individuals had previously stopped ERT. Fifteen patients reported symptoms of SDB, all showing abnormal sleep studies. Two patients had obstructive sleep apnea (OSA), three patients showed both OSA and nocturnal hypercapnia, four individuals had nocturnal hypercapnia, and two patients had both OSA and daytime hypercapnia. Four patients showed normal apnea-hypopnea index and CO2 measures but nocturnal tachypnea, orthopnea, and significant RMW were present. Supine forced vital capacity (FVC) and positional drop of FVC were independent predictors of SDB. In patients with SDB, HRQoL was significantly reduced. NIV was initiated in 15 individuals and led to significant improvement of ventilation and oxygenation in the first night of treatment. Follow-up sleep studies revealed stable normoxia and normocapnia without deterioration of sleep outcomes for up to 40 months.In LOPD, SDB is common and comprises both hypoventilation and OSA. NIV significantly improves respiration already in the first night of treatment. NIV warrants nocturnal long-term normoventilation without deterioration of sleep quality.
Project description:BACKGROUND:Enzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT. METHODS:In this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head). RESULTS:Median age at start of ERT was 3.2?months (0.1-5.8?months), median age at study end was 5.6?years (2.9-18.2?years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit. CONCLUSIONS:We found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.