Background: Pompe disease is a glycogen storage disease caused by an autosomal recessively inherited deficiency in acid alpha-glucosidase, an enzyme responsible for lysosomal glycogen degradation. Late-onset Pompe disease (LOPD) presents primarily as a progressive proximal myopathy with respiratory involvement. Since 2006 an enzyme replacement therapy (ERT) is available. In our study we investigated the long-term effectiveness of ERT in a population of late-onset Pompe disease and tried to identify prognostic factors influencing treatment response. Methods: In this prospective, single center study we followed-up 21 patients with LOPD: 3 of them did not receive ERT because asymptomatic, 6 were excluded from the statistical analysis due to very severe disease and unreliability of outcome measures, leaving 12 patients with mild to severe disease on ERT to be included in the longitudinal analysis of treatment effectiveness. The main outcome measure to assess motor outcome was the 6-minute walking test (6MWT), the main outcome measure to assess respiratory outcome was upright forced vital capacity (FVC). Muscle strength assessed by hand-held dynamometry, muscle structure assessed by MRI, maximal inspiratory and expiratory pressures (MIP/MEP), supine FVC, postural drop (Delta FVC) and nutritional parameters such as fat free mass (FFM) and Phase Angle (PhA) by body impedance analysis (BIA) were also assessed as secondary outcome measures. Results: Median follow-up duration was 12 years (range 2-15). The overall improvement in 6MWT was most evident during the first year (p=0.010), with a tendency to return to baseline values within the first three years, followed by a relative stabilization and then a slow worsening, beginning 6 years after ERT start and continuing thereafter (p=0.04 after T9 and p=0.026 after T12). At the final follow-up, the 6MWT was usually lower than at the start of treatment (mean -15.9 + 35.64 %, range +23 to -100 %). Better motor outcome was observed in patients with higher CK values at the start of ERT (p=0.046), lower BMI (p=0.040) and shorter disease duration (p=0.065, n.s.). Unlike for 6MWT, there was no significant improvement in FVC during the first year of treatment, followed by a relatively stable course, with mild worsening between T6 and T9 being the only significant change (p=0.011). FVC was not influenced by any of the outcome predictors we tested for. Supine FVC showed a worse response to treatment. At the individual level, 58.3% of patients had a significant initial improvement in either motor or respiratory outcome, or both, within the first year of ERT. Depending on the outcome measured, 50% (for 6MWT) to 58.3% (for FVC) of patients experienced a secondary decline. Still, at the final follow-up 66.6% of patients had equal or better 6MWT and/or upright FVC compared to baseline. We failed to find robust outcome predictors, except for a tendency for shorter disease duration, better initial 6MWT, higher CK levels, lower BMI and higher FFM at baseline in patients with better motor outcome, and a better final overall outcome in patients with better baseline 6MWT and better body composition (in terms of FFM and PhA). Conclusions: Although many patients experience some secondary decline after the first 3-5 years, the majority of patients with PD benefit from long-term ERT. There is high inter-individual variability; a better body composition in terms of FFM and PhA seems to predict a better response.
Introduzione e razionale: La malattia di Pompe è una glicogenosi (malattia da accumulo di glicogeno) a eredità autosomica recessiva, causata dalla carenza dell'enzima alfa-glucosidasi, responsabile della degradazione del glicogeno lisosomiale. La malattia di Pompe ad esordio tardivo (late-onset Pompe disease = LOPD) si manifesta clinicamente con una miopatia prossimale lentamente progressiva e con coinvolgimento respiratorio. Dal 2006 è disponibile una terapia enzimatica sostitutiva (enzyme replacement therapy = ERT). In questo studio abbiamo valutato l'efficacia a lungo termine della ERT in una popolazione di pazienti con malattia di Pompe ad esordio tardivo e abbiamo cercato di identificare predittivi di risposta alla terapia. Metodo: In questo studio prospettico abbiamo seguito, in un unico centro, 21 pazienti con LOPD: 3 di questi non sono stati trattati con ERT perché erano asintomatici; 6 sono stati esclusi dall'analisi statistica perché con malattia molto grave e, di conseguenza, scarsa affidabilità delle misure di outcome; 12 pazienti malattia da lieve a grave trattati con ERT sono stati inclusi nell'analisi longitudinale dell'efficacia del trattamento. L’esito motorio è stato valutato mediante il test del cammino di 6 minuti (6MWT), l'esito respiratorio mediante la capacità vitale forzata (FVC); entrambe queste misure rappresentano gli endpoint primari. Quali misure di outcome secondarie sono stati analizzati anche: la forza muscolare valutata mediante dinamometria manuale, la struttura del muscolo scheletrico mediante RM, le massime pressioni inspiratorie ed espiratorie (MIP/MEP), la FVC in posizione supina, la caduta posturale della FVC (Delta FVC) e i parametri nutrizionali quali massa magra (FFM), massa grassa, e angolo di fase (PhA), valutati mediante analisi dell'impedenza corporea (BIA). Risultati: La durata mediana del follow-up è stata di 12 anni (range 2-15). Il miglioramento complessivo del 6MWT è stato più evidente durante il primo anno (p = 0,010), con una tendenza a tornare ai valori basali entro i primi tre anni, seguita da una stabilizzazione relativa e quindi da un lento peggioramento, a partire dal sesto anno dopo l'avvio della ERT (p = 0,04 dopo T9 e p = 0,026 dopo T12). Al follow-up finale, il 6MWT era solitamente inferiore rispetto al basale (media -15,9 + 35,64%, intervallo da +23 a -100%). L’esito motorio era lievemente migliore in pazienti con valori di CK più elevati all'inizio di ERT (p = 0,046), BMI inferiore (p = 0,040) e durata di malattia inferiore (p = 0,065, n.s.). A differenza del 6MWT, durante il primo anno di trattamento non vi è stato alcun miglioramento significativo della FVC; seguiva un decorso relativamente stabile, con un lieve ma significativo peggioramento tra T6 e T9 (p = 0,011). La FVC non sembra influenzata da nessuno dei fattori prognostici testati. La FVC in posizione supina ha mostrato una scarsa risposta al trattamento. A livello individuale, il 58,3% dei pazienti ha avuto un miglioramento motorio, respiratorio, o di entrambi i parametri, entro il primo anno di ERT. Dal 50% (per 6MWT) al 58,3% (per FVC) dei pazienti ha manifestato un peggioramento tardivo; tuttavia, al follow-up finale, il 66,6% dei pazienti mostra un 6MWT e / o FVC uguale o migliore rispetto al basale. Non siamo riusciti a identificare solidi e sicuri fattori prognostici, ad eccezione di una tendenza ad un outcome motorio e globale migliore in pazienti con: durata inferiore di malattia, migliore 6MWT basale, livelli più elevati di CK basale, BMI inferiore, e migliore composizione corporea (in termini di FFM e PhA). Conclusioni: Anche se alcuni pazienti presentano un declino secondario dopo i primi 3-5 anni di trattamento, nella maggioranza dei pazienti con LOPD la ERT si mantiene efficace anche nel lungo termine. Una migliore composizione corporea in termini di FFM e angolo di fase sembrano predire una migliore risposta.
Long-term Effectiveness of Enzyme Replacement Therapy in a Population of Late-onset Pompe Disease
JEHNE, SUSAN ANDREA VIKTORIA
2019/2020
Abstract
Background: Pompe disease is a glycogen storage disease caused by an autosomal recessively inherited deficiency in acid alpha-glucosidase, an enzyme responsible for lysosomal glycogen degradation. Late-onset Pompe disease (LOPD) presents primarily as a progressive proximal myopathy with respiratory involvement. Since 2006 an enzyme replacement therapy (ERT) is available. In our study we investigated the long-term effectiveness of ERT in a population of late-onset Pompe disease and tried to identify prognostic factors influencing treatment response. Methods: In this prospective, single center study we followed-up 21 patients with LOPD: 3 of them did not receive ERT because asymptomatic, 6 were excluded from the statistical analysis due to very severe disease and unreliability of outcome measures, leaving 12 patients with mild to severe disease on ERT to be included in the longitudinal analysis of treatment effectiveness. The main outcome measure to assess motor outcome was the 6-minute walking test (6MWT), the main outcome measure to assess respiratory outcome was upright forced vital capacity (FVC). Muscle strength assessed by hand-held dynamometry, muscle structure assessed by MRI, maximal inspiratory and expiratory pressures (MIP/MEP), supine FVC, postural drop (Delta FVC) and nutritional parameters such as fat free mass (FFM) and Phase Angle (PhA) by body impedance analysis (BIA) were also assessed as secondary outcome measures. Results: Median follow-up duration was 12 years (range 2-15). The overall improvement in 6MWT was most evident during the first year (p=0.010), with a tendency to return to baseline values within the first three years, followed by a relative stabilization and then a slow worsening, beginning 6 years after ERT start and continuing thereafter (p=0.04 after T9 and p=0.026 after T12). At the final follow-up, the 6MWT was usually lower than at the start of treatment (mean -15.9 + 35.64 %, range +23 to -100 %). Better motor outcome was observed in patients with higher CK values at the start of ERT (p=0.046), lower BMI (p=0.040) and shorter disease duration (p=0.065, n.s.). Unlike for 6MWT, there was no significant improvement in FVC during the first year of treatment, followed by a relatively stable course, with mild worsening between T6 and T9 being the only significant change (p=0.011). FVC was not influenced by any of the outcome predictors we tested for. Supine FVC showed a worse response to treatment. At the individual level, 58.3% of patients had a significant initial improvement in either motor or respiratory outcome, or both, within the first year of ERT. Depending on the outcome measured, 50% (for 6MWT) to 58.3% (for FVC) of patients experienced a secondary decline. Still, at the final follow-up 66.6% of patients had equal or better 6MWT and/or upright FVC compared to baseline. We failed to find robust outcome predictors, except for a tendency for shorter disease duration, better initial 6MWT, higher CK levels, lower BMI and higher FFM at baseline in patients with better motor outcome, and a better final overall outcome in patients with better baseline 6MWT and better body composition (in terms of FFM and PhA). Conclusions: Although many patients experience some secondary decline after the first 3-5 years, the majority of patients with PD benefit from long-term ERT. There is high inter-individual variability; a better body composition in terms of FFM and PhA seems to predict a better response.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11632