This study in a large international cohort of patients with Pompe disease showed enzyme replacement therapy to have a positive effect on patients’ physical health status (PCS) and their participation in daily life. The use of ERT halted the progressive decline in physical health status and participation observed pre-treatment; during the first two years of ERT patients’ physical health status even improved. Patients’ mental-health status (MCS) remained the same throughout the entire follow-up including the pre-treatment period.
The significant improvement in the PCS during the first two years of treatment was most noticeable in the role physical domain, which increased by 9 score-points per year, reflecting a large increase in patients’ ability to perform their work and other common activities. Two physical health domains were below the population norm in our Pompe cohort: physical functioning and role physical (see also Hagemans et al 2004). These domains improved over the entire treatment follow-up, as did general health, explaining the increase in PCS scores after the start of ERT.
The improvements in the physical functioning and role physical domains may have been due to the positive effect of ERT on muscle function and strength seen in other studies (Angelini et al 2012; Bembi et al 2010; de Vries et al 2012; Orlikowski et al 2011; Regnery et al 2012; van der Ploeg et al 2012; van der Ploeg et al 2010). In addition to the three domains that improved, bodily pain is important to determining the PCS level. In the first two years after the start of ERT, bodily pain stabilized, but with longer treatment it declined, indicating more pain. This may signify that ERT is only partially curative. Only one other study (in two patients) has provided information on the effect of ERT on pain; this showed that pain decreased in the year after the start of ERT (Vielhaber et al 2011). Recently, pain was also shown to be a relatively common symptom in treated and untreated patients alike (Gungor et al 2013).
Ours is the first study in adult Pompe patients to examine the effect of ERT on their participation in daily life. Patients’ reduced physical health status at start of ERT was mirrored by their lower level of participation in daily life. The impact of Pompe disease on participation and the decline in participation over time before ERT has previously been described in a group of 40 Dutch patients (Hagemans et al 2006), and was confirmed by the current study. Compared to the decline observed prior to ERT, the stabilization that took place during treatment should be seen as an important effect of therapy: for patients with Pompe disease, it is very valuable to maintain rather than lose a certain level of social activities.
Our observation that the MCS remained stable even without treatment is consistent with the outcomes of previous studies showing that adult Pompe patients have the same mental-health status as healthy individuals (Hagemans et al 2004; Kanters et al 2011). Over time, patients with a chronic disease such as Pompe disease may adapt to their situation by changing their standards, values and conceptualizations; this may explain their stable mental-health scores during follow-up. During ERT, there was an improvement in only one of the four domains that chiefly determine the MCS: vitality, which assesses the level of energy. This corroborates previous findings in this cohort in which ERT reduced the level of fatigue measured by the Fatigue Severity Scale (Gungor et al 2013).
As shown in earlier analyses of this survey, more severely affected patients had worse physical health and handicap scores than those less severely affected (Hagemans et al 2004 and Hagemans et al 2007a). Nevertheless, no difference was observed between these groups in the effect of ERT on these outcome measures. While this could suggest that ERT is equally beneficial in the experience of the patient, the results of these subgroup analyses should be interpreted with caution as we could not adjust for other factors that may differ between these patients.
This is the first time that significant positive effects of ERT on physical health status (PCS) have been demonstrated in such a large study with long follow-up, although they have been suggested by some other studies (Orlikowski et al 2011; Toscano and Schoser 2013). There are two possible reasons why such positive effects were not demonstrated by the pivotal 18-month placebo-controlled trial by van der Ploeg et al on the effects of ERT (van der Ploeg et al 2010). Firstly, while the original trial had a smaller study population, with 60 patients in the treatment arm and 30 in the placebo arm, our own study followed 174 patients both before and after the start of therapy. Secondly, while follow-up in the original trial was 78 weeks, median follow-up in our study was 4 years before start of ERT and 4 years afterwards. The fact that sufficient follow-up time and a large number of patients are required was also demonstrated by our earlier study of 38 untreated Dutch patients, a limited study with only one year of follow-up in which we found no significant deterioration in physical health status (Hagemans et al 2004). The same population was included in the current study: now, with a long pre-treatment period and a larger study group, the deterioration in PCS in untreated patients became significant.
Randomized controlled trials are generally seen as the gold standard for assessing the effects of treatment. However, while they are an important means of showing the short-term effect of drugs, their limited duration does not allow for the assessment of long-term treatment effects. Our own longitudinal survey supplements the evidence obtained from such trials by enabling the long-term treatment effects to be evaluated in a broad patient population that also includes severely affected patients who would normally be excluded from a trial. It is also the case that international surveys and registries are the only way to obtain sufficient patient numbers for rare disorders such as Pompe disease. Our study thus has the advantage of incorporating a large cohort of Pompe patients of different ages and severities across different countries over a long follow-up period (up to 10 years).
The recruitment of patients through patient organizations might be seen as a limitation of this study, as it could result in the exclusion of patients at the more or less severe end of the spectrum. However, the demographic and clinical characteristics of our study population show that patients were included across the entire spectrum of adult Pompe disease. Although the SF-36 is a generic instrument that may not necessarily cover all the domains that are relevant in Pompe disease, we chose to use it because it is readily available and is also widely used in many different disorders. While more comprehensive information could be derived by using a disease-specific scale such as the R-Pact (van der Beek et al 2013), the R-Pact was not available when the survey was started.
Because patients’ perceptions of their health-related quality of life and participation in daily life can provide important information about the impact of a disease on patients’ lives, they are increasingly used in clinical research and practice. In 2006, the Food and Drug Administration (FDA) and The European Agency for the Evaluation of Medicinal Products (EMEA) both acknowledged the importance of such outcomes (US. FDA 2009; European Medicine Agency 2004). In the study of Pompe disease, the chronic progressive character of the disease means that patients will probably need lifelong therapy. While patients’ lives might be negatively affected by the possible burden of bi-weekly infusions, our results show that this burden is outweighed by the positive effects of ERT.
In conclusion ERT positively affects quality of life and participation in daily life of adult Pompe patients. Before treatment, physical health status and participation declined progressively. After the start of ERT, both stabilized. The effect on physical health status seemed to be greatest in the first two years after ERT. The mental-health status of these patients did not seem to be affected. These results reinforce the evidence available on the efficacy of ERT, showing that as well as its beneficial effect on muscle strength, pulmonary function and survival, ERT also improves patients’ perceived participation and quality of life.