Using data from the Pompe Survey, a long-term, disease-specific database using patient-reported outcome measures, we were able to perform the first study on survival and prognostic factors in adults with Pompe disease.
Over a prospective follow-up period of 7 years 34 of 268 patients died, 23 of them prior to ERT. Some of these patients died relatively young (23 years) and some reached very high ages despite Pompe disease (78 years). By using cumulative death probabilities of persons from the general population matched by age and gender, our study shows for the first time that mortality in adults with Pompe disease is higher than in the general population.
We also found that in our group of patients, diagnosed at a median age of 38 years, 17% died ten years after diagnosis. The median (50%) survival was estimated at 27 years after diagnosis. In an earlier study on the relation between disease severity and disease duration based on Pompe Survey data, we showed that 10-15 years after diagnosis 50% of the patients were wheelchair-bound or ventilator dependent [24
]. Thus, although Pompe disease in adults generally manifests as a slowly progressive disorder, it seriously affects the lives of patients.
Several factors in our study had a significant effect on survival. For patients without a wheelchair or respiratory support the 5-year survival from entry was 95%, while for patients with a wheelchair and respiratory support this was 74%. In practice this means that patients with a wheelchair and/or respiratory support have a shorter life expectancy at any age compared to patients without wheelchair and respiratory support. RHS score at study entry, indicative of the level of handicap or participation, also was significantly associated with survival. Whether the RHS score is also useful as a prognostic tool in clinical practice is a topic for further investigation.
The strength of our study is its prospective design, the regular follow-up, the representation across countries, and the large sample size, especially for a rare disorder such as Pompe disease. In orphan diseases, it is quite unique to be able to gather information on a large group of patients over so many years, especially prior to therapeutic intervention. Our prospective data collection was achieved by relying on patient reported outcome measures through a close collaboration with patient organizations. This approach enabled data collection without the support of a large physician's network that is -in orphan diseases-usually activated only after the introduction of a therapy. Our approach may stand model for data collection in other rare diseases. Since almost all newly diagnosed Pompe patients currently start with enzyme replacement therapy, this study might have been the very last chance to collect data on the natural course of Pompe disease.
Nevertheless, some methodological issues need further attention. Firstly, our patients were followed from 2002 onwards, which means that the majority entered the study at some cross-sectional point of their illness. The ideal method would have been to follow all patients from the time of disease onset or diagnosis until death. However, if we had applied those restrictions our study population would have been too small and the follow-up period would have been too short. Therefore, the next best thing was to also include the patients diagnosed before entering the study. This led to so-called 'left-truncated' data, with a grey area between diagnosis and study entry in which other patients may have died without entering our study, and could have caused an overestimation of the median survival. Additionally, because all data in the Pompe Survey are provided voluntarily, some deaths among enrolled patients who eventually became censored due to loss-to-follow-up (n = 37) may not have been reported.
Second, differences in wheelchair and ventilator use were observed between countries, with the Dutch patients tending to be less severely affected on average. This may be explained by the fact that the Dutch group includes almost all patients known in the Netherlands, while the inclusion through patient organizations in the other countries may have led to a larger proportion of more severely affected patients. This may have affected the estimation of median survival time, but does not influence our main conclusions that mortality in adults with Pompe disease is higher compared to the general population and is associated with disease severity.
Furthermore, our patients were followed for up to 7 years, but median follow-up time was 3.5 years. Although a longer follow-up of untreated patients would offer more insight in their survival, such a study will be difficult to do as most patients currently receive ERT.
Because our aim was to investigate the natural course survival, we censored patients at the initiation of ERT. This means that 11 patients who died after start of ERT were not included as deceased patients in our initial analysis. Most (n = 9) of these patients died within 1.5 year after start of ERT, or stopped ERT after a few infusions. As this treatment period is relatively short, we also performed analyses including these patients. Excluding these patients could have led to an underestimation of the number of deaths as these patients were already severely affected at the point they started ERT. All of them were wheelchair-bound and/or used respiratory support and most probably would also have died without ERT. For the same reason, in our comparison of death probabilities between the Dutch subgroup and the general population we also included the 4 patients who died shortly after start of ERT.
Unfortunately, information on cause of death was lacking for the majority of the deceased patients. However in our study, mortality was compared with the data obtained from the Dutch Central Bureau of Statistics, which reports deaths irrespective of the cause. This comparison showed that the difference in mortality between the two groups was statistically significant. This in itself is important information, which can be used to evaluate the severity of disease and may serve as a reference when comparing the mortality of patients under treatment. With regard to the reported causes of death, it seems likely that death due to respiratory insufficiency is related to Pompe disease [25
]. Other causes, such as aortic dissection can also (in)directly be related to Pompe disease, as it may be a consequence of glycogen accumulation in vascular smooth muscle [27
Whether timely start of ERT can increase survival of adults with Pompe disease is currently unknown. In a recently published randomized controlled trial of alglucosidase alfa in late-onset Pompe disease, significant differences in walking distance and pulmonary function between the alglucosidase alfa and placebo groups were found [16
]. Considering these results, and given the fact that most patients die of respiratory failure, it might be expected that ERT will also positively influence life expectancy. The present study, in which we show that Pompe disease has a serious negative impact on the life span of untreated adult patients, allows for future evaluation of the effect of ERT with respect to this important parameter.