Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS)

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare, life-limiting, multisystemic, X-linked lysosomal storage disease. The disorder is caused by mutations in the IDS gene, which encodes the lysosomal enzyme iduronate-2-sulfatase (I2S; EC 3.1.6.13) (Neufeld and Muenzer 2001). Deficiency in I2S activity leads to gradual accumulation of glycosaminoglycans in organs and tissues throughout the body. The resulting signs and symptoms can include both somatic and neurological involvement and are progressive in nature (Neufeld and Muenzer 2001; Wraith et al 2008a; b). Those affected by MPS II are almost always males (Neufeld and Muenzer 2001), with an estimated incidence of 0.6–1.3 per 100,000 live male births (Meikle et al 1999; Poorthuis et al 1999; Baehner et al 2005; Tylki-Szymanska 2014).

Clinical presentation in patients with MPS II is highly variable and the disorder has a broad spectrum of severity (Neufeld and Muenzer 2001). For clinical purposes, patients are generally considered to be in one of two categories according to the presence or absence of cognitive impairment. In patients with cognitive impairment, somatic involvement is usually severe and of early onset and may include coarse facial features, bone and joint abnormalities, short stature, respiratory and cardiac disease and hearing abnormalities. Somatic involvement in patients without cognitive impairment can range from being severe with early onset to much less severe with later onset (Young et al 1982; Young and Harper 1983; Neufeld and Muenzer 2001; Schwartz et al 2007; Wraith et al 2008b); this group of patients usually exhibits minimal or no neurological involvement.

Management of patients with MPS II requires a multidisciplinary approach involving a range of specialties such as cardiology, neurology, psychology, pulmonology and orthopaedics (Wraith et al 2008a; Muenzer et al 2009; Scarpa et al 2011). Disease-specific treatment in the form of enzyme replacement therapy (ERT) with recombinant I2S (idursulfase [Elaprase®]; Shire, Lexington, MA, USA) became available in the USA in 2006 and Europe in 2007, and alleviates many of the somatic signs and symptoms of the disorder (Muenzer et al 2011); before this, symptomatic management was the only possible treatment approach.

The life expectancy of untreated patients with MPS II is considerably shorter than that in the general population. Individuals with severe cognitive impairment typically die in their second decade, usually as a result of respiratory obstruction and/or cardiac failure (Neufeld and Muenzer 2001; Wraith et al 2008b; Jones et al 2009). Those who experience only somatic involvement may survive into their fifth or sixth decade (Neufeld and Muenzer 2001; Wraith et al 2008b; Jones et al 2009). Survival has improved since 1985, hypothesized to be a result of improvements in supportive care and an increased awareness and understanding of the disease; the latter factors may have led to increased recognition of less severely affected patients and thus an increase in overall life expectancy (Jones et al 2009; Muenzer et al 2009; Scarpa et al 2011). The impact of ERT with idursulfase on survival and causes of death in patients with MPS II has not yet been evaluated.

The Hunter Outcome Survey (HOS) is a large multicentre, observational registry that was launched in 2005 to collect real-world data on the natural history of MPS II and the long-term safety and efficacy of ERT with idursulfase (Wraith et al 2008a, Muenzer et al 2017). The aim of this analysis was to compare survival in idursulfase-treated and untreated patients with MPS II. Causes of death were also evaluated.

In this first analysis of survival and causes of death in idursulfase-treated and untreated patients with MPS II, we demonstrate improved survival with intravenous idursulfase therapy. Multivariate Cox regression modelling indicated a 54% lower risk of death in treated than in untreated patients, and patients with cognitive impairment had nearly a fivefold higher risk of death than those without. The most common causes of death in patients in this analysis were respiratory failure, cardiac arrest and pneumonia.

There are a multitude of factors that may impact the relative clinical outcomes in treated and untreated patients with a complex, variable, multi-systemic disease such as MPS II. Among these are potential differences in overall clinical management and care between patients receiving ERT and untreated patients. Clinical characteristics or levels of disease severity may also differ between the two groups. However, the demographic characteristics of the treated and untreated patients in our analysis had a high degree of similarity, including the proportion of patients with cognitive impairment. The primary Cox model adjusted for potential confounding factors and for any variables that were imbalanced between the two groups (e.g. region). We explored the potential impact of differing levels of medical intervention and supportive care by including the number of surgeries as a covariate in a secondary model, but found no significant impact on survival. A further factor may be access to treatment. The primary Cox model indicated a greater risk of death in Latin America than in other regions; it is possible that this is a result of local challenges in accessing intravenous idursulfase therapy or specialist healthcare, although further investigation would be needed to confirm this. It should be noted that there is always the possibility of an impact on the study results from unmeasured variables.

There are several age-related covariates that could have been included in the primary Cox model. Of these, we chose age at diagnosis as this is well-defined and is typically well-recorded according to the date of the confirmatory biochemical or genetic test. In contrast, age at symptom onset may be based on recollection of previous signs and symptoms after formal diagnosis of MPS II; the date may not be clear cut and the judgement of the relationship of the symptom with MPS II may be subjective. Use of just one of these age-related covariates also resulted in inclusion of more patients in the primary Cox model, as well as eliminating any potential for co-linearity.

In this analysis, we also demonstrated that patients with cognitive impairment have a much higher risk of death than those without. This is consistent with a previous analysis of a smaller, retrospective, population from the HOS registry that showed that cognitive impairment substantially reduced survival (Jones et al 2009). It is important to note that the binary and subjective nature of the ‘Cognitive impairment? yes/no’ question in HOS results in some limitations, for example in capturing the extent of progressive cognitive decline. Nonetheless, categorization of patients on this basis provides useful insight into the occurrence of cognitive impairment and its impact on survival. Intravenously delivered idursulfase does not cross the blood–brain barrier in therapeutic concentrations and would not be expected to address the cognitive aspects of disease directly (Muenzer et al 2006; Muenzer et al 2012). The most common causes of death in our analysis (respiratory failure, cardiac arrest and pneumonia) had a somatic component; in addition, patients with neurological involvement may also have severe somatic disease. The multisystemic and progressive nature of MPS II means that a single cause of death is unlikely to reflect the full clinical picture in each patient. Nonetheless, the contribution of somatic aspects of disease to mortality is consistent with the positive impact of intravenous idursulfase on survival; approaches that aim to deliver therapeutic enzyme to the central nervous system are in development (Noh and Lee 2014; Muenzer et al 2016).

Registries such as HOS are especially valuable for rare diseases: the ability to follow a large number and broad spectrum of patients for a long period of time enables us to build on the knowledge gained in the formal clinical studies that are often restricted in scope (Muenzer et al 2017). However, registry data have some inherent limitations. For example, all data are collected during routine clinical evaluations and so there will be unavoidable differences between sites in the frequency of follow-up visits, the investigations performed at each visit and in standardization of the data collected (Muenzer et al 2017). The nature of the study population meant that various definitions of survival time were considered for use in this analysis; the period from birth to death or last-recorded clinic visit was chosen because there was no common variable for the start of intervention (intravenous idursulfase therapy). Although this approach does not adjust for time not receiving ERT, it is more robust than using other starting points, such as HOS entry. It should also be noted that it is possible for patients to remain enrolled in the registry but be lost to follow-up and with their survival status at the time of the data extract therefore not recorded. Loss to follow-up in the analysis population was minimized by requesting updated information from the sites with patients for whom more than 3 years had elapsed between the most recent recorded visit and the date of data extraction, to ensure that updated information was entered in as many instances as possible. We did observe a greater loss to follow-up in the untreated than in the treated group; this imbalance between the groups perhaps reflects that patients receiving intravenous idursulfase visit the clinic more frequently and are more closely monitored than those who are not receiving infusions. As with any registry, it was not possible to control the size of each patient group. In addition, randomization of patients to the treated and untreated groups, which would minimize channelling bias, is not possible with registry data. However, the patients included in this analysis are believed to be representative of the broader MPS II population and both groups are considered to be comparable.

Our analysis in patients with MPS II also adds considerably to our overarching understanding of ERT and survival in the broader context of all MPSs. Only limited data are available for MPS I and MPS VI (Dornelles et al 2014; Giugliani et al 2014); whilst these small studies indicate a possible survival benefit with ERT, our analysis is the first to show an impact in a large population of treated and untreated patients. Overall, despite the complexities of the data, our analysis demonstrates a survival benefit with intravenous idursulfase treatment in patients with MPS II.

We demonstrate for the first time increased survival with intravenous idursulfase treatment in a large population of patients with MPS II: median survival was 33.0 (30.4, 38.4) years in treated patients and 21.2 (16.1, 31.5) years in untreated patients, and an adjusted Cox model demonstrated a 54% lower risk of death (95% CI: 0.29, 0.72) for treated compared with untreated patients. These results provide a valuable addition to our understanding of the long-term benefits of intravenous idursulfase therapy in patients with this rare, debilitating disease.