Disease burden of spinal muscular atrophy in Germany

Spinal muscular atrophy (SMA) is an autosomal recessive, inherited neuromuscular disease that affects the spinal anterior nerve cells. It leads to predominantly proximal muscle and diaphragm weakness and paralysis, along with respiratory distress, progressive disability, reduced working capacity and high health care needs. Infantile forms significantly reduce life expectancy [1, 2]. In >90 % of cases the disease is caused by homozygous deletions within the survival motor neuron 1 (SMN1) gene on chromosome 5q13 [3]. SMA caused by SMN1 deletions is usually classified into three phenotypes characterized by age of onset and the best motor function achieved. SMA type I (Werdnig-Hoffmann) is the most common and severe subtype, and SMA type III (Kugelberg-Welander) with onset >18 months and achievement of independent walking represents the mildest one [4]. SMA is so far not curable; and patients need long-term symptomatic multidisciplinary medical care to maintain mobility, independency, ventilation and nutrition [5]. Living with SMA is challenging not only for patients but also for their families and caregivers, as well as medical personnel and the society. Economic analyses and health services research for SMA have not been conducted in any great detail to date, but are urgently needed with regard to emerging innovative therapies. To be able to compare health care expenditures for the current symptomatic treatment and care with costs of future curative therapies, cost evaluations are mandatory. Our study provides a detailed analysis of the cost of illness (COI) of SMA, differentiating between the SMA subtypes in Germany. However, the burden of SMA cannot be reduced to an analysis of cost items only. Considering the disease-specific challenges and the individual burden it is also necessary to analyze important aspects for the affected individual as health-related quality of life (HRQOL).

In this study, we performed a comprehensive analysis of the disease burden in SMA by evaluating direct and indirect cost as well as the disease-specific HRQOL. Our results revealed a mean direct COI of €54,721/y per patient which was about 14 times higher than the average health expenditure per patient in Germany in 2013 [19].

The highest overall demand for medical and care services was identified in SMA I, resulting in significantly higher cost compared to that of SMA II and III. Nevertheless, SMA I patients utilized respiratory devices and sleep laboratory tests to a lower extent than SMA II patients. Although respiratory failure is the most frequent cause of death in these young children [4], we found that not all of them were ventilated, which is in line with the patient characteristics within the German SMA registry (Table 1). The low ventilation rates in SMA I patients in Germany could be attributed to differences regarding the availability of expert SMA treatment centers, or different preferences of physicians and parents towards ventilation [12]. The use of medical aids seemed to be of secondary importance in SMA I, maybe due to the reduced physical development of SMA I patients. More importantly, this result might even suggest a possible shortage of medical aids (e.g. care aids or adapted beds) for this age group. The results of our study contribute to the transparency of the current consumption of resources of SMA patients in Germany. The use of psychological assistance turned out to be low in general, although previous publications showed a need not only for patients but also for the parents faced with a devastating disease affecting their kids [20]. Moreover, access to inpatient and outpatient rehabilitation programs seemed to be low, possibly revealing a supply gap in specialized rehabilitation centers.

As far as we know, this is the first study conducting a detailed health services evaluation to investigate the economic burden of SMA in Germany. Larkindale et al. analyzed the COI of different neuromuscular diseases (SMA, ALS, DMD, DM) in the US in 2010. However, COI results for SMA were not mentioned in the publication due to the small sample size and difficulties in an adequate classification of SMA subtypes [21]. This emphasizes the need for a detailed analysis of a genetically defined and comprehensively diagnosed group of SMA patients and highlights the importance of our study. Nevertheless, the results for SMA were published online by the US muscular dystrophy association (MDA). In contrast to our findings, higher costs were found in the patient group with diagnosis before/at age 3 ($184,647 per patient), but lower costs for patients with later onset ($45,750 per patient) [22]. These discrepancies may result from (1) differences in the origin of data (commercial, Medicare, patient-reported), (2) the definition of different subgroups (age at diagnosis vs. defined SMA subtypes), (3) the methodological differences in valuing COR, (4) general disparities between the US and German health care systems, e.g. incentives for both health care providers and patients or compensation systems, (5) differences in standards of care as recently analyzed by Bladen et al. [12] and (6) the varying characteristics of the populations with regard to morbidity and demography. These factors may influence country-specific COR and resulting cost and therefore limit the transferability and comparability of results between different countries [23]. That is precisely why our findings cannot easily be translated to other countries or other diseases. Nevertheless, the MDA study roughly confirms our results of higher cost in SMA I/SMA with early onset, which result from the higher level of COR and the care needed by these severely affected patients [22]. We previously reported similar results for dystrophinopathies in Germany and showed that health care expenditures increased with the progression of the disease and the increasing loss of an individual’s self-dependency [6].

According to our results, SMA type I patients caused the highest informal care cost, reflecting both the severity of the disease and greater need for care. SMA I patients typically have a drastically shortened life expectancy of <2 years [24, 25]. Even healthy babies and young children are demanding with regard to the attention and care that needs to be provided by the parents. Although we have assessed the informal care along with its cost in SMA, the comparability regarding the effort which is usually devoted to healthy children remains limited because of lack of publications in this field. Recently, COI analyses assessed informal care as a main cost driver in neuromuscular diseases, showing an increasing loss of family income together with increasing care need and dependency [6, 21, 26]. These findings fully apply to SMA. We found that a high proportion of working parents (esp. of SMA I patients) had to reduce or even quit their jobs to be able to care for their affected child, leading to a reduced family income. We estimated the average annual informal care cost per patient at €20,170. Since we excluded working parents from our care cost estimation to prevent double counting of indirect cost and informal care cost, our results may even underestimate real care expenditures (for example, the average annual informal care cost per patient including working and non-working parents is much higher at €34,871). Besides care cost, indirect cost was previously described as a major cost driver in dystrophinopathies [6, 26] and our results show similar findings in SMA. We estimated that indirect cost was most prominent in SMA II and III due to the loss of productivity of patients and/or their parents. Moreover, partners took over a major part of care in the group of adult patients, mainly in SMA III. Since we only analyzed the employment status of the patient itself or of one parent, indirect cost may be much higher when taking the second parent and/or other family members into account.

Altogether, we estimated a total economic burden of €106.5 million per year in Germany using prevalence data from Northern England [18]. Obviously, more precise assessments of country-specific epidemiologic data are urgently needed. One major step might be the implementation of patient registries in rare diseases like SMA. For this study, we utilized the German SMA patient registry (www.​sma-register.​de) [12] resulting in a response rate of >70 %, which is a very good result for a cross-sectional study dealing with sensitive areas of life such as cost, handicaps and individual problems.

Patient-reported outcomes (PRO) as HRQOL help to understand the perceived health state from a patient perspective, e.g. the individual impairment resulting from symptoms and disabilities, and reveals impacts on other dimensions of independent living [27]. Particularly in chronic diseases, HRQOL results can illustrate needs and shortcomings in health care, hopefully leading to improvements in services for adult [28] and pediatric/adolescent patients [29, 30]. In our study, HRQOL increased from SMA I to the milder SMA III phenotype, which is consistent with the results of a previous study in SMA II and III, in which a higher HRQOL in SMA III compared to SMA II had been shown [31]. Interestingly, in a Brazilian study, the self-reported HRQOL of children with SMA II/III (aged >4y) was irrespective of motor ability and SMA subtype (SMA II: 55.85 vs. SMA III: 52.94) [32]. However, they utilized the Autoquestionnaire Qualité de Vie Enfant Imagé (AUQEI) to assess HRQOL, a generic tool covering function, family, leisure, autonomy and other parameters, while we used the disease-specific instrument PedsQL™^©to better determine differences between the SMA subtypes. Additionally, the assessment of different disease-related dimensions allows for a more precise comprehension of the important problems of patients in their daily lives. Thus, SMA had the most important impact on the dimensions ‘problems with the neuromuscular disease’, which encompasses disease-associated handicaps, and, secondly, ‘family resources’, which is related to familial financial and social aspects. The results of our study are confirmed by the results of a recent investigation in the Czech Republic in which the disease-specific HRQOL in SMA patients aged 3–18 years was similarly analyzed with the PedsQL™^© 3.0 Neuromuscular Module [33].

A potential limitation of our study might be a bias due to the utilization of a SMA patient registry to recruit study participants. Patients and families join the registry voluntarily; therefore, highly compliant and dedicated participants may be overrepresented. Furthermore, although SMA I is the most common SMA subtype, the life expectancy of patients is very limited. Given the low prevalence and small number of cases in this subgroup, our cost data for SMA I must be seen against this background. Additionally, in a retrospective study, recall bias may be a systematic error when estimating COI based on patient reported data from the past. Moreover, we used minimum prices to estimate the economic burden, possibly leading to the underestimation of the exact COI, and as mentioned above, the indirect cost may be much higher particularly when taking the impact on more than one family member into account.

In summary, our study provides the first comprehensive economic analysis of SMA in Germany from the perspective of patients, their families and society. Different innovative therapies are currently being investigated ‘from bench to bedside’, e.g. gene therapy, molecular therapy with antisense oligonucleotides, and small molecules, which hopefully will soon be available to treat this devastating disease [34, 35]. In this context, our study results show that new innovative therapies modifying the severity of SMA into a milder phenotype have the potential to reduce COR together with COI. However, innovative therapies may go hand in hand with high cost due to research and particularly clinical development activities. Considering this, a precise estimation of overall cost is not feasible. Modifying the severity of SMA towards a milder phenotype may be connected with improvements in patients’ quality of life. Although COI in SMA II was seen to be almost as high as in SMA I, SMA II patients showed a significantly higher quality of life. This further underlines the huge need for early-stage treatment and adequate support to reduce COR and to improve HRQOL.

We analyzed the disease burden of SMA in Germany from a health economic perspective. This study is highly important for patients, families and caregivers as well as for the pharmaceutical industry. Concerning emerging therapies, giving equal priority to assessing the clinical and health economic situation may facilitate the translation of clinical research results into clinical practice. Importantly, our study contributes to a more comprehensive understanding of health care delivery issues related to SMA and neuromuscular diseases in general.