Abstract
Background:
To estimate the value of treatments in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with cost data. This, in turn, requires that cost data be regularly updated.
Objectives and Methods:
This study is part of a cross-sectional retrospective study in 16 countries collecting current data on resource consumption, work capacity, health-related quality of life (HRQoL) and prevalent symptoms for patients with MS. Descriptive analyses are presented by level of severity, from the societal perspective, in 2015 Danish Kronor (DKK).
Results:
A total of 830 patients (mean age of 54 years) participated; 78% were below retirement age and of these, 43% were employed. Employment was related to disease severity, and MS was felt to affect productivity at work by 73% of patients, most often through fatigue. Overall, 95% and 65% of patients felt that fatigue and cognition, respectively, were a problem. Mean utility and costs were 0.770 and 196,900DKK at Expanded Disability Status Scale (EDSS) 0–3, 0.619 and 287,300DKK at EDSS 4–6.5, and 0.302 and 533,250DKK at EDSS 7–9. The average cost of a relapse was estimated at 19,000DKK.
Conclusion:
This study illustrates the burden of MS on Danish patients and provides current data that are important for the development of health policies.
Introduction
While health economics as a discipline has long been part of academic work as well as health services, cost-effectiveness analyses for new treatments have not been a mandatory part of decision-making for the funding of hospital drugs in Denmark. This is about to be changed as the Danish Regions’ central government implements a new prioritisation structure (the Medicine Council) with the remit to assess the added value of new medicines in relation to associated costs. The economic evaluations will include drug acquisition costs and direct healthcare costs such as hospital admissions, rehabilitation, home-assistance, transports, and investments. 1 With this reform, Danish data on resource utilisation and related costs are likely to inform funding decisions.
The availability of treatments has led to changes not only in patient management, but also in earlier and better diagnosis and adjustments in the diagnostic criteria themselves. One of the consequences in this regard is that the recorded prevalence of the disease is quite different from that estimated two or three decades ago. 2 The most recent estimate puts prevalence at 189/100,000 population based on a registered number of multiple sclerosis (MS) patients of 17,500 in 2008 in the Swedish MS registry. 3 In Denmark, Bentzen et al. have estimated the change in prevalence between 1950 and 2005, using the Danish MS registry established in 1956. The Danish MS registry receives information from all departments of neurology, the National Hospital Discharge Register, the MS rehabilitation hospitals and pathologists. It is considered to have a validity of 94% and is at least 90% complete. 4 In this timeframe, standardised prevalence has increased from 58.8 to 154.5 per 100,000 population. The increase is likely to be due to better and much earlier diagnosis after a clinically isolated event rather than a change in the disease frequency. 5 One must therefore also expect a different distribution of the type of MS and the severity of the disease: a larger proportion of patients in the early stages of the disease and with less disability (a low score on the Expanded Disability Status Scale (EDSS)).
It is therefore important to update the information on the burden of MS, and this study is part of a European-wide effort in 16 countries, endorsed by the European Platform of MS societies (EMSP) 6 and carried out with the support of national MS Societies. It uses a similar methodology as the last European survey in 2005 that, however, did not include Denmark. 7 This study is hence the first effort of this magnitude in Denmark.
Materials and methods
The detailed methodology for the European survey is published separately. 11 We therefore only provide a short summary of the general methods, and issues specific to Denmark.
Data
The study aimed to estimate all costs related to MS: hospitalisation, rehabilitation, consultations, diagnostic procedures and tests, medication, community care, family support and production losses (sick leave, early retirement, invalidity). In addition, information on major symptoms such as fatigue and cognition, health-related quality of life (HRQoL) as well as self-assessed disability using descriptions based on the EDSS was collected.
Data were collected with a standard questionnaire, at a single point in time, for a retrospective period of time. The latter was varied depending on the question to minimise recall bias: 1 month for use of drugs, community services and family help; 3 months for hospitalisation, consultations, tests, sick leave and relapses; and 12 months for major investments. Resource utilisation is reported for these time periods, while cost calculations are annualised.
Disease information such as the type of MS, disability (EDSS), HRQoL, utility (EuroQol 5 Dimensions (EQ-5D) 8 ), symptoms (fatigue and cognition), and the effect of MS on work related to the current day or week. For comparability across countries, 6 utilities are estimated with the original value set developed in the United Kingdom. 9 In Denmark, Wittrup-Jensen et al. 10 established a national tariff applying the same methodology as used for the UK tariff, and we therefore also present utilities established with the local tariff.
Costs
Costs are estimated from the societal perspective, including all costs regardless of who ultimately is responsible for them. Patient co-payments and patients’ out-of-pocket expenses are thus included. The cost of a relapse is calculated as the difference in quarterly costs between patients with or without a relapse and an EDSS score between 0 and 6, excluding resources unlikely to be directly affected during the quarter by a relapse (invalidity, early retirement, disease-modifying treatments (DMTs)).
Unit costs for the individual resources were taken from public sources and are described in the paper on methodology. 11 Results are reported in Danish kronor (100 DKK = 13.4€ 2015 average).
Patients
The objective was to include a sample where all levels of disease severity (defined by EDSS) were represented in sufficient numbers to allow analysis. This highlights how costs and HRQoL change as the disease progresses and provides the necessary data for cost-effectiveness analysis of treatments that are expected to change the course of the disease. As a consequence, the study population does not represent national prevalence of MS in Denmark and mean results for the sample are not meaningful. They can neither be extrapolated to national costs without careful adjustment, nor can they be compared directly to the results in other studies. We therefore report results by EDSS and by disease severity groups only (mild MS EDSS 0–3, moderate MS EDSS 4–6.5 and severe MS EDSS 7–9).
Data collection
In anonymous surveys, it is difficult to include a fully representative patient population, and changes in the management of MS, in particular earlier diagnosis, have increased this challenge. In addition, participation will depend heavily on the methods used for the survey: collecting data in MS centres tends to overestimate the number of patients with early disease and on treatment with DMTs; collecting data from members in patient organisations may lead to the opposite. Internet surveys will bias towards early disease and better education, while postal mailings may do the opposite.
In Denmark, the vast majority of patients are followed in the MS Registry, and contacting these patients would likely provide the least biased sample. However, as the European study was organised in collaboration with patient organisations, and for reasons of consistency, patients were contacted by the Danish Scleroseforeningen. The data were collected during the second half of 2015, after approval by the national ethics commission (Den Nationale Videnskabsetiske Komité) and the data protection agency (Datatilsynet). The Scleroseforeningen invited 4037 members by electronic mail to participate in the online survey or to return a printed version by post. All participants chose to answer online (response rate 21%).
Results
A total of 830 evaluable responses were received, and geographic distribution was representative. Respondents came from Hovedstaden (26%), Midtjylland (23%), Nordjylland (9%), Sjaeland (19%) and Syddanmark (23%). The population in these regions represents 31%, 23%, 10%, 15% and 21%, respectively. 12
Within the European study, the Danish participants were among the older. Age and EDSS drive the proportion of patients with relapsing disease indicated for DMT treatment, the number of patients actually on DMTs, to some extent the proportion reporting a relapse, and the proportion of patients of working age. Thus, the proportions of patients with relapsing disease, on treatment with DMTs and reporting relapses, as well as the proportion of working age was in the lower range among the 16 countries. 6
Table 1 provides the details on demographics, employment and patients’ disease.
Sample characteristics.
SD: standard deviation; EDSS: Expanded Disability Status Scale; DMTs: disease-modifying treatments; RRMS: relapsing-remitting multiple sclerosis.
Of total sample (n = 830).
Of patients of working age (N = 649).
Of patients working (N = 285).
Demographics and employment
The age of respondents in Denmark ranged from 21 to 90 years (mean: 54.3, median: 55, SD: 10.3); women represented 74%; 75% lived with their family and only five patients were in a nursing home at the time of the survey. Education levels were comparable to the general population: 11% of patients had basic education, 74% had a secondary or a professional degree, and 15% a university degree, compared to 26%, 59% and 15% in the population between 15 and 69 years of age. The higher proportion of people with primary education can be explained by the younger age group in the official statistics. 13
In the Danish sample, 649 patients (78%) were below effective retirement age (62 for women and 63 for men 14 ). Of these, 276 (43%) patients were formally employed or self-employed. Nine patients above retirement age also worked, bringing this group to 285 patients (or 34% of the full sample). The mean age in this group was 49 years. This compares to an employment rate of 79% in the population aged 15–64 years in the last quarter of 2015, 82% for men and 68% for women. Employment of women between 35 and 54 years was 85% and between 55 and 64, 63%. 15 The majority of patients worked part time (85%), and of these, only 17% did so because of MS. This is very different from the general population where 7.6% worked part time in 2014. 16
Few employed patients reported sick leave: 14 patients were on long-term sick leave (3–12 months) for an average of 5.9 months, and 18 patients (6.3%) reported a short-term sick leave during the past 3 months, for a mean duration of 15.9 days. Despite the low number, it is higher than the national averages: 3.6% of the working population for an average of 8.5 days, or 4.7% and 10.9 days for women. 17
Employment decreased rapidly with advancing disease, as shown in Figure 1. Of non-employed patients below retirement age, 52% indicated MS as the reason for leaving the workforce.
Proportion of patients below retirement age employed or self-employed. In all, 649 patients (78.2%) were below retirement age, and of these, 42.5% were employed or self-employed. Among these, 14 patients were on long-term absence.
Most employed patients felt that MS affected their productivity at work (73%) and only 15% indicated that they had no problems, while 13% had not answered the question. The severity of the effect covered the entire range from 0 to 10, with a mean of 3.1 (SD: 2.5) (Figure 2). Fatigue was considered the most bothersome symptom at work (69%), followed by difficulties thinking (33%), mobility (30%), pain (21%) and low mood (7%).
Mean score on the visual analogue scales (0 = no problem; 10 = severe problems) for fatigue, cognitive difficulties and impact of MS at work (only for patients working).
Disease information
Data on disease characteristics are summarised in Table 1. The mean EDSS was 4.2 (SD: 2.4), but due to the large sample, all levels of EDSS were well represented, yielding a stable analysis. The mild group represented 42% of the sample, the moderate group 40% and the severe group 18%. It is difficult to judge how closely this represents the distribution in the Danish MS patient population. Although the Danish registry is one of the most complete, regular EDSS assessments are only done for patients on treatment with DMTs. This will bias the sample with available EDSS towards disease as illustrated by the current distribution: 65%, 30% and 5% in the severity groups defined for our study (personal communication, Melinda Magyari MD PhD, The Danish Multiple Sclerosis Registry).
The proportion of patients with relapsing-remitting multiple sclerosis (RRMS) was 45.3% and with secondary progressive multiple sclerosis (SPMS) 22.0%. In view of the age of the sample, this appears reasonable. However, 25.7% of patients reported primary progressive multiple sclerosis (PPMS). This is high, particularly in view of the most recent data from Sweden, 18 and attests to the difficulties for patients to distinguish between disease types, particularly SPMS and PPMS. Thus, we did not include the disease type in our analyses and focus instead on EDSS levels, despite the fact that DMTs are indicated especially for relapsing disease. DMTs were used by 43% of the sample, with usage declining with higher EDSS levels, as expected (Table 1). Among users, 33% were on their first DMT treatment. First-generation DMTs were used by 37% of patients (Table 2).
Type of DMTs used (N = 637).
DMT: disease-modifying treatment.
Relapses in the preceding 3 months were reported by 95 patients (11.4%); of these, 66% occurred in the past month. However, a quarter of respondents (25.7%) were unsure whether they had a relapse or not, and we assumed that the answer was no. Thus, the mean relapse rate over 3 months was estimated at 0.2 (SD: 0.5). Corticosteroids were used by 28.4% of all patients with relapses, or 3.3% of the total sample.
Symptoms and HRQoL
Fatigue was an issue for 98% patients who answered the visual analogue scale (VAS) (N = 820). The mean score was 5.3 (SD: 2.5) for the sample, and 4.9, 5.6 and 5.7 for patients with mild, moderate and severe disease, respectively (Figure 2).
Similarly, a majority of patients felt that they suffered from cognitive difficulties (65%). The mean VAS score among this group with difficulties was 4.5 (SD: 2.0), and increased with disease severity: 4.3, 4.6 and 4.9 in the mild, moderate and severe groups, respectively. For the full study sample (assigning 0 to the group with no problems), the mean score was 2.9 (SD: 2.7) with scores of 2.8, 3.1, 2.8 in the three groups (Figure 2).
Among the five domains of HRQoL included in the EQ-5D, only self-care did not represent problems for a majority of patients. Both the severity and the type of domain changed with advancing disease (Figure 3).
Proportions of patients at different levels of disease severity experiencing difficulties in the five domains of the EQ-5D (EuroQol 5 Dimensions). The ability for self-care is only affected in severe disease, while anxiety is similar at all disease stages, albeit relatively mild.
Utility
Utility decreased with advancing disability (EDSS) (Figure 4). Mean utility in this specific sample of patients was 0.625 and 0.719 using the UK and Danish value sets, respectively.9,10
Utility by EDSS level estimated with the EQ-5D using both the UK and Danish value sets.8,9 Utility is calculated by relating the scores of the five domains (1 = no problems; 2 = some problems; 3 = severe problems) to a health state valuation system established with the general population. The differences in the valuations may be partly due to small methodological differences, partly due to specific national characteristics.
Resource utilisation
Resource utilisation is presented in Table 3. Health-care resources (except medication) were collected for a 3-month period. Hospitalisation was rare: 3% of patients were admitted as inpatients, 4% as day admission, rehabilitation centres were used by 5%. In all, 65% of patients had consultations and 22% had investigations and tests, most often magnetic resonance imaging (MRI) scans (brain 11%, spine 5%). Medications for MS and MS-related symptoms were used by 77% of patients during the past month. Symptomatic prescription drugs (excluding corticosteroids) were used by 22% of patients, most often for spasticity, walking and pain. Non-prescription drugs were purchased by 53% of patients.
Resource utilisation, healthcare and community services.
SD: standard deviation; MRI: magnetic resonance imaging; DMT: disease-modifying treatment; OTC: over the counter drug.
Medical devices or specific investments for MS were required by 23% of patients during the past year, most often for walking aids.
Assistance from community and social services was provided to 17% of patients, evenly spread between home help, transportation and personal assistants. Services were concentrated in the severe group of patients, where personal assistants supported 33% of patients. Help from family was used by 40% of patients, on average 13.2 (SD 11.5) days per month and 3.4 (SD 4.4) hours per day. As for personal assistance, informal care was related to disease severity (Figure 5).
Intensity of use of informal care (number of days and hours per day during the past month). Use is concentrated in the more severe groups: 40% of patients rely on family help: 18.7% in the mild, 51.6% in the moderate and 62.2% in the severe group. In the severe group, 33% of patients also have support from personal assistants.
Investments in equipment and devices to aid patients’ mobility were made during the past 12 months for or by 190 patients (23%), most often for modifications to the house or the car and walking aids.
Costs
Total mean annual costs per patient for patients with mild, moderate and severe disease and by EDSS score are presented in Figure 6 and Table 4.
Mean total annual costs per patient by level of EDSS. Total costs increase with disease severity, but the type of resources change. Healthcare costs dominate in early disease, while production losses, informal care and particularly community services (personal assistants) dominate in severe disease.
Total mean annual cost per patient by disease severity (mild, moderate, severe), N = 830 (DKK 2015).
DKK: Danish Kronor; EDSS: Expanded Disability Status Scale; SD: standard deviation; DMT: disease-modifying treatment.
The average cost of relapses during a 3-month period was estimated at 19,037DKK. The use of all resources increased, with 38% of the cost difference due to inpatient admissions, 16% to consultations and 12% to both community services and informal care (Figure 7).
Mean total 3-month costs for patients below EDSS 6.5 with and without a relapse. The cost of a relapse is calculated as the difference between the two groups, excluding DMTs, invalidity and early retirement (19,037DKK). The difference arises essentially from hospitalisations, consultations, personal assistance and informal care.
Discussion
The aim of this study was to provide detailed information on the economic and health burden of MS in Denmark, and to assess the impact of fatigue and cognitive symptoms on daily living.
Although Denmark has one of the oldest and most complete patient registries in Europe,19,20 few economic studies have been published. Jennum et al. 21 analysed the socioeconomic consequences of MS in a nationwide study of 10,849 MS patients compared to a sample of matched citizens. The study included direct healthcare costs and production losses and estimated the mean annual cost per patient to 15,000€. Excluding direct non-medical costs (investment, community services and informal care), mean annual costs in our sample amount to around 30,000€ of which one-third is for DMTs. The difference is for a number of reasons. First, our data include all medical and paramedical contacts of patients while registries and population data are generally limited to hospitalisation and outpatient attendance. Second, the use of DMTs may have increased since 2012 and more patients are treated with the newer generations of DMTs that carry a higher cost. Third, and most importantly, our study may include a sample with more disability and more active disease.
Costs in our study are heavily dependent on the distribution of the sample over the EDSS range. In addition, although age is correlated with EDSS, it has an independent effect on production losses, as these are only relevant for patients below retirement age. As our Danish sample does not represent prevalence and has a relatively high mean EDSS and mean age, mean costs per patient are meaningless. We therefore present our results only by EDSS or in three groups of patients with mild, moderate and severe disease.
There is a large difference in the employment rate in our sample and the general population in Denmark. A large proportion of patients that were not employed indicated that this was due to MS (52%). If these patients had been working, the employment rate in the sample would be slightly above the population rate. This is not surprising in view of the high education level in the sample, and illustrates well the impact of MS on work and daily life. It is interesting to observe that workforce participation declines to below 50% already at EDSS 3 where physical disability is limited. The same observation has been made in all countries of this European survey and may indicate that symptoms not included in the assessment of EDSS such as fatigue may play a greater role than anticipated. It seems that fatigue and cognitive difficulties, reported by the majority of patients even with mild MS, have been underestimated, and probably have an important influence on work and activities in early stages of the disease. A similar observation can be made for utility, which declines by almost 20% between EDSS 0 and 3.
Utilities for the sample were calculated with both the original tariff by Dolan et al. and the more recent Danish value set.9,10 The difference between the two appears to be explained by a slight difference in the methodology used to establish the tariff that leads to higher values in more severe health states.
We present results from the societal perspective, hence all costs regardless of who bears them. While this may not provide data suitable for individual payers, nor correspond completely to the guidelines for economic evaluation currently discussed in Denmark, 1 it is justified by a number of factors. First, a majority of costs in MS do not fall on the healthcare budget, but on communities, families and the economy. Second, cost of illness studies relate to the disease, not to administrative or financing units, and third, health economic theory is based on a societal view in the same way as market authorisation takes a societal view.22,23
In conclusion, the study presented here provides information on overall resource consumption in MS, including data that is generally not included in registries and databases. In addition, the effect of symptoms such as fatigue and cognition are explored, and results indicate that further research into their role in patients’ limitations in activities of daily living and in particular workforce participation is warranted.
Footnotes
Acknowledgements
The authors are grateful to Lasse Elbrønd Skovgaard (Scleroseforeningen) for making the survey available to members; to Melinda Magyari (Danish MS Registry) for sharing information; to Jennifer Eriksson and Johan Dalén (MAPI Group) for organisational and statistical support; to Barbara Rosengren for language editing and to Cara Harley for formatting.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: P.VR. has received consulting fees from Allergan, Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. G.K. has received consulting fees from Almirall, Bayer, Biogen, Merck Serono, Novartis, Oxford PharmaGenesis, Sanofi Genzyme and Teva. J.B., D.C., and M.G. were at the time of the study employed by the MAPI Group, a research company acting as consultants to pharmaceutical companies.
Funding
The author(s) declared receipt of the following financial support for the research, authorship and/or publication of this article: European Health Economics and MAPI have received funding for the full research and production of the manuscripts from Biogen.