Abstract
Introduction:
To estimate the value of interventions in multiple sclerosis (MS) – where lifetime costs and outcomes cannot be observed – outcome data have to be combined with costs. This requires that cost data be regularly updated.
Objectives and methods:
This study is part of a cross-sectional retrospective study in 16 countries collecting data on resource consumption and 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 EUR 2015.
Results:
A total of 5475 patients (mean age 52 years) participated in Germany. In all, 84% were below retirement age, and of these, 51% were employed. Employment was related to disease severity, and MS affected productivity at work for 80% of patients. Overall, 96% and 78% of patients experienced fatigue and cognitive difficulties as a problem, respectively. The mean utility and total annual costs were 0.786 and 28,200€ at Expanded Disability Status Scale (EDSS) 0–3, 0.586 and €44,000 at EDSS 4–6.5 and 0.273 and €62,700 at EDSS 7–9, respectively. The mean cost of a relapse was estimated at €2500.
Conclusion:
This study provides current health economic data on MS in Germany that are important for the development of health policies and for estimating the value of the current and future treatments.
Introduction
The societal impact of chronic diseases is high and their management, including the use of innovative treatments, is increasingly in the focus of policy makers, payers, clinicians and researchers. A number of factors other than clinical efficacy may have an impact on the adoption of innovations and the optimisation of care, for example, access to care, cost, medical education and degree of cooperation between different healthcare providers. In light of this, Germany passed legislation to improve access to care and follow-up of care within the ‘sick funds’, the ‘GKV-Versorgungsstärkungsgesetz’ in 2016 (http://www.bundesgesundheitsministerium.de). One of the objectives of this law is also to promote healthcare research through a special fund (Innovationsfond). New forms of healthcare organisation and healthcare research will be supported by this fund. In this context, studies focusing on clinical practice and routine patient care, such as burden of illness surveys, gain in importance.
In multiple sclerosis (MS), major clinical efforts have been made in the past two decades, and innovative treatments have been included in national and international, evidence-based guidelines. The availability of these disease-modifying treatments (DMTs) has led to changes in patient management and to focus on earlier and better diagnosis and adjustments in the diagnostic criteria themselves.1–3 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.4,5 Recent data on the exact prevalence in Germany are scarce and studies disagree. Petersen et al. 6 found that nearly 200,000 people insured in the statutory health insurance had a diagnosis of MS in 2010, while an analysis of administrative claims data in Bayern found that prevalence had increased from 0.123% to 0.175% between 2005 and 2009. 7 With diagnosis already possible after a clinically isolated event, 3 one must also expect a different distribution of the type of MS and the severity of the disease compared to a decade ago: a larger proportion of patients with relapsing-remitting disease and thus of patients in the early stages of the disease with less disability.
It is therefore important to update the information on the burden of MS described in a number of studies.8–10 The study presented here is part of a European-wide effort in 16 countries, endorsed by the European Platform of MS Societies (EMSP) and carried out with the support of national MS societies. 11 It uses a similar methodology as the last European survey in 2005 12 where Germany was also included. 10
Materials and methods
The detailed methodology for the European survey is published separately. 13 We therefore only provide a short summary of the general methods and issues specific to Germany.
Data
The study aimed to estimate the costs of all healthcare and other resource utilisation 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 cognitive difficulties, health-related quality of life (HRQoL) as well as self-assessed disability using descriptions based on the Expanded Disability Status Scale (EDSS) was collected.
Data were collected with a standard questionnaire, at a single point in time, for a retrospective period of time. The latter 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; 12 months for major investments such as changes to the house or the car. Resource utilisation is reported for these time periods, while cost calculations are annualised.
Disease information such as course of MS, disability (EDSS), HRQoL, utility (EuroQol five dimensions (EQ-5D) 14 ), symptoms (fatigue, cognitive difficulties) and the effect of MS on work related to the current day or week. For comparability across countries, 15 utilities are estimated with the original value set developed in the United Kingdom. 16 In Germany, Greiner et al. 17 established a national tariff applying the same methodology as used for the UK tariff with 339 individuals from the general population, and we therefore also present utilities established with this local tariff.
The handling of missing data for the cost calculation is explained in more detail in the article describing the methods. 13 For resource use, we present actual answers without any imputation for missing responses. Also, no imputations are made for missing information on disease status, symptoms and HRQoL.
Costs
Costs are calculated 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 of 0–6; patients who were unsure were excluded from the estimation. Invalidity, early retirement and DMT costs are not considered in the calculation, as these are unlikely to be affected within 3 months.
The unit costs for the individual resources were taken from public sources and are described elsewhere. 15 The results are reported in EUR 2015.
Patients
The objective was to include a sample where all levels of disease severity (defined by EDSS) were represented in sufficient numbers to permit analysis, rather than a prevalence sample. This allows highlighting 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. The mean results may thus not be representative and should neither be extrapolated directly to national costs nor be compared directly to the results in earlier studies. We therefore report the results by disease severity groups only (mild MS EDSS 0–3, moderate MS EDSS 4–6.5, severe MS EDSS 7–9).
Data collection
In anonymous surveys, participation will depend heavily on the methods used for recruitment: collecting data in MS centres tends to overestimate the number of patients with early but severe disease and on treatment with DMTs; 18 collecting data from members of patient organisations may lead to the opposite. Internet surveys will bias towards younger patients with better education. Postal mailing may bias towards older patients but can lead to a higher response rate as seen in the Swedish study in these series. 19
The German participants in the study presented here were members of the German MS society (DMSG). The data were collected during the winter of 2015/2016. The German MS society inserted the study questionnaire and return envelope in their quarterly news bulletin sent to 47,000 individuals by postal mail. Considering the very large distribution compared to other countries in the study, the study was to be closed when 5000 answers were received.
The study was approved by the ethic committee of the Landesärztekammer Baden-Württemberg.
Results
A total of 5475 evaluable responses were received. The majority of participants returned the questionnaire by post (88%) which implies a certain proportion of missing answers. The geographical distribution of respondents represented almost perfectly the proportion of inhabitants of the different federal states, with the exception of North Rhine-Westphalia (Nordrhein Westfalen) that was slightly over-represented. 20
Table 1 provides details on demographics, employment and disease.
Sample demographics and disease information.
MS: multiple sclerosis; EDSS: Expanded Disability Status Scale; SD: standard deviation; RRMS: relapsing-remitting multiple sclerosis; DMT: disease-modifying treatment.
Of total sample (n = 5475).
Of patients of working age (N = 4590).
Of patients working (N = 2386).
Demographics and employment
The age of respondents in Germany ranged from 22 to 82 years (mean 51.8 years, median 52 years, SD 11.0 years). Women represented 74% of the sample; 76% lived with their family and 62 patients (1%) lived in a nursing home at the time of the survey. Education levels in our sample were comparable to the general population of that age group: 3% of patients had basic education, 68% a secondary or a professional degree and 27% a university degree. This compares to 4% of the population with primary education, 62% with upper secondary education and 30% with tertiary education. 21
The majority of patients in the sample were below retirement age (defined as effective retirement age, 61.6 years for women and 62.1 for men 22 ): 4590 patients (84%). Of these, 2337 patients (51%) were employed or self-employed. Forty-nine patients above retirement age also worked, bringing this group to 2386 patients (or 44% of the full sample), with a mean age of 46.6 years. This compares to an employment rate of 78% in the general population age 20–64 years, 74% for women and 80% for men.23,24 However, only slightly over a third of employed patients worked full time, on average 40.4 hours per week. Part-time employees worked on average 22 hours. This compares to 27% of employees working part-time in the general population. 24 Sick leave during the past 3 months was reported by 524 patients (22%), with a mean duration of 14.6 days.
Employment decreased rapidly with advancing disease, as shown in Figure 1. Of non-employed patients below retirement age, 41% indicated MS as the reason for leaving the workforce.
Proportion of patients below retirement age who are employed or self-employed; 4590 patients (84%) were below retirement age, and of these, 51% were employed or self-employed. Among these, 52 patients were on long-term absence.
Most employed patients felt that MS affected their productivity at work (80%), and only 14% indicated that they had no problems related to work, while 6% had not answered this question. The severity of the effect covered the entire visual analogue scale (VAS) range from 0 to 10, with a mean of 3.5 (SD 2.6; Figure 2). Fatigue was considered the most bothersome symptom (63%), followed by difficulties with thinking (38%), mobility (31%), pain (19%) and low mood (16%).
Mean score on the visual analogue scale (0 = no problem; 10 = severe problems) for fatigue, cognitive difficulties and impact of MS at work (only for patients working). Proportions calculated on the full sample who answered the question, assigning 0 to patients with no problems.
Disease characteristics
Data on disease characteristics are summarised in Table 1. The mean EDSS in the sample was 4.0 (SD 2.5), and EDSS scores covered the entire range evenly, with the exception of EDSS 9 (33 patients). The mild group represented 47% of the sample, the moderate group 35% and the severe group 18%.
The proportion of patients with relapsing-remitting multiple sclerosis (RRMS) was 46%, with secondary progressive multiple sclerosis (SPMS) at 28% and with primary progressive multiple sclerosis (PPMS) at 17% (3% missing). This is relatively close to the expected distribution, with however a higher proportion of PPMS patients than in recent studies.4,25 It suggests, as we found in previous studies, that patients were insecure in their answers regarding the type of disease. We therefore did not include the disease type in our analyses and focussed on EDSS levels instead. DMTs were used by 58.5% of the sample, with usage declining with higher EDSS levels, as expected (Table 1). Among users, 26% were on their first DMT treatment; first-generation DMTs were used by 60% of users (Table 2).
Type of DMTs used (N = 3205 a ).
DMT: disease-modifying treatment. aMissing information on the type of DMT for two patients.
Relapses in the preceding 3 months were reported by 626 patients (11%), of which close to half occurred in the past month (Table 1). However, 882 patients (16%) were unsure whether they had a relapse or not, and we assumed that the answer was no. Thus, the mean relapse rate over a 3-month period was estimated at 0.1 (SD 0.4). Corticosteroids were given to 478 patients (76% of patients with relapses), in 90% of cases as infusion.
Symptoms and HRQoL
Fatigue and cognitive difficulties were an issue for the majority of patients, and both were related to disease severity (Figure 2). Fatigue was present in 96% of patients (2% missing). The mean VAS score was 5.3 (SD 2.4) for the whole sample, 4.9 for patients with mild disease and 5.6 for patients in the moderate and severe groups. Cognitive difficulties were present in 78% of all patients. The mean VAS score in this group was 4.7 (SD 2.2) overall, 4.4 in the mild, 4.9 in the moderate and 5.2 in the severe group. For the full study sample (assigning 0 to the group with no problems), the mean score was 3.7 (3.3, 4.0, 4.1).
All five domains of HRQoL included in the EQ-5D 16 displayed problems for a large proportion of patients: pain/discomfort for 71%, usual activities for 65%, mobility for 59%, anxiety/depression for 53% and self-care for 25%. Both the severity and the affected domains changed with advancing disease. Self-care was unaffected in patients with mild disease, but declined very rapidly with advancing disease with less than 20% without difficulties; mobility, pain and usual activities presented problems for almost all patients already with moderate disease; most noticeably, however, anxiety/depression was present in 40%–50% of the patients at all levels of disease severity (Figure 3).
Proportions of patients at different levels of disease severity experiencing difficulties in the five domains of the EQ-5D (EuroQol five dimensions). All domains represent problems for patients already in mild disease, except the ability for self-care that, however, declines very rapidly with worsening disease. Anxiety/depression is present with similar severity at all stages of the disease.
Utility
The utility scores declined with increasing disability (EDSS; Figure 4). The mean utility in this specific sample of patients was 0.628 and 0.756 using the UK and German value sets, respectively.
Utility by EDSS level estimated with the EQ-5D using both the UK and German value sets.15,16 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 and partly due to specific national characteristics where German scores are slightly higher throughout.
Resource utilisation
Resource utilisation is shown in Table 3. Hospitalisation in Germany was high compared to most other Western European countries in our study (comparable to Austria and Belgium). During the preceding 3 months, 532 patients (10%) were admitted as inpatients, most often to a neurology ward, twice on average and for a mean of 11.1 (SD 10.6) days. Day admissions were reported by 207 patients (4%), on average once a month. Inpatient or day admissions to rehabilitation centres occurred for 268 patients (5%).
Resource utilisation, healthcare and community services.
SD: standard deviation; MS: multiple sclerosis; MRI: magnetic resonance imaging; DMT: disease-modifying treatment; OTC: over-the-counter.
The majority of patients (4922 patients, 90%) had a consultation during the past 3 months, most often with neurologists (81%), physiotherapists (45%) and general practitioners (35%). Investigations and tests were needed by 56% of patients, and medications for MS and MS-related symptoms were used by 89% of patients during the past month. Drugs other than DMTs and corticosteroids were used by 45% of patients, predominantly treatments for walking, spasticity and pain (34%). Non-prescription drugs were used by 53% of patients.
Investments in equipment and devices to aid patients’ mobility were made during the past 12 months for or by 35% of patients, most often for walking/mobility aids.
Community and social services were used by 21% of patients during the past month, most frequently home help and transportation. Help from family was used by 46% of patients, on average 17.7 (SD 11.8) days during the past months and 3.8 (SD 4.7) hours per day. Both community services and informal care were related to disease severity (Figure 5).
Intensity of use of informal care (number of days and hours per day during the past month). Overall, 46% of patients rely on family support. Use increases with advancing disability, with 19% of patients in the mild, 60% in the moderate and 84% in the severe group relying on family.
Costs
The 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 patients by level of EDSS. Total costs increase with disease severity, but the types of resources change. DMTs dominate costs in very early disease, but production losses are a sizeable proportion of cost from EDSS 2 and higher. In severe disease, production losses, informal care and community services dominate.
Total mean annual cost per patient by disease severity (mild, moderate, severe), N = 5475 (EUR 2015).
EDSS: Expanded Disability Status Scale; DMT: disease-modifying treatment.
The average cost of a relapse for patients with an EDSS of 0 to 6 was estimated at €2468. All types of costs increased during a relapse, with inpatient admissions representing 36% of the additional cost, sick absence 21% and informal care 15% (Figure 7).
Mean total 3-month costs for patients below EDSS 6.5 with and without a relapse (514 and 3936 patients, respectively). The cost of a relapse is calculated as the difference between the two groups, excluding DMTs, invalidity and early retirement (€2468). The difference arises essentially from inpatient admissions, sickness absences and informal care.
Discussion
This study provides an update to the current understanding of the burden of MS on patients, the healthcare system and society in general in Germany based on a cross-sectional survey conducted in 2015.
The German sample is the largest in this European survey, due to the large number of MS patients in Germany and the very wide distribution of the paper questionnaire. The response rate was seemingly low, 12%, but was in large part due to the decision to limit participation to around 5000 patients. Nevertheless, the sample was geographically representative, with educational levels matching the general population, and well spread over the entire disease severity. Despite the responses mainly in paper form, missing answers were limited. Thus, while the sample may not match prevalence in terms of disease severity or type of MS, the results by EDSS are representative.
Disease symptoms and utilities were very similar to those found in all the other countries, attesting to the fact that the severity of the disease affects patients in the same way regardless of jurisdiction or healthcare systems. Not surprisingly, family support (informal care) was found to be at a similar level to the other countries as well.
Resource utilisation, while reflecting the clinical needs of patients, has also to be seen in the light of the organisation of the German healthcare system, medical traditions and cultural norms. Germany has in the past been found to have high hospitalisation and consultation rates for MS patients.9,10 The pattern of consultations is similar to that found in the 2005 survey, while inpatient admissions have decreased from 25% to 10%. 10 Nevertheless, the rate of admissions remains the highest among Western European countries, and the proportion of patients having a consultation with a neurologist in the past 3 months is the highest in the study overall. There are likely several reasons for this, among them the medical tradition of seeing patients every 3 months in line with the payment system, and also the fact that a majority of patients are followed by private office–based neurologists.
The use of DMTs in this study is slightly higher than in the 2005 survey (59% versus 50%) 10 and higher than found by analyses of claims data in 2010 (50%).6,7 This could be due to a bias in our sample, and also to a possibly more widespread usage in recent years, with a larger number of DMTs to choose from. An indication of this might be that 45% of patients were on DMTs that were licensed within the past 10 years (second-generation treatment).
An important finding of this study is the overwhelming presence of fatigue in almost all patients and the importance of cognitive difficulties, regardless of disease severity. Similarly, problems with anxiety and depression are present at the same level (in around 50% of patients) throughout the disease. While our data do not allow the investigation of causal effects, it is of note that in all 16 countries in the study a substantial number of patients are not able to work due to MS already very early in the disease and with basically no physical disability. In Germany, 18.5% of patients in the mild group (EDSS 0–3) receive an invalidity pension. Thus, the results of our study corroborate previous findings in German MS patients that ‘invisible’ symptoms such as fatigue, cognitive difficulties and mood disorders may have an enormous impact on work ability. 26
In conclusion, these data characterise various aspects of the burden of MS on patients and society and capture patterns of resource utilisation that could inform future policy recommendations. In addition, these data provide input into cost-effectiveness analyses for reimbursement decisions.
Footnotes
Acknowledgements
The authors are grateful to Michaela Mai (DMSG) for making the survey available to members; to Karin Berger (University Clinic of Munich) for health economic review; to Jennifer Eriksson and Johan Dalén (MAPI Group) for organisational and statistical support; to Markas Gedminas (Medscinet) for construction of the on-line platform; 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.F. has received speaker’s fees and honoraria for advisory boards from Almirall, Bayer, Biogen Idec, Novartis, Merck Serono, Roche, Sanofi Genzyme and Teva. He has participated in pharmaceutical company–sponsored trials by Almirall, Biogen Idec and Novartis. None resulted in a conflict of interest. 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.