Societal costs of multiple sclerosis in Ireland

Abstract

Aims: This paper evaluates the impact of multiple sclerosis (MS) in Ireland, and estimates the associated direct, indirect, and intangible costs to society based on a large nationally representative sample.

Materials and methods: A questionnaire was developed to capture the demographics, disease characteristics, healthcare use, informal care, employment, and wellbeing. Referencing international studies, standardized survey instruments were included (e.g. CSRI, MFIS-5, EQ-5D) or adapted (EDSS) for inclusion in an online survey platform. Recruitment was directed at people with MS via the MS Society mailing list and social media platforms, as well as in traditional media. The economic costing was primarily conducted using a ‘bottom-up’ methodology, and national estimates were achieved using ‘prevalence-based’ extrapolation.

Results: A total of 594 people completed the survey in full. The sample had geographic, disease, and demographic characteristics indicating good representativeness. At an individual level, average societal cost was estimated at €47,683; the average annual costs for those with mild, moderate, and severe MS were calculated as €34,942, €57,857, and €100,554, respectively. For a total Irish MS population of 9,000, the total societal costs of MS amounted to €429m. Direct costs accounted for just 30% of the total societal costs, indirect costs amounted to 50% of the total, and intangible or QoL costs represented 20%. The societal cost associated with a relapse in the sample is estimated as €2,438.

Limitations and conclusions: The findings highlight that up to 70% of the total costs associated with MS are not routinely counted. These “hidden” costs are higher in Ireland than the rest of Europe, due in part to significantly lower levels of workforce participation, a higher likelihood of permanent workforce withdrawal, and higher levels of informal care needs. The relationship between disease progression and costs emphasize the societal importance of managing and slowing the progression of the illness.

Keywords:

• Cost of illness study
• internet-based recruitment
• multiple sclerosis
• survey design
• indirect costs
• intangible costs
• epidemiology
• Ireland

Introduction

Multiple sclerosis (MS) is a complex, chronic inflammatory disease of the central nervous system (CNS). The condition is characterized by demyelination and axonal loss, resulting in neurological functional impairment, which may lead to high levels of disability¹.

Due to a typical young age of onset—arising between 20–40 years of age²—and the chronic course of the condition, MS impacts heavily on the lives of those with the disease, including disruption to work, social, personal, and family life. As well as functional impairment and disability, common symptoms of MS include visual disturbances, altered sensation and abnormal speech, swallowing disorders, fatigue, bladder and bowel problems, sexual dysfunction, and mood impairment³.

The general employment-related consequences of MS have been documented, with high levels of absenteeism, presenteeism, and permanent withdrawal from the workforce due to MS commonly reported^4–6. This restriction in professional activities—during highly productive years for most adults—allied with symptoms such as weakness, fatigue, and cognitive impairment, can also lead to depression and isolation, further impacting the quality-of-life (QoL) of those with the condition⁷. Lifetime prevalence estimates of depression in PwMS are high, typically ∼50%—more than two-fold that experienced in the general population^8,9.

Prevalence estimates for MS vary from less than five cases per 100,000 people in Asia to one to two cases per thousand in the US and Northern Europe¹⁰. Geographically, Ireland has been recognized as being a high-risk area for MS, in line with the seminal research of Allison and Millar¹¹ in the 1950s and prevalence studies showing rates from 73 cases per 100,000 to a high as 290 cases per 100,000 in county Donegal—the most northerly part of the country^11–14.

Relapsing-remitting MS (RRMS) is the most common form of MS, with ∼80–85% of all people with MS (PwMS) experiencing a relapsing–remitting (RR) onset of the disease, with ∼65% of those, in time, entering the secondary progressive phase (SPMS)¹⁵. RRMS is characterized by episodic exacerbations of neurological signs or symptoms which typically appear over a period of several days and stabilize, with complete or partial recovery. As the signs and symptoms of CNS dysfunction persist after relapses or otherwise progress between relapses, the diagnosis progresses to SPMS. A smaller proportion, ∼10%, of people present with primary progressive MS (PPMS), for whom progressive neurological disability occurs from onset¹⁶.

The economic cost of MS has been studied in several countries, with some variation apparent in the results^4,5,17–20. This variation is largely a consequence of differences in unit costs, study methodologies, and treatment practices.

The aim of this study is to measure the impact and societal cost of multiple sclerosis (MS) in Ireland from a nationally representative sample of the Irish population living with the disease. Previous research in this area has relied on clinic-based samples and medical-led assessments¹⁹. However, it is unclear how well a particular clinic-based sample may represent the wider population of people living with MS (PwMS), and there is some concern that direct face-to-face interviewing may bias results, due to a social desirability effect.

In this study, a novel approach to recruitment and data gathering is taken. First, the survey was designed with guidance from the international literature and local clinical neurologists, as well as patient representatives from the national advocacy group—MS Ireland. The survey was designed with an emphasis on the self-reported experience of living with MS, and evaluation of costs included a comprehensive range of items from direct to indirect, as well as the currently intangible costs that reflect non-market aspects of disease. Recruitment was communicated across social and traditional media platforms, and respondents were able to participate via the internet or by postal return.

The objectives of this paper are to generate new estimates of the societal costs associated with MS in Ireland, and to add these to the existing international MS literature. This study will also estimate variation in use of services and economic costs of MS in Ireland across the main types and severity stages of the disease, and the costs associated with specific disease activity (i.e. relapses).

The new estimates from this nationally representative sample will enrich the information base with respect to MS in Ireland; will facilitate a comparison to clinic-based surveys nationally and internationally; and highlight the full societal costs of MS.

Methods

Study design

This is a retrospective study, with a cross-sectional design using internet-based surveying. Internet surveying is a relatively new method of sample selection, and is thought to be particularly suited to investigating diseases prevalent in younger populations. It has been used previously in similar studies in Europe and Canada^5,18.

The evaluation methods use a micro-level or bottom-up data strategy where the majority of costs are estimated based on resources detailed by a sample of individuals with MS and extrapolated to the national level.

The perspective is a societal cost of illness in a 1-year period where economic costs take into account both direct and indirect costs, as well as estimates of the intangible costs; as discussed further below.

Recruitment

The study population included people registered with MS Ireland, a national patient association in Ireland (n = 6,098). MS Ireland invited by email the members of their own organization to participate; where no email was available, a postal invitation was sent.

The self-reported survey was hosted online for one month in the spring of 2015, and paper questionnaires were made available for those who did not have access to the internet and wished to participate. To ensure confidentiality, all data from the surveys were anonymized.

People with MS, who may not be members of MS Ireland, were notified of the survey in the national press and through new media channels (i.e. blogs, Twitter, Facebook). Respondents could enter the survey once they confirmed a clinical diagnosis of MS or clinically isolated syndrome (CIS), their age of at least 18 years, and their informed consent to participate.

Survey design

To ensure reasonable comparability, the Irish questionnaire was adapted from ones used in previous multi-national studies^4,18. All data were collected via the questionnaire. Demographic background variables included age, gender, marital status, living arrangements, employment status, reduced working hours, presenteeism, and early retirement due to MS. Disease information included age of onset, duration of disease, type of MS, and self-reported disability severity, assessed by three symptom vignettes based on the EDSS classification system and prior literature to reflect the three classes of disablement—mild, moderate, and severe see Figure 3. Relapses were defined as: the appearance of new symptoms related to MS or very definite worsening of old symptoms, which lasted for at least 24 h, occurred after a period of symptom stability, and were not associated with a high temperature, an infection, or any other health trouble.

Information on direct resource utilization was collected through questions based on the Client Service Receipt Inventory (CSRI), and adapted to the setting of the study. The CSRI is a research instrument applied for the collection of information on costs, and has been widely used in cost of illness studies^19,21. The length of the recall period varied depending on the expected frequency of resource use, e.g., for inpatient admissions a recall period of 12 months (i.e. 1 year) was given, while for “investigations and diagnostic tests” and GP visits a 6-month period of recall was given; for home help a 1-week recall period was used. For non-routine items such as “mobility and other living aids” (e.g. crutch, wheelchair, utensils) and “home modifications”, the full duration of the disease was used for recall.

Questions on productivity losses covered early retirement due to MS, absenteeism, reduced working hours, and presenteeism. Information was also collected with respect to informal care, where questions were asked about the hours of care provided and whether the caregiver had officially reduced their working week or given up their own job in order to provide care.

HRQoL data were collected using the commonly used, validated survey instrument EQ5D-5L. This instrument measures QoL over five dimensions; mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents rank their health state in each of the five dimensions. Preference elicitation studies for the EQ-5D-5L are on-going; consequently, in order to convert each health state to a single utility value, it was necessary to map the EQ-5D-5L to the EQ-5D-3L value set using the “EQ-5D-5L Crosswalk Index Value Calculator”²². The “crosswalk” UK population value set was used in this study, to ensure comparability with earlier studies⁴. Utility is measured on a cardinal scale anchored at 1 (perfect health) and 0 (absence of life/dead). Valuations less than zero (as low as –0.594), reflecting health states “worse than death” (WTD) can exist. In addition, respondents are also asked to report their self-rated health via the EQ-VAS; a tool, which uses a 20-cm vertical visual analog scale, with endpoints ranging from 0–100, and asks the individual to label their health between zero “the worst health you can imagine” to one “the best health you can imagine”²³.

Data and sample characteristics

A total of 825 participants entered the survey. Of these, 198 respondents did not complete or submit their answers at the end of the survey, another 22 reported not having a diagnosis of multiple sclerosis (or clinically isolated syndrome), eight respondents did not indicate their consent; one person indicated not being 18 or older. In addition to this, two respondents gave consistently implausible responses and were also excluded.

In total, 594 people were included in the final sample, 20 of those were postal responses. The EuroQol EQ-5D-5L component linked to the survey was completed by 91% of respondents (n = 542).

The statistical features of the sample are described in Table 1. As expected, and consistent with the epidemiological literature^24,25, the majority of our sample were female, at ∼71%. The mean age was 47 years, and 78% of our sample were between the ages of 30–59 years. The bulk of our sample were married or cohabiting (65%). A sizable proportion of our sample reported that they were in paid employment (42.8%) and, of those working, 74% were doing so in a full-time capacity. The average age of disease onset was just over 32 years of age. The mean duration of disease—that is the period of time since first developing MS symptoms—was nearly 15 years.

Table 1. Key sample demographics and disease information.

Variable	n	Mean
Age (years)	594	47.03
Female	424	71.38
Male	170	28.62
Single	156	26.31
Married/cohabiting	388	65.32
Widowed	11	1.85
Separated/divorced	38	6.41
Live alone	116	19.83
Live with others	464	79.32
Live in a care home	5	0.85
In receipt of informal care	374	63.0
Employment status
Employed	254	42.8
Full time (>30 hrs week)	188	74.0
Household duties	55	9.2
Student	25	4.2
Retired due to age	29	4.9
Retired early due to MS	162	27.3
Unemployed, but seeking work	24	4.1
Leave of absence	14	2.4
Unable to work, but intend to return	41	6.9
Disease information
Age at MS onset (years)	594	32.3
Duration of disease (years)	594	14.7
Course of disease
Relapsing remitting	374	62.9
Secondary progressive	97	16.3
Primary progressive	66	11.1
Benign	13	2.2
Clinically Isolated Syndrome	7	1.2
I do not know	37	6.2
Disability severity (self-reported)
Mild	342	57.6
Moderate	211	35.6
Severe	41	6.9
Relapses
Relapse in previous 12 months	247	41.6
Average number of relapses	240	1.8
Confirmed by a Neurologist	131	53.0

The majority of our respondents (63%) reported having the relapsing remitting form of the disease, 16% reported having secondary progressive MS (SPMS) and 11% had primary progressive disease; over 6% reported not knowing their current course of disease. Almost 42% reported having had a relapse in the past year, with an average of 1.8 reported relapses per respondent; 53% reported that the relapse they had experienced last year had been confirmed by a neurologist.

Disease severity was self-assessed using three broad categories of disability. The descriptive parameters for “mild”, “moderate”, and “severe” categories were taken from the Expanded Disability Severity Scale (EDSS). Most of the respondents in our sample reported having mild disability from MS (57.6%), 35.6% reported having moderate MS, while some 7% reported having severe disability.

In terms of age, gender, and disease features associated with MS, our sample characteristics were consistent with the existing international literature^4,5,18,19,26. It was also the case that the geographical dispersion of our study sample closely resembles that of the general population of Ireland. Therefore, we can assume our sample is broadly representative of the national population of people living with MS in Ireland.

Methodology—evaluation

The process of economic evaluation follows three steps: identification, measurement, and costing. Earlier sections discussed identification and measurement—and the overview of the data collection survey. In this section, the specific costing aspects are detailed and discussed.

Table 2 presents the various healthcare services surveyed and the frequency of use in the sample. The unit costs associated with each type of healthcare service, used for evaluation, are presented in Table 3. Where applicable, unit costs were adjusted to the year 2015, using the Consumer Price Index for health²⁷. Where standardized unit costs were not available, for example the cost of mobility supports or living aids and adaptations, they were extrapolated from costs reported for Ireland in the literature²⁸. Home adaptations were calculated on the basis of the average payment received for the Housing Adaptation Grant for People with a Disability in 2014, plus 5%—as the grant covers 95% of the cost. To account for timeframe, these costs were annualized, assuming a life-span of 5 years (mobility/living aids) or 10 years (home modifications), as well as factoring a discount rate of 4.0% per annum¹⁹.

Table 2. Healthcare resource use—direct costs.

Type of resource (n = 594)	% using resources	Annual mean per user
Nights in hospital	21.2	8.6
Nursing home	0.7	126.5
Rehabilitation centre	1.7	47.3
Respite centre	3.4	10.0
MRI	59.9	2.1
CAT scan	10.8	1.3
Blood tests	67.2	4.4
Lumber puncture or spinal tap	9.8	2.4
Neurology clinic or infusion site	61.8	5.2
Other outpatient	38.2	5
ED, not overnight	6.6	2.6
GP	83.5	7.2
Neurologist	71.4	3.4
Other doctor, e.g. Cardiologist	17.2	4.4
Physio	40.4	14.6
Occupational therapist	15.7	7.4
Social worker	3.2	3.2
Speech therapist	2.9	5.8
MS Ireland case worker	16.0	5.3
HSE home help (annual hours)	7.2	312
HSE PA (annual hours)	3.5	255
Private paid carers (annual hours)	5.4	525
Aids and adaptations
Wheelchair	20.1	1.0
Crutches/Walking frame	30.6	1.0
Home modifications	25.4	1.0
Medicalised bed	6.6	1.0
Vehicle modifications	25.9	1.0

Table 3. Source of unit costs (where applicable, costs were adjusted to the year 2015, using the Consumer Price Index for health)²⁷.

Type of resource	Source of unit cost	Unit (per:)	Costs, 2015 €
Hospital inpatient^a	HSE-casemix (inpatient DRG)	night	€658
Nursing home^b	NHSS	week	€982
MS Rehabilitation/respite	O’Connell et al.^48	day	€157
Hospital outpatient consultation	HSE-casemix (average cost per case for an OPD attendance)	visit	€227
Lab investigations	Tilson et al.^51/Bourke et al.^52	PwMS	€692
Investigations and outpatient procedures	HSE-casemix (daycase DRG)	visit	€824
GP	Laya Healthcare Survey	visit	€46.26
Neurologist	HSE salary scales	hour	€163.10
Physio	HSE salary scales	hour	€31.60
Occupational therapist	HSE salary scales	hour	€31.60
Social worker	HSE salary scales	hour	€31.60
Speech therapist	HSE salary scales	hour	€31.60
MS Ireland case-worker	Expert opinion	hour	€22.00
Medication	Fogarty et al.^19	PwMS	€6,759
Aids & Adaptations	Public price-lists, Housing Adaptation Grant for People with a Disability, Smith et al.^28	PwMS	€687
Formal care (home-help)	HSE salary scales	hour	€20.70
Private paid help at home	Private company pricelist	hour	€22.43
Productivity losses	CSO, gross gender specific mean earnings, 2014 (women)	hour	€21.30
Productivity losses	CSO, gross gender specific mean earnings, 2014 (men)	hour	€22.68
Informal care	CSO, mean hourly wage, 2014	hour	€21.90
Intangible costs	Henriksson et al.^30	PwMS	€9,038

Table adapted from Fogarty et al.¹⁹.

Abbreviations. DRG, diagnosis-related group; GP, general practitioner; HSE, Health Service Executive; lab/rad investigations, laboratory, radiological and other investigations; MS, multiple sclerosis; OPD, outpatient department; CSO, Central Statistics Office.

^aWeighted average of HIPE b68(a) & b(68)b, cost per-diem applied on the basis of reported length of stay.

^bCost per person in long-stay care is based on the maximum weekly financial support available from the HSE under the Nursing Home Support Scheme (NHSS). The costs used reflects both private and public institutions.

Individuals were not asked to report current medication use as part of this study. The national cost of medicines for MS is available from alternative sources, and average medication costs by disease category was well estimated in previous Irish research by Fogarty et al.¹⁹ These average costs were used and weighted to reflect the distribution of disability severity within the nationally representative sample.

Productivity losses were valued following the human capital (HC) approach, where the production forgone due to illness-related absence is valued at market prices for labor²⁹. Productivity losses associated with short-term sick leave and offically reduced working hours were based on national gender-stratified mean hourly earnings, while MS-related permanent withdrawal from the workforce was valued using gender-stratified mean annual earnings. Productivity losses associated with presenteeism¹ were calculated by measuring the reported effect of MS-related symptoms on optimal work performance, on a 0–10 scale, during the previous week. The cost of presenteeism associated with MS was, thus, calculated by annualizing work performance affected; the same method as applied to work-time missed and presenting the lost productivity in terms of mean gender-stratified annual earnings.

As an extension of the Human Capital approach, informal care time was valued using the opportunity cost method; earnings foregone as a result of time spent caregiving (up to a maximum of 40 h per week) was valued using the national gross mean hourly earnings in Ireland.

Intangible costs, i.e. costs due to pain and suffering, are difficult to value and, consequently, are often omitted from cost of illness studies. However, in Henriksson et al.³⁰, the authors provide an interesting approach in estimating these costs in a sample population of people with MS. This methodology for valuing intangible costs has subsequently been used in a number of MS cost of illness studies^4,31–33, and for studies in other disease areas^34,35. We approach valuing intangible costs using the same methodology, that is, by calculating the difference in mean utility values between our sample and an age- and sex-matched sample from a general population³⁶. This method generates an estimate of the number of quality-adjusted life-years (QALYs) lost by the MS sample in 1 year.

By assigning a value to (or a willingness to pay) a QALY, intangible costs due to MS can be calculated. Although there is no market price or international consensus value for a QALY, we construct our estimate assuming a WTP in the range of €20,000–€45,000 in Ireland. These figures were chosen as they correspond to the thresholds of cost-effectiveness acceptability which are commonly referenced to determine whether new health technologies are funded in Ireland³⁷.

Differences in the demographics and resource use between groups, stratified by disability severity or disease type (i.e. RRMS, SPMS, or PPMS) were compared by ANOVA and Wilcoxon–Mann–Whitney test, for parametric and non-parametric data, respectively. Statistical significance is based at the 0.05 level throughout. Stata 13 was used for all statistical analysis.

Supplementary to our calculation of the costs associated with MS in general, the specific costs associated with experiencing MS relapses were also calculated. This too has been examined in Hawton and Green’s³⁸ study on the resource use associated with MS relapse. Respondents to the survey were asked to recall their most recent relapse and to answer questions framed under the following headings: medical costs of relapses, care needs during a relapse, and the impact of relapse on productivity. This approach, which is consistent with the direction taken to calculate the costs associated with MS in general, allowed us to estimate the direct and indirect costs associated with a single MS relapse. The resulting estimate was multiplied by the average number of relapses reported by those who experienced a relapse in the past year, thus providing an annual estimate for the cost of relapses in Ireland.

Results

The annual societal costs attributable to MS are estimated in this section in the categories of direct, indirect, and intangible costs. See Figure 1 for a breakdown of the total costs per person with MS.

Direct costs

Over 21% of the sample had stayed overnight in a hospital in the last year; on average each user stayed 8.6 nights, and the mean across the entire sample was 1.8 nights. On average, 60% of our sample had two MRIs in the last year. The majority of our sample (83.5%) reported visiting a GP 7.2-times in the last year. With respect to neurologist visits, 71.4% of our sample reported 3.4 consultations. Investigations and tests were also reported by the study respondents, for example 67.2% reported having 4.4 blood tests in the last year; proportionately less reported visiting a physio. However, the mean usage for this group was high, at 14.6 visits per year. The use of formal care services, such as HSE home help (7.2%), HSE personal assistants (3.5%), and private paid carers (5.4%), was less commonly reported by our study respondents, with annual hours of 312, 255, and 525, respectively.

Medication costs and costs attributable to outpatient care contribute the largest share to direct costs, at 45% and 25%, respectively; while hospital/rehabilitation costs constitute a further 10%. The remaining 20% of direct costs are costs attributable to formal care, diagnostics, aids and adaptations, and nursing home or respite care (see Table 4). The direct healthcare costs associated with MS amount to €14,895.

Table 4. Productivity losses (hours) and informal care resource use (hours).

Employment variables	%	Mean in recall period	Total hours annually
Women (n = 424)
Officially reduced working week (h/week)	15.1	13 (4.6)	39,862
Extra hours missed in the last week (due to appointments, etc.)	8.5	14.3 (12.9)	24,720
Retired early due to MS	24.7	n.a.	n.a.
Presenteeism (% of work performance affected)	43.2	18.1 (25.3)	n.a.
Men (n = 170)
Officially reduced working week (h/week)	12.4	10.8 (5.1)	10,942
Extra hours missed in the last week (due to appointments, etc.)	25.4	14.4 (14.3)	12,476
Retired early due to MS	33.5	n.a.	n.a.
Presenteeism (% of work performance affected)	41.8	20.8 (45.5)	n.a.
Informal care
Weekly hours of informal care provided (per person with MS)	63	12 (11.4)	233,030

Depression and anxiety

A total of 229 people in our sample have (since the onset of MS) been treated for depression and/or anxiety, representing 38.55% of our total sample. This represents a sizable disparity between those with MS and the general population. In the general population the annual prevalence of mental health problems including depression and anxiety is estimated as being 10%³⁹. However, our estimate was not a 1-year prevalence estimate, therefore we assumed, as was reported in Koch et al.⁴⁰, that two-thirds of those who reported previously being treated for depression or anxiety would report depressive symptomology in the previous year. This gave us a figure of 15% of our sample population who would be free of depression and/or anxiety if the prevalence rates in the MS population were analogous to that of the general population. We then assume 3.3 and 0.7 extra GP visits per year, where 3.3 and 0.7 visits represent the difference between the annual mean GP visits for those with depression and anxiety compared with the national population (over 50) who are free of these mental health conditions⁴¹. To this, we allocated annual medication costs of €202.25 and €8.43 attained from IMS Health data, for depression and anxiety, respectively.

We, therefore, estimated the annual direct cost of depression and anxiety (GP and medication use) as being €321 per person affected. Given the excess prevalence of depression within the MS population, we estimate the excess direct healthcare cost of depression in the MS population as being in the region of €48 per PwMS per year.

Indirect costs

Total annual indirect costs were estimated at €23,750 per PwMS. The factors contributing the largest proportion of indirect costs were productivity losses accrued due to having to permanently withdraw from the workforce due to MS (39%). As MS impacts people who are in the prime of their working lives, a considerable number of PwMS are forced to leave the workforce prematurely. This is a notable characteristic in the existing MS literature^4,5,18,19,26.

This was followed by the hours of informal care provided to those with the condition (36%). Presenteeism, which relates to lost productivity at work due to MS, constitutes 11% of total indirect costs and is higher than the estimates relating to absenteeism (6%) or officially reduced working weeks (8%).

Intangible costs

In our sample, the EQ-5D-5L was completed by 541 people. The mean utility for the sample was 0.587. Compared to the UK population norm of 0.86, this represents almost a 32% decrease in self-reported HR-QoL³⁶. Differences in HR-QoL were apparent across disease severity, see Table 5. There were also significant differences between men and women in our sample, with scores of 0.507 and 0.619, respectively (p < .01).

Table 5. EQ-5D sample characteristics (mean utilities).

EQ-5D-5L	n (%)	Mean (SD)
Entire sample
Mean EQ-5D-5L index value	541 (100)	0.59 (0.29)
Sex
Women	386 (71.3)	0.62 (0.26)
Men	155 (28.7)	0.507 (0.33)
By MS severity
Mild	312 (57.7)	0.718 (0.19)
Moderate	192 (35.5)	0.492 (0.22)
Severe	37 (6.8)	−0.027 (.26)
Disease course
RRMS	346 (63.4)	0.67 (0.20)
SPMS	90 (16.6)	0.34 (0.33)
PPMS	55 (10.2)	0.39 (0.34)
Relapse in past year
No	307 (56.7)	0.60 (0.30)
Yes	234 (42.3)	0.57 (0.28)
Visual analog scale (entire sample)
VAS	541 (100)	63.34 (21.7)

The cohort of 541 people experienced a total loss of 150.46 QALYs due to MS during the year, or an average of 0.278 QALYs per person per year (0.353 for men, 0.248 for women). The current guidelines with respect to “value for money” threshold or “willingness-to-pay” for a unit of effect (life year or QALY) in Ireland is up to €45,000 per QALY. To gauge a conservative estimate, we used an average value between €20,000 and €45,000, for a QALY lost. Intangible costs for MS in Ireland were, therefore, calculated in the range of €5,562–€12,515 per person per year; the mid-point of which, €9,038, will be used as the estimate for the purpose of this study.

Summary of average costs and sub-group analysis

The annual societal costs attributable to MS as estimated above in the categories of Direct, Indirect, and Intangible costs amount to an average of €47,683 per person, per year. The direct costs constitute 31.2% of total costs; the indirect costs account for 49.8% of total costs; intangible costs account for 19%.

As discussed earlier, MS can manifest and progress in three ways or stages: primary or secondary progressive or relapsing-remitting MS; it can also be characterized by three disease severity stages. In the next sub-sections, the costs of MS are estimated for each delineating aspect, and an analysis of the cost attributable to the incidence of a relapse is also examined.

Disease course

MS can manifest in three main ways depending on the stage of disease, as previously noted. The most common form of MS in the population is relapsing-remitting MS (RRMS). Here we examine how costs differ for people with RRMS compared to primary or secondary progressive MS in previous cost of MS studies; costs vary across the disease course spectrum (see Table 6). When looking at the component costs—within each group—indirect costs forms a larger share of total costs than direct costs. The relative contributions of the cost components, however, differed among the sub-groups; for example, indirect costs comprised a smaller proportion of total costs in RRMS compared to both SPMS and PPMS sub-groups (47% for RRMS, 53% and 54% for those with SPMS and PPMS, respectively). However, for those with RRMS, direct costs (37%) comprised a larger proportion than those in the SPMS (25%) or PPMS groups (21%). Intangible costs also varied across disease types, with intangible costs composing 16%, 22%, and 24% for those with the relapsing-remitting, secondary-progressive, and primary-progressive forms of MS, respectively.

Table 6. Costs by disease course: RRMS, SPMS, and PPMS (€, 2015).

Disability level	Direct costs	Total indirect costs	Productivity costs	Informal care costs	Utilities EQ-5D	Intangible costs	Total costs (€,2015)
RRMS (69.6%)	15,285	19,831	12,965	6,866	0.673	6,696	41,813
SPMS (18.1%)	17,779	38,457	23,591	14,865	0.338	16,120	72,374
PPMS (n = 13.3)	12,306	31,605	17,623	13,981	0.389	14,170	58,081

Disability severity

An important contribution of our research is the ability to estimate societal costs by stage or severity of disability. Results are presented for those with mild, moderate, and severe MS (see Table 7). Within each grouping, indirect costs attributable to MS form a larger share of total costs than direct. However, the relative contributions of the cost components differed among the sub-groups; for example, indirect costs comprised a larger proportion of total costs in moderate compared to both mild and severe disability sub-groups (56% for moderate and 46% for both mild and severe). For those with mild MS, direct costs (36%) comprised a larger proportion than those in the moderate (24%) or severe groups (26%). There was a graded relationship between disability severity and intangible costs, those with intangible costs composing 15%, 20%, and 28% for those with mild, moderate, and severe MS, respectively.

Table 7. Costs by disability severity: mild, moderate, and severe (€, 2015).

Disability level	Direct costs	Total indirect costs	Productivity losses	Informal care costs	Utilities EQ-5D	Intangible costs	Total costs (€, 2015)
Mild (57.6%)	14,269	15,470	10,773	4,697	0.718	5,202	34,942
Moderate (35.2%)	13,696	32,671	20,088	12,583	0.492	11,490	57,857
Severe (6.9%)	26,298	46,223	24,851	21,372	–0.027	28,033	100,554

Cost of MS relapse

Supplementary to our calculation of the costs associated with MS in general, the specific cost associated with MS relapse was also calculated. Similar to the methodology followed to calculate the overall cost of MS, respondents were asked specific questions relating to direct and indirect resource use with respect to their most recent relapse experience. The breakdown of MS relapse cost components is shown in Figure 2.

Figure 1. Sub-groups of mean annual cost per PwMS (€, 2015) and percentage of total costs.

Figure 2. Breakdown of annual cost of MS relapse per person experiencing a relapse (€, 2015) and percentage of total costs.

We estimate the direct and indirect costs associated with a single relapse in Ireland at €1,715 and €723, respectively. Here, direct costs associated with relapse include: being admitted to hospital, tests, and other costs, such as travel and parking. Indirect costs consist of extra hours of care provided by others, and also costs accruing to productivity losses. This provides a total estimate of €2,438 for a single relapse. Of those who reported relapses in the last year, the average number per person was 1.85; therefore, we estimate the annual cost of relapses in Ireland as being €4,510 per person; this figure is comprised of annual direct costs of €3,173 and indirect costs of €1,337.

National level extrapolation of costs

To estimate the costs of MS at the national macro level, the estimates from our representative sample are extrapolated based on the epidemiology of the disease in Ireland, as discussed below.

Epidemiology

While there have been some important epidemiological studies of MS in Ireland that have looked at the latitudinal variation of the disease^{11–14,26,42}, there is currently no comprehensive study of the overall or national prevalence and incidence of MS in Ireland.

In an attempt to overcome this information deficit, estimates from a large UK population-wide study on incidence and prevalence of MS were adopted and extrapolated by age and sex to reflect the Irish demography. The result of this analysis was consistent with some informal estimates from health and social care service providers. As a result, and for the purposes of the overall cost of MS to society, we work on the assumption that there are 9,000 people living with MS in Ireland.

Extrapolating costs from the study sample to the general population of people with MS in Ireland and assuming there are 9,000 people in Ireland with MS: national annual direct, indirect, and intangible costs are estimated to be €134.1 million, €213.8 million, and €81.3 million, respectively. This provides for an overall total annual cost attributable to MS of €429.15 million.

Discussion

This aim of the study was to measure the impact of MS on a representative sample of the Irish population, and to estimate the associated economic cost to society. Our approach was to use a nationally representative sample of people with MS, to concentrate our analysis on the self-reported experience of those with MS, and comprehensively assess the resources allocated to the management and treatment of MS in Ireland.

Comparison to existing literature

The total cost attributable to MS in Ireland was estimated at €47,683 per person, per year. This estimate is in line with the conclusions in previous cost-of-illness studies of MS in Finland⁴³, France, Germany, Italy, Spain, and the UK; with total costs ranging between €36,400–€48,236 per person with MS⁵. While our estimate of €48,494 straddles the higher range reported in these studies, we have included a more complete range of costs and, in particular, we have included intangible costs—€9,038 per person each year—unlike in Karampampa et al.⁴⁴

With respect to the existing Irish literature, our estimate for total costs attributable to MS is higher than that reported in Fogarty et al.¹⁹, (€37,961). This difference is also primarily driven by the addition of intangible costs (€9,038), but also by our higher cost estimates associated with informal care (€8,646 vs €6,145). Interestingly, our nationally representative population-based sample had many similar characteristics (age, gender, disability severity) to samples recruited at neurology clinics. The general consistency of study results, therefore, may serve to alleviate concerns about the external reliability of clinic-based CoMS work in the literature.

Direct costs

We estimate the total direct costs per person in our study as being €14,895, as such direct costs contribute to 38% of our total cost estimate. When comparing with the existing international literature, this figure is relatively low (see Table 8). This may be a consequence of study respondents in the CoMS literature, typically being recruited via specialized clinics^4,5,17,19,31. In the present study, respondents were recruited though a patient organization—indicating that, on average, clinic based studies may have respondents suffering from more advanced MS than rings true in a more representative sample. Indeed, when comparing with the previous Irish study, nearly twice as many respondents reported having severe MS (12.7% vs 6.6%)⁹.

Table 8. Direct and indirect costs as a proportion of total costs: cross-country comparison.

Country	Author	Year	Direct cost	Indirect costs
UK	McCrone	2008	28%	72%
UK	Kobelt	2000	28%	72%
Ireland	Current study	2015	38%	62%
Norway	Svendsen	2006	39%	61%
Spain	Kobelt	2012	42%	56%
Netherlands	Kobelt	2006	42%	58%
Ireland	Fogarty	2014	45%	55%
Canada	Karampampa	2012	46%	64%
Germany	Kobelt	2006	47%	53%
Australia	Taylor	2007	57%	43%
US	Adelman	2013	77%	23%
France	Karampampa	2006	85%	15%

Strikingly, a systematic review of CoMS studies conducted in the US estimated that 77% of total costs (in five studies) were driven by direct costs. It is likely that this is a function of relatively high costs of DMTs and symptom management therapy in the US. Indeed, on average, 50% of the total costs were attributed to prescription medication²⁸.

Disease progression and costs

Our results also clearly highlight disability severity as a key driver of the societal cost associated with MS; as disability increases, so too does the economic burden. The total cost associated with moderate MS (€57,857) was 70% higher than our estimated cost for those with mild MS (€34,942); while the cost associated with severe MS was approximately three times the total cost for those with mild MS (€100,554). This finding echoes that of previous studies in the MS cost of illness literature, for example in Karampampa et al.⁴⁴ the total cost associated with moderate MS (€39,923) was almost double their estimated total cost for people with mild MS (€21,174), while the total cost incurred by patients with severe MS (€64,270) was roughly 3-times the total cost for people with mild MS. So too in Ruutiainen et al.⁴³, where the mean total annual cost of MS was €46,994, which increased with advancing disease from €10,835 (mild) to €109,901 (severe). In a previous Irish study (Fogarty et al.¹⁹), a similar pattern emerged. However, the costs associated with severe MS was almost 5-times that of mild MS (€95,968 vs €19,696), while the estimated cost representing moderate MS was over double that of mild MS (€44,851 vs €19,696).

One of the main factors driving the disparity in total costs associated with mild, moderate, and severe MS was the graded relationship between direct healthcare resource use and disability severity. For example, as the impact of disability increased, so too did the number of days spent in hospital. Significant differences were apparent when comparing those with mild (7.3 days) and moderate MS (9.8 days) and between those with mild (7.3 days) and severe MS (11.2 days) (p < .05).

A similar pattern emerged with respect to physiotherapy sessions, as those with severe MS reported having 10 physiotherapist sessions in the previous 6 months, three and four sessions more than those with moderate and mild disability, respectively (p < .05).

The ubiquity of MS severity as a predictor of total costs, here and throughout the literature, highlights the importance of good disease management in the early stages of illness; delaying progression is, therefore, important from an economic perspective, as well as the more obvious clinical and patient outcomes perspective.

Indirect costs

Workforce participation and productivity

Productivity losses as a consequence of MS are estimated at €15,863 per person each year and constitute 65% of our total indirect costs. MS is associated with productivity losses and shocks for a variety of reasons. Since the average age of onset is between 20–40 years, MS impacts people in the prime of their working lives and professional careers. Furthermore, for those who experience relapses, or are unable to walk unaided, or who experience extreme fatigue, it can be difficult to sustain a normal working life. This is apparent in our study, where 26% of those in employment felt it necessary to change jobs due to their condition, while close to 70% felt that the disease had limited their career potential.

Consequently, for those with MS, finding and remaining in employment can be a pervasive issue often resulting in substantial personal and societal loss. This is illustrated by the employment rates in our study, where less than 42% of men and 44% of women report being in paid employment. These figures represent a 24% and a 38% decrease in the national averages for women (56.9%) and men (67.6%), respectively⁴⁵. Low employment rates are also reported in the international literature: in the Kobelt et al.^4,17,31 European study, the proportion of those who worked ranged between 25–40%, while, in the Fogarty et al.¹⁹ Irish study, the corresponding figure was 40%.

As one would expect, employment status varied by disease severity in our study (mild: 56.4%, moderate: 26%, severe: 15%) and disease type (RRMS: 51.0%, SPMS: 21.9%, PPMS: 27.2%). Advancing disease severity is precipitating this sizable drop in employment. In our study the average age of those with mild disease was 43 years, while for those with moderate MS the mean age was 51 years; this suggests a particular shift away from employment as people progress from mild to moderate MS.

Our study highlights the considerable work-life challenges associated with having MS in Ireland, and the substantial productivity losses associated with such challenges. Particularly striking in this respect is the significant proportion of our study sample that felt it necessary to permanently withdraw from the workforce as a consequence of their condition. While legislation and changes in attitudes mean that workplaces are becoming more disability friendly, our findings demonstrate that more could be done to improve employment opportunities and to foster flexible work practices that may help to enhance the work-life prospects of those living with MS in Ireland.

Informal care arrangements

In our study, informal care costs amounted to €8,648 per person, comprised 35% of our total indirect costs, and constituted 22% of our total costs (excluding intangible costs). The costs attributable to informal care varied by disability severity (Mild MS: €4,697, Moderate: €12,583, Severe: €21,372) and by course of illness (RRMS: €6,866, SPMS: €14,865, PPMS: €13,981). This variation by severity and disease course is also reflected in the literature^4,5,19. Informal care costs for those with mild MS were, however, considerably higher in our study compared with that reported in Fogarty et al.¹⁹ (€4,697 vs €820) and in Karampampa et al.⁴⁴ (€4,697 vs €830). This may be partly due to differing methodologies used to classify disability severity. In this study, the level of disability severity was self-reported, whereas in both Fogarty et al.¹⁹ and Karampampa et al.⁴⁴ respondents were assessed by clinicians and categorized based on EDSS scores—perhaps intimating higher levels of disability severity in our mild sub-group and/or the inclination for respondents to self-report mild disability.

We did not distinguish between carers who were in paid employment and those who were not, using a similar approach to Fogarty et al.¹⁹ where caregiving was valued at the wage the caregiver would earn if in paid employment, based on national mean annual earnings. This common approach may over-estimate the actual productivity losses to society if no value is placed on personal or leisure time. To ensure a more conservative estimate, we applied a cap on caregiving time of 40 h per week, again in keeping with the approach used by Fogarty et al.¹⁹. If the upper limit cap is removed, the average caregiving hours per week becomes 15.3, valued at an annual cost of €11,101 per person; compared to our primary and more conservative estimate of €8,648. A further method, when valuing caregiving time, is to do so at the national minimum wage (€8.65 per hour)⁴⁶. Following this approach, we estimate an annual cost attributable to informal care, in our study, of €4,321 per person with MS.

Intangible costs

While multiple sclerosis is associated with a significant cost burden, the condition also impinges significantly on the quality-of-life of those with the condition. We assessed quality-of-life in this study by applying the commonly used validated survey instrument EQ5D-5L to estimate the utility or health-related quality-of-life (HrQol) of people living with MS.

The utility values estimated in our study are consistent with that estimated in the international literature^4,5, and also in previous Irish research⁴⁷. Indeed, the mean utility value of 0.59 estimated here is analogous to that reported in Fogarty et al.¹⁹. Consistency in this respect was expected, as previous studies in the area have demonstrated that, even when comparing utilities across as many as nine European countries, utility values were almost identical⁴.

Extending the EQ-5D analysis to include a monetary estimate for the clearly diminished HrQol associated with multiple sclerosis allowed us to present an estimate for the intangible costs associated with the condition. While typically not included in cost-of-illness studies, applying monetary values to such intangibles as self-care, pain, mobility, and anxiety or depression offers a vehicle to highlight the tremendous hidden costs associated with having a long-term, progressive, chronic condition such as multiple sclerosis. Furthermore, intangible costs have been included in previous studies of the cost of MS^4,30 and, by including the same, we can offer intangible cost estimates that can be compared to those reported in previous studies.

In our study, by calculating the difference in utilities between our sample and an age- and sex-matched sample of the general population in the UK³⁶, the utility loss due to MS translated into a mean QALY loss of 0.28. Using the same methodology, a remarkably similar mean QALY loss of 0.27 was reported in Kobelt et al.⁴, while, in Henriksson et al.³⁰, due to lower mean QALY estimates, this value was smaller (0.185). In Kobelt et al.^4,31, the authors apply a threshold value of €50,000 to their QALY loss estimates and also apply a figure 3-times the gross domestic product (GDP) per capita. Following the latter approach would imply a threshold value of €119,619 for Ireland and a resulting intangible cost estimate of €32,297. Following a more conservative approach, we use threshold values of €20,000 and €45,000, in which the willingness-to-pay for a unit of effect (life year or QALY) in Ireland is expected to lie. Using these values for a QALY lost, intangible costs for MS in Ireland are calculated as being in the range of €5,562–€12,515 PwMS.

Figure 3. Disease severity classification question and relapse occurrence questions.

Relapse costs

The use of direct and indirect healthcare that was specific to the respondents’ last relapse was also examined in our work, providing a new estimation of the costs associated with a single MS relapse (€2,438).

The average cost per relapse in the previous Irish research⁴⁸ was estimated at €3,571, some 46% higher than the estimate provided in the present study. The principal factor driving this disparity is the proportion of those who required inpatient care as a result of their relapse. In our data, 18% reported staying overnight in hospital, while in O’Connell et al.⁴⁸ 32% of participants required such care. This difference highlights the differences than can emerge depending on the sample characteristics, and the value, therefore, of more nationally representative samples over clinic-based sample for estimating full economic costs.

The nature in which relapses are reported in this study is also likely to have had the effect of our sample being over-represented by those reporting having experienced mild relapses, some of which may have been considered sub-clinical if assessed by a neurology team. However, in estimating societal costs, self-reported experience is important. While a global definition of a MS relapse was provided to the study respondents, a person’s definition of a relapse may not be the same as a medical definition. Indeed, just over half of those experiencing relapses reported having them confirmed by a neurology team, so we cannot rule out that those in our study had difficulties in differentiating between mild MS symptoms and relapses. Our study focuses on the personal experience offered by the respondents.

Limitations

While we have been rigorous in estimating the economic cost of the various aspects of multiple sclerosis in Ireland, this study had a number of limitations.

First, and similar to all cost-of-illness studies which utilize self-report data: our cost estimates rely solely upon self-reported estimates by our study respondents, which may be open to recall bias. For example, it has been recognized that respondents tend to under-report their hospitalizations for longer recall periods and over-state for shorter⁴⁷. However, there is also evidence that self-reported resource utilization data is as reliable as other sources, including administrative records⁴⁹. Furthermore, the instrument we used to assess resource use in this study is the most commonly applied in cost-of-illness studies, and its reliability and validity have been previously established⁵⁰. We also acknowledge a limited amount of data on specific medication use for the sample. Questions on the use of medication were not considered necessary for estimating the societal costs, as MS medicines are disease-specific and can be readily imputed using macro data (e.g. PCRS data; IMS data)—this approach also helps to minimize responder burden. To allow for a more complete picture of these costs on the individual level, average medication costs were calculated based on Fogarty et al.’s¹⁹ clinic-based study and adjusted to reflect the level of disability severity seen in the nationally representative sample.

Conclusions

We estimated the annual cost of MS to Irish society at €429 million per year, or close to €48,000 for every individual with MS. The economic cost of MS in considerably larger than the direct healthcare costs provided by formal healthcare; in fact, up to 70% of costs associated with MS do not feature on financial accounts, but are, nonetheless, real costs to individuals and society. In devising and evaluating public policy and health service planning, it is important that these costs are not ignored.

Indeed, one of the key drivers of the hidden costs is associated with early and enforced workforce withdrawal. Our results clearly highlight that, as disability severity increases, total costs attributable to MS also increase, while health-related quality-of-life decreases significantly. With this in mind, healthcare interventions designed to delay disability progression, enabling PwMS to maintain workforce participation for longer, are likely to have the effect of reducing overall costs associated with MS, while also significantly improving quality-of-life for people living with the disease.

Transparency

Declaration of funding

The study was part-funded by Novartis Ireland. IE02/NEU16-CNF017 Ethics approval was obtained from University College Dublin (UCD) Human Research Ethics Committee in February 2015.

Declaration of financial/other relationships

PC is a PhD candidate at UCD and an employee of Novartis Ireland. DO is an employee of Novartis Business Services Centre, Dublin, Ireland. CM is an employee of SVUH, Dublin. He has received research grant support from Bayer, Biogen, Genzyme, and Novartis; served on advisory boards for Biogen, Genzyme, and Novartis; and received speaker’s honoraria from Biogen, Genzyme, and Novartis. KO is an employee of The Mater Hospital, Dublin, Ireland. AL is an employee of MS Ireland. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

A poster of preliminary results was presented at ECTRIMS, London, 2016.

Acknowledgments

The authors thank Ms Shauna Preston, who provided research assistance throughout the early stage of this project; Ms Shauna Corless, who provided administrative support throughout the later stage of this project; Ms Ava Battles, Ms Harriet Doig, and other staff of MS Ireland, who facilitated and supported recruitment to this study; and Irish people living with MS who participated in this research.

Note

Notes

1 Presenteeism relates to lost productivity at work due to health problems. Presenteeism arises when a person attends for work, but is not performing their duties as expected in terms of quality or quantity.