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Economic costs associated with an MS relapse

Published:September 14, 2014DOI:https://doi.org/10.1016/j.msard.2014.09.002

      Highlights

      • Multiple sclerosis relapse costs are determined by the severity of the episode.
      • Even low intensity relapses can have significant financial implications.
      • Higher intensity episodes were associated with higher baseline disability.
      • Indirect costs were mainly attributed to loss of earnings.
      • Relapses can significantly increase annual multiple sclerosis related costs.

      Abstract

      Background

      Multiple sclerosis (MS) commonly affects young adults and can be associated with significant disability resulting in considerable socioeconomic burden for both patient and society.

      Aims

      The aim was to determine the direct and indirect cost of an MS relapse.

      Methods

      This was a prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration, expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals and travel costs.

      Results

      Fifty-three patients had a clinically confirmed relapse. Thirteen were of low intensity; 23 moderate intensity and 17 high intensity with mean costs of €503, €1395 and €8862, respectively. Those with high intensity episodes tended to be older with higher baseline EDSS (p<0.003) and change in EDSS (p<0.002). Direct costs were consistent in both low and moderate intensity groups but varied with length of hospital stay in the high intensity group. Loss of earnings was the biggest contributor to indirect costs. A decision to change therapy as a result of the relapse was made in 23% of cases, further adding to annual MS related costs.

      Conclusions

      The cost of an MS relapse is dependent on severity of the episode but even low intensity episodes can have a significant financial impact for the patient in terms of loss of earnings and for society with higher annual MS related costs.

      Keywords

      1. Introduction

      Multiple sclerosis (MS) is the most common disabling, non-traumatic neurological condition affecting young adults. In the early stages the disease follows a relapsing-remitting (RRMS) course, in which episodes of neurological dysfunction are followed by periods of recovery. However, about 50% of relapses result in increased residual disability (
      • Hirst C
      • Ingram G
      • Pearson O
      • Pickersgill T
      • Scolding N
      • Robertson N.
      Contribution of relapses to disability in multiple sclerosis.
      ,
      • Lublin FD
      • Baier M
      • Cutter G
      Effect of relapses on development of residual deficit in multiple sclerosis.
      ) and over time the majority of patients will enter the secondary progressive phase (
      • Confavreux C
      • Vukusic S.
      Natural history of multiple sclerosis: a unifying concept.
      ) with significant impact on quality of life and increasing economic burden (
      • Karampampa K
      • Gustavsson A
      • Miltenburger C
      • Eckert B.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from five European countries.
      ). High relapse activity in the first two years of diagnosis are predictive of time to sustained disability, early conversion to secondary progressive MS and earlier mortality (
      • Leray E
      • Yaouanq J
      • Le Page E
      • Coustans M
      • Laplaud D
      • Oger J
      • et al.
      Evidence for a two-stage disability progression in multiple sclerosis.
      ,
      • Scalfari A
      • Neuhaus A
      • Daumer M
      • Muraro PA
      • Ebers GC.
      Onset of secondary progressive phase and long-term evolution of multiple sclerosis.
      ).
      The economic cost associated with relapses and subsequent disability is considerable. Disability is assessed using the expanded disability status scale (EDSS) (
      • Kurtzke JF.
      Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
      ). Scores of EDSS≤3 indicate that patients are independently mobile with minimal disability; 4–6.5 mean higher levels of disability generally with restriction of the mobility and may require an aid to walk; EDSS≥7 reflects a high level of assistance for all activities of daily living. TRIBUNE (
      • Karampampa K
      • Gustavsson A
      • Miltenburger C
      • Eckert B.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from five European countries.
      ), a multicentre study initially carried out in five European countries examined the costs associated with MS; the annual cost for those with EDSS≤3 ranged from €13,534 to €22,561 increasing to €28,524–€43,984 for EDSS 4–6.5 and €39,592–€65,395 for EDSS≥7. A similar study carried out in Ireland (
      • Fogarty E ea.
      Resource use and economic consequences associated with multiple sclerosis.
      ) showed mean annual costs of €19,000, €45,000 and €95,000 for mild, moderate and severe disease, respectively.
      The cost of managing a relapse is dependent on the severity of symptoms. In a recent American study (
      • Parise H
      • Laliberte F
      • Lefebvre P
      • Duh MS
      • Kim E
      • Agashivala N
      • et al.
      Direct and indirect cost burden associated with multiple sclerosis relapses: excess costs of persons with MS and their spouse caregivers.
      ) the mean annual costs for low or medium intensity episodes were US$9212 (€6731) and US$21,119 (€15430) for high intensity episodes. In a Canadian study (
      • Karampampa K
      • Gustavsson A
      • Miltenburger C
      • Kindundu CM
      • Selchen DH.
      Treatment experience, burden, and unmet needs (TRIBUNE) in multiple sclerosis: the costs and utilities of MS patients in Canada.
      ) 50% of RRMS patients with EDSS ≤5 experienced at least one relapse over the previous year with an increased cost of CA$10,512 (€6902) when compared to those who were relapse free. They estimated the mean cost of a relapse was CA$6402 (€4203) and was similar to a European multicentre study (
      • Karampampa K
      • Gustavsson A
      • Miltenburger C
      • Eckert B.
      Treatment experience, burden and unmet needs (TRIBUNE) in MS study: results from five European countries.
      ,
      • Karampampa K
      • Gustavsson A
      • van Munster ET
      • Hupperts RM
      • Sanders EA
      • Mostert J
      • et al.
      Treatment experience, burden, and unmet needs (TRIBUNE) in Multiple Sclerosis study: the costs and utilities of MS patients in The Netherlands.
      ). Both these studies however, were based on patient questionnaires, without clinical confirmation of the relapse and relapses were not stratified according to level of severity.
      The aim of this audit was to prospectively determine both the direct and indirect costs associated with a clinically confirmed MS relapse of varying severity.

      2. Patients and methods

      2.1 Study design

      This was a prospective audit conducted over 18 months from January 2011 to June 2012 at St Vincent׳s University Hospital, Dublin, a university teaching hospital with a large secondary and tertiary referral MS service. It included a review of the medical notes and patient questionnaire.

      2.2 Patients

      Consecutive patients presenting, with a relapse confirmed by their treating neurologist were invited to participate. A relapse was defined as new or recurring neurological symptoms present for at least 24 h, based on objective clinical evidence and absence of fever or known infection. Relapses were classified according to previous publications as low intensity, moderate intensity and high intensity episodes (
      • O׳Brien JA
      • Ward AJ
      • Patrick AR
      • Caro J.
      Cost of managing an episode of relapse in multiple sclerosis in the United States.
      ). A low intensity episode was defined as evidence of minimal disability on examination requiring only symptomatic management or a short course of oral steroids. Moderate intensity episodes were treated with intravenous steroids in the outpatient setting either as a day case in the infusion therapy unit in the hospital or if available at home and high intensity episodes required hospital admission.

      2.3 Patient assessments

      Participants had their age, gender, employment status, disease duration from symptom onset, MS subtype and use of disease modifying therapy (DMT) recorded. EDSS at the time of the relapse was determined by the treating neurologist and noted, as was their EDSS from their previous clinic visit. Patients completed a questionnaire to determine direct and indirect costs associated with the relapse. Direct costs included GP visit, relevant investigations (bloods tests, infection screen, and imaging tests), additional clinic visit, consultation with MS clinical nurse specialist and other allied health professionals, medication prescribed and admission costs (day case and inpatient).
      Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals, cost of travel and parking.

      2.4 Costing

      Patients completing the questionnaire provided their indirect costs which included costs of travel, loss of earnings, need for childcare and non-hospital-related medical costs. The hospital accounts department provided direct admission costs. All blood tests were carried out in the hospital and prices were calculated based on our hospital׳s pathology price listings. A number of MRI centres are routinely used by people attending the MS service with considerable variability in pricing. As a result of this a mean from the MRI costs of two private and two public hospitals was taken as the mean MRI scan cost in the low and moderate intensity groups. In the high intensity group the cost of an MRI was calculated directly by the hospital accounts department. The average cost of an outpatient visit was applied rather than individual staff costs as it was felt to be more representative of total cost. This was calculated at €144 per visit for 2012 and based on the Standardised Irish Health Service Executive National Casemix Program (
      • Dorris DR
      • Nguyen A
      • Gieser L
      • Lockner R
      • Lublinsky A
      • Patterson M
      • et al.
      Oligodeoxyribonucleotide probe accessibility on a three-dimensional DNA microarray surface and the effect of hybridization time on the accuracy of expression ratios.
      ). Staff costs were calculated as set out by the Health Information and Quality Authority (HIQA)

      Guidelines for the Economic Evaluation of Health Technologies in Ireland, 2010

      . The hospital pharmacy department carried out all medication pricing.

      2.5 Statistical analysis

      Descriptive statistics were carried out to summarise the baseline characteristics of the study population. Between group differences were examined using a one-way ANOVA. SPSS 20 was used for all analyses.

      3. Results

      3.1 Patient characteristics and relapse severity

      A summary of baseline characteristics relative to each relapse is outlined in Table 1. Fifty-three clinical relapses were documented during the study period: 13 were considered low intensity; 23 moderate intensity and 17 high intensity; the differences in gender ratios between groups reflects the small sample size. Patients with high intensity relapses tended to be older with a significantly higher baseline EDSS (mean 3.6, p<0.003) than those in the low intensity group. They also had a significant increase in their EDSS (mean 2.3, p<0.002) during their relapse compared to the low and moderate intensity group. There was no difference in disease duration between groups despite a higher rate of SPMS with superimposed relapses seen in both the moderate and high intensity groups. Multifocal relapses and those affecting the spinal cord were more likely to require hospitalisation. Higher rates of employment were seen in the low intensity group.
      Table 1Baseline characteristics of the study population relative to each relapse and stratified as per relapse intensity.
      Relapse intensity
      Low (n=13)Moderate (n=23)High (n=17)
      Gender (%)
      Male154865
      Female855235
      Age (years)
      Mean (SD)30.5 (7.4)36.3 (8.8)38.9 (12.1)
      Disease duration (years)
      Mean (SD)5.9 (5.7)8.1 (7)6.7 (7.3)
      MS subtype (%)
      RRMS1007047
      SPMS with relapses03053
      DMT use (%)
      Yes627560
      1st line888080
      2nd line132020
      Type of relapse (%)
      Optic neuritis3140
      Spinal cord547459
      Brainstem15226
      Other0035
      EDSS
      Baseline, mean (SD)1.1 (0.6)3.1 (2)3.6 (2.4)
      Baseline EDSS was significantly higher than the low intensity group only (p<0.003).
      Change, mean (SD)1.1 (0.6)1.0 (0.7)2.3 (1.8)
      Change in EDSS was significant in high intensity group compared to both low and moderate intensity groups (p<0.002).
      Employment (%)
      Currently employed775241
      Not working due to MS82247
      Not working by choice0136
      Full-time education15136
      low asterisk Baseline EDSS was significantly higher than the low intensity group only (p<0.003).
      low asterisklow asterisk Change in EDSS was significant in high intensity group compared to both low and moderate intensity groups (p<0.002).
      A decision to initiate or change DMT was made on the basis of the relapse in 12 patients, 3 in low intensity relapse group, 3 in moderate relapse group and 6 in the high intensity group. This was associated with a subsequent increase in annual costs from between €2840 and €21,352 per person.

      3.2 Multiple relapses

      This group was further subdivided to those who had a single relapse (n=33) and those who had more than one relapse (n=9). Baseline characteristics and treatment history are compared between these two groups and outlined in Table 2. Significant differences were found between groups in relation to gender with a higher rate of males, relapse severity with more high intensity episodes and DMT use in the multiple relapse group. Baseline EDSS was also higher amongst this group but not significantly so.
      Table 2Comparison of baseline characteristics and treatment history between those with a single relapse and those with more than one relapse.
      Single relapse (n=33)Multiple relapses (n=9)
      Gender (%)
      Significant differences: gender (p<0.001).
      Male87
      Female252
      Age (years)
      Mean (SD)35.7 (10.2)35.7 (10.1)
      Disease duration (years)
      Mean (SD)8.2 (5.6)5.3 (8.1)
      MS subtype (%)
      RRMS2140
      SPMS with relapses7960
      Relapse severity (%)
      Significant differences: relapse severity (p=0.019).
      High intensity1855
      Moderate intensity5230
      Low intensity3015
      EDSS
      Baseline, mean (SD)2.4 (2.0)3.4 (2.2)
      Change, mean (SD)1.3 (1.0)1.7 (1.6)
      DMT use (%)
      Yes
      Significant differences: DMT use (p<0.001).
      4980
      1st line8187
      2nd line1913
      Change in treatment (%)2125
      low asterisk Significant differences: gender (p<0.001).
      low asterisklow asterisk Significant differences: relapse severity (p=0.019).
      low asterisklow asterisklow asterisk Significant differences: DMT use (p<0.001).

      3.3 Cost of a low intensity relapse

      The mean cost of a low intensity relapse in 13 patients was €503 (range: €0–€1317). One patient reported symptoms that were felt to be consistent with a sensory relapse at a routine outpatient appointment. No medical attention was sought at the time and as there were no indirect costs thus there was no cost associated with this relapse. Direct costs accounted for the majority with a mean of €400 (range: €0–€985). This included contact with MS clinical nurse specialist, clinician review, medications and further investigations. Of this group 6 had an MRI scan with a mean cost of €236 per person. Five patients required treatment with oral steroids and an MRI was ordered in six cases. The mean indirect costs were €104 (range: €0–€1125). One patient however, reported significant loss of earnings of €1125 which, when excluded the mean cost was €17. Only two patients reported they were unable to work due to their symptoms (1 and 6 days, respectively). All costs have been summarised in Table 3 and reflects mean costs across the group.

      3.4 Cost of a moderate intensity relapse

      Twenty-three patients had a moderate intensity relapse requiring outpatient treatment with intravenous steroids. The mean total cost was €1395 (range: €658–€4563). Direct costs outweighed indirect costs with a mean of €972 (range: €658–€1441) and €438 (range: €0–€3645), respectively. In all cases the patient had made direct contact with the MS specialist nurse and a relapse assessment visit was arranged. In 14 patients, an MRI was requested to further assess the level of disease activity and this equated to an average €278 per person. Table 3.
      Table 3Summary of direct and indirect costs associated with a clinical relapse depending on relapse intensity. (All prices in € and expressed as mean per relapse).
      Relapse intensity
      Low (n=13)Moderate (n=23)High (n=17)
      Direct costs
      Contact with MS Nurse Specialist232714
      Neurologist review11114468
      Denotes patients who were seen in outpatient clinic prior to admission (n=8).
      Other doctor review1400
      Medications858440
      Radiology236278163
      Pathology87167
      Allied Health00471
      Day care04450
      Inpatient costs004098
      The cost of medical review has been included in inpatient costs.
      Total direct costs4009725421
      Indirect costs
      Travel93573
      Parking1834
      Loss of earnings923192995
      Disability00686
      Spouse׳s loss of earnings07682
      Childcare0.775.460
      Meals01136
      Total indirect costs1044383441
      Total relapse cost50313958862
      low asterisk Denotes patients who were seen in outpatient clinic prior to admission (n=8).
      low asterisklow asterisk The cost of medical review has been included in inpatient costs.
      Twelve patients were in full time employment and reported an average of 6 (range: 0–15) days of work lost associated with the relapse, with a mean loss of earnings of €585. There was also an increase in travel costs and parking as patients had to attend daily for 3 days for steroid treatment.

      3.5 Cost of a high intensity relapse

      Seventeen patients required admission to hospital due to the severity of their symptoms. Of these eight were seen in the outpatient clinic as relapse assessment and admitted directly and the remainder were admitted through the emergency department. Hospital admission was associated with a significant rise in cost to a mean of €8862 (range: €1512–€38,587). The in-hospital length of stay ranged from 2 to 44 days (mean 10.5) and direct costs associated with admission ranged from €989 to €19,795 (mean €5421). All except one patient was investigated with inpatient MRI scan. The relatively low cost of radiology in this group reflects our hospital׳s pricing of MRI scans which is considerably lower than a number of other radiology centres in our area. Mean indirect cost was €3441 (range: €0–€34,239). Seven patients were working at the time of the relapse and five reported days of work lost (mean: 72.8, range: 7–210). Mean loss of earnings amongst these patients was €7273. Two patients had to go on disability benefit and one patient was unable to return to their previous role due to permanent disability as a result of the relapse.

      4. Discussion

      The cost of an MS relapse is determined by the severity of the episode and the baseline disability level of the subject. Direct costs accounted for the majority of the low and moderate intensity episodes and were more consistent across each group compared to the high intensity group. Higher costs were driven primarily by hospital admission and length of stay. A significant increase in EDSS during the relapse was seen in the high intensity group and multifocal and spinal cord relapses were more likely to require admission due to higher associated disability. Similar to a previously published American study (
      • O׳Brien JA
      • Ward AJ
      • Patrick AR
      • Caro J.
      Cost of managing an episode of relapse in multiple sclerosis in the United States.
      ), hospitalisation was associated with a six fold increase in cost when compared to those managed with steroids as a day case. This might be expected to reduce further if there was an option of administering steroids in the home setting, which at present is not available within the public health service and only covered by a limited number of private insurance policies.
      Greater variability was seen in indirect costs across all three groups as might be expected from the diverse demographics of a relatively small patient sample. Unsurprisingly, the main component of this figure was loss of earnings. MS typically affects young adults when they are most economically productive. High rates of early retirement on medical grounds are seen in patients with MS with significant socioeconomic consequences for the individual, their family and society as a whole. Both age and disability status are independent predictors of employment in MS (
      • Krause I
      • Kern S
      • Horntrich A
      • Ziemssen T.
      Employment status in multiple sclerosis: impact of disease-specific and non-disease-specific factors.
      ) and those in employment reported higher quality of life when compared to their unemployed counterparts (
      • Pack TG
      • Szirony GM
      • Kushner JD
      • Bellaw JR.
      Quality of life and employment in persons with multiple sclerosis.
      ). A German study found higher rates of employment amongst RRMS patients who were on DMT and felt the introduction of DMT use had a positive influence on employment amongst German RRMS patients (
      • Korchounov A
      • Tabatadze T
      • Spivak D
      • Rossy W
      • Krasnianski M.
      MS related employment and disease modifying treatment in the German working population: 1994–2009.
      ). In our patients, levels of MS related unemployment (early retirement) were highest amongst those requiring hospitalisation and this group tended to be older, with higher EDSS scores at baseline.
      The currently available first-line DMTs for RRMS reduce relapse activity by approximately 30% (
      • IFNB-MS-Study-Group
      Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group.
      ,
      • Jacobs LD
      • Cookfair DL
      • Rudick RA
      • Herndon RM
      • Richert JR
      • Salazar AM
      • et al.
      Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG).
      ,
      • Johnson KP
      • Brooks BR
      • Cohen JA
      • Ford CC
      • Goldstein J
      • Lisak RP
      • et al.
      Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.
      ,
      • PRISMS
      Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis.
      ). Long-term efficacy however, in terms of preventing disability progression is less clear (
      • Ebers GC
      • Traboulsee A
      • Li D
      • Langdon D
      • Reder AT
      • Goodin DS
      • et al.
      Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.
      ,
      • Shirani A
      • Zhao Y
      • Karim ME
      • Evans C
      • Kingwell E
      • van der Kop ML
      • et al.
      Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis.
      ,

      Shirani A, Zhao Y, Karim ME, Petkau J, Gustafson P, Evans C, et al. Investigation of heterogeneity in the association between interferon beta and disability progression in multiple sclerosis: an observational study. Eur J Neurol. 2013.

      ,
      • Uitdehaag B
      • Constantinescu C
      • Cornelisse P
      • Jeffery D
      • Kappos L
      • Li D
      • et al.
      Impact of exposure to interferon beta-1a on outcomes in patients with relapsing-remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study.
      ). The average cost in Ireland is €15,000 per year for first-line therapy rising to €22,000 per year for second-line agents and are a significant contributor to the direct costs early in the disease. Cost-effectiveness has yet to be proven (
      • Noyes K
      • Bajorska A
      • Chappel A
      • Schwid SR
      • Mehta LR
      • Weinstock-Guttman B
      • et al.
      Cost-effectiveness of disease-modifying therapy for multiple sclerosis: a population-based study.
      ) and can depend on the model used but earlier treatment is associated with improved survival and quality adjusted life years (QALY) (
      • Kobelt G
      • Texier-Richard B
      • Lindgren P.
      The long-term cost of multiple sclerosis in France and potential changes with disease-modifying interventions.
      ,
      • Pan F
      • Goh JW
      • Cutter G
      • Su W
      • Pleimes D
      • Wang C.
      Long-term cost-effectiveness model of interferon beta-1b in the early treatment of multiple sclerosis in the United States.
      ). High relapse activity early in the disease is a significant predictor of the need to switch to second line therapies (
      • Portaccio E
      • Zipoli V
      • Siracusa G
      • Sorbi S
      • Amato MP.
      Switching to second-line therapies in interferon-beta-treated relapsing-remitting multiple sclerosis patients.
      ) and further impacts on cost. Sixty-two per cent of our patients were on DMTs (82% first-line, 18% second-line) and the pattern of use was similar across the 3 groups. The relapse in question resulted in a change of medication in 23% cases further increasing annual MS related costs.
      One of the limitations of this audit is the relatively small number of patients and the findings only reflect the costs at a single specialist MS unit. At present, treatment patterns vary across Ireland as not all hospitals have a neurologist on site or the facilities to deliver steroids in an outpatient setting. A number of proposals have been made to move away from the traditional two-tier (private and public) health service seen in Ireland including the establishment of a policy of money following the patient. The aim of such a model would be to standardise the level of care in terms of both cost and quality of service delivered in both public and private sectors. It is hoped that this will improve efficiency and promote cost-effective models such as giving steroids in the home or outpatient setting.
      Another limitation of our study is that mild relapses by their nature are likely to be underreported by patients and thus underrepresented in our cohort.

      5. Conclusions

      This is the first report looking at both indirect and direct costs in a clinically confirmed relapse amongst an Irish population and showed that even low intensity episodes can have significant financial implications both for the patient, in terms of loss of income and for society, with increasing annual MS related costs due to initiation or change of treatment.

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