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Cost-Analysis of Relapsing-Remitting Multiple Sclerosis in Italy after the Introduction of New Disease-Modifying Agents

http://www.medscape.com/viewarticle/484004

Aug 3, 2004
Pierluigi Russo; Alessandro Capone; Andrea Paolillo; Francesco Macchia; Federica Ranzato; Gianfranco Costantino; Luca Degli Esposti; Luciano Caprino
Clin Drug Invest 24(7):409-420, 2004

Abstract and Introduction

Abstract

Background and Objective: During the last decade, several agents have proven to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS), for example interferon-ß (IFNß) and glatiramer acetate. This study aimed to perform a cost-analysis of the treatment of patients with RRMS in Italy after the introduction of these new agents.

Study design: This was a retrospective observational study with systematic patient inclusion.

Methods and Results: Data gathered from 630 patients with confirmed RRMS over a 2-year period were evaluated. Overall, the direct cost over 2 years reached €11073100 thousand, corresponding to a per-patient cost of €17576 (year of costing, 2001). The cost of disease-modifying agents represented approximately 77% of the total expenditure. IFNß accounted for 94% of the expense of disease-modifying agents, corresponding to a 2-year cost per patient of €20223. Although glatiramer acetate and immunoglobulins were also associated with a high level of expense, these were prescribed in only 3.8% and 1.1% of patients, respectively. Using regression analyses, IFNß therapy, disability, number of days spent in hospital per year and the frequency of magnetic resonance imaging procedures were the main predictors of total costs.

Conclusion: Based on the results of this study, IFNß treatment considerably modified the management of RRMS and was associated with a rise in cost of treatment per patient.

Introduction

Multiple sclerosis (MS) is a disabling illness characterised by chronic demyelinating inflammation of the white matter of the central nervous system. The disease is more common in females, and onset usually occurs between 20 and 40 years of age. The disease can significantly impair patients' quality of life.[1] MS may manifest itself as motor dysfunction (weakness and spasticity) and/or sensory or peripheral nervous system disturbance (bowel, bladder and sexual dysfunction); psychiatric symptoms (depression) and cognitive impairment are also common.

Approximately 90% of patients with relapsing-remitting MS (RRMS) experience acute exacerbation of neurological symptoms followed by at least partial resolution. The remaining 10% show steady progression from onset (primary progressive MS).[2] About 50% of RRMS patients eventually enter into the secondary phase in which progressive disability arises, with or without acute exacerbations. Finally, approximately 10% develop 'benign' MS, associated with minimal functional impairment.[2]

Disease progression leads to deterioration in the patient's functional status, which eventually renders work-related tasks as well as routine daily activities difficult to perform.[3] Therefore, MS represents a major health problem with significant physical, economic and emotional implications.

In Italy, recent surveys focusing on MS have shown a prevalence of 69 per 100000 population (estimated in the province of Ferrara, Middle-North Italy), with the highest estimate in Sardinia (ranging from 103 to 144 per 100000) compared with the other regions.[4-6] Based on the assumption that the prevalence of MS in Italy (56195973 inhabitants, excluding those resident in Sardinia)[7] might correspond to the estimate found in Ferrara province, it was calculated that 38775 patients would be affected by MS. This number was increased to about 41000 subjects when the cases in Sardinia (1648044 residents) were also included.[7]

Recently, a study was undertaken to evaluate the socioeconomic impact of MS in Italy prior to the introduction of new disease-modifying agents.[8] The 3-month direct cost per patient was €1102 (€5118 total cost; year 1996), and this estimate may correspond to about €181 million per 41000 patients.

Since 1993, interferon-ß (IFNß)-1b has proved tobe an effective disease-modifying agent in RRMS.[9,10] Subsequent studies demonstrated the efficacy of other drugs, such as IFNß-1a and glatiramer acetate.[11-13] All these therapeutic agents reduced the number of relapses and delayed disability progression in patients with RRMS, although with differences in the magnitude of treatment effect between molecules.

After 1996, several IFNß and glatiramer acetate preparations became available in Italy for the treatment of patients with RRMS. However, because of their high cost, the introduction of these agents may have increased direct per-patient costs.

The aim of this study was to perform a cost-analysis of the treatment of patients with RRMS in Italy after the widespread use of new disease-modifying agents in clinical practice.

Patients and Methods

A multicentre, observational study was carried out including 630 patients with RRMS. Twenty-two Italian centres participated in the study: seven located in the North, six in Central Italy, and nine in the South (18 centres from Public Hospitals, and four from University Hospitals). Each centre enrolled the first 20 or more consecutive patients starting from 1January 2000. Subjects were considered eligible if RRMS diagnosis was confirmed at the enrolling centre to avoid potential lack of information in the case of patients who moved from other sites.

Patients with unconfirmed MS were excluded according to the diagnostic criteria proposed by McDonald et al.;[14] in addition, subjects with progressive MS courses or with benign MS were not included in the study.

Data Collection

Since 1996 in Italy, IFNß therapy has been dispensed to patients only in the presence of defined criteria,[14] and the physician is required to report patient information in a predefined clinical chart approved by law. Therefore, in the current study, physicians at each medical centre retrieved information of each enrolled patient by a retrospective analysis of all clinical data recorded between 1 January 1998 and 31 December 1999. Data collected included demographic characteristics, duration of MS and disability level (measured using the Expanded Disability Status Scale [EDSS]).[15] Diagnostic procedures, number of visits, day-hospital and hospital admissions (including reasons for admission and length of stay) were recorded.

For each drug administered during the 2-year period, the daily dose, route of administration and number of days of treatment per year were also collected. Subsequently, drugs were classified as one of the following: disease-modifying agents (i.e. IFNß-1a, IFNß-1b, glatiramer acetate, azathioprine, cyclophosphamide, mitoxantrone and immuno-globulins), drugs for the treatment of relapses (i.e. corticosteroids), or medications for the care of concomitant disorders or for the management of MS symptoms. These latter agents were further categorised according to their respective indications: treatment of spasticity (e.g. baclofen, botulinum toxin and benzodiazepines), neurogenic pain (e.g. carbamazepine and gabapentin), fatigue (amantadine), psychiatric disorders (antidepressants, anxiolytic benzodiazepines and antipsychotic drugs), and genitourinary dysfunction (e.g. oxybutynin and tolterodine).

Finally, data related to the requirement for disability aids and frequency of physical therapy sessions were also collected.

Cost Data

The economic impact of MS was modelled by attributing a cost value to each health resource utilised by subjects under survey. The health resources expenses were analysed adopting the Italian National Health System (INHS) perspective.

The health resources evaluated in this study were included in the following categories: drugs, laboratory analysis and diagnostic procedures, hospital admissions (ordinary or day-hospital), medical visits, physical therapies and disability aids.

With regard to resources utilised outside the hospital, medication costs were calculated by multiplying the market price of the daily dose of each drug by the total number of days of treatment. On the other hand, the tariffs of the National List for Ambulatory Care (Ministry Decree [DM] 22 July 1996 - Specialised ambulatory assistance services allocated according to the National Health Service and relative tariffs) were employed to estimate the expenditures for laboratory analysis, diagnostic procedures, medical visits or physical therapies performed outside the hospital. The cost of disability aids (i.e. wheelchairs and walking frames) was also calculated according to the INHS tariffs (DM 27 August 1999 - Regulations for the presentation of prosthetic assistance allocated according to the National Health Service: conditions for allocation and tariffs). Market prices were used for all other aids (crutches, urinary catheters, etc.).

With regard to resources utilised inside the hospital, the Diagnostic Related Group (DRG) tariff relating to "Multiple sclerosis and cerebellar ataxia" was used to quantify the expenditure of each ordinary admission (DRG 13, equal to €2661.82 for up to a maximum stay of 43 days, and €202.97 for each extra day), while the one-day DRG 13 tariff of €228.79 was applied for each day-hospital entry. The DRG tariff is based on a decree by the Ministry of Health (DM 30 June 1997 - Update of tariffs for hospital assistance services allocated according to the National Health Service and relative tariffs).

Although the economic value of some health resources was based on tariffs as proxy for production costs, these were the best estimates available.

All monetary values were expressed in Euros (year of costing, 2001), and no discounting of costs was applied. Despite the fact that tariffs were established between 1996 and 1999, these represented the real monetary amounts reimbursed in 2001 by the INHS for services rendered.

Statistical Analysis

Continuous variables were expressed as means and standard deviations (SDs) or medians and interquartile ranges, according to data distribution. Categorical data were presented as absolute and percentage frequencies, and between-group comparisons were performed using Pearson's c2 tests.

In order to compare the cost per patient with increasing levels of disease severity, the classification scheme proposed by Murphy et al. was adopted to categorise each subject ['asymptomatic' (EDSS <1), 'mild' (EDSS 1-3.5), 'moderate' (EDSS 4-6), or 'severe' (EDSS >6)].[16] In spite of the usual skewness in the distribution of expenses, the comparisons between groups of costs per patient (i.e. an arithmetic mean) required the appropriate use of parametric statistics. Although these methods are known to be reasonably robust to non-normality, they can be used in the presence ofhomogeneity of variances.[17] The assumption of the latter was checked by Levene's test and Brown-Forsythe's test, with a p-value </=0.05 rejecting the hypothesis ofhomogeneity. A one-way analysis of variance (ANOVA) was used to compare the cost per patient according to disease severity; the post-hoc comparison was performed by Duncan's test.

A multivariate linear regression model was applied to evaluate the relationship between the cost of disease management and demographic, clinical and therapeutic variables (age, gender, duration of disease, number of relapses per year, degree of disability, number of magnetic resonance imaging [MRI] procedures performed, IFNß therapy and sum of hospitalisation days plus day-hospital stays). This regression model was applied on untransformed cost. In order to verify the results, the model was also utilised after logarithmic transformation of costs to avoid distortion induced by the asymmetrical nature of cost distributions.[18]

Results

The evaluated cohort of RRMS patients included 630 cases, comprising 220 males and 410 females (malefemale ratio 11.9). The mean age (± SD) of subjects was 37.6 ± 9.9 years and the mean (± SD) disease duration was 7.8 ± 4.9 years (median value 6.8 years, interquartile range 4.6-10.0 years). According to the disease severity criteria, 10% of patients were 'asymptomatic', 65% had 'mild' disease, 21% had 'moderate' disease, and 4% had 'severe' disease.

Table I. Summary of the 2-Year Costs of Managing Relapsing-Remitting Multiple Sclerosis (MS) in Italy (Year of Costing, 2001)
 
Health resources € × 1000 (%) Cost per user (95% CI) Cost per patient (95% CI)
Diagnostic procedures and laboratory analyses 231.8 (2.1) 688 (628-748) 368 (326-410)
Drugs
Disease-modifying agents 8543.8 (77.2) 18374 (17650-19098) 13562 (12734-14389)
Drugs for the treatment of relapses 99.0 (0.9) 252 (234-271) 157 (142-172)
Drugs for the treatment of MS symptoms 43.0 (0.4) 253 (212-294) 68 (54--82)
Medical visits 64.4 (0.6) 104 (100-107) 102 (99-106)
Day-hospital admissions 755.0 (6.8) 2533 (2329-2738) 1198 (1060-1337)
Hospitalisations 774.6 (7.0) 3602 (3372-3834) 1229 (1074-1384)
Physical therapy and disability aids 561.5 (5.0) 2496 (2288-2703) 891 (772-1010)
Total 11073.1 (100.0) 17717 (16843-18591) 17576 (16700-18452)

CI = confidence interval.

Table I summarises the costs of resources that were directly utilised for the care of the RRMS patients cohort. Overall, the cost of disease management over a 2-year period was approximately €11.1 million, corresponding to a total expenditure of €17576 (95% CI 16700, 18452) per patient. The cost of disease-modifying agents represented 77% of the total expenses. Each remaining health resource category accounted for less than 10% of the total cost, with hospitalisation and day-hospital admissions representing approximately 7%, diagnostic procedures and laboratory analyses 2.1%, and medical visits and other drug classes 1% or less. Physical therapy and disability aids were employed on 225 patients (35.7% of the entire cohort) with the following distribution: 223 continual physical therapy sessions, 13 wheelchairs, 7 walking frames and 15 crutches. The cost of rehabilitation was €562000 (5% of the total expenses), with a 2-year cost per patient of €891 (95% CI 772, 1010).

Table II. Utilisation and Costs of Diagnostic Procedures and Other Health Resources in Patients with Relapsing-Remitting Multiple Sclerosis (Year of Costing, 2001)
 
Health resources No. of users (%) Two-year cost [€ (%)] Cost per user (€)
Diagnostic procedures
Brain MRI 239 (35.5) 131820.0 (61.5) 551.5
Brain-spinal cord MRI 99 (14.7) 78330.8 (36.5) 791.2
Spinal cord MRI 17 (2.5) 4350.6 (2.0) 255.9
Subtotal MRI 280a(41.5) 214501.4 (100.0) 766.1
Screening
Immunological screeningb 19 (2.8) 6007.4 (34.7) 316.2
EP 96 (14.2) 7614.4 (2.4) 79.3
Otherc 21 (3.1) 419.7 (18.9) 20.0
General screeningd 91 (13.5) 3274.0 (44.0) 36.0
Subtotal screening 149a(22.1) 17315.5 (100.0) 112.4
Total 674 (100.0)    
Other resources
Medical visits 620 (92.0) 64376.6 (4.0) 103.8
Day-hospital admission 298 (44.2) 755007.0 (48.6) 2533.6
Hospitalisation 215 (31.9) 774590.0 (47.4) 3602.7
Subtotal 622a(92.3) 1593973.0 (100.0) 2562.7
Total 674 (100.0)    

aPatients could have used more than one health resource.
bLymphocyte subpopulations, autoantibody profile.
cCerebrospinal fluid examination, electroencephalogram, electromyogram, audiometric examination, urodynamic examination, visual field test, ophthalmologist visit.
dHaematochemistry, electrocardiogram, echography, etc.

EP = evoked potentials; MRI = magnetic resonance imaging


Table II shows details of utilisation and costs of both diagnostic procedures as well as other health resources in the study population. With regard to diagnostic procedures, MRI was the most costly and most frequently used, accounting for approximately 42% of all investigations (including laboratory analyses) and 93% of total expenses incurred (with a per-user cost of €766). Although immunological screening was performed in a few cases (2.8%), the expenditure per user for this procedure (€316) was immediately below that of MRI. Despite the fact that the cost per user of evoked potentials was low (€79), these tests accounted for 2.4% of the cost of laboratory analyses as they were used quite frequently (i.e. in 14% of patients).

The last part of table II gives the frequencies and costs of medical visits, day-hospital admissions and hospitalisations. A total of 3116 medical visits were conducted over the 2-year period, involving 92% of patients. During the same period, there were also 3300 days of day-hospital stays (in 44% of patients) and 291 hospital admissions (involving approximately 32% of the subjects). Reasons for hospital admissions included treatment of relapses (52%), diagnostic procedures (31%), evaluation of disease progression (16%), and other causes (1%). Overall, the total 2-year expenditure for medical visits and hospitalisations amounted to approximately €1594000, corresponding to a cost per user of €2563.

Table III. Utilisation and Costs of Medications in Patients with Relapsing-Remitting Multiple Sclerosis (Year of Costing, 2001)
 
Drugs No. of users (%) Two-year costs Cost per user (€)
Disease-modifying agents   × 1000 (%)  
IFNßa 399b (63.3) 8069.14 (94.4) 20223.4
IFNß-1a 226 (35.9) 4682.91 (54.8) 20720.9
IFNß-1b 179 (28.4) 3386.23 (39.6) 18917.5
Immunosuppressantsc 60 (9.5) 36.18 (0.4) 602.9
Immunoglobulin 7 (1.1) 8.90 (0.1) 6959.3
Anticancer drugsd 15 (2.4) 48.72 (0.6) 593.6
Glatiramer acetate 24 (3.8) 380.88 (4.5) 15869.9
Subtotal 465b(73.8) 8543.82 (100.0) 18373.8
Total 630 (100.0)    
Drug for relapse treatment   € (%)  
Corticotropin 14 (2.1) 835.6 (0.8) 59.7
Betamethasone 9 (1.3) 140.4 (0.1) 15.6
Dexamethasone 42 (6.2) 1357.6 (1.4) 32.3
Methylprednisolone 356 (52.8) 95977.3 (96.9) 269.6
Prednisone 53 (7.9) 653.5 (0.7) 12.3
Deflazacort 2 (0.3) 33.3 (0.1) 16.7
Subtotal 392b(58.2) 98997.7 (100.0) 208.0
Total 674 (100.0)    
Symptomatic treatment   € (%)  
Spasticitye 49 (7.3) 6280.3 (14.6) 128.2
Neurogenic painf 74 (11.0) 8980.1 (20.9) 121.4
Fatigue (amantadine) 29 (4.3) 4691.6 (10.9) 161.8
Depression/psychiatric disordersb 58 (8.6) 14333.9 (33.3) 247.1
Genitourinary dysfunction 5 (0.7) 825.1 (1.9) 165.0
Other 54 (8.0) 7931.5 (18.4) 146.9
Sub-total 170b(25.2) 43042.4 (100.0) 253.2
Total 674 (100.0)    

aIFNß refers to IFNß-1b (Betaferon® [Schering AG, Berlin, Germany] 8MIU every other day, subcutaneously) and IFNß-1a (Avonex® [Biogen, Cambridge, MA, USA] 30g once a week, intramuscularly; Rebif® [Serono, Geneva, Switzerland] 22g three times a week, subcutaneously).
bPatients could be exposed to more than one treatment option. cAzathioprine and one case of cyclosporin.
dMitoxantrone, cyclophosphamide and methotrexate.
eBaclofen, botulinum toxin, diazepam.
fCarbamazepine, gabapentin, valproic acid, amitriptyline.
IFN = interferon; SSRIs = selective serotonin reuptake inhibitors.

Table III shows the details of both utilisation and costs of medications in the study population. On the whole, the most widely prescribed disease-modifying agent was IFNß, which was given to 63.3% of patients (IFNß-1a accounting for 35.9% and IFNß-1b for 28.4%). Approximately 94% of the cost of all disease-modifying agents was due to IFNß treatment, with a 2-year cost per user of €20223. Although glatiramer acetate and immunoglobulins were also associated with a high per-user cost (€15870 and €6959, respectively), these agents represented <5% of the total expenses incurred for disease-modifying agents as they were not widely prescribed (given in 3.8% and 1.1% of patients, respectively).

Following IFNß, the immunosuppressants, particularly azathioprine, were the most frequently used (i.e. in 9.5% of patients). However, of great interest is the fact that among the disease-modifying agents, immunosuppressants had the lowest cost per patient (about €603).

Corticosteroids (usually used for the treatment of MS relapses) prescribed most often included intravenous methylprednisolone (used in 53% of patients) and oral prednisone (used in approximately 8% of patients). The overall per-user cost for corticosteroids was €208.

Drugs given for the symptomatic treatment of RRMS corresponded to a total 2-year cost of €43042. Medications for neurogenic pain and psychiatric disorders were prescribed in 11% and about 9% of patients, respectively. Drugs for psychiatric disorders, neurogenic pain and spasticity accounted for 33%, 21% and 15%, respectively, of the total 2-year cost assigned for symptomatic therapeutics. The per-user cost for symptomatic treatment was €253.

Table IV. Interferon (IFN) ß Treatment and Cost Per Patient by Disease Severity (Year of Costing, 2001)
 
Disease severity IFNß Total Cost per patienta (€) 95% CI (€)
yes (%) no (%)
Asymptomatic (EDSS <1) 27 (43.6) 35 (56.4) 62 11205 8226, 14184
Mild (1 </= EDSS </=3.5) 283 (68.9) 128 (31.1) 411 18095b 17047, 19143
Moderate (3.5 > EDSS </=6) 80 (60.6) 52 (39.4) 132 19603b 17685, 21522
Severe (EDSS >6) 9 (36.0) 16 (64.0) 25 14146 9655, 18636
Total 399 (63.3) 231 (36.7) 630  17576 16700, 18452

aHomogeneity of variances verified by Levene's test, p = 0.324, and with Brown-Forsythe's test, p = 0.542.
bp < 0.001 vs asymptomatic patient group.
CI = confidence interval; EDSS = Expanded Disability Status Scale.

Table IV provides information on the use of IFNß therapy and related per-patient costs by disease stage (as determined by EDSS score). RRMS patients for whom an IFNß therapy was prescribed had predominantly 'mild' or 'moderate' disease (c2= 24.3; p < 0.001; 3 degrees of freedom [df]). As a result, significant differences in the cost per patient by disease stage were found [F3, 626 = 9.6; p < 0.001], that is, the mean cost was found to be significantly higher in patients with 'mild' or 'moderate' stages (i.e. in patients with the highest frequency of IFNß treatment) compared with 'asymptomatic' or 'severe' stages.

Table V. Multiple Linear-Regression Analyses of the Cost of Relapsing-Remitting Multiple Sclerosis Management in Italy (Year of Costing, 2001)a
 
Variable ? 95% CI p-Value Adjusted mean € (95% CI)
Age (y) 0.01 0.04, 0.05 0.710  
Gender
from female to       15262 (14453, 16071)
Male 0.01 0.03, 0.05 0.771 15403 (14417, 16389)
Duration of disease (y) 0.02 0.07, 0.03 0.396  
No. of exacerbations 0.03 0.08, 0.01 0.107  
EDSS groups:
from 'asymptomatic' to       13143 (11666, 14620)
'Mild' 0.02 0.08, 0.02 0.269 14831 (14217, 15444)
'Moderate' 0.08 0.03, 0.13 0.002 16957 (15886, 18027)
'Severe' 0.03 0.03, 0.10 0.256 16399 (14021, 18778)
MRI (total count) 0.05 0.01, 0.10 0.009  
IFNß therapy:
from 'presence of treatment' to       24428 (23540, 25314)
'Absence of treatment' 0.78 0.83, 0.74 <0.001 6237 (5305, 7170)
Total days of hospital and day-hospital stays 0.23 0.18, 0.27 <0.001  

an = 630 patients evaluated, multiple R2 = 0.74; F(10, 619) = 179; p < 0.0001.
CI = confidence interval; EDSS = Expanded Disability Status Scale; IFN = interferon; MRI = magnetic resonance imaging

The multivariate linear regression model (table V) demonstrated that IFNß therapy was the strongest predictor of RRMS management cost (ß = 0.78). Moreover, the number of MRI procedures and total days of hospitalisation (both regular and day-hospital) were also positively related to the expenses for RRMS management (ß = 0.05 and ß = 0.23, respectively).

With regard to disability, the regression model adjusted the cost per patient for each EDSS group excluding the effect on mean cost of the other variables (including the presence/absence of IFNß therapy). The result showed that there was a rise in the per-patient expenditure with disease progression up to a plateau reached between the 'moderate' and 'severe' stages.

The regression model explained 74% of the variability in cost data (multiple R2 = 0.74). Similar findings were obtained using a regression model in which log-transformed cost was considered as a dependent variable (multiple R2 = 0.62).

Discussion

This is the first Italian study exploring health-resource utilisation in patients with RRMS after the introduction of new disease-modifying agents (IFNß and glatiramer acetate).

The current study provides evidence based on randomised clinical trials relating to the use of IFNß treatment in patients with RRMS.[9-12] During the study period, 73.8% of patients with RRMS were treated with disease-modifying agents, with IFNß being the most widely prescribed (63.3%).

Glatiramer acetate and immunoglobulins, which have also demonstrated their efficacy in reducing clinical relapses,[1] and have per-user costs quite similar to that of IFNß, were prescribed in only 3.8% and 1.1% of patients, respectively. This might be due to the fact that glatiramer acetate is considered an alternative choice if adverse events occur during IFNß treatment or to the lower clinical efficacy of immunoglobulins when compared with IFNß.[2]

Overall, the physicians' approaches to disease management seem to be significantly influenced by the availability of new disease-modifying agents, especially IFNß, inducing a relevant change on both the pharmacoutilisation and economic burden of MS.

The cost-of-illness studies of MS before the introduction of IFNß showed that indirect costs were greater than direct costs, representing about 60-90% of total expenses.[8,16,19-24] In the study performed by Amato et al.,[8] a cohort of Italian patients with MS (including cases with progressive disease course) was followed for three months in 1996. The expenditure per patient ($US1 = 1543 Italian lire, year of conversion 1996) was $US6423 (varying from $US4739 in subjects with a 'mild' impairment to more than $US9554 in patients with 'severe' impairment), and was mainly composed of indirect costs (78.5%).

A cross-sectional study involving several Euro-pean countries highlighted relevant differences among nations in the 3-month costs per patient (year of costing 1996).[16] The UK showed the highest total expenses, ranging between $US5125 and $US14622 according to disease stage (from 'mild' to 'severe'). The cost per patient in the UK was followed by that in Germany ($US2772 [mild] and $US5701 [severe]) and France ($US1928 [mild] and $US5678 [severe]). Again, the total cost was mainly composed of indirect costs.

In Sweden, the economic burden of MS was evaluated by a cost-of-illness study using a top-down approach of costing. The annual expenditure per patient was about $US26705 (calculation derived from Henriksson and Jonsson[19]), which was mainly composed of indirect costs (i.e. 78.7%).

With regard to North America, three studies investigated the per-patient cost of MS in the US and one in Canada.[20-23] The first analysed the 3-year expenditure for 165 patients followed in two Veterans Affairs Medical Centres; the cost per patient per year amounted to $US35000 (85% indirect costs; year of costing not reported).[20] In the second survey, including 606 patients who were members of the National Multiple Sclerosis Society, based on 1994 data, the annual cost per patient was $US34000 (about 57% indirect costs).[21]

The third study,[22] using the administrative billing databases of insurance companies, showed that MS-insured patients were two to three times more expensive to manage than non-MS-insured subjects; the direct cost per patient ranged from $US7677 (for privately insured patients, year 1995) to $US11331 (for Medicaid disabled patients, for the years 1991-1996).

In Canada, using a top-down approach of costing, the annual expense per patient (year 1994) was $Can18673, comprising 64% of indirect costs.[23]

On the whole, economic evaluations conducted before the introduction of new disease-modifying agents evidenced a positive relationship between the economic burden of MS and disease severity, but this correlation mainly depended on the growing impact of indirect costs.[24]

The burden of disease after the introduction of new disease-modifying agents was analysed by model simulation,[25-28] and, less frequently, using population-based surveys.[29] Two cost-utility studies focusing on IFNß-1b showed a relevant estimate of the cost per quality-adjusted life year (QALY) gained in the UK: the prime analysis evaluated RRMS patients and calculated a cost of £ 328300 and £ 228300 (year of costing, 2000) over 5 and 10 years, respectively;[25] the second one assessed secondary progressive MS patients and estimated money gained per QALY at £ 1.0 million over 30 months (year of costing, 1995).[29] A cost-effectiveness analysis on IFNß-1b treatment of patients with RRMS in Canada estimated a cost-per-disability-year avoided of $Can189000 (corresponding to $US125000).[26]

With respect to IFNß-1b, IFNß-1a appears to be more cost-effective: compared with patients who did not receive disease-modifying agents, the estimate of the cost per QALY gained in the UK ranged from £ 27036 after 2 years of treatment with IFN-1ßa to £ 37845 after 20 years of treatment (year of costing, 1995).[27] Recently, a cost-effectiveness study evaluated the cost per EDSS-months saved comparing the treatment of RRMS patients with IFNß-1a at a dosage of 44g subcutaneously three times weekly with IFNß-1a at 22µg subcutaneously three times weekly or placebo, in the UK and France (year of costing, 2000).[28] In the UK, the highest dosage of IFNß-1a employed was associated with a cost per EDSS-months saved ranging from £ 1433 (€2316) to £ 453 (€733), when compared with 22µg subcutaneously three times weekly and placebo, respectively.[28] In France, IFNß-1a at the highest dosage again was more costly and more effective, with a cost per EDSS-months saved ranging from €1396 to €712, with regard to IFNß-1a at low dosage and placebo, respectively.[28] All these models provided approximations to the cost-effectiveness that were critically dependent on variation of the cost of IFNß treatment.

The current study provided a population-based estimate of the main direct costs after the introduction of new disease-modifying agents. About 79% of the total expenditure was represented by drugs, of which 77% was for disease-modifying agents, almost exclusively due to IFNß therapy (about 94%). Thus, the availability of new disease-modifying agents with evidence-based demonstration has substantially influenced the pharmacoutilisation pattern in the disease management of patients with MS. Infact, prior to the introduction of IFNß, the drugrepresented about 10% or less of the direct cost.[8,16,19,23] Furthermore, the percentage of expenditure dedicated to medication did not increase with disease severity. According to the stage of disease used by Murphy et al.,[16] in the UK it was equal to 3% in patients with 'mild' disease, increased to 10% in patients with 'moderate' disease, and then fell to 4% in patients with 'severe' disease. A similar pattern was observed in France and Germany.[16] Moreover, this study showed a rise in cost per patient at the initial stages of disease, while that directly involved in disease management tended to decrease in patients with a 'severe' stage of the disease, compared with patients with a 'moderate' stage (p < 0.05 at post-hoc comparison). This pattern could depend on the positive relationship between costs and frequency of IFNß use. Indeed, IFNß treatment was most beneficial to patients in the mild-to-moderate disease stage (according to the EDSS score), i.e. at the initial stage when relapses were more frequent.

Overall, the prescription of IFNß was the strongest predictor of increased disease management costs; a positive relationship between costs and frequency of recursions to MRI was also found. In fact, due to its high sensitivity, MRI has become pivotal in diagnosing MS and in monitoring treatment effects as well as disease progression.[30-32]

Expenses related to the treatment of relapses appeared to be consistent with recent guidelines,[1] which recommend the administration of intravenous methylprednisolone in the first days of a relapse (mainly during a day-hospital admission) followed by oral prednisone therapy.

In this study, the pattern of use of medications indicated for the treatment of MS symptoms appears to be in agreement with the recent increased focus on this aspect of MS care and management.[1] The latter may be attributable to the availability of new drugs (e.g. botulinum toxin for spasticity), new routes of administration (e.g. implantable pumps for intrathecal baclofen delivery), and to a growing awareness of the effect of MS symptoms on patients' quality of life.

There are some limitations in the current study. Firstly, patients in more severe disease stages could have been included in the study. However, only 4% of the evaluated cohort was represented by subjects with a 'severe' MS course, and the composition of the overall cohort by sex, age and EDSS score was overlapped with that observed in a large population-based database of MS in Italy.[33] Secondly, the frequent prescription of IFNß in patients with 'mild' disease showed that, with regard to IFNß therapy, physicians focus their attention on patients in early stages of the disease.

With regard to cost-analysis, some components of the total expenses, such as indirect costs (i.e. productivity losses and informal care) as well as intangible costs, were not considered. In addition, some direct costs were not analysed, i.e. consultations with general practitioners or nurse interventions, transportation costs and out-of-pocket expenditures. However, these direct costs represented <5% of the total cost of MS in Italy.[8] Although the study was not designed to assess these types of expenses, it is reasonable to expect that the actual cost would be higher than the estimated one, particularly for patients with moderate-to-severe disease.

Although the study examined resources utilised in 1998-1999, drug costs were calculated using monetary values in 2001. In the case of glatiramer acetate, the market price was considered, even if the drug was distributed only as 'compassionate' treatment during the 2-year study period. Furthermore, some resources were evaluated using tariffs as proxy for production costs. In spite of the fact that these were introduced over a timespan ranging from 1996 to 1999, the monetary values represent the real amount reimbursed to the Italian regions by the INHS.

Conclusion

In conclusion, this study provided a cost-analysis of the resources utilised for RRMS management in Italy following the introduction of new disease-modifying agents. The total 2-year cost of 630 patients affected by RRMS was estimated at approximately €11.1 million, corresponding to a cost of €17576 per patient. Furthermore, the study demonstrated that physicians' approaches to MS management have changed significantly (i.e. IFNß being the most frequently prescribed disease-modifying agent and MRI now being a routine diagnostic tool), probably as a natural consequence of the results reported in randomised clinical trials.

Considering the previous economic evaluation conducted in Italy prior to the introduction of IFNß and glatiramer acetate,[8] the direct cost per patient over 2 years would have been equal to €10336 (reported at 2001 values). Thus, the availability of new disease-modifying agents in Italy might have increased the direct cost per patient by about 70%. However, the increase in current expenditure should result in short- and long-term clinical benefits and future savings.[27] While this study highlights that physicians' choices of therapy are based on evidence of clinical appropriateness, further population-based studies examining the economic burden of the treatment of RRMS using IFNß, in terms of indirect costs and patients' quality of life, are required.

Funding Information

This study was supported by an unrestricted grant from Industria Farmaceutica Serono SpA.

Disclaimer

All opinions presented in this paper were expressed by the authors with full autonomy.

Reprint Address

Correspondence and offprints: Dr Pierluigi Russo, Department of Human Physiology and Pharmacology, University of Rome "La Sapienza", Rome, Italy.

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