British Columbia Multiple Sclerosis Database Research Articles

PND54 - A LONG TERM ANALYSIS OF THE CLINICAL AND COST EFFECTIVENESS OF GLATIRAMER ACETATE USING FINAL 10-YEAR RESULTS FROM THE UK MULTIPLE SCLEROSIS RISK SHARING SCHEME

The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established in 2002 to provide UK patients’ access to glatiramer acetate (GA) and beta interferon and included a 10-year observational study to assess the long-term effectiveness of these therapies. The objective of this analysis was to assess the clinical- and cost-effectiveness of GA using the final, 10-year data from the RSS. The primary outcome of the RSS was accumulation of disability, which was measured using the Expanded Disability Status Scale (EDSS) and as loss of utility. EDSS scores were measured annually and utility was derived using data that reported EQ5D scores for different EDSS states. A continuous Markov model was used to project the accumulation of disability in untreated patients, using natural history data from the British Columbia Multiple Sclerosis database (BCMS). Implied hazard ratios (HR; treated vs untreated) for both EDSS score and utility were calculated, with cost-effectiveness based on NHS list price (£513.95 per 28 days) and expressed as quality-adjusted life years (QALYs). A 50-year time horizon was used with a 50% treatment waning effect applied at 10 years. 755 GA and 898 BCMS patients were included in the analysis, with baseline characteristics being similar (female: 77% vs 74%, respectively; mean age at disease onset: 30.2 vs 29.2 years). GA was associated with a 16.5% (HR 83.5%) reduction in EDSS progression and 25.0% reduction in utility loss (HR 75.0%) vs no treatment. The cost per QALY for GA using the utility HR was £17,841. When nursing/infrastructure contributions were included, the cost per QALY fell to £11,220. This final, 10-year analysis of the RSS demonstrates the long-term efficacy of GA in terms of disability progression. At NHS list price, GA is highly cost-effective based on these data.

Modelling disease progression in relapsing-remitting onset multiple sclerosis using multilevel models applied to longitudinal data from two natural history cohorts and one treated cohort.

The ability to better predict disease progression represents a major unmet need in multiple sclerosis (MS), and would help to inform therapeutic and management choices. To develop multilevel models using longitudinal data on disease progression in patients with relapsing-remitting MS (RRMS) or secondary-progressive MS (SPMS); and to use these models to estimate the association of disease-modifying therapy (DMT) with progression. Secondary analysis of three MS cohorts. Two natural history cohorts: University of Wales Multiple Sclerosis (UoWMS) cohort, UK, and British Columbia Multiple Sclerosis (BCMS) cohort, Canada. One observational DMT-treated cohort: UK MS risk-sharing scheme (RSS). The UoWMS database has > 2000 MS patients and the BCMS database (as of 2009) has > 5900 MS patients. All participants who had definite MS (RRMS/SPMS), who reached the criteria set out by the Association of British Neurologists (ABN) for eligibility for DMT [i.e. age ≥ 18 years, Expanded Disability Status Scale (EDSS) score of ≤ 6.5, occurrence of two or more relapses in the previous 2 years] and who had at least two repeated outcome measures were included: 404 patients for the UoWMS cohort and 978 patients for the BCMS cohort. Through the UK MS RSS scheme, 5583 DMT-treated patients were recruited, with the analysis sample being the 4137 who had RRMS and were eligible and treated at baseline, with at least one valid EDSS score post baseline. EDSS score observations post ABN eligibility. We used multilevel models in the development cohort (UoWMS) to develop a model for EDSS score with time since ABN eligibility, allowing for covariates and appropriate transformation of outcome and/or time. These methods were then applied to the BCMS cohort to obtain a 'natural history' model for changes in the EDSS score with time. We then used this natural history model to predict the trajectories of EDSS score in treated patients in the UK MS RSS database. Differences between the progression predicted by the natural history model and the progression observed at 6 years' follow-up for the UK MS RSS cohort were used as indicators of the effectiveness of the DMTs. Previously developed utility scores were assigned to each EDSS score, and differences in utility also examined. The model best fitting the UoWMS data showed a non-linear increase in EDSS score over time since ABN eligibility. This model fitted the BCMS cohort data well, with similar coefficients, and the BCMS model predicted EDSS score in UoWMS data with little evidence of bias. Using the natural history model predicts EDSS score in a treated cohort (UK MS RSS) higher than that observed [by 0.59 points (95% confidence interval 0.54 to 0.64 points)] at 6 years post treatment. Only two natural history cohorts were compared, limiting generalisability. The comparison of a treated cohort with untreated cohorts is observational, thus limiting conclusions about causality. EDSS score progression in two natural history cohorts of MS patients showed a similar pattern. Progression in the natural history cohorts was slightly faster than EDSS score progression in the DMT-treated cohort, up to 6 years post treatment. Long-term follow-up of randomised controlled trials is needed to replicate these findings and examine duration of any treatment effect. The National Institute for Health Research Health Technology Assessment programme.

A population-based study comparing multiple sclerosis clinic users and non-users in British Columbia, Canada.

Background and purposeMuch clinical knowledge about multiple sclerosis (MS) has been gained from patients who attend MS specialty clinics. However, there is limited information about whether these patients are representative of the wider MS population. The objective of this study was to compare incident MS cases who were MS clinic users to non‐users of the specialty MS clinics in British Columbia, Canada.MethodsThis was a retrospective record‐linkage cohort study using prospectively collected data from the British Columbia Multiple Sclerosis database and province‐wide health administrative databases.ResultsThere were 2841 incident MS cases between 1996 and 2004 including 1648 (58%) that had registered at an MS clinic (‘clinic cases’) and 1193 (42%) that had not (‘non‐clinic cases’). Gender and socioeconomic status distributions were similar; however, non‐clinic cases were older, accessed health services more frequently and had a higher burden of comorbidity than clinic cases. Only 1% of the non‐clinic cases had filled a prescription for an MS‐specific disease‐modifying therapy, compared to 51% of the clinic cases.ConclusionsOur findings have several important implications: even within a publicly funded healthcare system, a high proportion of individuals with MS may not access a specialty MS clinic; the needs of MS patients managed in the community may differ from those referred to an MS clinic; findings from studies involving clinic‐based MS cohorts may not always be generalizable to the wider MS population; and access to population‐based health administrative data offers the opportunity to gain a broader understanding of MS.

Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator

In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada. In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective. 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2]). Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible. Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme.

Assessment of cancer risk with β-interferon treatment for multiple sclerosis

The risk of cancer after exposure to the β-interferons (IFNβs) for multiple sclerosis (MS) has not been established. We assessed whether IFNβ treatment for MS is associated with cancer risk or the risk of specific cancers in a population-based observational study. The British Columbia MS database was linked to the provincial Cancer Registry, Vital Statistics death files and Health Registration files. Using a nested case-control design, MS cancer cases were matched with up to 20 randomly selected MS controls at the date of cancer diagnosis by sex, age (± 5 years) and study entry year using incidence density sampling. Associations between treatment exposure and overall or specific (breast, colorectal, lung and prostate) cancers were estimated by conditional logistic regression, adjusted for MS disease duration and age. Tumour size at cancer diagnosis was compared between treated and untreated patients using the stratified Wilcoxon test to explore potential lead time bias. The cohort included 5146 relapsing-onset MS patients and 48,705 person-years of follow-up, during which 227 cancers were diagnosed. Exposure to IFNβ was not significantly different for cases and controls (OR 1.28; 95% CI 0.87 to 1.88). There was a non-significant trend towards an increased risk of IFNβ exposure in the breast cancer cases (OR 1.77; 95% CI 0.92 to 3.42), but no evidence of a dose-response effect. Tumour size was similar between IFNβ treated and untreated cases. There was no evidence of an increased cancer risk with exposure to IFNβ over a 12-year observation period. However, the trend towards an association between IFNβ and breast cancer should be investigated further.

UK multiple sclerosis risk-sharing scheme: a new natural history dataset and an improved Markov model

ObjectivesIn 2002, the UK's National Institute for Health and Care Excellence concluded that the multiple sclerosis (MS) disease modifying therapies; interferon-β and glatiramer acetate, were not cost effective over the...

Retinal nerve fiber layer thickness in benign multiple sclerosis

Background/objective: Retinal nerve fiber layer (RNFL) thickness has been linked to brain atrophy in multiple sclerosis (MS). However, little is known about retinal atrophy in ‘benign’ MS. We compared RNFL thickness in benign MS with healthy controls. Methods: Patients with benign MS (Expanded Disability Status Scale (EDSS) ≤ 3; ≥15 years’ disease duration), identified through the British Columbia MS database, along with age-matched healthy controls, were recruited. RNFL thickness was measured using spectral-domain optical coherence tomography. Analysis of variance (ANOVA) was used to compare groups. The association between RNFL thickness and MS patient characteristics was examined via linear mixed-effects models (adjusting for within-patient inter-eye correlations and history of optic neuritis (ON), where appropriate). Results: Overall, 29 benign MS patients and 29 healthy controls were included, totaling 116 eyes. RNFL thickness was lowest for the benign MS eyes, with and then without a history of ON, followed by healthy controls (mean=73.2 µm, SD ± 0.4; 89.9 µm, SD ± 12.5; 96.7 µm, SD ± 10.4; p<0.02). RNFL thickness was associated with a history of ON (p<0.0001), but not EDSS or disease duration (p>0.1). Conclusions: RNFL thickness was lower in patients with benign MS than healthy controls, regardless of the previous history of ON. However, no association was found between RNFL values and disability or MS disease duration.

Characteristics of multiple sclerosis in aboriginals living in British Columbia, Canada

Objectives: The objectives of this study were to identify and describe the demographic and clinical characteristics of multiple sclerosis (MS) in aboriginals in British Columbia (BC), Canada and compare these findings with non-aboriginal MS patients. Methods: This retrospective chart and database review accessed patient information from the linked BC-wide MS clinical and genetics databases. Data gathered included: demographics (age, sex and ethnicity); clinical characteristics (MS onset date, disease course and disability scores (Expanded Disability Status Scale [EDSS]). Aboriginals were identified via the database linkage augmented by physician and nurse recall. Two non-aboriginal comparator groups with definite MS were selected. Group one included all definite MS patients in the BC MS database, and group two comprised MS patients matched by sex, age at onset and initial disease course. Patient characteristics were compared using the Student’s t-test, chi-squared test, and Kaplan–Meier survival analysis was used to examine disease progression (time to sustained and confirmed EDSS 6) Results: We identified 26 aboriginals with MS, of which 19/26 (73%) were female, 23/26 (89%) had relapsing-onset MS and a mean onset age of 31.1 years. There were no significant differences between the MS aboriginals and the non-matched (n = 5708) comparator group with respect to age, sex or disease course (p > 0.1), However, aboriginals progressed more rapidly to EDSS 6 from disease onset (p < 0.001) when compared with the matched and unmatched comparator groups. Conclusion: We identified a small, but important cohort of aboriginals with MS; being the largest identified to date. There was evidence of more rapid MS progression in aboriginals compared with non-aboriginals.

Long-Term Persistence With the Immunomodulatory Drugs for Multiple Sclerosis: A Retrospective Database Study

BackgroundImmunomodulatory drugs (IMDs) for multiple sclerosis (MS) have been available in Canada since 1995 and are currently the most commonly prescribed treatment for MS. However, relatively little is known about the long-term persistence to these drugs. ObjectiveThe purpose of this study was to describe patterns of, and factors associated with, long-term persistence to the first-line IMDs in an MS population in British Columbia, Canada. MethodsStudy data were collected from the British Columbia MS database. Adults from British Columbia with definite MS who were prescribed a first-line IMD (interferon beta-1b, interferon beta-1a [subcutaneous and intramuscular], and glatiramer acetate) from January 1, 1995, through December 31, 2008, were eligible for the study. Time to discontinuation of use of all first-line IMDs (ie, switching among IMD therapies was allowed) and the initially prescribed IMD was assessed using Kaplan-Meier survival analysis and multivariate Cox regression. ResultsA total of 1896 patients were included. Mean (SD) age was 40.2 (9.5) years, and 75.1% were female. Median time to discontinuation of all first-line IMD therapies was 6.3 years (95% CI, 5.8–6.7 years). Patients with a longer disease duration and higher level of disability were at higher risk for discontinuing use of the IMDs. Age, sex, and the initial IMD were not associated with discontinuation. Persistence appeared to have decreased over time (P = 0.01 for trend). Median time to discontinued use of, or switching from, the initially prescribed IMD was 2.9 years (95% CI, 2.5–3.2 years). ConclusionsApproximately half of the MS patients discontinued use of their IMD within 6 years. It is unknown whether this persistence is adequate because uncertainties remain regarding the optimal level of persistence to the IMDs. Further investigation is needed to examine why some individuals are more at risk for discontinuation of IMD therapy and why, in contrast to other chronic diseases, persistence to IMDs in patients with MS has not improved over time.

Temporal trends of disability progression in multiple sclerosis: findings from British Columbia, Canada (1975–2009)

Background: Recent natural history studies suggest that multiple sclerosis (MS) is a more slowly progressing disease than previously thought. These observations are from studies separated by time, geography and methodological approach. Objectives: We investigated whether MS disease progression has changed over time in British Columbia, Canada. Methods: The British Columbia MS database was queried for relapsing-onset MS patients with symptom onset from 1975 to <1995, first assessed within 15 years from onset and with at least two Expanded Disability Status Scale (EDSS) scores. Latest follow-up was to 2009. Patients were grouped by 5-year onset intervals (1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995). Outcome was defined as time to reach sustained and confirmed EDSS 6 within 15 years of disease duration. Kaplan–Meier analysis was used to compare: the proportion of patients reaching EDSS 6 (primary analysis) and the time to EDSS 6 (secondary analysis) across the time-period groups. Results: A total of 2236 relapsing-onset MS patients (73.4% female; mean age at onset: 32.3 ± 8.8 years) were included. No significant temporal trend was found in the proportion of patients reaching EDSS 6 within 15 years from onset (28.5%, 26.4%, 27.7%, 22.3% for intervals 1975 to <1980, 1980 to <1985, 1985 to <1990, 1990 to <1995, respectively; p = 0.09) or in survival curves for time to reach the outcome (p = 0.14). Conclusions: Rates of disease progression remained relatively stable over two decades of MS onset in British Columbia, Canada. Our results suggest that differences in disease progression findings between natural history studies may be related to factors other than time period.

Does Relapse Frequency Predict Poor Outcome in Multiple Sclerosis

In relapsing–remitting multiple sclerosis (RRMS), is relapse occurrence or frequency predictive of either major disability (sustained need for aid in walking) or entry into the secondary progressive (SPMS) phase? To find out, researchers retrospectively examined data on almost 2500 patients from their unique (in the Western Hemisphere) population-based British Columbia Multiple Sclerosis database. The primary outcomes were time to Expanded Disability Status Scale (EDSS) score of 6.0 and time to SPMS. The authors first assessed outcomes with Kaplan-Meier “survival” curves for three levels of frequency of bouts occurring only within the first 5 years after MS onset. They then used Cox proportional hazard ratios (HRs), adjusted for sex, age at onset, and nature of …

The natural history of primary progressive multiple sclerosis

Primary progressive multiple sclerosis (PPMS) carries the worst prognosis of the multiple sclerosis (MS) subtypes and is currently untreatable. A previous analysis of the British Columbia MS database challenged the view that disability progression is rapid in PPMS, but identified few predictors of disease progression. Here, we extend previous analyses in an updated PPMS retrospective cohort study of prevalent cases. We used Kaplan-Meier survival analyses and Cox regression models to investigate the influence of gender, age at onset, and onset symptoms on time to and age at Expanded Disability Status Scale (EDSS) 6.0 in patients with PPMS. Of 5,779 patients with definite MS, 552 (10%) had PPMS. Median time to EDSS 6.0 was 14.0 years (95% confidence interval [CI] 11.3-16.7), reached at a median age of 58.6 years (95% CI 56.8-60.3). Sensory onset symptoms were associated with a longer time to and an older age at EDSS 6.0 (multivariable hazard ratios 0.55 [95% CI 0.35-0.87] and 0.54 [0.35-0.85]). Younger age at disease onset was associated with a longer time to but a younger age at EDSS 6.0. Gender and other onset symptoms were not associated with these outcomes. Fifty patients with PPMS (9%) fulfilled criteria for benign MS (EDSS < or =3.0 after 10 years' disease duration). We identified 2 predictors of a slower disease progression in primary progressive multiple sclerosis. Sensory onset symptoms were associated with both a longer time to and a higher age at Expanded Disability Status Scale (EDSS) 6.0. A younger age at disease onset was associated with a longer time to EDSS 6.0, but patients with an early disease onset reached EDSS 6.0 at a younger age.