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agate
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Joined: 17 May 2006
Posts: 5694
Location: Oregon
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 Posted: Thu May 09, 2013 6:21 pm Post subject: (Abst.) Time to secondary progression in PwMS on DMDs |
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From Multiple Sclerosis Journal, May 9, 2013:
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Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs
H Tedeholm1
J Lycke1
B Skoog1
V Lisovskaja2
J Hillert3
C Dahle4
J Fagius5
S Fredrikson3
A-M Landtblom4
C Malmeström1
C Martin6
F Piehl3
B Runmarker1
L Stawiarz3
M Vrethem4
O Nerman2
O Andersen1
1Sahlgrenska University Hospital, Gothenburg, Sweden
2Department of Mathematical Sciences, Chalmers University of Technology and Department of Mathematical Sciences, University of Gothenburg, Sweden
3Karolinska University Hospital, Huddinge, Sweden
4Department of Clinical and Experimental Medicine/Neurology, University of Linköping, Sweden
5Department of Neurology, University Hospital, Uppsala, Sweden
6Institute of Clinical Science, Danderyds Hospital, Sweden
Oluf Andersen, University of Gothenburg, Institution of Neuroscience and Physiology, Gröna Stråket 11, Department of Neurology, Sahlgenska University Hospital, Göteborg, SE-413 45, Sweden. Email: oluf.andersen@neuro.gu.se
Background:
It is currently unknown whether early immunomodulatory treatment in relapsing–remitting MS (RRMS) can delay the transition to secondary progression (SP).
Objective:
To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort.
Methods:
We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995–2004, n = 730) and a historical population-based incidence cohort (onset 1950–64, n = 186). We retrospectively analyzed the difference in time to SP, termed the “period effect” within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis.
Results:
We found that the “period” affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53).
Conclusion:
Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given. |
The entire article can be seen here. |
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agate
Site Admin
Joined: 17 May 2006
Posts: 5694
Location: Oregon
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| Posted: Thu May 09, 2013 6:28 pm Post subject: Editorial on treatment effectiveness studies |
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An editorial in the same issue of Multiple Sclerosis Journal (May 9, 2013) sheds more light on this topic:
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Observational studies of treatment effectiveness: useful, useless or somewhere in between?
Ruth Ann Marrie
Departments of Internal Medicine and Community Health Sciences, University of Manitoba, Canada
Ruth Ann Marrie, Health Sciences Center, GF-533, 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada. Email: rmarrie@hsc.mb.ca
Approximately 85% of persons with multiple sclerosis (MS) initially present with a relapsing–remitting disease course,1 characterized by relapses and periods of remission during which clinical findings remain stable. In the early 1990s, the first clinical trials of interferon-beta showed that these immunomodulatory therapies consistently reduced relapse rates in MS, and signalled a new therapeutic era.2 Relapses are important because of their financial, emotional, and social costs.3,4 However, most individuals with relapsing–remitting MS will transition eventually to a secondary progressive course, in which physical and cognitive disability gradually progress with or without ongoing relapses.1 The burden of such disability is substantial, thus therapies which prevent disability progression are needed. Although clinical trials of first-line immunomodulatory therapies suggest that available agents reduce short-term disability progression,2 clear evidence of their long-term impact on disability progression is lacking.
In this issue of Multiple Sclerosis Journal, Tedeholm et al. address the clinically relevant question of whether immunomodulatory therapy delays the transition from relapsing–remitting to secondary progressive MS (SPMS).5 They compared the time to SPMS in a treated contemporary cohort and in an untreated historical cohort. The contemporary cohort included a subset of 730 individuals participating in the Swedish MS Registry who had relapsing–remitting MS with onset during the period 1995–2004. They were treated with first-line immunomodulatory therapies, defined as interferon-beta or glatiramer acetate. The historical cohort included 186 untreated individuals with relapsing–remitting MS who were identified from the population-based Gothenburg Incidence Cohort and had disease onset during the period 1950–1964. The independent variable of interest in the survival (‘time to SPMS’) analysis was the time between disease onset and treatment initiation. Covariates considered were sex, age at MS symptom onset, whether onset was monofocal or polyfocal, and whether the symptoms at onset were predominantly explained by lesions in afferent rather than efferent tracts. After accounting for these covariates, they found that the time to SPMS was shorter in the historical cohort than in the contemporary cohort (hazard ratio (HR) 3.15; p=0.002 in men and HR 1.87; p=0.02 in women). Further they posited that this difference is partly attributable to the use of immunomodulatory therapy in the contemporary cohort, although the association of treatment and time to SPMS was not statistically significant in men or women.
Prior studies have assessed whether immunomodulatory therapies delay disability progression, with variable findings. A recent Italian study evaluated the impact of treatment with interferon-beta or glatiramer acetate on time to SPMS in 478 untreated patients and 606 treated patients.6 Among patients considered to be at the highest baseline risk of SPMS, treatment was associated with a lower risk of SPMS 20 years after MS onset, being 25.4% in treated patients and 64.4% in untreated patients (relative risk (RR) 0.23; 95% confidence interval (CI): 0.15–0.35). Among patients considered to be at the lowest baseline risk of SPMS, treatment was still associated with a lower risk of SPMS (RR 0.27; 95% CI: 0.13–0.56). It is uncertain whether this study adequately accounted for indication biases related to the use of treatment or not. Another recent Canadian study estimated the effect of interferon-beta on time to an Expanded Disability Status Scale score of six using 868 treated patients, 820 contemporary untreated patients, and 959 historical untreated patients considered eligible for treatment according to contemporary guidelines.7 Treated patients did not have a lower risk of disability progression when compared to the contemporary untreated cohort (HR 1.30; 95% CI: 0.92–1.83) or when compared to the historical untreated cohort (HR 0.77; 95% CI: 0.58–1.02).
Observational studies of long-term treatment effectiveness face multiple methodological challenges which limit their internal and external validity, including the lack of randomization, lack of standardization of data collection, selection biases, small sample sizes, immortal time bias, and confounding. The Tedeholm et al. study illustrates some of these challenges. The historical cohort was population-based but the contemporary cohort was not. The Swedish MS Registry captures less than 60% of persons with MS in Sweden, and less than half of the centres involved in the registry contributed data for this study.5 Nearly 30% of the remaining registry cohort was excluded because they had not been treated, or had not been treated with a first-line therapy, or had also been treated with a second-line therapy. Thus the contemporary cohort lacks generalizability, and might be expected to differ from the historical cohort due to differences in selection criteria. In fact, when compared to the historical cohort, a higher proportion of patients in the contemporary cohort had complete remission after the first relapse (75% vs 68%), while a lower proportion had monofocal symptoms at onset (80% vs 93%). Also, it is likely that other unmeasured factors differed between the two groups. Recent studies suggest that the demographic and clinical characteristics of MS are changing with time. Along with a rising female to male sex ratio, a progressively earlier age of symptom onset has been observed in some regions.8 These observations suggest that the natural history of the disease, including disability progression may also differ in contemporary as compared to historical cohorts, irrespective of treatment. Other secular changes in care may also influence outcome. Studies using historical controls are well recognized to favor treatment.9
Despite these limitations, observational studies of treatment are still needed for several reasons. Clinical trials of many years’ duration are not feasible or ethical, and we lack adequate surrogates of long-term outcome. Observational studies can also inform us regarding treatment outcomes for the subgroups of patients who are excluded from clinical trials, such as those who are at the extremes of age or who have comorbidities. Further, well-designed observational studies do not overestimate the size of treatment effects as compared with those in short-term randomized, controlled trials.10 The utility of such studies for estimating long-term treatment effectiveness in MS can be improved by using prospective, population-based designs with standardized data collection methods. Study cohorts must be better characterized with respect with respect to demographic and clinical characteristics, as well as other potential factors which may influence outcome such as socioeconomic status, access to care, health behaviours, and comorbidities.7 Finally, accounting for the effects of treatment would be far easier if we could better predict disability outcomes in MS.
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Article Notes
Funding
Supported in part by a Don Paty Career Development Award from the MS Society of Canada (to RAM).
Disclosures
Ruth Ann Marrie receives research funding from: Canadian Institutes of Health Research, Public Health Agency of Canada, Manitoba Health Research Council, Health Sciences Centre Research Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Rx & D Health Research Foundation, and has conducted clinical trials funded by Bayer Inc. and Sanofi-Aventis.
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[References omitted.] |
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