New natural history of interferon‐β–treated relapsing multiple sclerosis

Abstract

Objective:To investigate the impact of interferon-beta (IFN␤) on disease progression in relapsing-remitting multiple sclerosis patients. Methods: A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFN␤-treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. Results: The IFN␤-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24 -0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p Ͻ 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p Ͻ 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38 -0.95 for time from first visit; HR, 0.54, 95% CI, 0.34 -0.86 for time from date of birth; p Յ 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings. Interpretation: IFN-␤ slows progression in relapsing-remitting multiple sclerosis patients.Ann Neurol 2007;61: 300 -306 Few experienced in the long-term management of multiple sclerosis (MS) patients would disagree that the development of unremitting disability progression represents the major adverse event in the course of this illness, and as a consequence, it is the most important target for clinical trials to evaluate their real cost effectiveness. Whether long-term treatment with the current interferon-␤ (IFN␤) products in relapsingremitting MS (RRMS) can alter the development of long-term disability is not yet known, but it can be surmised from short-term randomized controlled trials (RCTs) 1-3 and their continuous extensions at no more than 4 years 4 and 5 years. 5 This is the stage at which immunomodulatory therapy is likely to be most effective, but then the long-term benefits on disability have to be projected from the results generated during a much earlier and briefer period in the natural disease course. Long-term RCTs would undoubtedly provide definitive evidence, but they are impractical and considered by many to be unethical. 6 More recently, further data have been collected in noncontinuous and/or retrospective, open-label extensions of the IFN␤ RCTs 7-10 ; but in these studies, the protection against bias afforded by randomization was largely lost.11 Moreover, patients enrolled in the placebo arms of RCTs do not represent the natural history of MS because they are selected for having frequent attacks during a set interval before the study....

Long‐term evolution of multiple sclerosis disability in the treatment era

“…This transition rate of 1% annually is lower than reported from natural history studies but similar to a more recent retrospective analysis in an interferon-treated population. 41 Similarly, evolution of sustained disability in this cohort was slower than expected. At 16.8 years after onset, 10.7% (95% CI 7.2 to 14%) of patients had reached an EDSS ≥6 whereas in some natural history studies 50% of the cohort had reached an EDSS 6 by 15–16 years, albeit it with wide confidence intervals.…”

Interferon-β Treatment for Multiple Sclerosis

“…88 A recent observational study used propensity score weightings to adjust survival curves in determining the long-term effects of interferon treatment. 89 The investigators followed over 1500 patients with RRMS (1103 treated with interferon-␤ and 401 untreated) for up to 7 years. Patients treated with interferon-␤ experienced a significantly lower rate of conversion to SPMS (HR ϭ 0.38, 95% CI ϭ 0.24 -0.58, P Ͻ 0.0001), and a lower incidence of progression to EDSS 6.0 (requiring unilateral walking assist) (HR ϭ 0.60, 95% CI ϭ 0.38 -0.95, P Ͻ 0.03).…”

Confounders in natural history of interferon‐β–treated relapsing multiple sclerosis

“…This analysis showed that even a small imbalance between treatment arms in a parameter that doubled the risk for reaching the end point would eliminate the statistical significance of findings for Expanded Disability Status Scale outcomes. 1 However, the results for secondary progression end point were more robust. Therefore, statistical adjustment can indeed compensate for even major imbalances; furthermore, sensitivity analysis can also help define to what extent a potential residual imbalance could account for observed outcomes.…”

“…Olivier Gout, MD Trojano and colleagues, 1 based on their observational study, suggest that interferon-␤ slows progression in relapsing-remitting multiple sclerosis patients. They have used propensity scores to correct significant differences between interferon-␤-treated and untreated control groups, and then conducted a sensitivity analysis to detect how the magnitude of an unmeasured binary confounder might affect the propensity score adjusted hazard ratios.…”

“…Taking account of these confounders may change the result of their study. We thank Dr Koch and colleagues and Dr Gout for their attention to our article 1 and for giving us the opportunity to stress further the usefulness of appropriate statistical analyses for enhancing the quality of observational studies.…”