CME Author: Vicki Brower
Study Authors: J. William L. Brown, Alasdair Coles, et al.; Ari Green
Target Audience and Goal Statement:
Neurologists, internists, and family medicine specialists
The goal was to determine the association between the use, type, and timing of disease-modifying treatments (DMTs) for multiple sclerosis (MS) with regard to the risk of conversion to objectively defined secondary progressive disease from relapsing-remitting MS.
- For MS patients with relapsing-remitting disease, what is the association between DMTs and the risk of conversion to secondary progressive MS?
- Are there any differences among DMTs with regard to postponing conversion to secondary progressive MS, and if so, which are the most effective?
- Does treatment timing matter in postponing conversion to progressive disease?
Study Synopsis and Perspective:
MS patients treated initially with newer DMTs, namely, fingolimod (Gilenya), natalizumab (Tysabri), or alemtuzumab (Lemtrada) had a lower risk of converting to secondary progressive MS than patients who began treatment with glatiramer acetate (Copaxone) or interferon beta (Rebif), according to a new study.
But compared with MS patients who received no treatment, those who were initially treated with any of these therapies, or even with glatiramer acetate or interferon beta, had a lower risk of disease conversion to secondary progressing MS, according to Tomas Kalincik, PhD, of the Royal Melbourne Hospital in Australia, and colleagues. The authors noted that “no licensed therapies have shown greater reduction in relapse rates than natalizumab or alemtuzumab.”
The effects of all treatments in this international observational cohort study were more significant when they were begun within the first 5 years of disease onset, they wrote in JAMA.
“This has been a very large question for some time: Can we really show that earlier use of these disease-modifying therapies actually results in a delay of entry into secondary progressive phase of the illness?” said John Corboy, MD, of the University of Colorado in Denver, who was not involved in the study.
When MS patients are younger and have relapses, they often have very good recovery and a significant part of their functionality remains, but once they go into a secondary progressive phase and reach certain points, disability accrues, Corboy said. “With the median age of onset of that phase being 40 to 45, that means that still quite young individuals are developing significant irreversible disability,” he told MedPage Today.
The cohort study, which was not directly funded by drugmakers, included 1,555 patients with clinically defined MS (72% female, mean baseline age 35). The study included data from 1998 to 2012 from three data sources: untreated patients from the University Hospital of Wales; treated patients from MSBase, an observational cohort of real-world data of MS patients in 29 countries; and additional patients in Europe treated with alemtuzumab before it was licensed.
Patients had at least one Expanded Disability Status Scale (EDSS) score within 6 months before baseline, and at least two EDSS scores after baseline. The untreated cohort received no DMTs; the treated cohort followed published protocols. Patients were followed for a minimum of 4 years.
Using a validated definition of secondary progressive MS based on disability progression and preceding relapses, the researchers examined the rate of conversion between different DMTs and untreated patients; the rate of conversion with fingolimod, natalizumab, or alemtuzumab versus glatiramer acetate or interferon beta; and treatment within 5 years versus after 5 years of disease onset. They propensity-matched untreated to treated patients on age, sex, annualized relapse rate in the year before baseline, EDSS score, and disease duration.
Key findings of the study included:
- Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR 0.66, 95% CI 0.44-0.99, P=0.046; 5-year absolute risk 7% vs 12%, median follow-up 5.8 years)
- Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR 0.71, 95% CI 0.61-0.81, P<0.001; 5-year absolute risk 12% vs 27%, median follow-up 7.6 years)
- Patients started on fingolimod (HR 0.37, 95% CI 0.22-0.62, P<0.001), natalizumab (HR 0.61, 95% CI 0.43-0.86, P=0.005), or alemtuzumab (HR 0.52, 95% CI 0.32-0.85, P=0.009) also had a lower risk of conversion than untreated patients
- Risk of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset versus later (HR 0.77, 95% CI 0.61-0.98, P=0.03; 5-year absolute risk 3% vs 6%, median follow-up 13.4 years); when glatiramer acetate or interferon beta treatments were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years versus later, the HR was 0.76 (95% CI 0.66-0.88, P<0.001; 5-year absolute risk 8% vs 14%, median follow-up 5.3 years).
While these data indicate that initial treatment with glatiramer acetate or interferon beta was associated with lower risk of conversion to secondary progressive MS compared with untreated patients, the authors noted that “there is no consensus in the literature,” although previous observational studies were published before an objective progressive MS definition became available, and had heterogeneous methods.
JAMA 2019; DOI: 10.1001/jama.2018.20588; JAMA Neurology DOI: 10.1001/jamaneurol.2018.4932
Study Highlights: Explanation of Findings
This study provides evidence that treatment with any DMT within the first 5 years of disease onset reduces risk of disease conversion to secondary progressive MS. Older treatments do not lower risk as much as newer ones, but both drug types reduce risk of conversion to secondary progressive MS from relapsing-remitting disease in comparison to no treatment, or treatment over 5 years after disease onset.
Eighty-five percent of MS patients present with the relapsing-remitting disease. DMTs reduce relapse rates and disability accumulation.
“Within 20 years of disease onset, 80% of untreated patients with relapsing-remitting MS convert to a phase of sustained disability accrual, secondary progressive MS, which is responsible for much of the disease’s negative physical, psychological, and societal effects,” the authors wrote.
The study used a recently published validated definition of secondary progressive MS to examine the rate of conversion; until recently there was no rigorous definition.
“Recognizing there are significant limitations to this approach, and that there always are going to be some biases based on who started what medication when, this study is important and is an argument to continue the use of these long-term databases,” Corboy observed. “They collect real-world information that otherwise is extremely difficult to obtain.”
While neurology has lacked many therapies to treat its worst chronic disabling conditions, “in the last three decades, multiple sclerosis has been almost unique, with the development of therapeutic agents capable of targeting a salient aspect of disease pathogenesis (namely, adaptive immune dysregulation),” observed Ari Green, MD, of the University of California San Francisco, in an accompanying editorial in JAMA Neurology.
“Yet naysayers have persisted, arguing that the reduction in lesions seen on magnetic resonance imaging and reductions in relapse rates seen with these agents do not signify an effect on the long-term disability progression that characterizes the most terrifying clinical aspect of the disease,” he added. As a result, many algorithms have favored MS treatment based on cost and contracting rather than therapeutic efficacy.
While additional evidence about long-term effectiveness still is needed, “the ditherers must take note,” Green wrote: “The signs are strongly pointing to the benefits of early and aggressive treatment to forestall damage. Waiting on the sidelines does not appear justified.”
Kalincik and colleagues noted that there were numerous study limitations, which included its observational design: they could not ascribe causality or distinguish between prevention and delay of secondary progressive MS. Not having EDSS functional score components precluded using the secondary progressive MS definition with the highest combination of sensitivity, specificity, and accuracy, they added. The glatiramer acetate and interferon beta cohorts came from an earlier period, and different care practices at the time may have influenced results. Finally, the study also did not assess risks associated with DMTs.