Starting a highly effective treatment for relapsing-remitting multiple sclerosis (MS) soon after diagnosis is superior to starting an older, first-line agent and then escalating treatment, new research suggests.

An examination of data from two national registries showed that, compared with treatment escalation, initiation of a highly effective agent was associated with a 29% reduction in rate of 24-week confirmed disability worsening.

“Our study supports the growing body of evidence that early treatment with highly efficacious drugs is advantageous, at least over the older treatment escalation paradigm,” lead author Tim Spelman, MD, PhD, research coordinator, Department of Clinical Neuroscience at Karolinska Institute, Stockholm, Sweden, told Medscape Medical News.

The findings were published online August 16 in JAMA Neurology.

Danish vs Swedish Strategies

Among the many new therapies for MS that have been introduced in recent years, several have high efficacy — including natalizumab (Tysabri), fingolimod (Gilenya), and alemtuzumab (Lemtrada, Campath).

Evidence from clinical practice has suggested that beginning high-efficacy therapy within 2 years of disease onset improves long-term disability outcomes compared with delayed initiation of such therapy.

In the current study, researchers examined data from Denmark and Sweden to analyze the association between treatment strategies and clinical outcomes. Although patient populations and healthcare systems are similar in these countries, the treatment strategies differ.

“MS clinicians in Sweden have much more flexibility when it comes to prescribing disease-modifying therapies [DMTs], as evidenced by the popularity of off-label rituximab use in Sweden,” said Spelman.

On the other hand, Danish clinicians are limited to the strategy of treatment escalation.

Using both countries’ MS registries, the investigators identified patients between age 18 and 55 years at baseline who had relapsing-remitting MS or clinically isolated syndrome. Eligible patients began receiving a DMT between January 2013 and December 2016.

Confirmed Disability Worsening

The primary outcome was comparison of time to 24-week confirmed disability worsening between Danish and Swedish patients. The investigators defined this as an increase in Expanded Disability Status Scale (EDSS) score of at least one point from baseline that was sustained for 6 months.

Confirmed disability worsening was defined as an increase of 1.5 points if the baseline EDSS score was 0. If the baseline EDSS score was 5.5 or greater, the increase was required to be 0.5 points.

The analysis included 2700 patients (69.2% women; mean age, 36.1 years) from the Swedish registry and 2161 patients (68.1% women; mean age, 37.3 years) from the Danish registry. Overall mean follow-up time was 4.1 years.

Among the Danish Patients, 92.3% started a low to moderately effective DMT as their first treatment. The most common of these were teriflunomide (42%) and interferon beta-1a (29.8%).

About 66% of the Swedish patients started a low to moderately effective DMT as their first treatment. The two most common such therapies in this cohort were dimethyl fumarate (22.8%) and interferon beta-1a (22.8%).

In addition, 34.5% of the Swedish patients started treatment with a second-line or moderately to highly effective DMT, such as rituximab (Rituxan), natalizumab, or fingolimod, compared with 7.6% of the Danish patients.

Reduced Risk

The hazard ratio (HR) of 24-week confirmed disability worsening in the Swedish group compared with the Danish group was 0.71 (P = .004). The difference was greater still among patients in the Swedish vs Danish group who began therapy in 2015 or 2016 (HR, 0.69, P < .001).

When the investigators limited the analysis to the first DMT, the result still favored the Swedish group (HR, 0.80; P = .001).

In the secondary endpoint of 24-week confirmed EDSS score improvement, there was no significant between-group difference (HR, 0.97; P = .73).

However, the Swedish treatment strategy was associated with a 24% reduction in rate of achieving an EDSS score of 3 compared with the Danish strategy (P = .03). This difference was not observed in the earlier cohort (HR, 0.87; P  = .25) but it was in the latter cohort (HR, 0.73; P  = .001).

The likelihood of discontinuing treatment was lower in the Swedish group than in the Danish group (HR, 0.78; P  < .001). Lack of efficacy was the most commonly reported reason for discontinuation of the index treatment in the Danish group. Similarly, the likelihood of switching treatment was lower in the Swedish group (HR, 0.88; P  = .02).

“Even though other healthcare settings and countries are certainly more diverse in terms of patient population and payer or regulatory arrangements, we would argue that by selecting two very similar and homogeneous national settings, we were able to more directly attribute differences in clinical outcome to the national treatment strategy itself,” said Spelman.

Therefore, the results provide additional real-world evidence supporting the early initiation of highly efficacious therapy outside of Scandinavia, he added.

Spelman noted that the findings also may have regulatory significance. “This serves as a reminder for authorities that cost-based policies based on the perceived needs of the average patient may have consequences for some patients who are not average,” he said.

In addition, patients who receive a DMT of lower efficacy as a first treatment should be monitored thoroughly for the early identification of breakthrough disease and switched to a more effective DMT, said Spelman.

“Surprisingly Different”  

Commenting on the findings for Medscape Medical News, Anthony T. Reder, MD, professor of neurology at the University of Chicago, Chicago, Illinois, noted that the treatment strategies of Denmark and Sweden are “surprisingly different.”

“We’re talking about a fivefold difference in the use of the highly effective drugs. That’s pretty big,” said Reder, who was not involved with the research.

The differences in treatment reflect the criteria that physicians use to choose therapies, he added.

“I’d like to think that the people in Sweden and Denmark are putting their [most severely affected] people on the highly effective drugs,” said Reder.

However, Europe also takes a different approach to treatment than the United States does, he noted. European clinicians generally first prescribe platform therapies such as interferons before switching to IV infusions, which are more effective. Patients who do well on the platform therapies do not switch treatments.

“In the United States, we’re more likely to put everybody on the most effective drug from the beginning,” said Reder. “But we don’t switch people who are stable on the old drugs, because we know they work in these people.”

Strengths, Weaknesses

Use of national databases and the availability of disability data were among the study’s strengths. “This is a pretty good natural experiment,” said Reder.

He added that the criteria the investigators used to classify the treatments’ level of efficacy could be debated, although he agreed with them.

It also would have been interesting for the investigators to examine potential differences in clinical outcome between the various DMTs, but some of the treatment groups may have been too small for such an analysis, said Reder.

A biomarker that indicated which therapy a patient should receive would also have been helpful, he added.

Ocrelizumab (Ocrevus) and rituximab are anti-CD20 monoclonal antibodies, but only the former is approved for treatment of MS.

“The Swedes were way ahead of the game by using Rituxan. This is a very long-term treatment strategy that other countries won’t have,” said Reder. The difference in clinical outcome between the Swedish and Danish cohorts largely results from the difference in the use of rituximab, he added.

More broadly, the data indicate the large effect that DMTs have in patients with MS.

“There’s a dramatic reduction in the rate of decline of MS compared to the old untreated, natural history group — even in the group of patients here that are treated with a higher proportion of low-efficacy drugs,” Reder said.

The study was funded by the Swedish Research Council, the Swedish Brain Foundation, the Karolinska University Hospital, the Patient-Centered Outcomes Research Institute, the Swedish Multiple Sclerosis Research Foundation, the Swedish Federal Government, the Swedish Association of Persons with Neurological Disabilities, the Research Foundation of the Multiple Sclerosis Society of Gothenburg, the Edith Jacobson Foundation, and NEURO Sweden.

Spelman has received compensation for serving on scientific advisory boards, honoraria for consulting services, and funding for travel from Biogen. He has also received speaker honoraria from Novartis. Reder has disclosed no relevant financial relationships.

JAMA Neurol. Published online August 16, 2021. Abstract

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