Early high-efficacy MS drugs cut relapse risk, not progression

Early treatment with high-efficacy disease-modifying therapies (DMTs) lowered the risk of relapse-associated disability progression in people with multiple sclerosis (MS), but had no effect on disability progression independent of relapse activity (PIRA), a nationwide study in Denmark found.

People who received high-efficacy therapies as a first treatment were at a similar risk of PIRA — a type of disability that gradually accumulates even when relapses don’t occur — as those who started with a moderate-efficacy DMT and later escalated to a higher-efficacy treatment if needed.

The researchers said the findings suggest that “the inflammatory activity expressed by relapses and the neurodegenerative progression reflected in PIRA represent partially independent mechanisms requiring potentially different therapeutic approaches,” and highlight “an unmet need … for therapies that are effective against PIRA.”

The study, “Effectiveness of escalation versus early high-efficacy therapies on progression independent of relapse activity in multiple sclerosis: a Danish nationwide study,” was published in BMJ Neurology Open.

MS is caused by the immune system mistakenly attacking the myelin sheath, a protective layer around nerve fibers that helps them send electrical signals more efficiently. While relapses — periods of new or worsening MS symptoms linked to these inflammatory attacks — can contribute to disability accumulation over time, scientists now understand that PIRA may account for a substantial proportion of long-term disability.

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Treatment generally starts with moderate therapies

People with MS generally start treatment with moderate-efficacy DMTs (METs) and switch to high-efficacy therapies (HETs) if their disease remains active. However, growing evidence suggests that starting HETs earlier may be more effective at preventing relapses and associated disability accumulation.

Whether early use of HET can also reduce PIRA remains unclear, with previous studies yielding mixed results. To learn more, researchers analyzed data from Denmark’s nationwide MS registry, comparing how different treatment strategies influenced the risk of PIRA.

The study involved 3,316 adults with relapsing-remitting multiple sclerosis (RRMS) who started treatment between 2012 and 2022, at a mean age of 38.6. Participants were followed for a median of 7.4 years.

Most participants (82%) initially received METs and switched to HETs when needed, representing the escalation group. The remaining 18% started treatment directly with HETs.

In the escalation group, nearly half the participants (41.8%) received teriflunomide (sold as Aubagio and generics), with other common treatments including dimethyl fumarate (sold as Tecfidera and generics) and interferon beta (sold as Avonex, Betaseron, and others). In the HET group, participants most commonly used natalizumab (sold as Tysabri and Tyruko), followed by Ocrevus (ocrelizumab) and fingolimod (sold as Gilenya, Tascenso ODT, and generics).

Participants who started treatment with HETs were, on average, younger at treatment initiation and had been living with MS for a shorter time than those in the escalation group.

A greater proportion of the HET group had higher disability scores. They also tended to have a higher burden of relapses and brain or spinal cord lesions. The researchers adjusted for all these differences before the final analyses.

Most confirmed disability-worsening events in both groups were attributable to PIRA rather than relapses. However, the risk of PIRA did not differ significantly between the two treatment strategies.

After four years, 86.1% of people in the HET group and 84.4% of those in the escalation group remained free of PIRA.

In contrast, the risk of a relapse-associated disability worsening event was 75% lower with HETs than with escalation therapy. After nine years, the cumulative probability of experiencing this form of disability worsening was 2% among those who started HETs, compared with 8.2% among those who initially received METs.

The annualized relapse rate was also lower in the HET group, at 0.08, compared with 0.13 in the escalation group, representing a 40% lower relapse rate.

The researchers noted that because of this substantial reduction in relapses, it may be harder to accurately detect PIRA and distinguish it from relapse-related disability outcomes. Moreover, the observational nature of the study limited the scientists’ ability to evaluate whether additional factors, such as socioeconomic status or other health conditions, influenced the outcomes.

Despite these limitations, the data “indicate a therapeutic gap in the current treatment landscape with respect to mitigating PIRA,” the researchers concluded.