The advent of high-efficacy MS therapies has brought tremendous benefits, as well as huge debate over how and when to use this new class of treatment. While they may be more effective, they also come with more potentially serious side effects.
This, combined with patient-to-patient variations in disease course and treatment response, makes decisions around drug selection, initiation, and escalation extremely complex.
In the first of our two NeuroWebinars in May, Professor Xavier Montalban, Director of Neurology at the Multiple Sclerosis Centre of Catalonia (CEMCAT), Professor Gavin Giovannoni, Chair of Neurology at Barts and The London School of Medicine and Dentistry, Queen Mary University of London, and Professor Dalia Rotstein, Neurologist at Unity Health Toronto, Canada, discussed how and when to use these new agents.
New era, considerations
Together with early detection of MS, high-efficacy medicines have helped usher in a new era in MS care.
They have led to the emergence of no evidence of disease activity (NEDA) 3 as a clinical outcome measure. NEDA 3 combines three measures of disease activity, namely no clinical relapses, no confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS), and no new magnetic resonance imaging (MRI) lesion activity, and is seen by many as the gold standard treatment goal. How best to achieve NEDA 3, however, remains under debate.
Traditional approaches advocate for high-efficacy disease modifying therapies if first-line therapies, such as interferons, glatiramer acetate, and teriflunomide fail. But there is strong evidence, encapsulated by the “time is brain” concept, for the earlier use of more efficacious treatment.
A 2020 paper, published in The Lancet, for example, concluded that high-efficacy therapy commenced within two years of disease onset was associated with less disability six to 10 years later than when started between four and six years of onset.
Professor Montalban said that the 2021 ECTRIMS guidelines on MS treatment recommended that clinicians consider a high-efficacy treatment early on.
“I think all MS neurologists now accept that early treatment is fundamental. We have modified the long-term prognosis of MS because of the different diagnostic criteria we are using and because of the high-efficacy treatments,” he said during our webinar.
The risk/benefit profile of these agents, however, must be considered. While the potential serious adverse events (SAE) vary by drug class and mode of action, they can include, for example, an increased risk of haematologic abnormalities, infections, malignancy, secondary autoimmunity, neurovascular events, and teratogenicity.
Taking this into account, Professor Montalban said that “at the very least” high-efficacy therapies should be used “as early as possible” in those who have poor prognostic factors such as male sex, a high Expanded Disability Status Scale (EDSS), and inflammatory activity at baseline.
Professor Rotstein highlighted that MS was a “highly heterogenous disease” that is largely unpredictable at baseline. “The first year or two on immunomodulatory therapy can provide a valuable test of time about what intensity of therapy a patient may require long term… we then need to monitor them closely for the need to make a timely switch,” she said.
While there are currently no randomised controlled trials to guide treatment escalation, there is “quite a lot of consensus” across the different scores and guidelines.
Any relapse or an increase of one or more EDDS points would be “grounds for escalation,” she added. Changes on MRI, in terms of new lesions, and the size and location of lesions, may also prompt switching discussions, Prof. Rotstein said, recommending monitoring scans every six months.
Proactive and aggressive treatment
Professor Giovannoni, however, argued that everyone diagnosed with MS should be given the choice of a high-efficacy medicine from the start.
MS, he said, is a devastating disease that shortens life expectancy and reduces quality of life, and these risks need to be explained and accounted for when making treatment decisions.
“We have to try to prevent the damage, there is no point trying to fix it afterwards. The only way we can prevent the damage is with a much more proactive, aggressive approach when people present,” he said.
There is no hard or fast answer to this debate. Who is most likely to benefit from early treatment with high-efficacy drugs will depend on a range of factors, including the patient’s history, age, and comorbidities, the duration and the severity of their disease, and any previous exposure to DMTs.
One thing our webinar speakers all agreed on is that treatment approaches should be based on personal choice, and tailored to meet each individual’s risks and needs.
Interested in learning more about this subject?
 Freeman, L., Longbrake, E. E., Coyle, P. K., Hendin, B., & Vollmer, T. (2022). High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing–Remitting Multiple Sclerosis. CNS drugs, 1-15.
 Simonsen, C. S., Flemmen, H. Ø., Broch, L., Brunborg, C., Berg-Hansen, P., Moen, S. M., & Celius, E. G. (2021). Early high efficacy treatment in multiple sclerosis is the best predictor of future disease activity over 1 and 2 years in a Norwegian population-based registry. Frontiers in Neurology, 12, 693017.
 He, A., Merkel, B., & Brown, J. W. L. (2020). Zhovits Ryerson L, Kister I, Malpas CB, et al. Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study. Lancet Neurol, 19(4), 307-16.
 Montalban, X., Gold, R., Thompson, A. J., Otero-Romero, S., Amato, M. P., Chandraratna, D., … & Zipp, F. (2018). ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Multiple Sclerosis Journal, 24(2), 96-120.