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With the explosion of disease-modifying therapies in recent years, deciding the best treatment strategy for patients newly diagnosed with multiple sclerosis (MS) often is difficult, said Ellen Mowry, MD, of Johns Hopkins University in Baltimore.

"There's a great push in the field these days to consider starting with the stronger medications up front," Mowry stated in the 2021 presidential lecture at the Consortium of Multiple Sclerosis Centers (CMSC) annual meeting.

But whether that approach is the best for a given person with MS is unclear, she noted.

"While some observational studies suggest that higher-efficacy medications for MS may have some benefit with respect to longer-term disability, the studies have methodologic issues that make uncertain the full validity of the results, and they don't address treatment strategies, per se," Mowry told 麻豆传媒 in an interview after the lecture.

"People with MS and their clinicians deserve the most rigorous evidence available to make treatment decisions," she emphasized.

Two enrolling clinical trials, and , will test whether higher-efficacy versus escalation treatment strategies lead to differences in disability accrual or overall brain tissue destruction, Mowry observed. "That they use the gold standard of randomization will improve the confidence in the results, helping neurologists and people with MS confidently arrive at informed decisions about MS management," she said.

TREAT-MS will follow relapsing-remitting MS patients for up to 72 months, with primary endpoints including changes on the (EDSS) or on either the or (EDSS-Plus). DELIVER-MS is a parallel study with an observational arm and a randomized controlled trial arm; its primary outcome will be change in brain volume.

When few treatments were available, the typical approach was an escalation strategy, Mowry said in her CMSC lecture. But with advent of more therapies, that strategy is not as clear, and many researchers have argued for higher-efficacy therapies to be used early or first in the treatment plan.

While recent trials have shown that MS treatments can prevent new inflammatory events, it's not clear whether using the drugs as first-line therapy ultimately reduces the risk of sustained disability, Mowry pointed out. Nor is it clear whether a detectable benefit holds for all people with MS, or just a subgroup -- or what the safety implications may be of a one-size-fits-all approach.

Clinical trial populations and conditions aren't generalizable and don't represent real-world MS with its comorbidities, inconsistent treatment adherence, delays due to insurance authorization, safety concerns and infection risks, and other variables. Importantly, trials are not testing treatment strategies typically used in clinical practice, Mowry stressed.

Observational studies also have limitations: most cannot account for treatment choice and are subject to confounding by indication, Mowry noted. And in observational studies, it's often unclear whether treatments were escalated soon after breakthrough disease occurred.

Newly diagnosed patients often are concerned with treatment safety, especially with aggressive therapy -- a fear that became even more evident during the COVID-19 pandemic when infection risk was concentrated in a specific time period, she added.

In clinical practice, four factors often are considered before choosing an MS treatment: patient factors like risk tolerance, comorbidities, and reproductive status; disease factors like severity, phenotype, and prognostic signs; treatment factors like efficacy, safety, and tolerability; and system-related factors, like insurance coverage and access to services.

"In my patient population, most people have a mix of some higher-risk and lower-risk features," Mowry said. "How I advise my patients is that I try to be quite honest. I describe the escalation and early intensive therapy paradigms very broadly."

"I tell them that we don't have a great way of individualizing their treatment decisions at this point," she continued. "I check for absolute and relative contraindications to any given therapy and help first to narrow down the list. And then, we discuss the pros and cons again of each treatment strategy approach, given the therapies that are left, as well as the pros and cons of therapies within those approaches."

"If we decide to go the escalation route, we are very strongly conscientious about escalating if there's breakthrough disease," Mowry stressed. "For me, that means after the medication should have kicked in, if there's a new relapse or more than one new lesion, we may indeed escalate the therapy right away."

The discussion about treatment decision takes several appointments, typically in quick succession, she noted.

"We are so fortunate to be in an era where multiple disease-modifying therapies are available," Mowry said. "I think that there are reassuring trends and long-term outcomes that we think, at least in part, are due to use of these therapies. While there are emerging data from observational studies to suggest potentially benefit of higher efficacy therapies compared to a first-line or escalation approach, we really do need more definitive data to support the early treatment choices that people need to make."

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