MS Drugs Differ Most on Relapses, Not Disability, Real-World Study Shows

New multiple sclerosis (MS) patients treated with B-cell-depleting drugs or high-efficacy therapies had lower relapse rates and fewer brain lesions than those treated with oral drugs, but at 2 years, disability outcomes were similar, prospective data from the MultipleMS cohort showed.

Compared with oral platform therapies, B-cell-depleting therapies were associated with lower relapse incidence (incidence rate ratio 0.38, 95% CI 0.15–0.92) and greater T2 lesion volume reduction (volume ratio 0.87, 95% CI 0.76–0.99), reported Fredrik Piehl, MD, PhD, of the Karolinska Institute in Stockholm, and colleagues in Neurology Open Access. Trends were similar for high-efficacy therapies.

Changes in disability scores and levels of serum neurofilament light (NfL), a marker of axonal injury, did not differ among groups. Levels of serum glial fibrillary acidic protein (GFAP), a marker of astroglial activation or damage, decreased modestly overall, with larger reductions with oral therapies and relatively higher levels in the B-cell-depleting therapy and high-efficacy groups, Piehl and colleagues wrote.

“The treatment groups already differed in important patient characteristics, suggesting that doctors were to some extent selecting treatments based on the individual patient,” Piehl said in a statement. “Even so, B-cell-depleting therapies and other strong treatments were linked to fewer relapses and fewer MRI changes. But after 2 years, we did not see clear differences in disability scores.”

The advent of disease-modifying therapies (DMTs) transformed MS management, offering treatments that target inflammation and aim to slow progression, Piehl and colleagues noted.

“A major challenge is that worsening of MS disability represents a delayed phenomenon that is difficult to quantify in a comprehensive way,” the researchers observed.

Research has identified proxies that reflect the inflammatory and progressive components of MS biology, they said: NfL correlates with inflammatory disease activity like relapses and new MRI lesions, while GFAP seems closely linked to progression independent of relapse activity. “Similarly, focal MRI lesion accumulation reflects acute inflammation, while global and regional atrophy rates are associated with progressive disease features,” they added.

The MultipleMS findings “point toward a poor ability of high-efficacy therapies and B-cell-depleting therapies to reduce chronic inflammation despite their strong effect against acute inflammation,” noted Carmen Tur, MD, PhD, of the Multiple Sclerosis Centre of Catalonia in Barcelona, in an accompanying editorial.

Other studies have failed to find differences between high-efficacy and moderate-efficacy DMTs in preventing progression independent of relapse and MRI activity, Tur pointed out.

“Taken together, these results underscore an unmet therapeutic need and support the concept that chronic central nervous system-compartmentalized inflammation evolves largely independently of acute inflammatory activity,” she stated.

“In this context, the emergence of Bruton tyrosine kinase inhibitors and anti-CD40 ligand monoclonal antibodies, both designed to target mechanisms of chronic neuroinflammation, offers renewed hope to address this challenge,” she said.

The real-world MultipleMS study followed 509 newly diagnosed MS patients with no prior DMT exposure in seven European countries. Most participants (89%) had relapsing-remitting MS, and 63.9% were women. Mean baseline age was 33 years, and follow-up was completed at 2 years.

Participants were classified by initial therapy into injectable platform (17.1%), oral platform (29.9%), high-efficacy therapy (15.5%), B-cell-depleting therapy (19.8%), or untreated (17.7%) groups:

• Injectable platform drugs were interferon-beta or glatiramer acetate
• Oral platform drugs were dimethyl fumarate (Tecfidera) or teriflunomide (Aubagio)
• High-efficacy therapies were fingolimod (Gilenya), cladribine (Mavenclad), natalizumab (Tysabri), or alemtuzumab (Lemtrada)
• B-cell-depleting therapies were rituximab (Rituxan) or ocrelizumab (Ocrevus)

Disability scores were tracked with the Expanded Disability Status Scale (EDSS), a 0-10-point scale with lower values indicating less disability. The median EDSS score at baseline was 1.5 and the median disease duration was 0.66 years.

Baseline EDSS scores were 1.0 for patients started on injectable platform drugs and 2.0 for patients started on high-efficacy or B-cell-depleting therapies. “As expected, baseline characteristics considerably influenced DMT selection, partly because of restrictions on the use of high-efficacy therapies,” Piehl and co-authors noted.

“About nine of 10 who started B-cell-depleting therapies remained on the same therapy at 2 years, compared with five to seven of 10 in other treatment groups, while more than half of those initially untreated later initiated a DMT,” they reported.

The study was limited by its observational design and lack of randomization, the researchers acknowledged. Outcomes were limited to 2 years.

“Some treatments were linked to fewer attacks and fewer MRI changes, and by following this group for several more years, we will be able to determine whether differences emerge over the longer term,” Piehl said.