Disability May Accumulate in the Relapsing
Phase of MS

Erik Greb

October 25, 2021

Disability accumulation may occur independently of relapses for some patients in the early phase of relapsing-remitting multiple sclerosis (MS), according to new research.

Approximately 61% of confirmed disability accumulation (CDA) events in a multicenter study occurred independently of any relapse. The remaining CDA events were associated with relapses.

Dr Mattia Fonderico

"Our findings indicate that progression independent of relapse activity may begin very early in the disease course, in a considerable proportion of patients, in a phase that clinicians classify as relapsing-remitting," investigator Mattia Fonderico, MD, a resident in neurology at the University of Florence, Italy, told Medscape Medical News.

The findings were presented at the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021.

Two Phases of MS

Multiple sclerosis is understood to comprise a relapsing phase (with or without full recovery after relapses) and a secondary progressive phase. But in the pooled population of OPERA I and OPERA II study participants with relapsing-remitting MS, most CDA events occurred independently of relapse activity.

The current researchers sought to examine the contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to the first CDA event in patients with clinically isolated syndrome (CIS) or early relapsing-remitting MS. They also aimed to identify risk factors associated with RAW and PIRA.

The investigators extracted anonymized data from the Italian MS Registry in July 2020. Patients were eligible for inclusion if information was available on their clinical course, follow-up visit dates, Expanded Disability Status Scale (EDSS) score at each follow-up, the date of all relapses, the start and end dates of disease-modifying therapies (DMTs), and the types of DMTs.

In addition, eligible participants had CIS or relapsing-remitting MS at their first clinical evaluation. Their first neurologic evaluation occurred within 1 year of their first demyelinating event, they had at least three visits with EDSS evaluations, and follow-up lasted for at least 5 years.

The study's outcome was the first CDA event confirmed at 24 weeks. CDA events were classified according to their temporal association with relapses. If a relapse occurred within 90 days before or within 30 days after a CDA event, the latter was classified as RAW. Otherwise, it was classified as PIRA.

To identify predictors of the first 24-week CDA, the researchers used multivariable Cox proportional hazard regression models. They adjusted the data for variables including age, sex, disease duration, EDSS score, and number of relapses before the event.

DMT Reduced Risk

The investigators included 5287 patients in their analysis. At the first neurologic evaluation, 40% of patients had CIS and 60% had relapsing-remitting MS. At baseline, mean disease duration was 0.42 years, and mean EDSS score was 1.7. Mean follow-up duration was 11.4 years.

During follow-up, 45% of patients had a CDA event. Of these events, 61% were classified as PIRA and 39% as RAW. The patients in these two groups did not differ by sex or disability level at baseline or at the end of follow-up. At baseline, however, patients with RAW were younger (mean age, 30.3 years) than those with PIRA (mean age, 34.1 years).

Predictors of RAW events included younger age (adjusted hazard ratio [aHR], 0.99; P < .001), relapsing-remitting disease course (aHR, 1.54; P < .001), lower baseline EDSS score (aHR, 0.92; P = .003), shorter exposure to DMT (aHR, 0.15; P < .001), and a higher number of relapses (aHR, 1.06; P < .001).

Predictors of PIRA events included older age (aHR, 1.02; P < .001), relapsing-remitting course (aHR, 1.44; P < .001), longer disease duration (aHR, 1.52; P < .001), lower EDSS at baseline (aHR, 0.90; P < .001), higher percentage of time spent on DMT (aHR, 0.18; P < .001), and a lower number of relapses before the event (aHR, 0.93; P < .001).

Longer exposure to DMT reduced the risk of both PIRA and RAW (P < .001).

Early Treatment Crucial  

It is unclear whether PIRA signals the beginning of the secondary progressive course of MS or a specific phenotype of relapsing-remitting MS, said Fonderico. If it's the secondary progressive course, the "active/not-active with progression" phenotype from the 2014 Lublin classification would fit these patients. "The correlation between the occurrence of early PIRA events and long-term outcomes might help us elucidate this issue," said Fonderico.

The number of white-matter T2 and T1 lesions explains only a small fraction of the heterogeneity in clinical outcomes of MS. "Our results might help the clinician explain why some patients present insidious symptoms or signs of progression despite the lack of clinical inflammatory activity," said Fonderico, adding that the findings could not fully explain this discrepancy.

In the future, other measures of neurodegeneration (such as the rate of brain volume loss) and neuroinflammation (such as markers of microglial activation) might identify patients with relapsing-remitting MS and disability progression that appears unrelated to inflammation, said Fonderico.

RAW and PIRA are distinct and accepted sources of disability accumulation in MS, said Jennifer Graves, MD, PhD, associate professor of neurosciences and director of the University of California San Diego Neuroimmunology Research Program in La Jolla, who commented on the findings for Medscape Medical News.

But there is a third source: delayed development of disability from earlier relapses. This phenomenon is common in children, who appear to recover well from relapses. "That may be something that's more challenging to capture, but I think they did a good job of trying to capture what they could," said Graves, who was not involved in the study.

"The most encouraging result from these data is that DMT did not just ameliorate RAW, but it also looked protective for PIRA," she added. "On my review of the data, it looks like an 82% decrease in the hazard of PIRA when using relapsing MS therapies."

The findings thus support the decades of work on improving the efficacy of DMTs that control disease activity, said Graves. The data also "reinforce our desire to keep people quiet early in disease course to impact their long-term outcome and disability accumulation," she concluded.

The study was conducted without outside funding. Fonderico and Graves have disclosed no relevant financial relationships.

37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2021. Abstract 037. Presented October 13, 2021.

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