Worsening Disability in Absence of Relapses ‘Underestimated’ in MS

A substantial amount of disability worsening happens independently of relapses in people with multiple sclerosis (MS), including those in earlier stages of relapsing-remitting disease, a study in a large patient database reported.

While its findings “confirm relapses contribute to the accumulation of disability, primarily early in multiple sclerosis,” data also show that “progression independent of relapse activity can start early in relapsing, remitting MS” before becoming “the dominant driver of disability accumulation as the disease evolves,” Fred Lublin, MD, a study co-author, neurologist with Mount Sinai and director of its MS center, said in a press release.

The study, “How patients with multiple sclerosis acquire disability,” was published in Brain.

MS is characterized by relapses for most patients — times when existing symptoms rapidly worsen or new ones suddenly appear. Relapses are usually followed by remissions, periods of less intense symptoms.

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While patients can recover fully from a relapse, in some cases their symptoms become more disabling following a relapse. This incomplete recovery is called relapse-associated worsening, or RAW.

Progression independent of relapse activity (PIRA), or worsening disability in the absence of a relapse, is also known.

An international team of scientists conducted an analysis of data from the Novartis-Oxford MS dataset to better understand the relative contributions of RAW and PIRA in disability progression in MS.

Their analysis included data on 27,328 patients who had participated in clinical trials of MS treatments and had been followed for up to 15 years. The researchers also performed sub-analyses focusing only on patients in Phase 3 trials and its extensions and placebo-controlled Phase 3 trials, which generally were consistent with the overall results.

Among participants, about 90% had relapsing-remitting disease (RRMS), while about 6% had secondary progressive MS (SPMS) and about 4% had primary progressive MS (PPMS).

As expected, relapses were most common among RRMS patients and least common for those with PPMS, although relapses were reported in all groups. The risk of all-cause disability worsening (including both PIRA and RAW events) was generally higher among patients with progressive MS types.

Relapse-associated worsening occurred most frequently in RRMS patients and least frequently in PPMS patients, as predicted. But regardless of disease type, a relapse in the previous year was associated with a 31–48% increased risk of worsening disability. Other analyses suggested that older patients or those with more severe disability prior to a relapse were more likely to have worsening disability following a relapse.

Surprisingly, although RRMS is thought to be characterized mainly by relapses, worsening disability in RRMS adults more commonly happened through progression independent of relapse activity than through RAW (47.3% vs. 26.9%).

“Unexpectedly, PIRA had already begun in adult patients with RRMS: Sustained PIRA events occurred with similar or higher frequency to RAW events, in adult patients with RRMS,” the researchers wrote.

The finding “confirms that up to 50% of the disability accumulation in adult patients with RRMS is not associated with overt relapses,” they added.

Among patients with confirmed disability progression, PIRA contributed to disease worsening in a total of 47.3% of RRMS patients, 76.7% of those with SPMS, and 83.4% of those with PPMS.

“Our study confirms that PIRA has been underestimated as a contributing factor in RRMS: PIRA plays a significant role in disease worsening in adult RRMS and gradually becomes the principle way by which patients with multiple sclerosis acquire disability in progressive disease,” the researchers concluded.

They noted that RAW was the dominant driver of disability only among pediatric RRMS patients. For all other patients, PIRA was the main driver of worsening disability over time.

Analyses of the trial data also showed that disease-modifying treatments (DMTs) lowered the proportion of patients who experienced a relapse or worsening of disability. The effect of treatments was generally strongest among those with RRMS.

Overall, patients with minimal disability — a score of one in the Expanded Disability Status Scale (EDSS) — and assigned to trial placebo groups took about nine years to experience limitations in walking ability (EDSS score of four) and 18.5 years to require walking assistance (EDSS score of six). Those changes were seen more than three years later among patients given DMTs in the trials.

“Our study demonstrated that time to disability milestones can be delayed by several years with treatment, with the highest potential to gain time in the youngest, least disabled patients with multiple sclerosis,” the researchers wrote.

This study was supported by Novartis, and several Novartis employees are co-authors.