Progression without relapses drives most disability worsening in MS

Findings challenge traditional idea of relapses' role in early relapsing disease

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Most disability worsening events happen independent of relapse activity across all types of multiple sclerosis (MS), including clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS), a new study reports.

The findings challenge the idea that relapses are the main driver of disability worsening in early relapsing forms of MS, and that progression independent of relapses is exclusive to progressive forms of the disease, the researchers said in “Harmonizing Definitions for Progression Independent of Relapse Activity in Multiple Sclerosis,” which was published in JAMA Neurology.

MS has traditionally been divided into two general classifications. In relapsing forms such as RRMS, patients have relapses or flares when symptoms suddenly get worse, followed by periods of remission where they ease or vanish. Progressive MS types, which include primary progressive MS (PPMS) and secondary progressive MS (SPMS), are defined by disability getting worse apart from relapse activity.

The traditional view has been that, for people with RRMS, most disability worsening is associated with relapses, wherein a patient will have disabling symptoms that persist even after the relapse has resolved. Disability worsening occurring in the absence of relapses was considered a feature of progressive MS.

In recent years however, there’s been growing evidence that many people with RRMS also have disability worsening without relapses, similar to the disability worsening that’s defined progressive MS types.

Disability worsening without a relapse is sometimes called progression independent of relapse activity (PIRA). It’s also been referred to as “silent” progression.

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Scientists in Switzerland reviewed 48 large studies to assess the current understanding of PIRA in MS. The studies, which included several large clinical trials that tested MS treatments, covered data on tens of thousands of patients.

They found that, across all the studies, PIRA occurred in roughly 5% of RRMS patients a year. Although relapse-associated worsening has been thought to be the main driver of RRMS disability, the results suggested PIRA accounted for at least 50% of all reported instances of worsening disability. Since progressive forms of MS are already defined by progression without relapse activity, the findings show disability often worsens without relapse activity in all MS types.

The data generally suggested PIRA was more common in older patients who’ve had MS longer. But PIRA was the main driver of disability even in those with relatively early RRMS or with CIS, which refers to a single attack of MS-like disease.

“Observational and controlled clinical trials provide unequivocal evidence that PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes, including CIS and early RRMS, thus challenging the conceptual distinction between relapsing and progressive disease courses or stages,” wrote the researchers, who noted PIRA tended to account for a higher proportion of disability worsening events among patients treated with highly effective therapies. This is probably because these treatments are usually very effective at preventing relapses, so PIRA is more obvious when it occurs, they said.

Although the available data suggest PIRA is common in MS, the researchers said there’s not a standardized definition for it. Different studies have used varying criteria to define PIRA, which has made it difficult to draw clear comparisons across studies.

The researchers proposed a single harmonized definition to help standardize future research. Among other criteria, they said PIRA should only be considered when disability worsening occurs no less than 30 days before or 90 days after a confirmed relapse. They also suggested the disability worsening should be confirmed at least three months after the initial event and be sustained for at least a year.

“The proposed harmonized definition may balance sensitivity and specificity and improve the comparability of results in current and future cohorts and data sets,” wrote the scientists, who noted challenges in measuring PIRA also need to be addressed, such as figuring out how disease activity on MRI scans can best be incorporated into measures and finding more sensitive ways to measure disability.