Silent Progression in Relapsing MS Tied to Brain Volume Loss

Disability progression independent of relapse activity was tied to significantly increased brain volume loss in relapsing multiple sclerosis (RMS), a longitudinal study in Switzerland showed.

Compared with clinically stable patients, RMS patients who had worse disability without relapses had a higher rate of brain atrophy (mean difference in annual percentage change -0.36, 95% CI -0.60 to -0.12, P=0.02), according to Cristina Granziera, MD, PhD, of the University of Basel, and co-authors.

The difference was mainly driven by gray matter loss in the cerebral cortex, the researchers reported in JAMA Neurology.

The increased atrophy rates likely reflect ongoing diffuse neurodegenerative processes, especially in cortical gray matter, Granziera and colleagues observed.

“The measure of progression independent of relapse activity quantifies the proportion of disability worsening in multiple sclerosis patients, which is due to non-inflammatory neurodegenerative processes,” Granziera told MedPage Today.

“Our study addresses the question of whether MS patients experiencing progression independent of relapse activity exhibit higher brain atrophy rates than stable patients,” Granziera continued. “Answering this question is fundamental to understanding whether neurodegeneration is underlying progression independent of relapse activity events and whether we should act to prevent them.”

The association between worsening without relapse activity and diffuse neurodegeneration highlights the need to better stratify MS patients in clinical practice and optimize therapeutic regimens for these patients, she noted.

In 2019, researchers at the University of California San Francisco first used the term silent progression to describe long-term worsening independent of relapse activity in RMS and suggested that monitoring this activity may require a shift in how MS is evaluated and treated.

More recently, data presented at the 2022 ACTRIMS Forum showed that relapse-free, insidious disability worsening can occur early in RMS and could be predicted by cervical cord atrophy rate.

Granziera and co-authors evaluated 1,904 brain MRIs from 516 RMS patients in the Swiss Multiple Sclerosis Cohort. Most patients (67.4%) were women. At baseline, mean age was 41.4, and the median Expanded Disability Status Scale (EDSS) score was 2.0, indicating minimal disability.

Median follow-up was 3.2 years; data were acquired from January 2012 to September 2019. Standardized clinical assessments with EDSS calculation were performed every 6 or 12 months, and whether relapses had occurred was recorded at each visit.

Confirmed disability progression was defined as an EDSS score increase of 1.5 or more points if baseline EDSS was 0, 1.0 or more points if baseline EDSS was 1.0-5.5, or 0.5 or more points if baseline EDSS was greater than 5.5. Progression independent of relapse activity was defined as an episode of confirmed disability progression with no relapse during the 90 days before the EDSS increase and during the 6-month period between EDSS increase and confirmation of disability progression.

Of the 516 patients in the cohort:

• 46 had progression independent of relapse activity
• 122 had relapses
• 14 had progression independent of relapse activity and relapses
• 334 were clinically stable

Comparisons were made after propensity score matching for duration of follow-up, age, sex, disease duration, number of scans available, and disease-modifying treatment.

Patients who had progression independent of relapse activity had a median annualized increase in EDSS score of 0.20 points, compared with no increase for the relapse-only and clinically stable groups.

No differences in brain atrophy rates emerged between patients with progression independent of relapse activity and patients with relapses. Compared with clinically stable patients, patients with relapses showed increased whole brain atrophy (mean difference in annual percentage change -0.18, 95% CI -0.34 to -0.02, P=0.04), with accelerated gray matter loss in both cerebral cortex and deep gray matter.

The study had several limitations, Granziera and co-authors wrote. The criterion used to determine progression was based only on the EDSS and subtle worsening that didn’t lead to a higher EDSS score may have been overlooked, they pointed out.

“Furthermore, disease-modifying therapies may have constituted a bias in our study, which we tried to overcome by performing propensity score matching for treatment status and considering treatment groups in sensitivity analyses,” they added.