Progression Independent of Relapse Activity in MS Associated With Increased Atrophy Rates


Patients with relapsing multiple sclerosis who had progression independent of relapse activity were subject to global brain tissue loss similar to that of patients experiencing solely relapse activity.

Alessandro Cagol, MD

Alessandro Cagol, MD

Data from an observational, longitudinal cohort study showed that disability progression independent of relapse activity (PIRA) was associated with significantly increased brain volume loss in patients with relapsing multiple sclerosis (MS) and warranted further investigations on therapeutic approaches to prevent irreversible tissue loss in these patients.1

Led by Alessandro Cagol, MD, neurologist, University of Basel, the study included 1904 brain MRI scans from 516 patients with relapsing MS (mean age, 41.4 years; SD, 11.1) who were classified as either presenting with relapse activity only, PIRA episodes only, mixed activity, or clinically stable. Over a median follow-up of 3.2 years (IQR, 2.0-4.9), patients had mean difference in annual percentage change (MD-ADC) in brain volume/cortical thickness compared between groups and calculated after propensity score matching.

Patients were only included if they had 2 available brain MRIs, including 1-mm isotropic magnetization-prepared rapid gradient-echo and T2/fluid-attenuated inversion recovery, separated in time by at least 6 months. During the observation period, 46 patients experienced only PIRA events and no relapses, 122 patients relapse activity without PIRA, 14 patients with both PIRA and relapse activity, and 334 patients who remained clinically stable.

In comparison with stable patients, baseline brain parenchymal fraction was lower among those who presented with only PIRA activity (PIRA: median, 0.756 [95% CI, 0.715-0.788]; stable: median, 0.769 [95% CI, 0.747-0.807]; P = .045). On MD-APC, these patients showed accelerated volume loss for total brain volume (–0.36; 95% CI, –0.60 to –0.12; P = .02), total gray matter (GM; –0.59; 95% CI, –1.00 to –0.18; P = .02), and cortical GM (–0.71; 95% CI, –1.18 to –0.24; P = .02).

"These results point to the need to promptly identify patients with PIRA in clinical practice, because they may benefit from optimized therapeutic regimens,” Cagol et al wrote. "In this context, clinical trials to assess the potential benefit of treatment escalation/induction in patients with RMS and PIRA are warranted."

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Patients with solely PIRA activity also demonstrated faster ventricular enlargement in comparison to stable patients (MD-APC, 1.50; 95% CI, 0.47-2.55; P = .02). In addition, accelerated thinning was detected in the whole cortex (MD-ADC, –0.62; 95% CI, –1.06 to –0.16; P = .02), as well as in the temporal, frontal, parietal, insular, and cingulate cortical areas. In a subgroup of patients with PIRA who did not have radiological inflammatory activity during the entire follow-up (n = 26), investigators continued to observe accelerated atrophy rates when compared with a matched group of stable patients.

Among those who had relapse activity without PIRA events, investigators observed increased rates in total brain volume (MD-APC, –0.18; 95% CI, –0.34 to –0.02; P = .04) and total GM (MD-APC, –0.32; 95% CI, –0.59 to –0.06; P = .04), which were evident both in cortical GM (MD-ADC, –0.33; 95% CI, –0.61 to –0.04; P = .04) and deep GM (MD-APC, –0.31; 95% CI, –0.57 to –0.06; P = .04). Furthermore, these patients demonstrated accelerated thinning in the whole cerebral cortex (MD-APC, –0.31; 95% CI, –0.57 to –0.04; P = .04), as well as in the cortex of the temporal, parietal, occipital, insular, and cingulate lobes. During follow-up, 35 of the 122 patients with only relapse activity had confirmed disability progression, with no differences in atrophy rates between the 2 groups.

Following propensity score matching, there were no significant differences in atrophy rates among those experiencing only PIRA events vs those with only relapse activity. These findings were in line with, and expand on, the results of Cree et al,2 who reported increased total brain volume loss in association to both silent disease progression and overt inflammatory activity, without significant differences between the two. This study differed in that it identified GM atrophy as the main driver of accelerated brain atrophy among patients with PIRA and those with relapse activity. Additionally, it highlighted the involvement of the cerebral cortex in both patient groups and the involvement of deep GM in patients with relapsing forms of disease only.

1. Cagol A, Schaedelin S, Barakovic M, et al. Association of brain atrophy with disease progression independent of relapse activity in patients with relapsing multiple sclerosis. JAMA Neurol. Published May 16, 2022. doi:10.1001/jamaneurol.2022.1025
2. Cree BAC, Hollenbach JA, Bove R, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666. doi:10.1002/ana.25463
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