Chronic, Active Lesions Tied to More Aggressive MS

Chronic active lesions -- dark-rimmed spots indicating ongoing, smoldering inflammation on 3T or 7T MRI susceptibility sequences -- were common in multiple sclerosis (MS) and tied to disability accumulation, a prospective study showed.

Chronic lesions with a paramagnetic rim were associated with more aggressive disease and ongoing tissue damage and occurred even in MS patients treated with effective disease-modifying therapies, reported Daniel Reich, MD, PhD, of the NIH National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, and colleagues.

Until recently, these lesions could be detected only at autopsy, they stated in JAMA Neurology.

"In MS, the standard of care is to follow patients with MRI scans and to treat active inflammation," Reich said. "In this new work, we show that MRI can also detect and evaluate chronic smoldering inflammation which involves microglial cells -- the so-called 'police force' of the brain."

"This type of inflammation is relevant to accumulation of disability that is not strongly affected by current approved treatments for MS," Reich told MedPage Today.

"We found that smoldering plaques are more common in people with progressive MS, and that they can enlarge slowly over time while other plaques shrink," he added. Moreover, a histopathological analysis of tissue from a patient who died during the study showed that all rimmed lesions that had expanded in vivo had chronic active inflammation.

The findings provide "further validation of the utility of a new method of looking at MRI multiple sclerosis lesions by examining whether they have paramagnetic rims using a specialized acquisition sequence," noted Peter Calabresi, MD, of Johns Hopkins Medicine in Baltimore, who was not involved in the study. "This study convincingly shows that lesions with rims persist in a chronic active inflammatory state and are associated with degenerative features pathologically."

"This seminal research will allow pathological characterization of MS lesions in vivo, which has prognostic and monitoring value for clinicians and can be used by researchers to facilitate our understanding of disease pathogenesis," Calabresi told MedPage Today. "Assessment of rim lesions could be used to test the efficacy of therapies that target chronic active inflammation in the brain and not just peripheral immune cells, as is presently the case with available therapies for MS."

In the study, Reich and colleagues looked at 3T or 7T MRI results of 192 MS patients enrolled in a trial at the NIH Clinical Center from 2012 to 2018. Overall, 56% of patients had at least one chronic lesion with a paramagnetic rim: 44% had only rimless lesions, 34% had one to three rimmed lesions, and 22% had four or more rimmed lesions.

Clinically progressive MS was diagnosed 1.6 times more often in patients who had four or more chronic rimmed lesions than in patients with rimless lesions (P=0.03). Rimmed lesions occurred even in patients using the most currently available disease-modifying therapies, including natalizumab (Tysabri) and ocrelizumab (Ocrevus).

On average, patients with four or more chronic rimmed lesions reached motor and cognitive disability at a younger age than those with no rimmed lesions. They also had less white matter and smaller basal ganglia.

In a subset of 23 patients who had yearly MRI scans for 10 years or longer, rimless lesions shrank over time (-3.6% per year), but rimmed lesions were stable in size or expanded (2.2% per year, P<0.001). Rimmed lesions also had longer T1 times, suggesting more tissue destruction, Reich and colleagues noted.

Comparing scans to 10 lesions (five frontal, three parietal, two occipital) from brain tissue samples autopsied from a patient who had died during the trial, the researchers found that all 10 rimmed lesions that had expanded in vivo had chronic active inflammation.

The research had several limitations, the authors noted: it was subject to referral, recruitment, and enrollment biases and the findings may be influenced by the relatively small number of lesions in the study.

"The next step in our work is to look for specific biological mechanisms that may underlie the inflammation in smoldering plaques and to find treatments to suppress it," Reich said. "Identifying people who have smoldering plaques is just the first step in thinking about how to design new studies to test new types of drugs."

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