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Rim lesions in MS are common, prognostic, and potential treatment targets

credit: Scott Camazine/Science Source

BY JAKE REMALY

Chronic active lesions in patients with multiple sclerosis (MS) are common, predict more aggressive disease, and occur despite disease-modifying therapy, according to a study of about 200 patients with MS.


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While some MS lesions remyelinate or are inactive after an acute demyelinating event, chronic active lesions – also known as slowly expanding lesions or smoldering lesions – accumulate microglia or macrophages at the lesion edge, subtly open the blood-brain barrier, fail to repair, and result in axonal loss, the study authors said.

Dark-rimmed spots that represent ongoing, smoldering inflammation may be a hallmark of more disabling forms of multiple sclerosis.

Credit: Reich lab, NIH/NINDS

At first, researchers could study chronic active lesions at autopsy only. Then, investigators found they could detect chronic active lesions in vivo using 7-T and 3-T susceptibility-based MRI. The lesions appear as non–gadolinium-enhancing lesions with a paramagnetic rim. Prior studies of these rim lesions have had limited follow-up, however.

“We found that it is possible to use brain scans to detect which patients are highly susceptible to the more aggressive forms of MS. The more chronic active lesions a patient has, the greater the chances they will experience this type of MS,” said Daniel S. Reich, MD, PhD, senior investigator at the National Institute of Neurological Disorders and Stroke and senior author of the study, which was published in JAMA Neurology.

“We hope these results will help test the effectiveness of new therapies for this form of MS and reduce the suffering patients experience.”

Dr. Daniel S. Reich

FLAIR images show numerous white matter MS lesions of which 2 are magnified (inset, red arrows). Phase imaging at 7T phase/GRE reveals a hypointense ring corresponding with one lesion on FLAIR. The other lesion is not visible on 7T GRE (inset, arrows).

Credit: Mehta V, Pei W, Yang G, Li S, Swamy E, et al. (2013) Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions. PLoS ONE 8(3): e57573. doi:10.1371/journal.pone.0057573. / CC BY 2.5

“Our results support the idea that chronic active lesions are very damaging to the brain,” said Dr. Reich and colleagues. “We need to attack these lesions as early as possible. The fact that these lesions are present in patients who are receiving anti-inflammatory drugs that quiet the body’s immune system also suggests that the field of MS research may want to focus on new treatments that target the brain’s unique immune system – especially a type of brain cell called microglia. At the NIH [National Institutes of Health], we are actively seeking patients who want to participate in studies like these,” Dr. Reich said in a news release.

Credit: GerryShaw/Creative Commons/CC BY-SA 3.0

A clinical and radiologic cohort

The cohort included 209 adults with MS, diagnosed according to the 2010 McDonald revised criteria, who had 7-T or 3-T susceptibility-based brain MRI results. Patients were enrolled during January 2012–March 2018. Half were women, and 15% were African American.

The researchers analyzed data from 192 patients after excluding 17 patients with motion-associated MRI artifacts. In all, 117 patients (56%) had at least one rim lesion regardless of prior or ongoing treatment, Further, 84 (44%) had no rim lesions, 66 (34%) had one to three rim lesions, and 42 (22%) had four or more rim lesions.

The prevalence of clinically progressive MS was 1.6-fold higher among patients with four or more chronic rim lesions, compared with patients with no rim lesions (43% vs. 27%). “Rim lesions were present in the setting of treatment with most currently available disease-modifying therapies, including natalizumab and ocrelizumab,” the researchers said. “Individuals with four or more rim lesions reached motor and cognitive disability at an earlier age. Normalized volumes of brain, white matter, and basal ganglia were lower in those with rim lesions.”

credit: Simon Fraser/ SPL /Science Source

The researchers also examined the evolution of rim and rimless lesions in a subset of 23 patients who had received yearly MRI scans for 10 or more years.

“Whereas rimless lesions shrank over time (−3.6%/year), rim lesions were stable in size or expanded (2.2%/year),” the authors said. “Rim lesions had longer T1 times, suggesting more tissue destruction, than rimless lesions. On histopathological analysis, all 10 rim lesions that expanded in vivo had chronic active inflammation.”

Negative prognostic marker and potential treatment target

“Our results point the way towards using specialized brain scans to predict who is at risk of developing progressive MS,” Dr. Reich said.

“Figuring out how to spot chronic active lesions was a big step. … It allowed us to then explore how MS lesions evolved and whether they played a role in progressive MS,” said Martina Absinta, MD, PhD, the study’s first author.

The data indicate that “inflammation in chronic active plaques is a prominent feature of MS,” Dr. Absinta and colleagues wrote. Next, clinical trials may incorporate chronic active lesions as an outcome measure and assess whether treatments can reduce perilesional chronic inflammation. “Such trials will probably require treatments distinct from those currently used to limit MS relapses,” the authors said.

The research was supported by the intramural research program at the National Institute of Neurological Disorders and Stroke, the National Multiple Sclerosis Society, and the Conrad N. Hilton Foundation. Dr. Reich reported a collaborative research and development agreement with Vertex Pharmaceuticals and patents related to analyzing MRI data.

SOURCE: Absinta M et al. JAMA Neurol. 2019 Aug 12. doi: 10.1001/jamaneurol.2019.2399

Dr. Martina Absinta