'Smoldering' Rimmed Lesions in MS Linked to Worse Outcomes

Nancy A. Melville

August 21, 2019

This MRI of a man in his late 50s with relapsing MS shows a rim lesion. (Credit: Reich lab, NIH/NINDS)

Prospective tracking of "smoldering" chronic active lesions with notable darkened rims in people with multiple sclerosis (MS), previously only detectable upon autopsy, suggests the lesions are linked to greater and earlier disability and more progressive disease regardless of treatment with current therapies.

Daniel S. Reich, MD, PhD

The study adds significantly to previous findings from the research team linking the distinctive rimmed lesions to older patients, senior author Daniel S. Reich, MD, PhD, of the NIH's National Institute of Neurological Disorders and Stroke (NINDS), in Bethesda, Maryland, told Medscape Medical News.

The previous study "showed that rim plaques are more likely to form in older people, and the new paper says that those plaques are associated with worse clinical outcome, on average," Reich said.

"We usually think that younger people have more active disease, but these two studies together suggest that just because someone is older, they should still be watched closely."

Martina Absinta, MD, PhD

Their findings were published online August 12 in JAMA Neurology. Martina Absinta, MD, PhD, the first author on the paper, is now at Johns Hopkins School of Medicine, Baltimore.

On a research level, the findings add to ever-increasing interest in rimmed lesions as a potential new target for therapies, Reich added.

"Although we unfortunately do not yet have any treatments that repair existing rim plaques, new clinical trials are starting to crop up — we currently have two of them at NIH — and it may be time for clinicians to talk to their patients about participating in those."

"We think this is the next frontier in MS therapeutics," he said.

Limitations in neuroimaging have previously meant that, while brain lesions could be detected for diagnosing MS, tracking their changes over time, particularly the lesions that become chronic and active, was difficult. However, evolving technologies such as 7 Tesla (7T) magnetic resonance imaging (MRI) are breaking those barriers.

For the new study, the researchers used 7T as well as 3T susceptibility-based MRI to evaluate 192 patients with confirmed MS at the NIH's Clinical Center. The patients, who were 50% female and 15% African American, were enrolled beginning in January 2012 and evaluated until March 2018.

The results showed that of the patients, 117 (56%) had at least one chronic active rimmed lesion, regardless of their clinical phenotype or whether they were being treated with disease-modifying therapies, including natalizumab and ocrelizumab.

Specifically, 66 (32%) patients had one to three rimmed lesions (mean age, 47), and 42 (20%) had four or more rimmed lesions (mean age, 44), while 84 (40%) patients had no rimmed lesions (mean age, 47).

The results further showed that those with four or more rimmed lesions had motor and cognitive disability at an earlier age; they had lower levels of normalized volumes of brain, white matter, and basal ganglia; and they were 1.6 times more likely to be diagnosed with progressive MS compared with those without rimmed lesions (P = .03).

In a subset analysis taking a retrospective look at MRIs of 23 patients who had been scanned annually for 10 years, rimless lesions showed reductions in size over time (−3.6% per year), whereas the lesions with rims were either stable in size or expanded (2.2% per year; P < .001).

Using autopsied samples from a patient who died during the trial, the authors were further able to evaluate 10 rimmed lesions on histopathological analysis and found that all of the lesions that had expanded in vivo showed chronic activation.

"To our knowledge, the prospect of long-term in vivo monitoring makes it possible for the first time to determine [chronic active lesions'] contribution to disability and value as a treatment target," the authors write.

The findings show "patient-specific accrual of multiple chronic active lesions is a negative prognostic marker in MS."

Lesion Rim a Marker of Inflammation

The fact that rimmed lesion activity continued despite treatment was not necessarily a surprise as current therapies don't specifically target the mechanisms behind the lesions and their inflammation, they instead work by changing the immune system outside of the brain, Reich said.

"Inflammation in the rim plaques is associated with microglia, . . . and these are not affected by our existing therapies, or any effect of those therapies is at most very small," he explained.

Previous studies have meanwhile shown microglia/macrophage-mediated inflammation to represent key barriers for remyelination in MS.

"This is why new approaches and new treatment trials are needed, and why we think that combination therapy — attacking multiple different disease mechanisms — will be the wave of the future," Reich said.

The distinctive rim around the chronic active lesions is specifically caused by iron inside the microglia or macrophages, which is captured on MRI, Reich noted. Therefore, the distinctive ring can represent a small but important indicator of treatment efficacy as therapies evolve to address inflammation.

"We are hoping that this rim marker can be used not just to identify the plaques but also to gauge whether treatments we might try in the future are successful: If the rim marker goes away, then maybe the bad inflammation has subsided," he said.

As interest in inflammation and the potential negative role of microglia extends to other neurodegenerative diseases, including Alzheimer's disease, Parkinson's, and even stroke, insights into its role in MS carry heavy weight, Reich said.

"Scientists are realizing that there is substantial inflammation in all of these diseases, and that microglia, which normally are there to defend the brain from infection and injury, may be playing a negative role," he said.

"We're hoping that this convergence will spur development of new treatment approaches, and we think that early testing of new medications might be most easily done in MS because we have good imaging measures, such as the rim plaques."

In addition to the exploration of potential therapies, key research questions that also need to be addressed include why some people develop chronic active lesions in the first place, while others do not, and the previous findings from Reich's team that already offer some clues of an increased risk with older age at the time of lesion formation.

Instructions for Imaging Rimmed Lesions

Of note, while the NIH researchers were able to utilize high-powered MRI devices, Reich's team published instructions in 2018 in the American Journal of Neuroradiology for the use of lower-powered, high-resolution 3T MRI scanners to detect chronic active rim lesions.

"It's not too difficult," Reich said. "We used a particular approach that we developed in our lab, and this is available on a growing number of scanners — but there are similar techniques that may also be effective."

Commenting on the research, Daniel M. Harrison, MD, of the Department of Neurology, University of Maryland School of Medicine in Baltimore, noted that an important caveat is that patients with more total lesions, and by proxy, more rimmed lesions, can be expected to have greater disability.

"Thus, it is not clear that the relationship between the number of rimmed lesions seen in this study is truly an independent causative relationship, or is just yet another marker for overall how much MS has affected this patient in all ways," Harrison told Medscape Medical News.

While the findings make an important contribution to the literature on the link between the rimmed lesions and more aggressive disease, the clinical implications have yet to be determined, he added.

"So far all the data from this and other studies has been purely observational," Harrison said.

"There have been no studies as of yet to show if the development of this lesion type can be prevented or, once developed, can be reversed. Also, no studies have shown if making treatment decisions based on the presence/absence of this lesion type is appropriate or can be impactful," he said.

"Future work will need to address these questions before we can integrate measurement of this lesion type into the clinic. The first step in this will be to evaluate such measurements in the setting of a clinical trial of MS treatments."

Among key questions that will need to be tackled is the very nature and definition of the rimmed lesions, Harrison noted.

"Although the figures shown in the paper show very clear, distinct rims around lesions, in reality, there is no current, standard definition as to what constitutes a rimmed lesion," he said.

"Adjudication as to whether or not a lesion has a rim can be subjective, and without a common definition, comparison between studies will be difficult."

Support for this study was provided by the Intramural Research Program of NINDS, the National Multiple Sclerosis Society, and the Conrad N. Hilton Foundation. Reich reported a collaborative research and development agreement with Vertex Pharmaceuticals and patents issued for "Method of analyzing multi-sequence MRI data for analyzing brain abnormalities in a subject" and "System and method of automatically detecting tissue abnormalities." Harrison receives research funding from the NIH, the National MS Society, Genentech, and EMD-Serono; consultation honoraria from Genentech, EMD-Serono, Biogen, and Sanofi-Genzyme; and royalties from Up to Date Inc.

JAMA Neurol. Published August 12, 2019. Abstract

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