#ACTRIMS2021 – Benign Versus Aggressive MS – the Hunt for Clues

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by Forest Ray PhD |

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While researchers make progress in pinpointing markers of disease progression in multiple sclerosis (MS), identifying those that signal a benign MS disease course remains a significant challenge.

MS progression can vary widely between individuals, with some patients never acquiring significant disabilities — a condition often called benign MS — and others losing their ability to perform everyday living activities, which is referred to as aggressive MS. Knowing how to predict a person’s MS course is critical to quality care, as different therapeutic strategies will best benefit those most likely to do worse versus those most likely to do well.

Scientists often look to a person’s genes to try to explain individual MS behavior. But Mark Freedman, MD, a professor of neurology at the University of Ottawa, in Canada, suspects that other factors play a larger role.

“If nature really is the case and everything is in the genes, then the genes would define the course of the disease,” he said in a presentation titled “Benign and Aggressive MS – Nature or Nurture?” The talk was given online at the virtual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021, held Feb. 25-27.

Freedman pointed to studies involving twins, and families more generally, as one example in which genetics seems to play second fiddle in MS progression.

Identical twins show higher probabilities of sharing the same disease features, but their correlations are not perfect — indeed, just 30-50% — despite their identical genetic backgrounds.

Similarly, MS can affect multiple members of the same family, arguing for a genetic component, but as Freedman noted, “some have a very benign course, some have a very malignant course, some have relapsing, and some have progressive. It’s all over the place, so clearly genetics can’t really be calling all the shots here.”

Bone marrow transplants also call into question the contribution of genes to MS progression. Such transplants essentially replace patients’ immune systems without altering their genetic makeup.

The neurologist highlighted 24 cases in which transplant recipients stopped having attacks/relapses after the procedure. Another study showed that brain atrophy in MS patients slowed to that of age-matched controls over five years post-procedure, he noted.

“So if it’s all genes,” Freedman asked, “wouldn’t they start to have disease activity again? Wouldn’t they start to progress again?”

So far, patients’ Expanded Disability Status Scale (EDSS) scores and the duration of their MS appear as the strongest predictors of a benign course. Of note, EDSS scores are commonly used in MS as a measure of disability.

A systematic review of studies on benign MS indicated that having only one relapse in the first five years of the disorder, and an EDSS of no more than two after five years and no more than three after 10 years provided the strongest evidence that a patient would develop benign MS.

“How much disability is already there, pretty well stands out in most of these studies as a good predictor of how you will do down the road,” Freedman said.

In a retrospective study of 175 benign MS patients, done at the Ottawa Hospital MS Clinic, Freedman and his colleagues monitored patients with EDSS of no more than three, and with 10 years of disease duration. At 20 years, they compared who still had benign MS and who no longer did.

At that time, they found that 34% of patients had progressed to an MS form that was no longer benign (more active disease). This ratio narrowed, however, depending on a participants’ starting EDSS score. Specifically, approximately 28.2% of patients with EDSS under two had progressed, as had about 18.4% of those with EDSS under one.

Therefore, Freedman emphasized that a definition of EDSS of three or less at 10 years “is certainly not a sensitive definition [for benign MS] and doesn’t really give you security that those patients will continue to be benign.”

“MS is not always captured by the EDSS score,” he added. “Even [among] patients who were so-called benign [in the retrospective study mentioned above], a significant number of them still had cognitive impairments, suffered from fatigue — sometimes fatigue so bad they couldn’t work, they couldn’t do their activities of daily living. And more than half suffered from depression.”

A larger German study of more than 31,000 patients came to a similar conclusion, but also evaluated patients’ ability to work. Even within this population, many people with EDSS less than one were unable to work.

The researchers behind that study recommended defining benign MS as an EDSS of one or less, the absence of any disability, and the ability to work after 15 years of disease duration.

Certain early attacks also appear to show a strong prognostic value in MS progression. Those that involve the pyramidal and cerebellar brain regions, or the bladder, for instance, tend to show lasting changes on patients’ EDSS.

“The attacks,” Freedman said, “leave you with residual disease that can contribute to the progression.”

The number of MRI lesions in a patient’s brain also correlates with progression. In one study, patients with 10 or more lesions were more likely to have an EDSS of six at 20 years of follow-up. Conversely, other research showed that developing no new brain or spinal cord lesions over three years from MS onset was associated with an overall risk of developing secondary progressive MS of 0.9% versus 53.1% in the event of a new lesion.

In the end, it still appears easier to predict aggressive MS than benign, Freedman noted. More disability early on, more severe attacks, and evidence from biomarkers such as MRI lesions and high serum neurofilament levels all help make this assessment.

So, “how do you define benign disease?” Freedman asked in the conclusion of his talk. “That’s the hard [question].”

For now, Freedman says: “the only way to know these patients are going to be benign is to follow them long term.”

Regarding the question of nature (genetics) versus nurture, he said that “nature may dictate to some degree susceptibility but not necessarily [disease] course.” Freedman believes that “maybe nature has some involvement but nurture probably is more important.”

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