Smoldering MS May Warrant Unique Strategies

Smoldering-associated worsening (SAW) of multiple sclerosis (MS) deserves a broader, more comprehensive approach to diagnosis, treatment, and research that goes beyond neurologists’ understanding of progression independent of relapse activity (PIRA), according to a recently published international consensus. However, an outside expert said that promulgating the “smoldering” concept may stoke patient and provider confusion.

Although current disease-modifying therapies (DMTs) for MS exclusively target focal white matter (WM) inflammation, wrote authors led by Antonio Scalfari, MD, PhD, of Charing Cross Hospital, Imperial College London, London, England, many people with MS experience worsening disability in a more indolent fashion — despite stable inflammatory markers.

“The gradual accumulation of physical and cognitive disability is driven by smoldering pathological processes via biological substrates, which are different from those of acute focal damage and remain an important unmet therapeutic target,” they wrote in Annals of Neurology.

The same research team first described smoldering MS in a 2022 Therapeutic Advances in Neurological Disorders publication. In the present paper, Scalfari and colleagues reviewed emerging clinical, radiological, and pathological evidence and presented 29 consensus statements in areas ranging from the definition, pathology, and clinical manifestations of smoldering MS to appropriate biomarkers and best clinical practices.

Definition

By definition, the authors wrote, SAW encompasses PIRA but also includes a range of gradually worsening, relapse-independent symptoms that remain undetectable on standard assessments, including the Expanded Disability Status Scale (EDSS) or EDSS-Plus, especially in early disease. To capture symptoms such as subtle motor impairment, cognitive slowing, and fatigue, Scalfari and colleagues recommend tools such as neurological stress tests, fatigue/mood scales, wearable devices, and patient reported outcomes.

Disease Mechanisms

Pathologically, the authors wrote, smoldering MS may stem from intrinsic central nervous system processes that likely incorporate various glial, immune, and neural cells. Smoldering MS also could contribute to aging, and vice versa, the latter possibly through dynamics such as age-related exhaustion of compensatory mechanisms, reduction in remyelination efficiency, and telomere shortening, they added.

Clinical Implementation

Current MS management rests on crude estimates of physical disability and overemphasizes identifying relapses and new MRI lesions as the principal markers of disease activity, wrote Scalfari and colleagues. Instead, they suggested combining motor-associated assessments such as EDSS-Plus with cognitive gauges such as the Brief International Cognitive Assessment for Multiple Sclerosis.

Providers are uncomfortable identifying and discussing smoldering MS, authors allowed, because no licensed treatments target SAW. However, the authors wrote, a principal reason for discussing smoldering MS with patients is to help manage their expectations of current DMTs, which may have little effect on SAW.

‘More Than Lesions’

Bruce Cree, MD, PhD, MAS, professor of neurology at the University of California, San Francisco, School of Medicine, said that it is extremely important to raise awareness of physicians’ emerging understanding that “there is more going on in MS than lesions and relapses,” a concept that has been a work-in-progress for several years. He was not involved with the study but was asked to comment.

A 2019 Annals of Neurology report on the EPIC cohort co-authored by Cree labeled the disconnect between disability accumulation and relapse occurrence “silent progression.” The observation that disability accumulates in early relapsing MS independent of relapsing activity has been replicated in virtually every dataset worldwide, he added.

“What I don’t like about this article is the reliance on the term ‘smoldering’ and the acceptance that this is an actual phenomenon supported by data.” And authors’ leveraging “smoldering” into additional acronyms such as SAW likely will confuse rather than clarify physicians’ and patients’ understanding of the situation, Cree added. “Clinicians don’t need yet another snappy acronym.” Many are still trying to grasp the PIRA concept in relapsing MS, he said.

“One of the reasons this topic has become so important is that we recognize that even when we have very good control of relapsing disease activity — clinical relapses as well as radiographic large lesion formation on MRI — some patients still develop insidious worsening of disability. And the reasons for that are not well understood,” said Cree.

Accumulating disability absent relapse activity could stem from any number of microscopic inflammatory processes, possibly involving abnormal microglial activation, fibrinogen deposition, microscopic inflammatory infiltrates of CD8-positive T cells, or mitochondrial damage from iron deposition, he said. Or the processes driving PIRA may not even involve inflammation, he added. “We still don’t have a unifying way of understanding how these processes work.”

Cree said he suspects that despite investigators’ good intentions, the study’s sponsor, Sanofi, may have influenced the resultant messaging. The company’s tolebrutinib recently completed phase 3 trials in secondary progressive MS and relapsing MS, and a phase 3 trial in primary progressive MS is scheduled for completion in 2025. “A hallmark of Sanofi’s messaging has been this idea that there is smoldering inflammation occurring in MS that tolebrutinib is going to address,” he said.

If clinicians really knew what drove progressive MS, said Cree, “we would be keen on developing therapies targeting that fundamental process. But because we don’t know what’s driving it, we don’t know what to go after.”

The study was supported by Sanofi. Cree is a co-author of the GEMINI 1 and GEMINI 2 tolebrutinib studies.

John Jesitus is a Denver-based freelance medical writer and editor.