NeuroVoices: Antonio Scalfari, MD, PhD, on a Broader Perspective of Understanding Smoldering Disease in Multiple Sclerosis Progression

Previous research has revealed that the gradual progression of disability in multiple sclerosis (MS) is largely driven by underlying smoldering processes, which remains a therapeutic challenge, as noted by researchers. In a recent publication in Annals of Neurology, Antonio Scalfari, MD, PhD, and colleagues introduced the concept of smoldering-associated worsening (SAW) in MS, which encompasses both physical and cognitive symptoms.¹ This consensus-based framework outlined methods for identifying smoldering MS and proposed potential biomarkers to track SAW progression. The authors also emphasized the need to integrate smoldering MS into clinical practice and future research initiatives.

Several of those in the industry, including Sanofi, have culminated research on the drivers and mechanisms behind smoldering neuroinflammation in MS. Recently, the company stated that better understanding these pathways could pave the way for new strategies to detect and treat SAW, offering hope for improved patient care.² Sanofi also announced plans to present data from its phase 3 HERCULES study (NCT04411641) and other studies on tolebrutinib, an investigational Bruton Tyrosine kinase (BTK) inhibitor for relapsing MS, at the upcoming European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen, Demark, September 20, 2024.³

In a new iteration of NeuroVoices, Scalfari, a consultant neurologist at Imperial College Healthcare Trust and Northwest London Healthcare Trust, further discussed how the concept of smoldering disease redefines the understanding of progression in the field of MS. Scalfari, who also serves as an honorary senior clinical lecturer at Imperial College London, talked about the clinical implications of recognizing smoldering-associated worsening in patients with MS. Additionally, he spoke about how emerging treatments, such as BTK inhibitors, might address the unmet needs in managing smoldering MS.

NeurologyLive: For background, explain the concept of smoldering MS for those who may not be familiar with it. How does it differ from other more well-known forms of the disease?

Antonio Scalfari, MD, PhD: The idea of smoldering disease, or at least a smoldering component in MS, largely stems from the frustration of physicians who, for over the past 20 years, have been extensively using disease-modifying treatments. In most cases, we succeed in suppressing relapses and focal inflammatory lesions detected on MRI. Yet, a large proportion of these patients, despite therapeutic success in preventing any form of focal disease activity, continue to report disease progression or worsening. This reveals a discrepancy. On one hand, we’re effective at preventing focal inflammatory disease activity—whether symptomatic with relapses or asymptomatic, detected exclusively on MRI. On the other hand, this discrepancy suggests that other mechanisms, which are more subtle and harder to detect, may account for the disease’s worsening.

The first major breakthrough in this area came from trials of ocrelizumab ocrelizumab (Ocrevus; Roche). These trials highlighted that many patients, despite successfully suppressing relapses and MRI activity, were still experiencing motor deterioration. This was eventually labeled as progression independent of relapsing activity (PIRA). I think this was the starting point of the concept of smoldering MS, which is broader than PIRA. PIRA is a key component, but smoldering disease encompasses more than just progression independent of relapses.

However, the definition of PIRA has intrinsic limitations. It relies heavily on the Expanded Disability Status Scale (EDSS) plus the T25 walking test and the nine-hole peg test, all of which focus predominantly on motor performance. This focus tends to overlook worsening in other domains of the disease. After much discussion about PIRA’s limitations, we decided it was time to broaden the concept of progression in MS. Smoldering disease includes other symptoms not fully captured by PIRA, such as cognitive decline, fatigue, pain, bladder and bowel disturbances, and psychiatric conditions like depression. So, it’s a much broader concept than PIRA.

Our goal was to create a consensus among 15 experts in the field to properly frame the concept of smoldering disease. We coined the term "smoldering-associated worsening" to describe these various aspects of disease progression, which we believe are related more to smoldering disease activity than to focal inflammatory activity.

What impacts does this recently proposed concept have on clinical practice in diagnosing and managing smoldering MS?

It has had many practical implications. When we proposed the concept of smoldering-associated worsening, some critics asked, “What’s the point of highlighting this component if it can't be therapeutically addressed?” While we’ve become very effective at suppressing relapses and focal inflammatory activity, patients are still accumulating some disability, which is not sufficiently targeted by current disease-modifying treatments.

Our counter-argument is that we can’t remain stuck in the belief that the disease is exclusively driven by relapses and MRI-detected focal activity. Acknowledging the symptoms beyond focal inflammatory activity is the starting point for recognizing there is still unmet need in therapeutic management. Patients need to understand that while disease-modifying treatments are making the disease much less harmful, some aspects of MS progression remain unaddressed. Patients should proactively report symptoms beyond focal relapses, as this could guide future therapeutic targets and clinical endpoints to address these issues.

The smoldering-associated worsening concept also addresses patient frustration. It’s common for patients, and even clinicians, to feel like nothing more can be done once relapses are under control, yet patients still experience worsening. By acknowledging this element of disease progression, we can redefine therapeutic success. We may be succeeding in controlling certain aspects of the disease, but that doesn’t cover the full picture.

Another relevant implication is that the concept of smoldering MS calls into question the current clinical classification of MS into relapsing-remitting, secondary progressive, and primary progressive forms. It’s becoming clear that these distinctions are purely phenotypic and don’t reflect the underlying biology. Relapses and focal inflammatory activity coexist with the mechanisms driving smoldering disease, even in the early phases of relapsing-remitting MS. Over time, I believe we’ll move away from using terms like "secondary progressive MS" because the progressive element of the disease is present from the beginning, along with the relapsing component.

Is there anything else you’d like to say about how therapeutic targets for smoldering disease could shape the future of patient care?

In reaching a consensus on smoldering MS among 15 experts, we identified potential mechanisms that could be therapeutic targets in the future. We discussed biological mechanisms behind smoldering-associated worsening and focused on identifying potential markers—both radiological and clinical—that could be used to monitor smoldering disease activity.

Future efforts should concentrate on further confirming these observations. There’s already a lot of research looking at the role of slowly expanding lesions, cortical pathology, and radiological markers as potential endpoints in clinical trials aimed at addressing smoldering disease. A big area of focus now is on BTK inhibitors, which target microglia activity and the formation of slowly expanding lesions. This is an exciting field, and we’re eagerly awaiting the results of the BTK inhibitor trials, particularly those from Sanofi.

Transcript edited for clarity. Click here to view more NeuroVoices.

REFERENCES
1. Scalfari A, Traboulsee A, Oh J, et al. Smouldering-Associated Worsening in Multiple Sclerosis: An International Consensus Statement on Definition, Biology, Clinical Implications, and Future Directions. Ann Neurol. Published online July 25, 2024. doi:10.1002/ana.27034
2. Why Smoldering Neuroinflammation Must Be Part of the Discussion to Improve Care in Multiple Sclerosis. Sanofi. Published September 13, 2024. Accessed September 13, 2024. https://www.sanofi.com/en/magazine/your-health/smoldering-neuroinflammation-discussion-multiple-sclerosis
3. Press Release: Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. News release. Sanofi. September 2, 2024. Accessed September 3, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875