NeuroVoices: Fred Lublin, MD, on Shifting From Phenotypes to Spectrum-Based Perspectives to Advance Multiple Sclerosis Care

Fred Lublin, MD

(Credit: LinkedIn)

Current phenotyping in multiple sclerosis (MS) has largely focused on clinical classifications, such as relapsing-remitting, secondary progressive, and primary progressive forms, based on the patient’s presentation of the disease. While this approach is useful, it has limitations, as it fails to fully capture the complexity and heterogeneity of MS. As a result, there is growing interest in transitioning to biological phenotyping, which seeks to better understand the underlying mechanisms of the disease and refine diagnostic accuracy. Aligned with this shift, the recent 2024 McDonald diagnostic criteria for MS are evolving to incorporate biologically-driven metrics.

Updates to the criteria, shared at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, September 18-20, in Copenhagen, Denmark, allow for earlier diagnoses, including the identification of radiologically isolated syndrome (RIS), and introduce advanced MRI techniques, such as the central vein sign (CVS) and paramagnetic rim signs (PRLs). These developments reflect the increasing recognition of MS as a spectrum, underscoring the need for more precise and individualized diagnostic approaches. Furthermore, this progression in diagnostic techniques may pave the way for more targeted treatments, such as Bruton’s tyrosine kinase (BTK) inhibitors, which hold promise for managing progressive forms of MS and may play a crucial role in future therapeutic strategies.

At the Congress, Fred Lublin, MD, director of the Corinne Goldsmith Dickinson Center for MS and the Saunders Family Professor of Neurology at The Icahn School of Medicine at Mount Sinai, participated as a speaker in a scientific session on new phenotypes in MS. In a new iteration of NeuroVoices, Lublin discussed how emerging biomarkers and advanced imaging techniques, such as CVS and PRLs, have refined the understanding of the MS spectrum. He also talked about what educational strategies can be implemented to ensure clinicians adopt and apply the new diagnostic criteria effectively. Furthermore, Lublin talked about how BTK inhibitors could reshape therapeutic strategies for progressive MS, and the improvements in trial design that are needed to maximize their potential.

NeurologyLive: How would you describe the current phenotyping in MS, and particularly how it relates to our understanding of MS?

Fred Lublin, MD: Modern phenotyping has been ongoing for the last 26 years. To date, it has been representative of what the patient presents with. It’s a clinical construct where a patient presents with either relapsing-remitting disease or progressive disease. Progressive disease can be categorized as either secondary progressive, following a relapsing-remitting phase, or primary progressive, where the disease is progressive from the onset. We’ve also added concepts like clinically isolated syndrome, which refers to the first attack, and radiologically isolated syndrome RIS, where an MRI shows features suggestive of MS without a clinical attack. The main issue has been that these are all clinical constructs based on what the patient presents with at the time. However, the goal has been to achieve biological phenotyping, and while we are not there yet, we are making progress.

What I discussed [in my presentation] was a shift in how we approach MS, moving away from categorical classifications to viewing the disease as a spectrum. This perspective sees MS as a continuum where patients can move bidirectionally along the spectrum. For instance, a patient might experience a relapsing phase, a stable phase, and a progressive phase. The progressive phase can include periods of progression independent of relapse activity, which is essentially progressive disease under a different name. The challenge is to address these individual phases from a therapeutic perspective while educating both our colleagues and the patient community. Ultimately, the aim is to achieve fully biological characterizations, incorporating genetic background, underlying pathology discerned through advanced MRI metrics, and biomarkers. This is our goal for the near future.

Have there been any notable steps or progress in understanding the MS spectrum?

Several exciting advancements are aiding this effort. One is the development of advanced MRI techniques, such as identifying slowly expanding lesions and paramagnetic phase lesions. Another is immunophenotyping. Two particularly exciting breakthroughs include immunophenotyping within an MS population and identifying antibody signatures in patients at risk of developing MS before clinical onset. These innovations will guide us in better defining the underlying biology of MS. It’s one disease along a spectrum, and our task is to determine where each individual patient lies on that spectrum.

How has this shift in understanding influenced the way we approach treatment, whether by initiating high-efficacy therapies early or considering potential treatment switches?

Historically, MS classification was more rigid. For example, once a patient was deemed secondary progressive, that classification was fixed. While this remains technically true, it doesn’t capture the nuances of the clinical course. With a more dynamic, bidirectional approach, a patient in a progressive phase could stabilize and potentially develop relapses, moving back into a relapsing phase. This dynamic perspective better reflects the reality of the disease course.

What are your thoughts on the new changes to the diagnostic criteria for MS and what do you anticipate the downstream effects might be?

The new diagnostic guidelines are more comprehensive and complex. They allow for earlier diagnoses and represent the most significant changes since the McDonald criteria were introduced in 2000. These guidelines are more inclusive, enabling the diagnosis of MS in patients with RIS who have never had a clinical event. They also incorporate advanced techniques, such as CVS and PRL, though these are not mandatory. Clinicians can still rely on traditional clinical assessments. These updates change how we determine dissemination in space and diagnose primary progressive MS, necessitating extensive education for the medical community.

The challenges ahead include publication and dissemination of these guidelines, supported by robust educational programs. For over 30 years, we’ve been providing educational resources, and while this will be a test, it’s a challenge we have faced before.

What are your thoughts about BTKs inhibitors? Are you optimistic about them as a class therapeutic?

Regarding BTK inhibitors, the setbacks are not due to the inhibitors themselves but the design of clinical trials. Trials are structured to meet current needs until they no longer suffice. Now, we must rethink trial designs for relapsing disease. More importantly, we have a new opportunity in progressive disease. This opening allows us to refine our methods and improve how we assess and address progressive MS moving forward.

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