Pioneer in Defining Multiple Sclerosis Phenotypes Looks to Refine Definitions for a New Era

Fred Lublin, MD

The expert who helped define the MS clinical course and its stages (relapsing remitting, secondary progressive, etc) is helping lead the charge to redefine MS phenotypes, to better reflect what is now known about the disease.

In his Presidential Lecture at the Consortium of Multiple Sclerosis Centers (CMSC) 2024 annual meeting, neuroimmunologist Fred Lublin, MD, reflected back over the 30 years since MS first became treatable. “This was a seminal event in all of neurology, because it stamped MS as the leader in the burgeoning field of neurotherapeutics," said Lublin, who is the Saunders Family Professor of Neurology at the Icahn School of Medicine at Mount Sinai and Director of the Corinne Goldsmith Dickinson Center for MS in New York City. Although the treatment landscape now includes over 20 disease modifying therapies (DMTs) employing multiple mechanisms, they do not address the biggest challenge still on the horizon: the treatment of neurodegeneration that occurs independent of inflammatory activity.

It’s About Time—How Time Factors Into Phenotypic Designations

Lublin, along with colleague Stephen Reingold, are known for their seminal 1996 paper that described MS phenotypes. The 2013 update distinguished between progressive disease with or without of inflammatory activity. This concept of “active” MS was adopted by regulators for DMT labeling, but in a manner that is flawed, Lublin suggested, because it left out the critical element of time.

“By definition, all cases of relapsing or secondary progressive MS were active at some point. So without a specific time point, this terminology has no value,” he said. Defining that time point, such as inflammatory activity within the past year, is a more useful concept.

Similarly, the term NEDA, for “no evidence of disease activity,” has fallen out of favor recently, essentially replaced by 2 more specific terms, “relapse-associated worsening” (RAW) and “progression independent of relapse activity” (PIRA). All MS disability derives from one of these two processes, Lublin said, but there is still work to be done on defining the terms. He cited a recent paper that shows that these concepts change based on how stringently an MS relapse is defined, and as such the semantics can influence the way RAW and PIRA are reported in clinical trials.

Is All MS Progressive?

Speaking of semantics, the “all MS is progressive MS” is a theory floating around that Lublin would like to shoot down. “I very strongly object to that idea, based on how we currently define progression,” he stated. In his patient population followed over up to 45 years, Lublin described a subset who are still doing well clinically after many decades with MS. “I don't think that progression is inexorable in every patient,” he said. Finding genetic markers of disease severity is an important research goal, he noted.

Lublin also objects to labeling patients as having “progressive MS” because of the stigma it carries. “What a terrible message to give to our patients,” he remarked. Patients dislike this label, he added, because of the finality implied. “It suggests that you can’t go back.” A newer way of looking at the MS clinical course is with a dynamic approach that includes phases such as relapsing and progressive, but also stable, repair, inflammatory (adaptive and innate), and degenerative.

How we determine what’s happening pathologically in these phases will depend on newer scientific advances on the horizon, Lublin predicted. This new paradigm will include biologically based phenotyping using advanced MRI methods such as central vein sign (CVS) and paramagnetic rim lesions (PRL), fluid biomarkers such as neurofilaments (NfL) and glial fibrillary acidic protein (GFAP), along with genetic information.