Proposed Multiple Sclerosis Subtypes Could Benefit Patients, Researchers

by U.S. Medicine

March 5, 2016

VA Could Help Validate New Classifications

By Annette M. Boyle


The proposed categories “provide a sensible way forward for classifying patients and potentially for treating them, but it’s still something that has not been not adopted across the board.” Walter Royal, III, MD, associate director of research for the VA Multiple Sclerosis Center of Excellence-East and director of the Maryland Center for Multiple Sclerosis Treatment and Research.

BALTIMORE — Sometimes consensus sounds like controversy. In 2014, the International Advisory Committee on Clinical Trials in Multiple Sclerosis recommended a revision to the four subtypes of the disease in use since 1996. Articles and researchers continue to debate whether the committee properly characterized the phenotypes — and how much it matters.

The proposed categories “provides a sensible way forward for classifying patients and potentially for treating them, but it’s still something that has not been not adopted across the board,” said Walter Royal, III, MD, associate director of research for the VA Multiple Sclerosis Center of Excellence-East and director of the Maryland Center for Multiple Sclerosis Treatment and Research.

In part, the classifications have not been adopted as part of routine clinical practice, because clinicians and researchers are not certain the distinctions make a difference in treatment or outcomes. “If one does a clinical trial and looks at response in subgroups and sees no difference in outcome, then it probably wouldn’t make sense to apply those categorizations for making treatment decisions,” Royal told U.S. Medicine.

On the other hand, both researchers and patients could benefit by expanding the number of patients who could participate in clinical trials for new MS drugs by eliminating distinctions that might have little basis in biology.

Multiple sclerosis is the most-common central nervous system disorder affecting young adults. An autoimmune disorder, it is characterized by inflammation, demyelination and degenerative changes. Symptoms include fatigue, impaired mobility, mood and cognitive changes, pain, visual disturbances and elimination dysfunction.

The VA can play an important role in helping to determine whether the proposed subgroups matter in terms of medication choice and outcomes, according to clinicians. For such a heterogeneous disease, robust clinical trials require a large number of patients that are diverse in geography and demographics such as age, gender and race.

“The VA is very well suited in that regard,” said W. Joel Culpepper, PhD, associate director of Epidemiology and Outcomes for the VA MS Center of Excellence-East and assistant professor at the University of Maryland School of Pharmacy in Baltimore. “We may have the largest MS cohort in North America as well as a long history and many contributions to the epidemiology and clinical understanding of MS.”

Since 1998, more than 30,000 veterans who receive care through the VA have been diagnosed with multiple sclerosis. About 17,000 are seen by the VA annually.1

The proposed classifications bear many similarities to the subtypes used for the past 20 years and reflect how many neurologists in the VA and elsewhere have classified patients and thought about treating them, according to Royal.

The 1996 consensus established four phenotypes, or clinical-course descriptions: relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) and progressive relapsing (PR). Using this schema, about 85% of patients initially experience relapses and remissions (RR) of various neurological symptoms, with the majority transitioning to a steady worsening over time with fewer relapses (secondary progression or SP). The remainder of patients have a steady progression of the disease from the onset (primary progression or PP), though some also have distinct periods of relapse (progressive/ relapsing or PR).

No clear clinical, imaging, immunologic, pathologic criteria exist to delineate between the four subtypes, leading the advisory group to consider them all part of the “spectrum of progressive MS phenotypes and that any differences are relative rather than absolute.”

The advisory group recommended retaining the relapsing and progressive disease phenotypes, with modifications that included disease activity detected by clinical relapse or imaging (gadolinium-enhancing lesions or new or clearly enlarging T2 lesions) as well as progression of disability.

Clinically-isolated syndrome (CIS) also was added. “CIS is now recognized as the first clinical presentation of a disease that shows characteristics of inflammatory demyelination that could be MS, but has yet to fulfill criteria of dissemination in time,” the advisory committee wrote.

Studies show that patients with CIS and brain lesions detected through magnetic resonance imaging (MRI) have a high risk for subsequently receiving a diagnosis of MS. Conversely, clinical trials of MS disease-modifying therapies demonstrate effectiveness in reducing the number of CIS patients who experience a second exacerbation, which would lead to a definitive diagnosis of MS.2

Looking at the phenotypes of MS as part of a continuum rather than as pathologically distinct has a potentially significant impact on medication choices and research. Nearly all the drugs currently approved by the Food and Drug Administration for treatment of MS were tested in and approved for the relapsing-remitting subtype.

The new classification “would potentially allow the use of immunomodulating therapies in progressive patients who have evidence of active disease,” said Christopher Bever, MD, MBA, director of Biomedical Laboratory Research & Development, and formerly director of the VA’s MS Center of Excellence-East. Currently, those drugs are now used primarily in relapsing/remitting patients.

In addition, seeing the various phenotypes as points in a spectrum could provide “a basis for including patients in clinical trials based disease activity,” Bever pointed out. Adoption of the proposed categories “will allow the testing of immunomodulatory therapies in some patient groups that were not included in testing in the past and ultimately provide evidence to support the use of immunomodulatory therapies in those patient groups.”

Some physicians maintain the advisory group should have gone even further, eliminating subtypes entirely. “MS subtypes should be replaced by MS stages (radiologically isolated syndrome through secondary progressive MS) or more simply MS with or without disease activity or with or without progression,” wrote Francois Jacques, director of Clinique Neuro-Outaouais in Gatineau, Quebec, Canada, in response to the article recommending the revised categories.3

Calling the proposed subtypes “arbitrary and often diagnosed retrospectively,” Jacques argued that MS “is a progressive disease from the onset and that inflammatory pathologic processes persist well into the progressive phases of the disease.”

1 Culpepper WJ, Wallin MT, Magder LS, Perencevich E, Royla W, Bradham DD, Cutter G, Bever CT. VHA Multiple Sclerosis Surveillance Registry and its similarities to other contemporary multiple sclerosis cohorts. JRRD. 2015;52(3):263-272.

2 Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86.

3 Jacques FH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2015 Mar 3;84(9):963.


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