Understanding MS Disease Worsening and Progression

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The MD Magazine Peer Exchange “Strategies in the Management of Relapsing-Remitting Multiple Sclerosis” features a panel of physician experts discussing the importance of early therapy in multiple sclerosis treatment, factors that affect choice of management strategy, the need for ongoing monitoring, and other aspects of treating patients with multiple sclerosis.

This Peer Exchange is moderated by Fred D. Lublin, MD, FAAN, FANA, Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Icahn School of Medicine at Mount Sinai, New York.

The panelists are:

• Patricia K. Coyle, MD, professor and vice chair (Clinical Affairs) and director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, New York
• Clyde E. Markowitz, MD, associate professor of neurology and director of the Multiple Sclerosis Comprehensive Care Center at Perelman School of Medicine, University of Pennsylvania, Philadelphia,
• Claire S. Riley, MD, assistant professor of neurology and director of the Columbia University Multiple Sclerosis Clinical Care and Research Center, Department of Neurology, Columbia University, New York

Dr. Markowitz noted that many of the current MS management strategies and therapeutics have focused on T-cells. “We’ve been fairly good in controlling disease activity, at least from the relapsing inflammatory phase. But then, maybe about a decade ago, we started asking the question, ‘Could antibodies be involved?’” he said.

As more has been learned about NMO (neuromyelitis optica) antibodies, researchers are focusing more on B-cells and whether or not they play a role in MS. “I think the most recent clinical trials with the monoclonal antibodies generated toward the B-cells have really changed our understanding of this disease—knowing that these B-cells, if you deplete them or block them, can actually modulate disease activity equally or maybe even better than some of the T-cell approaches,” Markowitz said.

He said that when we look at MS as a disease, we can’t put it into the category of either a T-cell or B-cell mediated process. “It’s a combination of both, and now we’re able to take an approach which may hit both arms, or be selective toward B-cells, or be selective toward T-cells. But I think it really changes our understanding of this disease.”

Dr. Coyle pointed out that although we know MS is an immune-mediated disease, we should not forget about the genetic component and the environmental component in understanding this disease.

“We’re close to identifying all of the associated risk susceptibility genes, which are ultimately going to give us very important insight. We’re learning that environmental factors like vitamin D deficiency, smoking, adolescent obesity, Epstein-Barr virus infection, particularly clinical infection, increase the risk of developing MS,” Coyle said.

Dr. Lublin asked the group, “Does inflammation beget degeneration? Does degeneration beget inflammation? Are they separate processes?”

“It’s interesting that even in our earliest cases, CIS (clinically isolated syndrome) for example, you can see loss of volume in deep nuclei where there are not necessarily active inflammatory plaques, thalamic atrophy, and things like that early on. My suspicion is that there’s probably degeneration from the beginning—that it’s not just a latter phase of the disease,” said Dr. Riley.

Dr. Markowitz responded, saying, “There’s good data that cytokines can cause a variety of injury to oligodendrocytes, and you have loss of volume on that basis. So, it could be driven by the immune response. There’s also a possibility that maybe some of that neurodegeneration that’s occurring generates a secondary immune response as kind of the cleanup. And then in the cleanup processes, maybe it causes some additional damage.”

According to Dr. Coyle, the important observation is that the data that supports neurodegeneration is present from the very onset, but the clinical expression of that neurodegeneration, meaning gradual worsening progressive, is not seen until mid-life.

“But there’s also inflammation throughout the entire process of MS—the focal inflammation of the relaxing phase and the diffuse inflammation of the progressive phase. We have preliminary data showing that anti-inflammatory agents do affect neurodegeneration favorably, at least early in the disease process. The hope is we will be able to prevent transition to secondary progressive MS by using anti-inflammatory agents early. And, of course, if we could get neurodegenerative agents with progressive MS, that would be wonderful,” she said.