Medicine & Research

The State of MS Research

By David E. Jones, M.D.

Multiple sclerosis is an inflammatory condition of the central nervous system that likely occurs when a genetically susceptible individual is exposed to an environmental trigger. Although it is not a very common disease (old estimates suggest 400,000 affected individuals in the United States), it is the most common cause of nontraumatic disability in young adults in the U.S. today. Given this, there are numerous groups that advocate for patients with MS, including MS Focus: the Multiple Sclerosis Foundation. There is also a tremendous amount of research effort being devoted to understanding and treating the disease; for example, more than 8,000 people recently attended the European Consortium for Treatment and Research in MS in Barcelona, Spain last fall. Most research is performed under fairly rigorous conditions, increasing the chances that what is learned is actually true and useful for patients with MS.
As it is difficult to treat what is not understood, much of the research is being aimed at increasing our understanding of MS. One of the big efforts is to identify risk factors for developing MS; the International MS Genetic Consortium has identified more than 150 genes that may increase the risk of MS; and work continues to identify potential environmental triggers. Besides continued evidence supporting the role of late exposure to the Epstein-Barr virus (the causative agent of mononucleosis) and vitamin D deficiency as environmental triggers for MS, recent work also suggests that a high-salt diet may be deleterious in animal models of MS. It also appears that the bacterial contents of the gut (microbiome) may differ in patients with MS compared with normal controls. All of these risk factors seem to relate to the function (or control) of the immune system. Although there is a lot of “buzz” on social media about the possibility of specific diets improving MS, there is very little data to support these claims, although it is interesting that dietary alterations can alter an individual’s microbiome.

There are currently 12 FDA-approved disease modifying treatments for relapsing forms of MS. The purpose of these medications is to reduce relapses, reduce new MRI activity, and thereby delay the progression of disability. The most recent addition to the therapeutic arsenal (Lemtrada) was shown to be superior to an injectable interferon (Rebif) and appears to have a durable effect after two courses of treatment, with a majority of patients in the clinical trials not requiring further treatment at five years. In the past year, exciting comparative data for two new disease-modifying treatments (daclizumab and ocrelizumab) have been released. Daclizumab is a monthly subcutaneous agent that may modulate the immune system by targeting CD25; of interest, a CD25 mutation was one of the first genetic abnormalities identified as a risk factor for MS. Ocrelizumab works by depleting several types of B-cells (involved with antibody-mediated immunity) and looks extremely effective in reducing MS activity.
It has long been recognized that there is an inflammatory component to MS, for which there are multiple disease-modifying treatments, as stated earlier. There is also a “degenerative” component to the disease that is demonstrable early, but probably dominates later in the course of the disease; however, the word “degenerative” probably overestimates our understanding of this phase of the disease. It is clear that MS affects both the insulation (myelin) of nerves as well as the wires (axons) of nerves. It is possible that the degeneration occurs when myelin is stripped from nerves, or it is possible that the remaining nerves wear out as they try to compensate for the nerves that have been damaged because of MS. Our lack of understanding of the degenerative component of the disease may explain our difficulty in finding effective treatments for progressive MS, although this is not due to a lack of effort.
The International Progressive MS Alliance has removed some of the political barriers to funding research in progressive MS and has helped foster cutting edge research regardless of where it is being done. A recently reported small trial of high-dose biotin supplementation suggested benefit for progressive MS, but further studies are needed to verify this effect. Although recent trials of Gilenya (for primary progressive MS) and Tysabri (for secondary progressive MS) did not meet their primary endpoints, it is exciting that the ORATORIO trial of ocrelizumab in primary progressive MS did meet its primary endpoint in a large Phase III trial. Trials of siponimod for secondary progressive MS and ibudilast for progressive MS are ongoing, so hopefully the recent positive momentum with progressive MS research continues.
Patients often ask why they feel worse when their MRI is reportedly stable. Advanced imaging techniques have demonstrated that conventional MRI does not tell the entire story. This knowledge may enable us to further explore the mechanisms and treatments for MS. Some techniques have allowed us to demonstrate that atrophy of specific parts of the brain occurs early and is often demonstrable at diagnosis; others are able to assess the integrity of the myelin around a nerve and show that what appears normal on conventional MRI is not necessarily normal. It is now clear that MS is a disease that affects the entire brain, including areas that are primarily the “wires” of nerves (white matter), and the cell bodies of nerves (gray matter). New PET scan techniques can highlight myelin and may be of value when attempting to demonstrate myelin repair (remyelination).
One of the largest unmet needs in MS is the ability to repair areas of previous damage and/or reverse disability. The Phase III trials for Lemtrada included an endpoint of sustained reduction in disability and were able to meet this endpoint, although the magnitude of the change was not large. Even more exciting is the possibility of remyelination: a compound (anti-LINGO) in development by Biogen showed evidence of remyelination in an early study of patients with optic neuritis, but the study of the same compound in patients with relapsing MS is still ongoing. Acorda Therapeutics also has a remyelinating agent in early development. Research involving the use of stem cells in MS continues, including work with bone marrow transplant (autologous hematopoietic stem cell transplantation) and mesenchymal stem cells; however, the role of these techniques still appears more anti-inflammatory and neuroprotective than restorative.
Another important aspect of MS care is managing patient symptoms and improving patient functionality. Research continues to try to understand and develop more effective mechanisms for treating fatigue, gait abnormalities, cognitive dysfunction, and other symptoms of MS. Although it may not get as much recognition in the mainstream media, advances in rehab technology represent another important cog of MS research. More and more data suggest that physical activity and exercise (in any form) is beneficial for MS, and wellness continues to be an important aspect of the management of chronic disease.
The field has come a long way since defining MS as a demyelinating disease that starts as an inflammatory process affecting the white matter of the brain, and it is truly remarkable how much has been accomplished since the approval of the first disease modifying therapy for MS in 1993. The future of MS research appears very bright, and this is great news for people affected by MS.
David E. Jones, M.D., is a fellowship-trained MS neurologist who works at the University of Virginia Health System and sees patients in the James Q. Miller MS Clinic. He is the chairman of the MS Section of the American Academy of Neurology and participates on the MS Coalition Emerging Therapies Collaborative. He serves on the Medical Advisory Board of the Multiple Sclerosis Foundation, the Healthcare Advisory Committee Council of the Multiple Sclerosis Association of America, and the Board of Directors of Can Do Multiple Sclerosis.