Medicine & Research

The Next Chapter in MS Care

By David E. Jones, M.D.

Multiple sclerosis is the most common cause of nontraumatic disability in young adults in the United States today. It can lead to significant physical, cognitive, and emotional impairment. MS is known to affect both the covering of nerves (myelin) as well as the nerves (axons) themselves in the brain and the spinal cord, and it is now known that this damage is mediated by both inflammatory and degenerative processes. It is suspected that MS occurs when a genetically susceptible person is exposed to an environmental trigger.

There is a tremendous amount of ongoing research relating to MS, and significant strides are being made in the areas of diagnosis and management of this disease. Evidence of this was seen at the recent joint European and Americas Consortium for Treatment and Research in MS (ECTRIMS / ACTRIMS), at which there were more than 7,000 participants and 1,000 scientific presentations.

Diagnosing MS

Today: Currently, the diagnosis of MS is a clinical one, as there is not a diagnostic test to verify or exclude the diagnosis. This can be frustrating for people in whom the diagnosis is initially ambiguous. Classically, a diagnosis of MS is made based on clinical attacks disseminated in time and space, with the caveat that an alternative explanation for the neurological symptoms is not found. MRI is often supportive of the diagnosis, and the McDonald criteria (last revised in 2010) allow the diagnosis to be made in a person who has had one clinical attack and MRI findings suggestive of MS. Supporting tests may include a spinal tap or visual evoked potentials.

One of the challenges with making a diagnosis of MS is the heterogeneity (diverseness) of the disease. This is obvious at several different levels: symptomatically, people have a wide variety of symptoms. Clinically, some have a very aggressive disease, while others seemingly have a benign course. Radiographically, there is a relatively poor correlation between an individual’s level of disability and the burden of disease on their MRI, although a high burden of MRI disease (or a follow-up MRI with new disease activity) is fairly predictive of eventual disability. Mechanistically, some people have a more inflammatory (relapsing) disease, while others may exhibit more of a degenerative (progressive) process. Researchers have described four different pathological subtypes of MS, and there is evolving data about different immunological subtypes of MS as well.

The Future: Given this, it will be  difficult to develop a single diagnostic test for MS, although certain signals (biomarkers) may be developed that will improve our diagnostic accuracy and perhaps improve our ability to predict the course of the disease. These should also help speed up diagnosis in some people, as it seems clear that earlier treatment leads to better outcomes. There may also be reasonable biomarkers (such as IL-17) for identifying MS relapses and for predicting treatment response. Another biomarker (CXCL13) may herald the transition from relapsing to secondary-progressive MS (SPMS).

Although the risk of a parent passing on MS to a child is relatively low (3 to 4 percent if one parent is affected, 10 percent if both parents are affected), there has been a large amount of research over the last decade in the realm of MS genetics. More than 50 genes associated with the risk of MS have been identified. In addition to potentially increasing our ability to predict disease and perhaps disease severity, these genes may give us new insights into the mechanisms of MS, which may lead to new therapies for the disease. Possible environmental risk factors for MS include exposure to certain viruses (including the Epstein-Barr virus), and there is ample evidence that vitamin D deficiency also plays a role in MS.

Treating MS

Today: There are eight FDA-approved disease-modifying therapies for relapsing MS, although four of these are in the same class (interferons). The drugs that are typically used first-line (Avonex®, Betaseron®, Copaxone®, Extavia®, Rebif®) have modest efficacy but good safety profiles; unfortunately, these medications are injectable. Novantrone is an IV chemotherapeutic agent with seemingly good efficacy, but its use has been limited by issues with cardiotoxicity and leukemia. Tysabri®, a monthly IV infusion, offers strong efficacy, but the risk of a viral infection of the brain (PML) limits its use somewhat. Gilenya® is the first oral disease modifying therapy approved for MS; however; its use requires significant monitoring, and its long term safety is not yet completely defined.

The Future: In the past year, there has been positive Phase III data presented for four possible new disease-modifying therapies for MS, and there are several agents that are in the midst of Phase III trials. Some of these (altemuzemab, rituximab/ocrelizumab) seem to raise the efficacy bar to new heights, while others (teriflunomide, daclizumab) offer good efficacy and safety. All of the aforementioned disease-modifying therapies seem to exert their effect by tempering the immune response, but some newer oral medications (BG12 and laquinimod) purport to limit degeneration and may be neuro-protective as well.

Choosing a therapy is often guided by experience (although an appropriate risk/ benefit analysis should be undertaken), and subsequently, the response to therapy is assessed. Given the aforementioned disease heterogeneity, people often have breakthrough disease on the chosen agent, necessitating a treatment change. In fact, every medication switch trial that has ever been done has been positive. Having to switch treatments because of suboptimal response is not only inconvenient, but it also may result in unnecessary loss of brain tissue or irreversible disability. MS clinicians sometimes initially chose a second-line therapy based on certain patient characteristics, including severe, multifocal attack, lack of recovery after an early relapse, or a high burden of disease on MRI at diagnosis.

There is already some data to suggest that we will have prospective biomarkers that will allow physicians to make better treatment decisions by more accurately predicting the appropriate therapy for the appropriate person at the appropriate time. One of the big questions is whether an anti-inflammatory or a neuro-protective agent (or both) is more appropriate. One of the other big pending research questions is whether a combination of two safer drugs will offer the efficacy of one of the more powerful but relatively less safe drugs.

Hopefully, there will be progress in the realm of CNS repair, which may offer hope of reversing disability. There is a molecule early in development that seems to inhibit a signal that halts brain development; conceptually, this will be a huge advance for people with SPMS, but certainly previous attempts to develop treatments for SPMS have not been successful. There is a lot of excitement about stem cells. Although the research in this area is still very early, there seems to be potential to reduce the inflammatory attack, protect cells against degeneration, and perhaps induce remyelination. 

Delivering MS Care

Today: Care of a person with MS does not end after choosing a disease-modifying agent; for many, that is just the beginning. Symptomatic management is also very important in MS care, and it often requires a multiple-disciplinary team to deliver. This team often includes nurses; physical, occupational, and speech therapists; psychologists and psychiatrists; urologists; ophthalmologists; and physiatrists (physical medicine and rehab physicians). There is now good data that appropriate exercise is beneficial for MS, and some people can achieve huge advances in function with the assistance of a qualified rehabilitation team and appropriate assistive devices.

The Future: One of the huge questions going forward is how health care reform will affect the care of the person with MS. The economics of health care and its demand for increased clinician productivity is directly at odds with the increasing complexity of both the risk/benefit analysis of the disease-modifying therapies and the coordination of an integrated rehabilitation effort. Frustration regarding the excessive cost of the disease-modifying therapies needs to be tempered with the realization that much of the research in MS is being funded by the pharmaceutical industry. These costs, however, may relate to the rapid growth in the number of obstacles to quality care that have been recently implemented by the insurance industry. In this climate, fewer new physicians are specializing in MS, even though the demand for MS specialists is higher than ever. Thankfully, the efforts of individuals and organizations with ties to MS are battling these trends, and allowing the aforementioned progress in the diagnostic, therapeutic, and rehabilitation realms to continue.

David E. Jones M.D., is a neurologist and MS specialist at the Lehigh Valley Physician Group in Allentown, Penn. He is a Graduate of Stetson University and The University of Massachusetts Memorial Medical Center. Member of American Board of Psychiatry & Neurology, and the MSF’s Medical Advisory Board.

(Reviewed 3/2012)