Research Developments for Multiple Sclerosis

The challenge concerning multiple sclerosis (MS) is not just understanding its cause. It also includes diagnosing the disease and understanding its progression and how patients respond to treatment.

MS is a chronic and often disabling disease that attacks the central nervous system, which is made up of the brain, spinal cord and optic nerves. Symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. The progress, severity and specific symptoms of MS are unpredictable and vary from one person to another.¹

MS can be diagnosed only after ruling out other conditions. This is because MS often presents with symptoms that are similar to other diseases. Yet, despite the fact that diagnostic criteria for diagnosing MS were updated in 2010, and guidance on how to discern MS from other look-alike disorders was updated in 2008, the misdiagnosis of patients who are later found to not have the disease is still far too high. And, the costs of treating these misdiagnosed patients is estimated to surpass $11 million annually for medical treatment alone, or about $40,000 per patient.²

Reasons for misdiagnosis are due to symptoms that mimic those of other nervous system disorders and, potentially, to the overreliance on MRIs. Diagnoses left to physicians who are not neurologists specializing in the disease often pose a real risk of misdiagnosis.³ In fact, a survey of MS specialists found that 95 percent have consulted with at least one patient who was incorrectly diagnosed, and 40 percent of specialists have seen three to five misdiagnosed patients in the last year. It is estimated that about 10 percent of patients who have been diagnosed with MS have some other disease4 that is later found to be a nonspecific brain abnormality, tumor-like lesion, small blood vessel ischemic disease, migraine, neuromyelitis optica or something else.

“The impetus now,” says Dr. Nick LaRocca, vice president of healthcare delivery and policy research at the National Multiple Sclerosis Society, “is to go back and re-examine the phenotype classification because it has important implications for not just establishing diagnosis, but also for classification of patients. There is an increasing interest in looking at patients prior to the point where they had their first event.” For instance, physicians are looking at a patient’s first demyelinating event, when a diagnosis could not yet be pinpointed, at which time the possibility of treatment could have been discussed with the patient. “When symptoms seem to suggest MS,” says Dr. LaRocca, “there is a dialogue between patient and physician to determine if they should go forward with treatment or wait to see what transpires.” Dr. LaRocca says the field has been moving in the area of earlier treatment because literature shows it helps prevent the compounding of symptoms. “There is the possibility of losing ground you can’t make up,” he says.

Today, new treatments and advances in research are giving new hope to people affected by the disease.

Interferon Beta

Fine-tuning a patient’s immune response to MS is one area of research showing promise in improving patient outcomes.

Anti-viral proteins such as interferon beta protein drugs are being tested in more than a dozen clinical trials as a method for reducing exacerbations and possibly slowing the progression of physical disability caused by the relapsing-remitting form of MS, as well as shortening the length and severity of attacks. Three U.S. Food and Drug Administration-approved drugs for treatment of relapsing-remitting MS in the beta interferon category are Avonex, Betaseron and Rebif.⁵

An observational study supported by the National Multiple Sclerosis Society and recently published in JAMA showed that interferon beta drugs (which are controversial as to the extent they slow disease progression)may not actually slow progression at all. The study was somewhat limited in that it viewed only treated versus untreated patients; it was not a randomized placebo-controlled trial, and the study authors themselves suggest that the debate will continue.⁶ The authors even list in their accompanying commentary a novel study showing that disease-modifying drugs (DMDs) do demonstrate a significant reduction in progression.⁷

Whether DMDs are found to slow progression or not, there is no question that this first-line therapy shows positive effects on relapse reduction and lesion outcomes.⁸

T Cell Suppression

Daclizumab (Zenapax), a monoclonal antibody and a key factor in indirectly suppressing T cell response in interleukin-2, has been shown in large-scale studies to be effective as an add-on therapy to interferon beta. It is now also being tested to see if it could be an effective stand-alone therapy as well.

Indeed, one study of daclizumab as a stand-alone therapy has shown a positive effect of daclizumab on stimulation of killer T cells and inhibition of lymphoid tissue inducer (LTi) cells. (This study is a first implicating LTi cells in an autoimmune disorder.) Patients taking the drug had reduced inflammation of cerebrospinal fluid (CSF) and a reduction of stem cell development into an LTi cell in favor of a natural killer cell (which explains why natural killer cells are expanded in patients taking daclizumab therapy).⁹

Also interesting in the study was the fact that the IgG index was reduced in patients taking the drug for six-and-a-half months as measured by inflammation of the CSF, though thus far the link is indirect. Researchers reasoned that LTi’s cell suppression should reduce growth of abnormal lymphoid follicles, which are believed to lead to chronic brain inflammation in those with MS. The CXCL-13 protein linked to lymphoid growth was decreased by approximately 50 percent, and the IgG index indicating antibody production decreased by more than 13 percent. If further research supports the findings that these cells play an important role in MS, the development of therapies that selectively inhibit LTi formation could be a useful therapy.⁹

B Cell Toxicity

Researchers are taking a close look at B cells, which are more active in the blood and brain of those with MS, and the possibility that these cells may produce toxic factors that harm brain cells, in particular those that make myelin. It appears that B cells may secrete a substance that is toxic to oligodendrocytes and either directly or indirectly impact myelin-making cells.

Though the evidence has not been confirmed, research trials of the cancer drug rituximab (Rituxan and MabThera) are looking at how the drug targets B cells and reduces MS relapses and brain lesions via a “genetically engineered chimeric monoclonal antibody that depletes CD20+ B cells through a combination of cell-mediated and complement-dependent cytotoxic effects and the promotion of apoptosis.”¹⁰ The drug is showing promise, though it has some side effects. Identifying the toxic substance(s) produced by B cells can serve as a new path for development of treatment therapies.¹¹

During a 48-week study, patients taking rituximab saw a significant reduction in the number of gadolinium-enhancing lesions and the number of relapses after just four weeks (the first dose), though the predominant mechanism for this is unknown. Because rituximab does not target plasma cells, it is thought that the outcome could be due to “lysis of memory B cells located in the peripheral blood and lymphoid tissues, or perhaps in the central nervous system. Interference with antigen presentation by B cells, or with activation of T cells or macrophages by pro-inflammatory B-cell cytokines such as interferon-γ and interleukin-12, may also play a role.” Patients who concluded the 48-week study overall saw a “rapid and complete depletion of CD20+ peripheral B cells (as measured by CD19 expression).”¹⁰ While this short study was not designed to assess safety of the drug, it shows promise in the potential for rituximab.

Another therapy currently in a Phase III study is ocrelizumab, an “investigational, humanized monoclonal antibody designed to selectively target CD20-positive B cells” and then interact with the body’s immune system to eliminate them.¹² These B cells appear to trigger a T cell attack on the nerve fibers of the brain, so by blocking the B cells, a T cell attack could be stopped.

The Phase II study of ocrelizumab showed the drug allowed patients to maintain a significant decrease in disease activity for nearly two years in those with the relapsing-remitting form of MS. During the study period, no patient who received a dose of 600 mg ocrelizumab developed a new or enlarging brain lesion (as measured by MRI), and two-thirds of those patients who completed the study were free of disease activity (as measured by MRI, relapses or neurological progression). Only 6 percent of the study participants taking ocrelizumab showed adverse effects.13 Patients with the primary-progressive form of MS have been included as part of the ocrelizumab Phase III study.¹²

Biomarkers

The study of biomarkers in MS patients is another exciting area of research, and nearly all major MS drugs have a biomarker-related study ongoing. However, at this point, it is yet unknown what the exact immune response of MS is. “There is a tremendous amount of interest in this,” says Dr. LaRocca, “because MS is so complex and varies so much from person to person. For instance, vision loss is a major problem for some, but for others vision is OK but they can’t walk. For others, it is cognitive. So, what do you pick as your criteria when looking at progression? At this point, we don’t know what that is.”

The present “sledgehammer” versus “scalpel” approach, as National Multiple Sclerosis Society blogger Julie Stachowiak, PhD, puts it, uses drugs that delete parts of the immune system and leave patients vulnerable to other diseases. Yet, there are a few new biomarker findings that show promise for the future of MS patients.14 The anti-JCV antibody test for those taking the immunomodulatory TYSABRI (natalizumab) indicates whether there is a risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection caused by the JC virus, that can be fatal or cause severe disability, and is characterized by progressive damage or inflammation of the white matter of the brain. Those testing positive for anti-JCV antibodies and taking TYSABRI less than 25 months have either a less-than-one-in-1,000-chance of developing PML if there was no prior immunosuppressant use, or a two-in-1,000-chance if there was prior immunosuppressant use. For those testing positive and taking TYSABRI between 25 months and 48 months, the risk of developing PML is either five-in-1,000 if there was no prior immunosuppressant use or 11-in-1,000 if there was prior immunosuppressant use. Those who test negative are at significantly lower risk for developing PML, as presence of the JC virus is necessary for the development of PML.

Other research in the area of biomarkers has not yielded equally successful results. For example, anti-myelin antibodies, analysis of microarray gene expression, and studies of CSF have not yielded specific and sensitive biomarkers for either the disease itself or the prediction for development. However, serum biomarkers monitoring therapeutic efficacy such as the titer of antibody to beta interferon already are used clinically.¹⁵

Much effort in biomarker research revolves around the monitoring of disease activity. At present, a disease “activation” panel of CSF biomarkers includes interleukin-6 or its soluble receptor, nitric oxide and nitric oxide synthase, osteopontin and fetuin-A.¹⁶

A recently published large-scale study in the journal Nature identified 29 new genetic variants and confirmed 23 others associated with MS. Most of these genes are related to immune function, and one-third have previously been identified for association with other autoimmune diseases. Many as well were associated with T cell function and proliferation.¹⁶

“In the next few years, we may see an ideal biomarker,” says Dr. LaRocca. “We’ll test a lot of things and find out what works and what doesn’t. That’s one reason negative studies are so important.” In the meantime, the complex causality of MS is both good news and bad. The bad news is that it’s harder to treat. But, says LaRocca, “maybe we can address factors that turn out to be easy. The more we know, the closer we will be.”

The Way Ahead

“We are fortunate that so many therapies are available and in the pipeline,” says Dr. LaRocca about the future for MS research and patient care. “Most importantly, we really want to see to it that those who have MS are able to live well with their disease. That’s the goal of the National Multiple Sclerosis Society, other MS organizations, physicians and researchers. We are keeping the focus on the person and working in a way that maximally benefits those with MS. The researchers who have dedicated their lives to this study should be congratulated as they are trying to accomplish a world free of MS.”