Featured Masters Questions and Answers
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James D. Bowen, MD
Medical Director, Multiple Sclerosis Center
Swedish Neuroscience Institute
What MS patient group(s) would be the best candidates to try the new oral MS drug, fingolimod, (assuming it is approved)?
People with relapsing-remitting multiple sclerosis (MS) who have never been on a disease-modifying treatment will have a choice between the standard injectable medications and the new oral medicine, fingolimod. Many of these patients will be attracted to the convenience of once-daily oral therapy. This convenience will need to be balanced against other factors, primarily safety and cost. For example, injectable therapies for MS such as beta interferon and glatiramer acetate have an extensive record of safety and long-term effectiveness. Fingolimod has been shown to be safe in studies to date, but these studies have only been 1 to 2 years in length. Some patients from the original trials are now enrolled in additional extension studies. There are approximately 5,000 patients in fingolimod studies, while the injectable MS therapies have much larger exposures, in some cases for 15 years or longer. Side effects that arise after years of exposure—or which happen very rarely—may not be revealed until larger numbers of patients have taken fingolimod. Another factor will be cost. The price for of fingolimod has not been announced, but this may play a role in determining insurance coverage. Discussions between the patient and the physician will determine the importance of these factors in each individual case.
Patients who are already taking a disease-modifying treatment will need to consider the effectiveness of their current therapy. If their therapy is not adequately controlling the disease, a change to another medication may be required. However, if they are doing well on current treatment, they will need to decide whether it is prudent to continue with a successful treatment, or to switch to a treatment that may or may not be as effective in their case.
There are some medical conditions that might be relative contraindications to fingolimod. In clinical trials fingolimod led to an increase in blood pressure. Although this change was slight, patients with poorly controlled hypertension might need to consider other treatments first. Likewise, the bradycardia that may be seen on the first dose will need to be considered in people with cardiac conduction defects. There were slight changes in pulmonary function measures that should be considered in patients with reactive airway disease or obstructive pulmonary disease. The rare cases of retinal edema seen on optical coherence tomography may impact the use of fingolimod in patients with conditions that can contribute to this risk, including diabetic retinopathy. Elevated transaminase levels, though rare, were also recorded. Finally, the effect of fingolimod on progressive forms of MS is unknown.
All of these factors will need to be weighed and balanced against the success of injectable treatments in individual cases, along with the psychosocial, dermatologic, and adherence aspects of using injectable therapies.
Rammohan KW, Shoemaker J. Emerging multiple sclerosis oral therapies. Neurology. 2010;74(Suppl 1):S47-S53.
Conway D, Cohen JA. Emerging oral therapies in multiple sclerosis. >Curr Neurol Neurosci Rep. 2010;10:381-538.
Cohen JA, Barkhof F, Comi G, et al; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;4;362:402-415.
What MS patient group(s) would be the best candidates to try stem cell treatments?
Among the several types of stem cells, those designed to replace damaged myelin (including embryonic stem cells) are not yet available for use. These stem cell treatments are offered through “medical tourism” in some countries, but it is difficult to recommend these in the absence of good data supporting their use. Similarly, stem cells used to produce growth factors or regulatory factors (including mesenchymal stem cells) are not generally available. The third type of stem cell, hematopoietic stem cells, has been available in selected centers for several years.
Hematopoietic stem cell transplantation is the modern method of performing a bone marrow transplant. This involves collecting stem cells from the blood of patients and then giving high doses of immunosuppressive medications (chemotherapy) in an effort to eliminate the parts of the immune system that are, in theory, causing MS. Immediately afterward, the stem cells collected before the immunosuppression are then returned to the patient by intravenous infusion. The advantage of using stem cells rather than bone marrow cells for this infusion is that several million stem cells can be infused, whereas with bone marrow only a few hundred are infused, greatly speeding up the recovery of blood cells. This procedures leads to a long-lasting shift in immune cell populations, such as an increase in CD8+/CD4+ ratios. It is also hoped that clones of immune cells directed against the nervous system can be eliminated.
It has been found that MS patients who are still having evidence of inflammation associated with their disease do best with this treatment. Also, those with lesser amounts of disability fare better. Most hematopoietic stem cell transplant programs require that patients have relapsing-remitting MS to ensure that they are still having inflammation. Most require an expanded disability status scale (EDSS) score of 5.5 or better (a score of 6.0 indicates that a cane is needed for gait). This aggressive treatment is usually reserved for patients who have very active disease, so most transplant programs require that patients have 2 or more attacks in the past 18 months, and that they worsen on their EDSS score over this interval. At least one standard MS therapy should have failed, assuring that the disease is not responsive to a less-toxic treatment. Patients must be free of other diseases that might complicate the transplant and must be 60 years of age or younger. With these criteria, mortality rates for the procedure are less than 5%. Following the procedures the disease remains well controlled in most patients. For example, in an analysis of European procedures by Farge et al, progression-free survival 5 years after the procedure was seen in 45% of the 345 MS patients who received transplants. Because early studies were not limited to the more select population described here, more specific efficacy data will not be known until current studies of hematopoietic stem cell therapies are completed.
Karussis D, Vaknin-Dembinsky A. Hematopoietic stem cell transplantation in multiple sclerosis: a review of the clinical experience and a report of an international meeting. Expert Rev Clin Immunol. 2010;6:347-352.
Capello E, Vuolo L, Gualandi F, et al. Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks. Neurol Sci. 2009;30(Suppl 2):S175.
Farge D, Labopin M, Tyndall A, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. Haematologica. 2010;95:284-292.