MSQR - V21. N1. Spring 2002
Douglas Jeffery, MD, PhD, Director, Wake Forest University School of Medicine Multiple Sclerosis Treatment Center, Winston-Salem, NC
Progress to Date
Multiple sclerosis (MS) is a neurological disease that usually leads to increasing disability over time. MS is characterized in the early stages by relapses, which are attacks lasting weeks to months in which certain functions are affected. For example, a patient might develop weakness in the lower extremities, impaired vision, or loss of balance, to name only a few. Typically the attacks resolve or get better, but some symptoms may not completely resolve. In between the attacks, if there are no new symptoms, the patient is said to be in remission. A remission does not mean that the patient is back to normal; just that there have been no new neurologic symptoms since the last attack.
These attacks are caused by lesions in the brain and spinal cord that damage myelin and axons. Axons are the wires of the nervous system and the myelin is a fatty layer that “insulates” the nerve cells. When the myelin is damaged the nerve cells can’t transmit electrical impulses and symptoms develop. Often, the nerve cells themselves are also damaged when the lesion forms. Since this process is irreversible, it is important to consider treating the disease at its earliest stages.
The lesions are formed as a result of an attack by the patient’s own immune system on the myelin within the brain and spinal cord. New lesions are inflammatory. At new lesion sites, there is a breakdown in the barrier between the bloodstream and the nervous tissue (the blood brain barrier) that allows immune cells to infiltrate into the lesioned area. This leads to swelling and the destruction of the myelin. With time, the inflammation ends and the swelling decreases. A new myelin layer can often form. The original lesion may remain vulnerable to additional immune attacks, however, and may be enlarged by new inflammation. On a magnetic resonance imaging (MRI) image, new and enlarging lesions with inflammation and disruption of the blood brain barrier show up as bright spots when a contrast-enhancing agent like gadolinium is used. New and active lesions are thought to be responsible for the sudden and worsening symptoms experienced by patients with MS during relapses.
Destruction of the myelin layer is serious enough, but growing evidence indicates that, even early in MS, the axons of the nerve cells that pass through a lesioned area can also be damaged. This damage is probably caused by intense inflammation (Jeffery, 2000). Unlike myelin, axons cannot grow back. On MRI images, areas where axons are damaged show up as “black holes.” Since black holes seem to be caused by the inflammation of new or newly active lesions, and since they represent nerve damage that can never be repaired, an important goal of treatment is to reduce or eliminate the occurrence of new lesions.
Current Research and Issues
One of the most important recent advances in treating MS is the discovery that interferon beta (IFNb) can reduce the number of relapses and slow the accumulation of disability in patients with MS. IFNb belongs to a naturally occurring class of molecules called cytokines. Cytokines are involved in regulating the immune system. IFNb is marketed in two forms. IFNb-1a is made in mammalian cells, and has the same protein composition as the naturally occurring human IFNb. IFNb-1b has some slight differences from the human IFNb, and is made in bacterial cells. Both have been shown to be effective in treating relapsing-remitting multiple sclerosis (RRMS).
Although the availability of IFNb has changed the way MS is treated and improved the outlook for many patients with MS, not all patients benefit equally from IFNb, and questions have been raised about how to provide the most effective treatment.
For example, while it seems clear that for many patients, IFNb can reduce the number of relapses and the numbers of new and enlarging lesions that can be seen by MRI, IFNb does not seem to slow brain shrinkage, another effect of MS. Moreover, in two out of three studies, IFNb did not slow the increase in disability of patients who had secondary progressive MS, the form of MS that eventually affects most patients originally diagnosed with RRMS (Khan, Caon, & Zabad, 2001). However, preliminary studies indicate that treatment with IFNb decreases the rate of conversion to secondary progressive MS. These findings led to the idea that IFNb might be most effective when given early, because it might help most by preventing the formation of new lesions and, thus, the damage caused by inflammation, but might not be particularly helpful once the neurological damage had become irreversible and progressive.
A recent study evaluated the effectiveness of giving IFNb early (Jacobs et al., 2000). This study examined whether patients who were considered to be at high risk for having a second neurologic attack, which would qualify them for a diagnosis of MS, might be less likely to have this attack if they were treated with IFNb from the time they first had symptoms of a demyelinating lesion. Weekly injections of a placebo or IFNb were given to 383 patients who had symptoms caused by a demyelinating lesion and whose MRIs showed older lesions that had not caused symptoms. The patients continued as subjects in this study until they developed MS or showed evidence of progressive disability. During the 3-year follow-up period, the patients taking IFNb were significantly less likely to develop MS than were the patients taking placebo: 35% of those taking IFNb versus 50% of those taking placebo. In addition, the patients taking IFNb had fewer new and enlarging lesions and a smaller increase in the total volume of lesions than did the patients taking the placebo (1% vs. 16% at 18 months). The study was stopped early because it showed that IFNb was effective in reducing the risk of developing MS.
Given the effectiveness of the treatment, it was unethical to continue to give patients a placebo to find out whether early use of the IFNb was beneficial in the long term. Nonetheless, in a previous study the number and volume of lesions seen early in MS were related to the amount of disability 10 years later. Therefore, early treatment with IFNb may translate into a long-term delay in the development of disabilities.
Another issue that came out of the original IFNb studies was that there are large differences among patients in how well they respond to treatment. In fact, one of the hallmarks of MS is its unpredictability, with some patients rapidly worsening and others having few symptoms and little disability for many years. This difference probably reflects the amount of disease activity in the nervous system. It is possible that patients with greater disease activity respond less well to a given dose of IFNb than do patients with less disease activity. In fact, when the existing studies are examined from the perspective of how large a dose of IFNb was given to patients, there is some evidence to suggest MS may have been slowed most in patients receiving the highest doses. More studies need to be done to find the optimum dose of IFNb to give patients with different levels of disease activity. In addition, ongoing studies of combination therapies, in which IFNb is combined with other medications to further suppress disease activity, will help identify good treatments for patients whose MS is not effectively managed by IFNb alone (Jeffery, 2000).
Another evolving question is how best to measure disease activity. Traditionally, disease activity has been measured by counting the number of relapses or by documenting increases in disability. These methods may not always reflect disease activity well, because relapses and disabilities can only be identified if a lesion affects a part of the nervous system that causes a symptom, like blindness or difficulty walking. A single new lesion can result in a relapse, and failure to recover from a single old lesion can cause permanent disability, if that lesion is in the wrong place. Relapses and increasing disability, therefore, don’t always signal a high level of disease activity. Conversely, there could be fairly high disease activity that does not trigger a relapse or disability. This might happen if, say, the new lesions were in a brain region that affected mood, memory, or reasoning. Therefore, using MRI to evaluate the number of new and enlarging lesions, and also the total volume of the lesions present in the brain, may provide a more reliable way to determine the amount of disease activity in the nervous system of any given patient.
Implications for Patient Care
The permanent damage of MS, at least early in the disease, is almost certainly due to the damage to axons and surrounding tissues caused by the inflammation of demyelinating lesions. This makes it critically important to prevent this damage from occurring in the first place by reducing disease activity. The finding that patients with pre-clinical MS were less likely to progress to definite MS (Jacobs et al., 2000) adds strength to the idea that MS should be managed aggressively from the earliest possible time, with IFNb being given, if possible, even before the patient has a second attack. Since disability may be a poor measure of disease activity, regular MRI scans may be used in conjunction with traditional measures to ensure that disease activity is being suppressed by treatment. If a relatively low dose of IFNb does not suppress disease activity, then a higher dose of IFNb could be tried, or the patient could switch to a non-INFb therapy such as glatiramer acetate or mitoxantrone. In the future, combination treatments may be able to prevent new lesion formation to the greatest extent possible.
References (*denotes suggested readings)
*Jeffery, D. R. (2000). Relationship between disease activity and dose-response relationships with beta interferon therapies in the treatment of multiple sclerosis. Journal of the Neurological Sciences, 178, 2-9.
Khan, O. A., Caon, C., & Zabad, R. (2001). Secondary progressive
Current treatment availability and future promise. Multiple Sclerosis Quarterly Report, 20(3), 1, 3-7.
*Jacobs, L., Beck, R. W., Simon, J. H., Kinkel, R. P., Phillip, R.,
et al. (2000). Intramuscular interferon beta-1a therapy initiated during
a first demyelinating event in multiple sclerosis. New England Journal
of Medicine, 343(13), 898-904.
Copyright © MSQR 2002