Advances in biotechnology have had a significant impact on the treatment of MS. For many years, treatment relied on the use of broad-spectrum immu-nosuppressive agents that had numerous toxicities. Early trials reported success with agents that did not withstand larger or more detailed investigations. Historically, the disease has been difficult to study because of the wide variability in presentation and clinical course. Large numbers of patients are necessary to show a consistent reproducible response from a drug. The gold standard for measuring disease activity has been the Kurtzke Expanded Disability Scale (EDSS). This 10- point scale, with half-step gradients, measures physical disability. Unfortunately, it is not a linear scale and is heavily weighted toward gait, especially in the middle range of the scale. Newer
Prognostic Features of Multiple Sclerosis Favorable Less favorable
Onset of disease before age 40 Onset after age 40 Monosymptomatic onset Polysymptomatic onset
Complete recovery of symptoms Lack of recovery from the first attack
Female sex Male sex
Optic neuritis or sensory Early cerebellar or motor symptoms at onset symptoms
Little disability at 5 years measures of disability include the Functional Composite, which evaluates gait (25-ft timed walk), upper extremity function (9-hole peg test), and cognitive function (Paced Auditory Serial Addition Test). MRI is used as a surrogate marker for disease activity.
Genetic engineering has led to the manufacture of compounds such as interferon-b (IFN-b), which is where produced by Escherichia coli or mammalian ovarian cells after gene insertion. Copaxone (glatir-amer acetate) is a synthetic compound made of four amino acids. These agents allow for selective immunomodulation and thus lower toxicity. There is conclusive evidence from large-scale trials that these agents are partially effective in the treatment of MS. IFN-b-1b (Betaseron) was the first of these agents to be assessed. The drug was shown to effectively decrease the risk of exacerbation of MS and had the effect of slowing accumulation of new lesions on MRI. Although the drug did not show an effect on slowing progression of disease, as measured by the EDSS, the effect on MRI led many to believe that the long-term outcome of a patient treated with this will be better than the expected natural history. IFN-b-1a (Avonex) was the second agent to be approved by the FDA. This drug has a similar effect on decreasing the rate of relapse. The primary end point of the clinical trial was efficacy in slowing disability as measured by the EDSS, and this drug has the unique feature of FDA approval for that indication. Copaxone was initially investigated as a potential agent to induce EAE. Conversely to what was expected in the animal model, there appeared to be a protective effect, which led to additional clinical trials. Copaxone decreases the risk of a relapse and has favorable effects on MRI. Currently, it is difficult to argue that one of these agents is superior to the others for treatment of relapsing-remitting MS. Fortunately, it allows for patients to have an option. Worldwide use and access are limited by the high cost ($12,000 per year) and administration (intramuscular or subcutaneous injections). The National Multiple Sclerosis Society has issued a recommendation advocating the use of these drugs early in the course of the disease based on increasing evidence that early treatment is likely beneficial in decreasing the inflammatory phase of the disease and preventing axonal injury. Recently, trials of secondary progressive MS have found mixed results with use of beta-interferons. Mitoxantrone (Novantrone) has received FDA approval in the United States for treatment of secondary progressive MS. This immunosuppressive agent was shown to be effective in European studies in slowing progression of individuals with secondary progressive disease or relapsing-remitting disease unresponsive to other therapies.
Future clinical trials will likely lack a placebo group because it is unethical to leave a patient untreated when partially effective therapies are available. As a result, larger and lengthier clinical trials will be necessary to show an effect of newer agents. Surrogate markers for disease activity, including MRI, will be used to assess the utility of drugs prior to large phase 3 trials needed to show clinical efficacy. As our understanding of the pathological processes of the disease increases, it is possible that different therapies will be indicated for different types of MS. For example, in individuals with a notable inflammatory component as determined by MRI or an other tool, use of immunomodulator therapies that have a specific effect on inflammatory aspect of the disease may be most beneficial. In other cases in which little inflammatory disease appears evident, growth factors or other means to stimulate regenesis of cell life may be more appropriate. In cases in which drugs are not shown to be efficacious for MS, the understanding of the pathophysiology of MS increases and thus the trials cannot be considered failures. Finally, until the cause of the disease is found, a cure is not likely. Fortunately, advances in understanding the disease process have been exponential in recent years, allowing hope for control, if not cure, for this disease in the near future.
See Also the Following Articles
BRAIN LESIONS • CEREBRAL WHITE MATTER DISORDERS • GLIAL CELL TYPES • MOTOR NEURON DISEASE
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