A similar trend toward reduced gadolinium-enhanced MRI lesions was found in a small study of 10 patients receiving glatiramer therapy. Comi, MD, oral communication, April The phase 3 studies convincingly demonstrated that each drug is partially effective, but precise comparisons are problematic. The studies were done by different investigator groups using separate primary outcome measures in separate patient populations.
Traditional clinical outcome measures, such as relapse rate and EDSS scores, are imprecise and not adequately standardized to allow direct comparisons among studies. Therefore, efficacy comparisons are based on expert opinions rather than definitive comparison studies. Data on the effects of glatiramer therapy on biological correlates of the MS disease process are currently limited. Since there are no studies comparing the efficacy of the available drugs within a single study, the question of relative efficacy is considered unresolved.
There is a growing consensus that disease-modifying therapy should be initiated early in the course of MS before irreversible disability has occurred. The rationale for early therapy includes 1 concerns that the immunologic process leading to tissue injury becomes more complex as time passes and may be more difficult to control with immunosuppressive therapy, 31 , 32 2 increasing awareness that the inflammatory process is active in many patients with RRMS during periods of clinical remission, 33 - 35 and 3 concern that the inflammatory process results in irreversible axonal injury 36 that accumulates over time during the relapsing-remitting stage of MS.
These considerations imply that disease-modifying therapy should be started when MS is definitively diagnosed because the patient is at risk for subsequent disability progression.
Identifying patients at higher risk for progressive MS for early therapy is an alternative to treating all patients at the time of diagnosis. Unfortunately, clinical features are only weak predictors of subsequent disease severity, and their value for assigning prognosis to individual patients is limited.
Disease severity as measured by cranial MRI scans at the time of onset of first symptoms has been shown to predict MRI and clinical disease progression. Identifying prognostic factors early in the course of MS is an important goal of future MS research. The optimal duration of therapy for MS has not been determined.
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For patients doing well, therapy should be continued, since a study of IFN-alfa-2a therapy showed increased disease activity when therapy was discontinued after 6 months. Standardized methods for evaluating patients receiving disease therapy are needed, including definitions for those patients who do not respond to treatment. The poor relationship between clinical relapses and the severity of brain inflammation implies that more accurate and sensitive markers of the pathologic process in RRMS will be required. Periodic cranial MRI scans may be useful in estimating MS disease activity and progression in some patients, to determine the need for disease-modifying therapy in patients with clinically benign disease, and to evaluate the response to disease-modifying therapy.
Studies are needed to precisely define the methods and frequency for using MRI to monitor patients receiving disease-monitoring therapy. Further studies on the use of neutralizing antibody tests in clinical practice are needed. Long-term benefits of the current drug therapies can only be surmised from existing studies because clinical trials run 3 to 5 years, while the disease course of MS unfolds over decades.
Clinical trials provide information on only a limited part of the overall disease course. Lengthy placebo-controlled studies are impractical because patients whose condition is deteriorating withdraw from them, making the studies less informative. Lengthy open-label studies do not provide definitive evidence about the efficacy of MS treatment, since patients who are doing well elect to continue receiving drug therapy, while patients whose condition is deteriorating stop drug therapy to try something else.
This results in observer bias favoring long-term efficacy. Despite their limitations, the studies suggest that available disease therapies are likely to have a beneficial effect on long-term disability, and this might translate into cost-effective treatment. Placebo-controlled trials for RRMS therapy are now impractical in regions of the world where effective disease-modifying agents are readily available. Furthermore, placebo-controlled trials for RRMS therapy are ethically questionable because of convincing evidence for meaningful, albeit partial, therapeutic benefits. The role of placebo-controlled trials is less clear in patients with SPMS, and this issue can be expected to change, as it has for patients with RRMS, with the emergence of effective therapies.
As results from these and other studies are published, placebo-controlled studies for patients with SPMS will become less practical and more ethically questionable. Since no therapy has demonstrated any benefit for primary progressive MS, placebo-controlled studies for this disease category are well justified. An international consensus conference on MS outcome measures pointed out limitations of traditional scales for MS clinical trials and indicated the need for new assessment systems that are multidimensional, quantitative, and include evaluation of cognition.
The task force recommended functional composites consisting of simple quantitative tests of neurologic function. It remains to be seen whether quantitative functional composites will prove to be advantageous compared with traditional measures, such as the relapse rate and the EDSS score. The rate of detection of new gadolinium-enhanced MRI brain lesions is 5 to 10 times higher than the rate of clinical relapses, 33 , 35 indicating that most new MRI lesions are clinically silent. Similarly, the relationship between the volume of hyperintense T 2 -weighted lesions and the EDSS score is also weak.
These findings raise the possibility that in the relapsing-remitting stage of MS, the disease process is subclinical to a substantial degree. The principal concern in this regard is that disability progression occurs only after a threshold of irreversible tissue injury has been surpassed.
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Studies are needed to validate traditional and newer MRI markers, such as brain and spinal cord atrophy, as primary outcome measures. With the advent of partially effective therapies, active arm comparison studies will be needed to make further progress in the field of MS drug therapy. VLA-4 is a clinically validated target for MS treatments, and antisense inhibition of the receptor has demonstrated effectiveness in published preclinical studies in animal models of the disease.
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Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. Arch Neurol — Google Scholar. Mannie MD, Dinarello CA, Paterson PY Interleukin 1 and myelin basic protein synergistically augment adoptive transfer activity of lymphocytes mediating experimental autoimmune encephalomyelitis in Lewis rats.
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Multiple Sclerosis Study Group Efficacy and toxicity of cyclosporine in chronic progressive MS: a randomized, double blind, placebo controlled clinical trial. What have we learned? Neuroimmunol — CrossRef Google Scholar. Raine CS Multiple sclerosis: immune system molecule expression in the central nervous system.
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Rott O, Cash E, Fleischer B Phosphodiesterase inhibitor pentoxyphylline a selective suppressor of T helper type 1, but not type 2-associated lymphokine production, prevents induction of experimental autoimmune encephalomyelitis in Lewis rats. Effect on T cell response to myelin basic protein and experimental allergic encephalomyelitis.
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