May 3, 2002
Scientists and clinicians from around the world presented results of multiple sclerosis research at the 54th Annual Meeting of the American Academy of Neurology (AAN), held in Denver on April 13-20. Here we summarize some of these efforts, and an update of the National MS Society’s MS Lesion Project, which was highlighted in a special plenary session. This is by no means inclusive of all MS research presented at the meeting: Out of over 1,100 presentations, some 197 were related to multiple sclerosis or MS animal models.
Update: The MS Lesion Project
Claudia Lucchinetti, MD (Rochester, MN) updated all AAN attendees on the progress of the National MS Society-funded MS Lesion Project during a special plenary session. This $1.8 million, five-year project is a collaboration of top neurologists and pathologists around the world, led by Dr. Lucchinetti, to study lesions (damaged areas in the brains of individuals with MS) for clues to different patterns of destructive immune factors, and to correlate findings with clinical manifestations of MS and MRI findings.
Dr. Lucchinetti reported preliminary results from studies of brain biopsies (tissue samples) from 145 patients. Previously, she and her colleagues had found four distinct types of lesions, which differed in the pattern of myelin (the substance that insulates nerve fibers) and nerve fiber loss and in the activity of immune cells and immune proteins. The team’s data suggest that within an individual, the lesion pattern is the same, but that it differs between individuals. The investigators propose that lesion patterns may relate to disease type and possibly to treatment outcomes.
Data related to disease type are still being analyzed. However, one new finding relates to the team’s analysis of lesion patterns in a small number of individuals who had received plasma exchange therapy, a blood-cleansing technique that has been used for severely progressive MS. They found that those whose lesion pattern included immune proteins known as “antibodies” were more responsive to plasma exchange therapy, while those without such a lesion pattern were less responsive. These data suggest that different patterns of tissue damage in the brain may be responsive to different kinds of treatments.
Future studies in this five-year project involve tracking individuals who had had brain biopsies taken in the past to determine current clinical status, and following them to determine if patterns of tissue damage are reflected in MRI scans. In fact, in preliminary analysis, people with another pattern of lesion, which involves immune cells known as macrophages, showed findings on MRI that were distinct from other participants. Dr. Lucchinetti’s team is continuing this research to further define possible lesion patterns and the underlying mechanisms.
Extension Studies of Prior Clinical Trials
Researchers reported the results of several extension studies. These are clinical trials for treatments that were extended by months or years to determine further information on the safety or effectiveness of an MS therapy.
Dr. Fred Lublin (New York, NY) and colleagues extended a study in which 33 individuals with relapsing-remitting MS using interferon beta-1a (Avonex®) were also given glatiramer acetate (Copaxone®) treatment for a second six months, resulting in no relapses or new lesions. While the study was too small to determine effectiveness, there were some hints of possible benefit of combined therapy, and the safety of the combination has been established. A larger study is planned.
Dr. Luca Durelli (Torino, Italy) and colleagues involved in the “INCOMIN” study compared Avonex vs. interferon beta-1b (Betaseron®) in 188 people with relapsing-remitting MS for a second year. MRI and clinical findings showed that Betaseron reduced signs of disease activity and progression more effectively than Avonex. The difference between the two treatments increased during year two.
Dr. Hillel Panitch (Burlington, VT) and colleagues reported on an extended study of two interferon beta-1a products, Rebif® vs. Avonex, given at different doses and different weekly schedules. (The results of the original, 24-week study helped Rebif to gain FDA approval in March 2002). At 48 weeks, in 677 individuals with relapsing-remitting disease, Rebif reduced the rate of relapse, reduced active inflammation as seen on MRI, and extended the time to first relapse more than Avonex. Most of the benefit seen with Rebif was achieved in the first 24 weeks, but the differences were maintained for 48 weeks. Abnormalities of liver function tests and decreases in white blood cell counts and injection site reactions, including pain, were more common in the Rebif group, although most were mild to moderate in severity. Increases in antibodies that may neutralize the effect of interferon were also more frequent with Rebif.
Dr. Catherine Dalton (London, UK) and colleagues followed 213 patients who had been enrolled in a six-month study of the monoclonal antibody natulizumab (Antegren®) versus placebo, for an additional six months after treatment stopped. While clear benefit on relapses and MRI were seen during the initial treatment period, once the treatment stopped, there were no significant differences in the number of relapses or new lesions between people who had taken Antegren in the treatment period and those who had been on placebo. This suggests that for treatment benefits to be sustained with Antegren, use of the agent most likely must be continued. Studies are underway to evaluate the longer-term effects of Antegren and Antegren in combination with interferon beta-1a (Avonex).
Dr. Kenneth Johnson (Baltimore, MD) and colleagues have followed 142 people taking Copaxone for relapsing-remitting MS for eight years, out of 251 who participated in the original study of Copaxone for relapsing-remitting MS that began in 1991. The relapse rate has fallen from 1.5 every five years to 1 every five years. Those who took placebo for the first 30 months of this study, and then crossed over to active treatment, have fared worse than those who started the study and have continued on active therapy. This suggests that later active treatment has not compensated for the lack of active treatment during the first 2.5 years of the study.
Other Clinical Studies
Researchers also reported results from other studies that involved experimental or FDA-approved therapies for treatment of MS disease activity and symptoms, evaluating the safety and/or effectiveness of these therapies or combinations of therapies. In all cases, these were reports of very small, not definitive studies. The results provide guidance for further studies, which in most cases are under way.
Dr. Marina Zvartau-Hind (Detroit, MI), a Sylvia Lawry Physician Fellow of the National MS Society, and colleagues gave the powerful immune-suppressing drug cyclophosphamide (Cytoxan®) to 14 people with rapidly progressive MS. All participants stabilized or improved, lasting to 36 months, despite the fact that treatment was stopped after six months. This potentially toxic therapy may present a treatment option for rapidly progressive MS, but further research is necessary to determine its safety and effectiveness in this population.
Several studies were presented on mitoxantrone (Novantrone®), an agent approved by the FDA in 2000 for worsening forms of MS. Dr. Gilles Edan (Rennes, France) presented safety information on Novantrone in 802 people with MS, gathered by 12 MS centers in France. They found the drug to be generally well tolerated, although patients were using the drug for less than the maximum tolerated dose to avoid cardiac toxicity. Also, two patients developed acute myelogenous leukemia, a higher incidence of this type of cancer than reported in the general population. Dr. Emanuelle Le Page, a colleague, evaluated 100 individuals who had received Novantrone and methylprednisolone for worsening relapsing-remitting MS before taking other MS therapies. Relapse rate and disease activity on MRI were reduced significantly in this group, and the author notes that this may indicate that Novantrone can be used before initiating other therapies in worsening relapsing-remitting MS. Furthers studies exploring this possibility are underway.
Dr. Douglas Jeffery (Winston-Salem, NC) and colleagues treated 10 people with worsening relapsing-remitting or secondary-progressive MS with Betaseron and Novantrone. In a short-term study, treatment was well tolerated, and relapse rates decreased by 74%. Dr. Daniel Mikol (Ann Arbor, MI) tested Novantrone and dexrazoxane (Zinecard®, a cardioprotective agent) in 26 people, and reports that the combination is safe and tolerable. He is continuing to study this combination to determine if it will decrease the risk of cardiac toxicity associated with Novantrone.
Dr. Eva Havrdova (Prague, Czech Republic) studied Avonex, azathioprine and low-dose steroids in 105 people with relapsing-remitting MS, and found that the combination was tolerable and reduced the relapse rate by 56% in one year and 72% in two years.
Dr. Christopher Kenney (La Jolla, CA) showed that ginkgo biloba (240 mg per day) was well tolerated in 23 people with mild MS, and possibly had a beneficial effect on attention, memory and fatigue. Larger and longer studies are necessary to confirm these findings.
Dr. James Miller (New York, NY) and colleagues studied sildenafil citrate (Viagra®) vs. placebo in 206 men with erectile dysfunction and MS. Treatment was effective in improving erections and sexual activity over periods ranging from 24 to 48 weeks.
Dr. Dean Wingerchuk (Scottsdale, AZ) found that 42% of 30 people with MS reported good or excellent improvement in fatigue levels when treated with aspirin, compared with 11% of the same individuals during a placebo phase. Further study is necessary to confirm findings and explore possible mechanisms.
Dr. George Kraft (Seattle, WA) and colleagues presented preliminary findings from a study of transplantation of blood stem cells in 26 individuals with severe, progressive MS. Twenty patients appeared to have stabilized over a short period after the procedure, but further observation is necessary to determine if stabilization will continue. The procedure has significant risks and side effects, and one death was reported in this study. More information is available in the bulletin, “Researchers Report Modest Success Transplanting Blood Stem Cells To Treat Severe MS” (http://www.nationalmssociety.org/Research-2002Apr17.asp).
Researchers also presented the results of studies using MRI and other imaging technologies to diagnose MS.
In two separate studies, Dr. Catherine Dalton (London, UK) and Dr. Silvia Di Legge (Rome Italy) evaluated the diagnostic criteria for MS that were recently proposed by a National MS Society-sponsored task force that formally incorporated MRI into the diagnosis of MS. Both studies indicated that the use of these new criteria resulted in a faster and more accurate diagnosis of MS than previous criteria.
Dr. Martin Hardmeier (Basel, Switzerland) found that a method of analyzing MRI, called “brain parenchymal fraction,” could detect brain volume changes in 129 people with relapsing-remitting MS in three months. This method might help determine the effects of MS therapies on brain volume during clinical trials. Dr. Nicola De Stefano (Siena, Italy) found that the volume of gray matter (the part of the nervous system that contains nerve cell bodies) was lower in people with MS than healthy individuals. These measures correlated with more disease activity, particularly in people with primary-progressive MS, indicating that decreases in gray matter may contribute to disability.
In a Society-funded project, Dr. Joonmi Oh (San Francisco, CA) and colleagues studied 47 people with MS, to determine whether different imaging techniques looking at different parts of the brain might be useful in diagnosing and understanding the various clinical courses of MS. Looking at the corpus callosum (nervous tissue that connects the right and left sides of the brain) enabled investigators to detect nerve fiber damage in people with relapsing-remitting or secondary-progressive MS. Studying the central region of the brain was more informative in those with primary-progressive MS. This study suggests new avenues for exploring underlying differences in disease pathology of different clinical forms of MS.
MS in Children
Several studies on MS in children were presented. Dr. Brenda Banwell’s team (Toronto) assessed cognitive function and academic achievement in 10 children with MS. Cognitive problems (particularly in visual learning and memory) were more widespread than reported in adults with MS, and were more severe in children who had had MS for a longer period.
Dr. Cecil Hahn and colleagues (Toronto) evaluated whether the newly revised diagnostic criteria for MS applied to a group of 17 children with the disease. Only 60% met MRI criteria for MS at the time of their second neurologic episode, indicating that the MRI features of adult MS are less common in children, and that specific MRI criteria may be necessary to help make a diagnosis of MS in children.
Basic and Clinical Laboratory Studies
Results of many basic and applied studies related to multiple sclerosis were also reported at the meeting, including the following studies.
Society-funded fellow Dr. Arnon Karni (Boston, MA) found that dendritic cells (cells important in initiating the immune attack) are activated in secondary-progressive and not relapsing-remitting MS. The results may clarify immune activity and responses to therapy.
In a project funded by the Society’s targeted initiative on genetics, Dr. Brian Weinshenker found a common variation in the sequence of DNA among men with MS from Northern Ireland, Sardinia and Minnesota, indicating a possible important source of genetic susceptibility in MS. Further research is necessary to more completely understand the nature and importance of this common genetic variation.
Dr. Rosetta Pedotti (Palo Alto, CA) reported on her National MS Society-funded project involving mice with the MS-like disease EAE. Her team found that deleting genes controlling immune molecules involved in allergic reactions improved EAE. If further study confirms these findings, she says, this research may present attractive options for using allergy treatments for MS.
Dr. Asim Diab (Dallas, TX) improved EAE using a molecule known as a PPAR-gamma ligand (ligands are molecules that can attach to the inflammatory molecule, PPAR-gamma, and modulate its activity). Similar agents are FDA-approved to treat diabetes, and have been used successfully in models of other autoimmune diseases. Further research is needed to determine safety and effectiveness in animal models of MS and people with MS.
Studies reported by Dr. Sawsan Youssef (Stanford, CA) and Dr. Oliver Neuhaus (Graz, Austria) and colleagues showed that several forms of statins (cholesterol-lowering drugs) could inhibit the immune attack in mouse models of MS and regulate immune responses in cells taken from individuals with MS. More research is needed to clarify whether statins can actually benefit people who have MS, and clinical trials are in progress and planned for MS. Further information is available in the bulletin, “Early Studies Suggest Lipitor® and Other Statin Drugs May Treat Rodent Models of MS” (http://www.nationalmssociety.org/Research-2002Apr23.asp).
Dr. Ram Sriram (Vanderbilt University, Nashville) and colleagues showed that bacteria that migrate and reside in brain tissues could make EAE worse, but that related strains of bacteria that infect an animal but do not migrate to the brain do not have such an effect. He believes that such “neurotropic” bacteria could have a role in exacerbating disease and thus may play a role in the disease course of MS as well.
-- Research Programs Department
© 2002 The National Multiple Sclerosis Society