September 18-21, 2002; Baltimore, Maryland
Posted 18th October, 2002
Omar Khan, MD, Associate Professor of Neurology and Medical Director, Multiple Sclerosis Clinic, Wayne State University, Detroit, Michigan.
Christina Caon, BSc, MSN, RN, Program Coordinator, Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, Michigan.
Medscape Neurology & Neurosurgery
Baltimore was the venue for the much-awaited second joint meeting of the Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS and ECTRIMS). In contrast to their respective annual meetings, this joint meeting of the ACTRIMS and ECTRIMS is held every third year to provide a common forum for clinical and basic science MS researchers from both sides of the Atlantic. Thousands of delegates with highly focused areas of interest in MS attended this year's joint meeting. Although presentations were made in all areas of basic and clinical research in MS, 3 areas were particularly emphasized: pathology of inflammation and axonal injury, neuroprotection, and clinical trial methodology. This review summarizes some of the key presentations including disease mechanisms and clinical trial research.
This year's meeting featured 2 keynote addresses.
Keynote Address : Central Nervous System (CNS) Inflammation and Its Pathological Substrates in MS
Professor S.K. Ludwin from Queens University, Ontario, Canada, discussed the fundamental pathology of MS inside the CNS, ie, inflammation, gliosis, and axonal loss. Although it is widely acknowledged that axonal injury leads to chronic neurologic deficits, continuous axonal loss in chronic MS lesions is less well understood. Both inflammatory and primary axonal degeneration may play a role. Mechanisms leading to axonal injury and subsequent gliosis need to be studied. Hereditary leukodystrophies and other diseases affecting axonal integrity may have implications for MS. This area of research may serve as the focus of therapeutic intervention in the future.
Keynote Address : Use of Neural Stem Cell Therapy in CNS Disease
Dr. E. Snyder from Harvard University, Cambridge, Massachusetts, presented novel concepts of neural stem cell (NSC) therapy with potential applications in MS. The inherent biology of neural stem cells endows them with capabilities of regeneration and repair ordinarily considered beyond the purview of neurologic disease. However, several issues need to be resolved before NSC therapy can be tested in neurologic disease. Most chronic progressive neurologic diseases including MS are characterized by extensive, multifocal neuropathology. This makes the target of NSC transplantation therapy difficult. Moreover, the survival of NSC in chronic inflammatory diseases like MS may render NSC therapy challenging. Nevertheless, in preliminary animal experiments involving myelin disorders as well as spinal cord injury, NSC therapy appears to be promising. The ability of NSC to "home in" on pathology inside the CNS makes it an appealing therapeutic approach in the future.
Platform Presentations : Pathophysiology
Apolipoprotein E epsilon4 May Be Associated With More Severe MS and Greater T-1 Black Hole Development
T1-weighted black holes are considered MRI substrates of destructive pathology in MS. Several studies have suggested that the presence of the apolipoprotein (Apo) E epsilon4 allele may be associated with more severe forms of MS.[6-8] However, these studies have looked at small patient samples, are retrospective, and suffer from the fact that Apo E epsilon4 occurs in approximately 20% to 25% of the general population.
Enzinger and colleagues from Karl-Franzens University, Graz, Austria, studied 99 patients with relapsing-remitting MS (RRMS) who underwent clinical examination and MRI scans at baseline and after approximately 2 years of follow-up. Genotyping for Apo E epsilon4 was also performed. In Apo E epsilon4 carriers, T1-lesion load and the proportion of black holes increased significantly in contrast to non-Apo E epsilon4 carriers in whom there was no significant increase. This study further substantiated the argument that the Apo E epsilon4 allele is associated with more aggressive disease course in MS and warrants testing in a large multicenter study.
Mechanisms of Axonal Loss
Although well described by Charcot, axonal injury in MS has been under intense study during the past few years.[10,11] The recognition of axonal transection in acute inflammatory disease has provided impetus for starting immunomodulating therapy early. Professor Bruce Trapp from the Cleveland Clinic Foundation, Cleveland, Ohio, highlighted 3 key mechanisms contributing to axonal loss in MS. The first is axonal transection during inflammatory demyelination. Second is progressive loss of chronically demyelinated axons (which may be the most important factor leading to progressive neurologic disability). Finally, axonal loss also occurs in the cerebral cortex and correlates with the degree of microglial activation in cortical lesions. In contrast to previously described MS lesions pathology, these lesions do not demonstrate perivascular cuffing and cellular infiltrate. The pathology of cortical lesions may help in understanding the relationship between cortical lesion formation and progressive neurologic disability.
Neuronal Damage Secondary to T-Cell-Mediated Cytotoxicity
MS is a presumed T-cell-mediated autoimmune disorder. Dr. F. Giuliani of the University of Calgary, Canada, reported a novel mechanism of T-cell-mediated toxicity to neurons. In an in vitro experiment, human fetal neurons were co-cultured with activated T cells. Neuronal counts were significantly reduced within hours of culture with activated T cells, compared with control cultures as well as unactivated T cells, which had no effect on neurons. Moreover, oligodendrocytes and astrocytes appeared to be unaffected by the cytotoxic effect of activated T cells. This study demonstrated that activated T cells can kill neurons in the absence of MHC-I expression since neurons generally do not express MHC-I molecules. The basic mechanism underlying this cytotoxicity was direct cell-cell contact. This study lends support to the use of cytotoxic immunosuppressive therapy for MS.
Role of Ciliary Neurotrophic Factor (CNTF) in Myelin Formation
Promotion of myelin formation and repair is of obvious interest in MS. Bruno and colleagues from Hôpital de la Salpêtrière, Paris, France, presented an interesting study eliciting the role of CNTF in myelin regeneration and repair. Neurotrophic factors belonging exclusively to CNTF induced a strong myelinating effect. Oligodendrocytes matured in co-cultures with CNTF family molecules. This study warrants exploration of CNTF molecules as therapeutic agents for MS. Unfortunately, the use of neurotrophic factors in MS and other neurodegenerative diseases has been plagued by issues relating to the optimal dose and route of administration.
Effect of Early Beta-Interferon Therapy on Conversion to Clinically Definite MS: Results After 4 Years of Therapy
A previously reported 2-year double-blind, placebo-controlled study found that IFN beta-1a given at 22 micrograms subcutaneously (mcg SC) once a week significantly reduced conversion to clinically definite MS (CDMS) when given to patients after the first attack. At this meeting, Professor G. Comi of the University of Milan, Italy, presented follow-up results of this study after 4 years of observation in which all patients received IFN beta-1a 22 mcg SC weekly for the last 2 years of the study. The primary end point remained conversion to CDMS, ie, occurrence of a second attack. The study showed a significant difference favoring treatment with IFN beta-1a during the first 2 years of therapy in the earlier double-blind, placebo-controlled phase of the study. However, during the open-label extension phase when patients in both treatment arms were receiving IFN beta-1a weekly, there was no significant difference in the rate to conversion to CDMS between the 2 groups. Thus, the benefits of treatment with IFN beta-1a 22 mcg weekly appeared to be limited to the first 2 years of therapy.
The Impact of Neutralizing Antibodies (NAB) to Interferon Beta on Clinical Efficacy
Professor P.S. Sorensen, Rigshospitalet, Denmark, presented the results of a prospective study to examine the effect of NAB to interferon beta on clinical efficacy of the drug. This was a 4-year prospective study in which 422 MS patients receiving interferon beta therapy underwent testing for NAB every 6 months. The investigators observed that NAB generally appeared within 12 months of starting therapy and at a higher rate with interferon beta-1b than interferon beta-1a therapy. Of interest, after 36 months of therapy, the NAB (including those against interferon beta-1b) began to disappear. During the period when NAB were present, patients experienced higher relapse rates. However, the presence of NAB demonstrated no effect on disease progression.
This study continues to support the data that interferon beta-1b is more immunogenic than interferon beta-1a preparations. But it remains unclear why NAB disappear after some time, an observation reported previously with NAB to interferon-1b. While having information on the NAB status of a patient may be useful in limited clinical settings, the decision to switch from interferon beta to a noninterferon therapy should largely be a clinical one.
Contrast Enhancing Lesions (CEL) and Axonal Loss
Dr. Joseph Frank, Neuroimmunology Branch, National Institutes of Health (NIH), Bethesda, Maryland, discussed the evolution of contrast enhancing lesions and their relationship to axonal loss. It was pointed out that while CEL are considered to be markers of acute inflammation, it is not clear if they are associated with brain atrophy. Monthly brain MRI scans have shown, at best, modest correlation with black hole formation on T1 scans and even weaker association with brain atrophy if measured for short periods of time, ie, less than 2 years. However, it appears that for CEL that are followed prospectively for longer duration, ie, 8 or more years, the likelihood of progression of brain atrophy is higher. However, further studies in large numbers of patients over prolonged periods of time need to be conducted in order to better understand the relationship between CEL, permanent T1-black holes, and brain atrophy. This may also provide us with biologic evidence that current therapies may have on the natural history of the disease.
Relationship Between Gadolinium Enhancement (GE) and T-1 Black Holes
Increasing evidence is being placed on T-1 black holes as markers of tissue destruction. It is believed that GE lesions evolve into permanent T-1 black holes. However, it is not known which factors may predict conversion into permanent T-1 black holes. Dr. Bagnato, Neuroimmunology Branch, NIH, presented results of a study in which 8 MS patients underwent 48 monthly MRI scans. Over the course of the study, they identified 878 new GE lesions of which only 158 (18%) evolved into T-1 black holes. These black holes persisted for a mean of 9.3 months. Duration of GE strongly correlated with the formation of black holes (P = .04). For each additional month of GE, the rate of black hole disappearance reduced by 22%. This study has highlighted the significance of black hole formation and the fact that the duration of GE is critical in predicting the formation of black holes. This may have important implications for clinicians in practice where random solitary MRI scans with GE sometimes influence the choice of therapy. Such practice may have to be reconsidered in view of the current data.
Therapies Targeting the Blood Brain Barrier (BBB)
Professor Miller, Institute of Neurology, London, United Kingdom, discussed targeting BBB as a therapeutic strategy in MS. This effect is visualized as rapid and robust suppression of GE on brain MRI scans often seen with interferon-beta therapy. However, it is unclear if targeting the BBB has a significant effect on disease progression. There are few data from the existing studies that show that targeting BBB has any significant effect on disease progression. New therapies target adhesion molecules such as anti-VLA 4 (natalizumab). This therapy, currently in phase 3 trials, has shown a robust reduction of GE lesions. The obvious question that needs to be answered is whether it will translate into equally robust clinical efficacy. This is an ongoing debate and has important bearing on clinical practice. One hopes that the phase 3 trial of natalizumab will provide the answers and clarify the paradox created by some studies in which suppression of GE was not accompanied by clinical benefit.
Neuroprotection and MS
Professor R. Hohfeld, University of Munich, Germany, discussed the emerging concept of neuroprotection in MS. Immune system cells can produce neuroprotective molecules from the neurotrophin family. This phenomenon, in turn, has raised the concept of "neuroprotective immunity." In MS, immune system cells produce brain-derived neurotrophic factor. In addition, endogenous CNTF has also been found to be protective in the animal model of MS, ie, experimental autoimmune encephalitis. However, preliminary observations in the animal studies have indicated that these neurotrophic factors confer clinical benefit by immunomodulation rather than neuroprotection.
At this point, it is unclear whether primary CNS neuroprotection can be achieved with neurotrophic factors and how applicable this approach will be in a diffuse demyelinating disease like MS. The delivery and dose of neurotrophic factors is an important issue that needs to be resolved before any human studies are undertaken. Nevertheless, neuroprotection is emerging as a therapeutic concept in its very early stages.
Interferon Beta Gene Therapy for CNS Disease
Professor S. Dhib-Jalbut, University of Maryland, Baltimore, presented an interesting study examining the direct delivery of interferon beta into the CNS. Interferon beta is administered by subcutaneous injection to patients with MS. By this route, the drug is partially effective; previous studies have suggested that interferon beta does not get inside the CNS unless administered intrathecally. Thus, there is interest in enhancing the efficacy of interferon beta therapy in MS by other methods of administration.
Dr. Dhib-Jalbut used a retrovirus that expresses the interferon beta gene in the mouse. This virus-containing interferon beta gene was then transfected into mouse bone marrow cells, and the bone marrow cells were then injected intravenously into irradiated mice. These cells reached inside the CNS and expressed interferon beta mRNA and protein. Mouse bone marrow cells containing control proteins also reached the brain but did not express the interferon beta gene or its protein. Thus, it appears that using bone marrow cells may provide a nontoxic mode of delivering interferon beta into the CNS. This holds tremendous promise for using interferon beta gene infected cells as a "Trojan horse" mechanism.
Comparing McDonald's Criteria With Poser's Criteria in Early MS
McDonald's criteria have largely replaced the earlier Poser criteria for the diagnosis of MS. McDonald's criteria use MRI measures of disease activity while retaining the essential ingredients of MS diagnosis, such as dissemination in time and space. Besides retaining clinical events, McDonald's criteria include brain MRI scans that may be repeated every 3 months to look for new GE or T2-weighted lesions as evidence of dissemination in time and space.
Montalban and associates, University Hospital Vall d'Hebron, Barcelona, Spain, conducted a study in 139 patients presenting with clinically isolated syndromes (CIS) suggestive of MS. All patients were followed for approximately 3 years and underwent a brain MRI scan within 3 months of the CIS and again at 12 months. At 12 months, 11% of participants developed definite MS according to Poser criteria compared with 37% using McDonald's criteria. Over the 3 years of follow-up, 80% of the patients who met the definition of definite MS according to McDonald's criteria developed definite MS according to Poser criteria. This study highlights the significance of obtaining brain MRI scans in patients presenting with CIS and offering treatment early if they show evidence of disease dissemination on MRI scans.
HLA Genetics and MS
The HLA-DR locus on chromosome 6p21 has been linked with MS. Professor S. Hauser, University of California at San Francisco, presented the results of an ongoing multicenter genetics study in a North American MS population. This study focusing on chromosome 6p21 showed that other than the DR locus, no other susceptibility locus within this chromosomal region could be identified. Individuals who inherit 2 copies of DR2 haplotypes have a higher risk of developing MS than those who have only 1 copy of DR2 haplotype. In addition DR2 homozygotes were less common in patients with clinically benign disease. This is the first study to shed light on the role of the HLA-DR locus in the pathogenesis of MS. However, it is not yet recommended that patients suspected of having MS undergo routine testing for HLA-DR2 haplotypes. A larger number of patients with prospective follow-up will be required to validate these findings. This study aims to accomplish these goals.
Pregnancy Hormone Estriol Therapy in MS
Previous studies have suggested that women are more susceptible to autoimmune diseases. Dr. R. Voskuhl, University of California at Los Angeles, conducted a study using the pregnancy hormone estriol in nonpregnant women with MS. This hormone is believed to play a significant part in the protective role of late pregnancy in women with MS.
In this study, nonpregnant women with MS received 8 mg of oral estriol daily for 6 months. The patients were followed for 6 months before and after treatment. Monthly brain MRI scans were obtained. Treatment with oral estriol reduced GE lesion number and volume, which returned to pretreatment levels once treatment was stopped. The greatest effect was seen in RRMS patients. Furthermore, oral estriol also demonstrated immunoregulation by reducing interferon gamma levels and delayed-type hypersensitivity responses. This pilot study paves the way for a larger study to further test this promising therapy in MS.
Interferon Beta-1b in Primary Progressive MS (PPMS)
This year's joint meeting included a Late-Breaking News session on the last day of the meeting. Of the 7 papers presented, 1 drew particular interest among the MS clinical investigator community.
PPMS comprises approximately 10% to 15% of the total MS population, and there are no effective treatments available as yet. There is considerable interest in exploring the efficacy of therapies approved for RRMS in patients with PPMS. Dr. X. Montalban, University Hospital Vall d'Hebron, Barcelona, Spain, presented the results of a single-center, double-blind, placebo-controlled study using interferon beta-1b in 73 PPMS patients randomized to receive interferon beta-1b at 8 MU or placebo SC every other day for 2 years. The primary end point was time to confirmed progression indicated by a 1-point change on Expanded Disability Status Scale measured at a 6-month interval. Patients also underwent annual brain MRI scans to evaluate conventional MRI measures as well as brain atrophy. Other secondary end points included MS functional composite measurements, depression scales, and fatigue severity scales.
Treatment with interferon beta-1b showed no significant benefit over placebo on the primary end point as well as several MRI measures including brain atrophy. Although discouraging, this study sheds light on PPMS being predominantly a noninflammatory disease process and the limitations of anti-inflammatory therapy like interferon beta in PPMS. One hopes that this will encourage investigators to consider therapies targeting neuroprotection, axonal-glial interaction, and regeneration as potential therapies for PPMS and eventually for relapsing forms of MS as well.
Medscape Neurology & Neurosurgery 4(2), 2002.
© 2002 Medscape