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Drs. Bruce Cree and Barry Singer, 2 expert neurologists in multiple sclerosis, will be discussing interesting issues presented at the 23 Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2007. The meeting was held from October 11 to 14 in Prague, Czech Republic.
Barry Singer, MD: Let us first discuss recent genetic data presented at ECTRIMS. David Hafler in his presentation entitled "Collaborative efforts to understand the genetic basis of MS" showed data from the first large-scale, fully replicated whole genome association scan aimed at identifying new potential genetic markers.
Bruce Cree, MD, PhD, MCR: Dr. Hafler discussed the data from the International Multiple Sclerosis (MS) Genetic Consortium's whole-genome association screened results. The main findings from this study are that one had very resounding confirmation of the role of class 2 human leukocyte antigen (HLA) molecules in MS pathogenesis. This information has been known for a long time, and the whole genome-wide association screen further emphasizes HLA antigens' importance, which speaks to the power of that particular locus in helping determine MS susceptibility.
The other aspect of that study that was interesting was the observation that 2 other regulatory genes involved in the immune system, the interleukin-2 (IL-2) and interleukin-7 (IL-7) receptors, also were involved in MS pathogenesis. The overall results of the screen were that there were probably several other areas that need to be further replicated, but at least so far, the top 3 candidates are all involved in the immune function in MS. This data is encouraging.
Dr. Singer: Yes, I agree that it is also exciting. One of the new potential treatments for MS is focused on the IL-2 receptor. Data presented at ECTRIMS on daclizumab showed some efficacy of the monoclonal antibody to the IL-2 receptor. This ongoing, phase 2, randomized, double-blind, placebo-controlled clinical study, known as the CHOICE trial, investigated the therapeutic benefit of adding daclizumab in patients who continually have active MS disease while receiving interferon-beta therapy. From a genetic standpoint, the genome screening in patients with MS may reveal new immune targets.
Dr. Cree: Right, if we understand the pathways that have been elucidated by the genetic studies, even if these pathways in terms of the specific alleles have only a very minor contribution to MS susceptibility, as is the case with the IL-2 and IL-7 receptor polymorphisms, tells us that those pathways are somehow involved. These new targets are potentially important candidates for directing therapeutic intervention.
For instance, in the CHOICE study, the monoclonal antibody against the IL-2 receptor, daclizumab, can profoundly influence MS management. Even though the IL-2 receptor, for example, has a minor contribution to MS susceptibility overall, it can really profoundly affect a target when there is a monoclonal antibody directed against it, such as daclizumab. The CHOICE study illustrated a statistically significant 72% reduction in the number of new or enlarged gadolinium-enhancing lesions (Gd+) at week 24 in patients who received the higher-dose arm (2 mg/kg subcutaneously every 2 weeks). In addition, both daclizumab treatment groups (low and high dose) had a reduced annualized relapse rate by around 35% compared to the placebo, although this did not reach statistical significance.
The genetic data is identifying potential targets for both monoclonal antibody and small molecule treatments directed toward those targets.
Dr. Singer: Another interesting presentation examined the adaptive immunity that is antigen-specific driven with B cells and T cells against central nervous system (CNS) myelin antigens vs the innate immunity with dendritic cells and activated microglia. Dr. Howard Weiner discussed the role of the innate immunity in progressive MS disease and its potential as a treatment target for MS. Patients with progressive MS have plaques with the activated microglia. Dr. Weiner observed increased expression of gamma-interferon and reduction of IL-13 in the dendritic cells from patients with secondary progressive MS.
Dr. Cree: There are several medications which are being developed that have anti-microglial activity. There is extensive microglial activation present in both secondary progressive and primary progressive MS, although the significance of this activation is not entirely clear. Is it an indication that activated microglia are somehow involved in causing ongoing myelin destruction? Or are they simply activated in response to the damage to myelin?
Various compounds are currently being investigated for their anti-activated microglial properties such as minocycline and statins.
Dr. Singer: Yes, I think there's also some pathologic information from the patients that had bone marrow transplant and then subsequently died. When the plaques and lesions were examined in these patients that had their B and T cells obliterated, ongoing demyelination was still seen in these patients. The microglia in the lesions that were still activated and causing damage. Therefore, preventing microglial activation may be a new therapeutic target to explore in order to reduce the likelihood of progressive of MS.
Dr. Cree: There are many challenges in understanding the pathogenesis of primary and secondary progressive MS. Drs. Compston and Coles described the challenges of progressive MS in patients treated with alemtuzumab. They found a very profound effect of treatment with alemtuzumab on contrast- enhancing activity and relapses in secondary progressive MS patients. Unfortunately they also found that over time, MS disability continues to progress in these patients. We know from the phase 2 trial with alemtuzumab, that alemtuzumab has very profound effects in terms of shutting down the immune systems, an effect we've known from the fludarabine-resistant chronic lymphocytic leukemia (CLL) experience, and that that effect translates into an impressive reduction in disease activity in relapsing MS.
The question remains why is it that secondary progressive patients continue to progress. The answer is still unknown. Experts suggest that activation of microglia is a part of the process, however, there are probably more processes involved as well. Certainly injury to axons has been long thought to contribute to the progressive aspects of multiple sclerosis, although that is really a matter of presumption. We have taken that to be a truism without really having any data to truly support progressive axonal damage. This led to the concept of aggressive treatment early on in the disease state to try and prevent axonal injury from occurring, and thereby hopefully stave off the secondary progressive changes.
Dr. Singer: Challenging the dogma, maybe there is something primarily neurodegenerative early on in the disease and the inflammatory component is actually secondary. Barnett and Prineas had presented data discussing that apoptosis can happen early in relapse and remitting patients even before inflammation comes into the site. It is still the chicken and the egg question, which is coming first? Is it an inflammatory process with neurodegeneration or neurodegeneration with secondary inflammation?
Dr. Cree: I agree. The observation of type 3 plaques described by Claudio Lucchinetti and colleagues are hard to understand if MS is purely an inflammatory disease.
Dr. Singer: Another new potential treatment with an interesting mechanism is FTY720 (fingolimid). There was data presented at ECTRIMS starting to look at direct CNS effects via S1P receptors. FTY720 affects not only the astrocytes but also oligodendrocytes and microglia. Neurons themselves all have S1P receptors. FTY720 can stimulate immature oligodendrocyte and adult oligodendrocyte lineages from rat cell culture, raising the intriguing possibility of remyelination.
In addition, investigators also created a knockout mouse, without the S1P receptor, and they found that that could block the development of experimental allergic encephalomyelitis (EAE) in the animals, independent of the FTY720.
Dr. Cree: Right, interesting. One of the things about FTY720, if you go back to the original phase 2 clinical trial that I have always puzzled over, is they had a very robust effect in terms of reduction in relapses. There was a 53 to 55 percent reduction in relapses; however only a 43 to -61 percent reduction in terms of contrast-enhancing activity was observed. It is usually the other way around. One typically observes a more robust effect in reduction of contrast-enhancing activity with immunological agents and a less robust effect in terms of relapses. Quite possibly, based on what was discussed at the meeting, FTY720 may be having direct effects within the central nervous system as well as effects in the peripheral immune system. If FTY720 is affecting the central nervous system, perhaps it is altering the number of relapses that way, and perhaps decreasing contrast-enhancing activity by its effects on the immune system.
Dr. Singer: Yes, it is interesting. In fact, there was one other presentation where you could use FTY720 intrathecally and it actually reduced the severity of experimental allergic encephalomyelitis without a change in the white blood cell count. It is pretty interesting how these new targets and new treatments can work. In terms of other oral medications, was there anything else that was particularly interesting to you?
Dr. Cree: Well, there were a number of presentations or posters on cladribine, but really we do not have any data on that yet in terms of efficacy. The results should be discussed at future meetings.
Dr. Singer: Yes, a couple of researchers presented safety data and thus far, it looks fairly safe. In one investigation, Giovannoni and colleagues compiled all the different clinical trials and included that data, which allowed for analysis on 1300 patients. There was also a smaller safety trial with cladribrine as an add-on to interferon beta-1a.
Dr. Cree: Do you think it is a great idea to study the use of a broad-spectrum immune suppressant in combination with an interferon?
Dr. Singer: It is important to determine the safety at least in a small cohort of patients since we know that combination therapy occurs in real-life situations. For example, mitoxantrone has been studied against placebo and works well for relapses and disability. However, when the RENEW trial looked at real-world experience, it seemed like it was as many as 70 percent of people were using it in combination with immunomodulatory therapy. There are risks clearly with natalizumab. Whether the combination of natalizumab and interferon beta-1a led to progressive multifocal leukoencephalopathy (PML) is still unknown.
In addition, data presented previously in the pivotal trials of patients treated with natalizumab was being rechallenged. The preliminary data showed that the risk of allergic reaction was apparently small; however, patients who received 1 or 2 does of natalizumab with a subsequent hiatus were at increased risk for a reaction.
Dr. Cree: In addition, there is some interesting data that discussed using plasma exchange for accelerating clearance of natalizumab in patients with multiple sclerosis. The results were quite convincing that natalizumab can be cleared for a patient in the event of PML. The patient who was at our center who got PML was, in fact, treated with plasma exchange exactly for that reason, and perhaps that is one of the things that contributed to his survival.
Dr. Singer: Dr. Cree, you are an expert on neuromyelitis optica [NMO]. Did you see anything either diagnostically or therapeutically that was intriguing to you?
Dr. Cree: Yes, there was data presented by Jacob and colleagues investigating the use of mycophenolate mofetil for the treatment of neuromyelitis optica. The study found an impressive effect in terms of reduction in relapses with treatment with mycophenolate mofetil. It is important to do this type of retrospective look, and we previously have done that with rituximab and shown that the number of relapses declines after treatment with rituximab.
Mycophenolate mofetil is an interesting drug. It is a broad-spectrum immune suppressant, but it does not deplete lymphocytes as much as other agents such as azathioprine. It tends to be a little bit easier to monitor and tends to be better tolerated, at least in my experience. There seems to be fewer side effects with mycophenolate mofetil. It is important to support use of mycophenolate mofetil in neuromyelitis optica, particularly when it is not possible to get patients treated with rituximab for insurance purposes, or when they cannot tolerate azathioprine due to some of the more common side effects such as gastrointestinal (GI) discomfort and so on.
There were a number of other interesting observations on NMO presented as well. Some interesting findings using animal models with myelin oligodendrocyte glycoprotein (MOG)-induced form of EAE in Norway rats were discussed by Collongues and colleagues. After inducing EAE in this brown Norway rat, which is a model for neuromyelitis optica, there is a tendency for involvement with the optic nerve and spinal cord. Further investigation showed that there was activity against the aquaporin-4 protein in the serum. The activity was directed against 5 peptides of which 2 were intracellular peptides and the remainder were extracellular peptides.
Now, it was not overwhelmingly convincing, but still it was remarkable that immunization with MOG could ultimately generate anti-aquaporin-4 antibodies, which really came as a surprise to me. One would have thought that immunizing with MOG would have generated anti-MOG antibodies, not anti-aquaporin-4 antibodies. One is left with trying to explain why there are antibodies against anti-aquaporin-4 antibodies in this rat which gets optic nerve and spinal cord involvement. Therefore, there must be something different about the rat's genetic background that predisposes it to developing antibodies against aquaporin-4 protein. At least that is one possible explanation for why that was observed.
Other studies are now looking at the genetics of neuromyelitis optica, and not too surprisingly, finding that the genetic basis for neuromyelitis optica is probably different from the genetic basis for MS. These studies are very small and are probably underpowered in order to do the type of genetic analysis necessary to really tease these things apart, but at least it is a start.
Dr. Singer: In terms of an existing therapy that is available with disease-modifying drugs, does anything stand out to you in terms of current medications? One particular poster on glatiramer acetate (GA)-specific T cells that were generated out of the cerebrospinal fluid, illustrated that the GA-specific cells were primarily Th2 cells. Furthermore, this demonstrated that GA-specific T cells can enter the CNS compartment of GA-treated MS patients to act locally within the brain.
Dr. Cree: In addition, Weber and colleagues showed that the GA has an affect on antigen presentation of monocytes and macrophages. It looks like GA probably has multiple mechanisms of action: certainly the Th1 to Th2 bias shift resulting in the cells that you described and also possibly by downregulating antigen presentation through its effect on monocytes. It's a very interesting compound, and it would be interesting, I think, to see whether the observations from EAE bear out in human trials.
Dr. Singer: Another area that was interesting was concerning cognitive function and MS. The CogniMS trial, which was first presented last year at ECTRIMS in Madrid, examined the cognitive function of around 430 patients with MS. As many as 40 percent of patients with MS had cognitive dysfunction early on. Cognitive function was investigated using 2 different doses of interferon beta-1a in this cohort of patients with MS over 2 years. The patients treated with higher dose actually had less cognitive impairment than those that were put on the lower dose. This study showed a dose-dependent significant effect early on in the treatment of MS.
Dr. Cree: That is interesting and important as well.
Dr. Singer: Yes, to show any benefit on cognitive function is clearly important. I know with my own patients this is one of the reason why I tend to be filling out disability forms. It is not necessarily physical disability, but a lot of the fatigue and cognitive issues that drive much of the disability.
Dr. Cree: Yes, those are the main causes of disability: fatigue, cognitive impairment, and ambulatory impairment, which is probably the third. All the while we have been thinking about MS, at least in terms of the Expanded Disability Status Scale (EDSS) scale, as being a disabling disease due to its ambulatory impairments; however, cognitive and fatigue are probably even more serious contributions to overall disability.
Dr. Singer: This leads us to the discussion once again as to whether to start treatment early on. As a personal view on the differences, it is quite striking in the differences of how MS is treated in Europe and Canada compared to the United States. In the United States, treatment is much more likely to be initiated early. In Prague in the Czech Republic where this meeting was held, there is limited access to treatment, clearly an impediment to getting on treatment. The data now with the BENEFIT trial about the advantages of starting early in preventing disability is tremendously important.
Dr. Cree: Initially, we had data on early treatment with interferon beta-1a and the clinically isolated syndrome that did not show an impact on disability. The data from the BENEFIT trial presented at ECTRIMS showed an impact on relapses as well as disability. Maybe this new data will make access to these medications in certain countries easier. For example, in Canada patients have to have clinically definite MS in order to receive treatment with either interferon or glatiramer acetate.
Dr. Singer: That is definitely true, the access is definitely limited. In fact, I was talking to a nurse practitioner who says that they cannot get routine follow-up magnetic resonance imaging (MRI) scans to monitor how patients are doing on therapy unless they are symptomatic. In my practice, I generally have to do a follow-up MRI 1 year after patients are in treatment, and maybe every 2 to 3 years after that. The treatment might be adjusted if I saw a number of enhancing lesions on a current treatment. Clinicians in some countries do not have the ability to monitor, radiographically, disease control.
Dr. Cree: In addition to the posters discussed previously, there was a poster discussing cognitive issues in patients with neuromyelitis optics, which to my knowledge has not been discussed before. This is interesting since neuromyelitis optics was typically thought of as a disease that spared brain damage. To my knowledge, this has never been looked at or reported before. Now there are cases where we now recognize patients may have the neuromyelitis optics antibody but have abnormal brain MRI scans. In these cases, one might expect to see cognitive impairment. This raised the issue that maybe there are issues occurring in neuromyelitis optics besides the obvious lesions involving the optic nerves and spinal cord.
Dr. Singer: We, as clinicians, are getting more sophisticated in our use of imaging, and perhaps we will be able to understand more of the pathology. One of the major areas of improvement is understanding and visualizing cortical lesions and observing demyelination within different layers of the cortex. Imaging cortical lesions may allow us to examine their role on cognitive dysfunction.
Dr. Cree: Yes, which leads us to another interesting topic about B-cell follicles within MS patient brains discussed at the meeting by Magliozzi and colleagues. They observed the B-cell follicles mainly in the meninges and adjacent to large cortical lesions. These cells may attribute to the cortical plaques we observe, and therefore contribute to the neurodegeneration and inflammation. What was interesting was that by using in situ hybridization, the investigators found that the B cells within these ectopic follicles can be hybridized to fragments of DNA from the Epstein-Barr virus (EBV). They theorized that the proteins that are latent proteins from EBV infections within these cells are also found within these ectopic follicles in patients with MS. Perhaps these are targets for cytotoxic CD8-positive T cells.
This is still an evolving story; however, these findings have several features with tantalizing connections to the pathogenesis of MS in terms of B cells being present in the central nervous system, in terms of EBV infection, and of the involvement of cytotoxic T cells. This study is going to generate a lot of controversy. Previously researchers have looked extensively for the presence of EBV in the brains of patients with MS, both within MS plaques and elsewhere, and to date no one found strong evidence suggesting that EBV-infected B cells are involved in MS. Thus Magliozzi and colleagues have made what seems to be a very striking observation.
On a particular note, there was an issue discussed briefly during the question and answer session, as to why they had only identified EBV by in situ hybridization, rather than by doing real-time polymerase chain reaction (PCR) to amplify up the EBV fragments, and the sequencing to prove that it is EBV. That raises the question, if it is all done by hybridization, is it possible that it is some other type of herpes virus other than EBV that the hybridization was reacting to?
Dr. Singer. I agree. It is known that many herpes viruses have been studied over the years.
Dr. Cree:. In summary, I found the whole meeting to be fairly interesting, some interesting information coming out in terms of novel treatments and further studies in MS pathogenesis. I think there's going to be a lot of things to follow up on in the months to come when these papers find their way into press.
Dr. Singer: Yes, the progress is very exciting. I think particularly for patients, like the ones I saw today, that the future is definitely promising. We are discovering new approaches and many different types of medications, not only just the orals and the monoclonals, but even vaccinations such as BHT-3009. Investigators are even studying fluoxetine hydrochloride.
Dr. Cree: Well it was great chatting with you Dr. Singer about the data presented at ECTRIMS.
Dr. Singer: Likewise. It's gratifying that so many of our colleagues are equally committed to helping to better understand and more effectively treat MS.
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