Genetic, environmental factors may together increase risk of MS through common cellular pathway

hollie — Wed, 01 Jun 2011 18:53:37 -0400

Scientists from Irvine, California and Toronto have just published an interesting study that explains how genetic and environmental factors may interact to cause MS. It's widely accepted that both types of factors are involved in triggering the disease, but so far very few ideas have been proposed and tested to show how this might happen. This study focused on a process called glycosylation, which is the attachment of certain sugars to proteins located on the surface of cells. The presence of these sugars affects how cells behave and respond to various signals, and in the case of immune cells, influences their ability to be activated to participate in an immune response. The research team had previously created a mouse model with genetic deficiences affecting glycosylation; these mice spontaneously developed an inflammatory demyelinating disease resembling MS, so the scientists hypothesized that this cellular function might also play a role in MS.

Through a series of studies, the team demonstrated that several MS risk factors (variants in the IL7RA, IL2RA, MGAT1 and CTLA-4 genes, and low levels of vitamin D) can alter the glycosylation process in ways that may both result in immune dysfunction and enhance the vulnerability of oligodendrocytes and neurons. In addition, these factors appear to have an increased effect when present together. The authors suggest that supplementation with vitamin D and N-acetylglucosamine may help to reduce the increase in MS risk associated with the glycosylation process.

Here's an article summarizing the paper, and here's the paper itself. The Accelerated Cure Project Repository provided DNA samples to Dr. Demetriou for this study, so we're pleased to have played a supporting role in generating these results.

ACP's Notes From the 2011 AAN Meeting in Honolulu

hollie — Wed, 04 May 2011 15:24:07 -0400

ACP's Notes From the 2011 AAN Meeting in Honolulu

American Academy of Neurology meeting April 9-16, Honolulu, Hawaii

Each year staff from Accelerated Cure Project attend the American Academy of Neurology annual meeting. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://www.abstracts2view.com/aan

continued...

The first AAN that Art and Hollie attended was also held in Honolulu (April 2003). You can read our notes from that meeting here if you're interested in knowing what the state of research was 8 years ago. Several interesting findings were presented at the 2003 meeting, including:

Insights into how gray matter is also affected in MS, including how gray matter lesions differ from those in the white matter, and why they're harder to detect
Results from early autologous stem cell transplantation attempts (the “immune system rebooting procedure”) – complication rates were higher back then but changes to the procedure have since made it safer
Compelling evidence that Epstein-Barr virus (EBV) antibody positivity is highly associated with pediatric MS (the same association exists in adult MS, but is not as striking since almost everyone is seropositive by the time they reach adulthood)
Early treatment response studies suggesting that the protein TRAIL could be a predictor of IFN-beta response – treatment response is still an active area of research and will increase in importance as new treatment options become available and people need guidance about which therapy would be best for them
Last but certainly not least, the discovery of a serum antibody (NMO-IgG) that can help diagnose neuromyelitis optica (NMO). This antibody is now known to bind to aquaporin-4 and researchers are busily trying to build on these findings to unravel the triggers and mechanisms of NMO. Brian Weinshenker (one of the original presenters, along with Vanda Lennon), won this year's Dystel Prize for his work on NMO-IgG as well as other significant contributions to the understanding and treatment of demyelinating diseases.

Monday 04/11:

For this conference, Hollie was joined by Sara Loud, ACP's repository director, and Evelyn (Evi) Strauss, executive editor of our forthcoming web community for MS researchers. Each of us made our way to Honolulu, Sara and Hollie traveling from Boston (long flights) and Evi from California (not-so-long flight). We met for an early dinner and then headed back to the hotel to get a good night's sleep.

Tuesday 04/12:

In the morning we went to the poster session (see the end of these notes for poster highlights) and the plenary session. We enjoyed the first part of Stephen Hauser's talk on what's in store for MS, but left before the end to meet with one of our repository users, Jennifer Yarden of Glycominds.

S01: Multiple Sclerosis: Imaging (Hollie)

[S01.001] Patients with Multiple Sclerosis Do Not Suffer from Cerebro-Cervical Venous Congestion
Florian Connolly, Friedemann Paul, Berlin, Germany, Jose M. Valdueza, Frehland Julika, Bad Segeberg, Germany, Klaus Schmierer, London, United Arab Emirates, Schreiber J. Stephan, Berlin, Georgia

A group that had previously investigated cerebral blood flow in MS to test the CCSVI theory (which postulates that reduced blood drainage of the central nervous system causes MS) repeated their study on a larger group of subjects (94 MS subjects and 20 controls). As in their previous study, they did not find any correlation between reduced blood flow and MS, although they noted that their study was not blinded. They also pointed out that there are difficulties in comparing the different techniques being used in CCSVI investigations – for instance, MR venography indicated an apparent stenosis in one location in a subject, but Doppler sonography indicated an increased blood flow there.

[S01.002] The Perfect Crime? CCSVI Not Leaving a Trace in MS. A Duplex Sonographic Study Following the Zamboni-Protocol
Christoph A. Mayer, Waltraud Pfeilschifter, Mathias W. Lorenz, Frankfurt am Main, Hessen, Germany, Max Nedelmann, Giessen, Hessen, Germany, Ingo Bechmann, Leipzig, Germany, Ulf Ziemann, Frankfurt am Main, Hessen, Germany

Another group decided to replicate the original Zamboni CCSVI data, using a sonographer, data analyst and statistician who were each blinded about MS/control status. 20 MS subjects (17 relapsing-remitting and 3 progressive) and 20 controls were enrolled and evaluated with duplex sonography. No meaningful differences were found between the two groups in terms of how many subjects had each of the individual Zamboni criteria, and only one subject (a control) fulfilled at least two criteria. Dr. Mayer speculated that the differences in these results compared with Dr. Zamboni's results could be due to use or non-use of blinding, or to the choice in the cut-off values used to classify fulfillment of the criteria. He stated that those values came from other studies that were not validated and not necessarily applicable for use in MS research. He concluded that the CCSVI hypothesis remains unconfirmed and said that he would discourage treatment based on the concept.

An audience member pointed out that this study didn't examine the same veins as Dr. Zamboni's study (I couldn't hear the reply). Another audience member pointed out that Dr. Mayer's institution is performing CCSVI interventions, but he replied that this activity was taking place in another department (radiology), not his (neurology).

[S01.003] Every Multiple Sclerosis Lesion Is a Black Hole: A Comparative Ultrahigh Field Strength MRI Study
Tim Sinnecker, Paul Mittelstaedt, Jan M. Dörr, Caspar Pfueller, Lutz Harms, Thoralf Niendorf, Friedemann Paul, Berlin, Germany, Jens Wuerfel, Lubeck, Germany

20 RRMS subjects were imaged using both standard 1.5T and high field strength 7T MRI. The number of lesions found at 7T using a certain technique called T1-weighted MPRAGE were double the number found at 1.5T, and this technique at 7T was able to identify every lesion found using T2 weighted MRI. 10 controls were also imaged; no lesions were found. Dr. Sinnecker wondered whether it would still be necessary to image using T2 in the future, since T1 MPRAGE has a high signal/noise ratio, good gray/white matter contrast, and cortical lesion detection capability. He also wondered whether every MS lesion can be considered a T1 “black hole” (a site of persistent axonal damage) since they all seem to show up as such using high field strength MRI. People commenting from the audience noted that this conclusion is premature without confirmation from pathology studies.

[S01.004] Column-Specific, Quantitative Diffusion Tensor Imaging in the Spinal Cord in Multiple Sclerosis
Jiwon Oh, Min Chen, Kathleen Zackowski, Baltimore, MD, Seth Smith, Nashville, TN, Jerry L. Prince, Peter A. Calabresi, Baltimore, MD, Daniel S. Reich, Bethesda, MD

One reason why MRI findings in MS often don't correlate with clinical outcomes is that often only the brain is imaged, whereas injury to the spinal cord can contribute significantly to disability. Spinal cord imaging is often not performed because it has a low signal to noise ratio and is sensitive to motion. Newer techniques such as diffusion tensor imaging (DTI), which measures microstructural tissue damage, and magnetic transfer imaging (MTI), which measures myelin content, might help. A pilot study to use these techniques in MS and control subjects found statistical differences between the two groups in measurements of the dorsal columns but not the lateral columns (which are smaller and harder to delineate). The next step will be to see whether these data correlate with functional measures.

[S01.005] Quantifying Remyelination in Multiple Sclerosis Using High Field (9.4T) Magnetic Resonance Imaging
Shoaib Y. Ugradar, Harry Parkes, Po-Wah So, David H. Miller, Samuel Jackson, Francesco Scaravilli, Klaus Schmierer, London, United Kingdom

Conventional MRI techniques are good at identifying white matter lesions, but not at distinguishing remyelinated from demyelinated lesions. Having this capability would be very helpful in testing therapies designed to stimulate remyelination. Dr. Ugradar described a study in which 9.4T MRI was used to image 14 post-mortem brain tissue blocks with visible white matter lesions (21 demyelinated and 4 remyelinated). It was possible to distinguish the remyelinated lesions because they were less hyperintense on T2 images than the demyelinated lesions. More samples need to be studied to achieve better distinction between demyelinated and remyelinated areas, but perhaps someday high-field strength MRI can be used for this purpose in clinical trials.

[S01.006] Neck Veins in Patients Followed in the MS Clinic: Magnetic Resonance Venography Findings
Katayoun Alikhani, Calgary, AB, Canada, Donald Lee, Marcelo Kremenchutzky, London, ON, Canada

This study used MR venography to see whether neck vein abnormalities were more common in people with MS. Patients scheduled for a clinical MRI related to MS, headaches, or other conditions (excluding stroke) were invited to participate in this study which involved spending a few extra minutes in the scanner. Staff were blinded, with all participants labeled as having “possible MS.” 65 subjects were enrolled (19 controls, 33 MS, 13 CIS/possible MS). The percentage of subjects with an abnormal MRV was similar across all of the groups. Abnormalities were associated with age, disease duration, and EDSS. Further studies are underway.

[S01.007] Increased Adenosine A2A-Receptor Binding in the Brain White Matter of Secondary Progressive Multiple Sclerosis Patients Detected Using [11C]-TMSX PET
Eero Rissanen, Jere Virta, Helin Semi, Juha Rinne, Laura Airas, Turku, Finland

Adenosine, a neuromodulator and regulator of inflammation in the CNS, has four different receptors. One of these, adenosine A2A, has variable effects depending on the physiological circumstances but one of its functions is to promote inflammation. To evaluate its role in MS, 8 SPMS subjects and 7 healthy controls were imaged with a PET scanner using a radioligand ([11C]-TMSX) that binds to the A2A receptor. Uptake of TMSX was significantly greater in the supraventricular white matter of MS subjects vs. controls. Its distribution was also greater in the normal appearing white matter of MS subjects, but no specific uptake was seen in lesions. Dr. Rissanen concluded that TMSX/PET might serve as a biomarker for burden of disease and that the A2A receptor may contribute to MS pathology. The next study will use the TMSX/PET technique in people with relapsing-remitting MS.

An audience member noted that caffeine has some effect on adenosine A2A and wondered whether caffeine intake has been studied in people with MS.

S10: Multiple Sclerosis: Genes and Environment (Evi)

[S10.002] New IFN-beta Targeted Genes in Multiple Sclerosis: Global Gene Expression Analysis in Plasmacytoid Dendritic Cells
Latt Latt Aung, Suhayl Dhib-Jalbut, Konstantin E. Balashov, New Brunswick, NJ

In their attempts to identify biomarkers that will be useful for treating or diagnosing MS patients, scientists are taking numerous approaches. This presentation described a pilot search for genes whose activity might reflect the presence of disease and response to treatment with IFN-beta-based medications. The researchers studied 9 MS patients and 8 healthy individuals; they focused on plasmacytoid dendritic cells (pDCs), which accumulate in MS patients, sense viruses such as EBV that are implicated in MS, and whose misbehavior can promote abnormal immune responses. By using magnets attached to antibodies that grab pDCs, the team separated these cells from others. Microarray analysis uncovered 23 genes whose baseline activity in pDCs is abnormally low in MS patients and rises after treatment and 37 genes whose activity is abnormally high in MS patients and falls after treatment. This work points toward gene candidates that might serve as therapeutic targets or markers of drug response.

[S10.003] Some Multiple Sclerosis Susceptibility Genes Are Associated with Relapse Severity and Recovery
Ellen M. Mowry, San Francisco, CA, Maria R. Blasco, Madrid, Spain, Jean Pelletier, Marseille, Cedex 5, France, Pierre Duquette, Montreal, QC, Canada, Pablo Villoslada, Barcelona, Spain, Irina Malikova, Christophe Picard, Marseille, France, Jamie McDonald, San Francisco, CA, Elaine Roger, Montreal, QC, Canada, Stacy Caillier, Jorge Oksenberg, Emmanuelle Waubant, San Francisco, CA

MS relapses vary in their severity and in patients’ ability to recover from them, and clinicians are eager to devise methods that help predict what type of disease course an individual can expect. Ellen Mowry and colleagues at UCSF have begun to test whether genes associated with MS susceptibility are also associated with attack severity or recovery. The study genotyped 354 patients from five centers in the US, Canada, and Europe, and Mowry presented some initial data. For example, CD58, a molecule that might promote T cell maturation or proliferation, is associated with reduced odds of having a serious second attack, and CD6, a molecule that promotes the Th1 immune response, is associated with increased odds of having a serious second attack and of failing to recover well. This work might help clinicians advise patients, stratify them, and treat more aggressively those at higher risk.

S11: Multiple Sclerosis: Imaging and Cognition (Hollie)

[S11.001] Regional Cervical Cord Atrophy in Patients with Relapsing-Remitting Multiple Sclerosis: A Cord Voxel-Based Morphometry Study
Maria Rocca, Paola Valsasina, Stefania Sala, Milan, Italy, Mark A. Horsfield, Leicester, LE, United Kingdom, Patrick Stroman, Kingston, ON, Canada, Martina Absinta, Giancarlo Comi, Massimo Filippi, Milan, Italy

This study involved the use of MRI to analyze loss of spinal cord tissue in subjects with RRMS and SPMS. Spinal cord atrophy was widespread in subjects with SPMS but clusters of atrophy were also found in RRMS subjects, particularly in the lateral and posterior cervical cord columns. Degree of atrophy correlated with disability and with conventional MRI measures of damage in brain tissue. An audience member pointed out an interesting discrepancy between this study, which showed abnormality in the lateral columns, and the study presented in the previous imaging session which did not.

[S11.002] Detection and Localization of Hippocampal Atrophy in Multiple Sclerosis Patients with Depression
Nancy Sicotte, Mary-Frances O'Connor, Los Angeles, CA, Stefan Gold, Hamburg, Germany, Raja Gill, Michael Montag, Yonggang Shi, Los Angeles, CA, Daniel Pelletier, San Francisco, CA, David Mohr, Chicago, IL

Depression is a common MS symptom, and the hippocampus is important for cognition and mood. This team decided to follow up on previous research which found a link between hippocampal atrophy and depression by using techniques better suited to larger studies. They analyzed 3T MRIs from 109 women with MS who had participated in a stress intervention study. Using a 3D volumetric method, they generated surface maps of the hippocampus and its subregions which could be used to measure atrophy. The volume of the right hippocampus (but not the left) was decreased in those subjects who had high depression scores. This association was not found in subjects who had been successfully treated for depression – their volumes were similar to the non-depressed subjects. Dr. Sicotte concluded that there could be areas of the hippocampus that are more susceptible to cortisol damage, and also noted that the scientific literature on depression varies on which side is more affected.

[S11.006] Regional Gray and White Matter Atrophy Are Largely Unrelated in Relapsing Remitting Multiple Sclerosis
Gianna Carla Riccitelli, Maria Rocca, Elisabetta Pagani, Vittorio Martinelli, Marta Radaelli, Andrea Falini, Giancarlo Comi, Massimo Filippi, Milan, Italy

This team performed a study that was similar to the spinal cord atrophy analysis described above, but involved brain MRIs. RRMS subjects and healthy controls were imaged using 3T MRI and the volumes in different areas were compared after identification and adjustment for lesions. Atrophy in the gray and white matter tended to occur in patterns of regional distribution (e.g., deep gray matter nuclei, fronto-parietal lobes, corpus callosum). White matter atrophy correlated with the presence of T1-hypointense lesions. Disease duration was related only to thalamic atrophy. Disability scores were associated with atrophy in the sensorimotor areas; neuropsychiatric scores were associated with atrophy in cognitive network areas.

[S11.004] Ultra-High Field MRI and Cognitive Dysfunction Associations within an MS Cohort
A. Scott Nielsen, Boston, MA, Caterina Mainero, Charlestown, MA, Nancy Madigan, R. Philip Kinkel, Boston, MA

This study investigated connections between MRI measures and cognitive impairment. 27 subjects with clinically isolated syndrome (CIS)/early MS (EDSS < 2), RRMS (EDSS > 2), or SPMS > 10 years were imaged using 7T MRI. They were also given cognitive tests that assessed different types of processing (executive function, processing speed, and learning/memory). Several MRI measures were associated with cognitive impairment, including white matter lesion load, cortical volume, total cortical lesions, and numbers of cortical lesions classified based on their location in the cortex – outer surface, inner surface, etc.

That evening we met up with Larry Tiffany, CEO of Diogenix, whose company has been a repository user and ACP collaborative partner for several years. Both Diogenix and Glycominds (mentioned above) are working to develop different types of blood tests aimed at helping with MS diagnosis, prognosis, and treatment decisions.

Wednesday 04/13:

Wednesday morning's plenary session included a presentation by Xavier Montalban from Barcelona entitled, “The 2010 MS Diagnostic Criteria: How to Use Them in a CIS Case.” Last year a new set of MS diagnostic criteria were published that simplify the use of MRI to help prove dissemination in time and space. With these criteria, in some patients, a single scan may be all that's needed to diagnose MS. He used an example of a person with a CIS to show how these criteria might result in an MS diagnosis if the evidence lines up correctly.

Dr. Montalban noted that simplifying the criteria in a way that makes it easier to diagnose MS makes it even more imperative to rule out alternative diagnoses to minimize the chance of a false ruling of MS. He also said that these criteria should only be used in people with a typical MS-like CIS. He predicted that the criteria would continue to evolve with further research, e.g., using higher field-strength MRIs and improving the detection of cortical lesions.

Following this session, Hollie had lunch with Steve Bushnell who specializes in biomarker development at Biogen, and Evelyn met with Cathy Carlson from the National MS Society.

S30: Multiple Sclerosis: Immunology (Hollie)

[S30.001] Lymphocytes and Fingolimod – Temporal Pattern and Relationship with Infections
Gordon Francis, East Hanover, NJ, Ludwig Kappos, Basel, Switzerland, Paul O'Connor, Toronto, ON, Canada, William Collins, Lixin Zhang-Auberson, Ana De Vera, Basel, Switzerland, Dejun Tang, East Hanover, NJ, Michael Looby, Basel, Switzerland, Francois Mercier, Cambridge, MA, Jeffrey Cohen, Cleveland, OH

The drug fingolimod (Gilenya) works by sequestering immune cells in lymph nodes. An important question concerning this drug is how long the peripheral immune system takes to return to normal if treatment is stopped. This research team analyzed blood samples from people in a clinical trial who had been taking fingolimod for at least three months before discontinuing it. Lymphocyte depletion in these subjects was sustained for as long as the drug was used (up to 5 years). Certain types of lymphocytes (CCR7+ naive and central memory T cells) were trapped in lymph nodes while others (CCR7- effector memory cells) were unaffected. When fingolimod was discontinued, on average, lymphocyte counts returned to the low side of normal at 6 weeks, and to normal at 3 months. These times applied to most subjects; however, some people took longer to return to normal.

No clear relationship was observed between lymphocyte count and overall infection rate or rates of lower respiratory tract or herpesvirus infections. An audience member asked whether any correlations had been found between the types of lymphocytes remaining in circulation and infections. Dr. Francis said that was a good question that had not yet been studied.

[S30.002] Increased Peripheral Blood CD5+ B Cells Predict Earlier Conversion to MS in High-Risk Clinically Isolated Syndromes
Luisa Maria Villar, Mercedes Espiño, Ernesto Roldan, Nieves Marin, Lucienne Costa-Frossard, Alfonso Muriel, Jose C. Alvarez-Cermeno, Madrid, Spain

B cells expressing the CD5 antigen on their membrane (CD5+ B cells) don't depend on T cells to activate an immune response and have been associated with intrathecal production of oligoclonal IgM antibodies. These cells have also been found in higher numbers in the cerebrospinal fluid (CSF) of people with MS compared with controls with other neurological diseases. In this study, 55 CIS subjects with oligoclonal IgG bands were followed for 3 years. Those with higher levels of CD5+ cells in their blood were more likely to convert to MS and had a higher number of relapses.

An audience member asked whether the team had looked at cytokine production in CD5+ and CD5- cells. Dr. Villar responded that IL-10 production may differ between the two types of cells (production might be decreased in CD5+ and increased in CD5- cells), since B cells from people with MS have been shown to produce lower levels of IL-10.

[S30.003] T-Helper (Th)22, a Newly Identified Lymphocyte Subset, Increases 1-3 Months before an MS Relapse and It Is Not Sensitive to IFN
Luca Durelli, Marinella Clerico, Orbassano, Turin, Italy, Simona Rolla, Turin, Italy, Giulia Contessa, Stefania F. De Mercanti, Angele Cucci, Orbassano, Italy, Valentina Bardina, Turin, Italy, Alessandra Di Liberto, Orbassano, Italy, Antonio Uccelli, Genova, Italy, Mauro Zaffaroni, Gallarate, Italy, Paola Cavalla, Turin, Italy, Luciano Rinaldi, Padova, Italy, Cristoforo Comi, Novara, Italy, Luisa Sosso, Turin, Italy, Roberto Cavallo, Asti, Italy , Pietro Quaglino, Torino, Italy, Franco Novelli, Turin, Italy

This study also focused on a particular lymphocyte type, Th22 cells. These cells produce IL-22 and also express CCR6 which is involved in epidermal immunity and remodeling. They do not appear to respond to interferon beta. Of 50 CIS subjects followed for up to 18 months, the 16 who converted to MS had a higher level of Th22 cells than the others. When exposed to myelin basic protein, Th22 cells from MS subjects responded, whereas no response was seen in cells from subjects with psoriasis. An increase in the ratio of Th22 to Th17 cells was found to predict a new MS relapse within three months. Dr. Durelli speculated that Th22 cells might bind with brain endothelial cells to initiate a relapse and recruitment of Th17 cells.

[S30.004] Dysregulated T-Cell Homeostasis in Pediatric MS: Old Cells in Young Patients
Bettina Balint, Juergen Haas, Alexander Schwarz, Alexandra Fürwentsches, Friedrich Ebinger, Benedikt Fritzsching, Heidelberg, Germany, Peter Huppke, Jutta Gaertner, Göttingen, Germany, Brigitte Wildemann, Heidelberg, Germany

The immune cell repertoire in adults with MS has been shown to be skewed toward cells generated by division of peripheral cells and away from new cells released by the thymus (this phenomenon is called immunosenescence or clonal exhaustion). Dr. Balint presented data showing that the same phenomenon also could be seen in pediatric MS subjects, although the effect was not as pronounced as in adults. Generally, the ratio of naive/memory cells in pediatric MS subjects was similar to that of healthy adults who were 20-30 years older. An audience member asked whether glatiramer acetate or IFN-beta had any effect on this phenomenon; Dr. Balint said that MS treatments had been shown to nudge the ratio of cells in MS subjects closer to that of controls.

[S30.005] Distinct Patterns of B-Lymphocyte Subsets in Peripheral Blood and Cerebrospinal Fluid of Patients with Multiple Sclerosis
Brigitte Wildemann, Miriam Milkova, Bettina Balint, Alexander Schwarz, Isabelle Bekeredjian-Ding, Juergen Haas, Heidelberg, Germany

This study examined patterns of B cells in blood and CSF of MS, CIS, NMO and healthy control subjects. In subjects with active RRMS and CIS, there is evidence for a greater migration from the blood to the CSF for class-switched memory cells and antibody-secreting cells. Higher concentrations of a B cell-attracting chemokine, CXCL13, were found in the CSF of MS subjects vs. healthy controls; levels of CXCL13 were associated with the number of mature B cells in CSF. Treatment with IFN-beta (but not glatiramer acetate) appears to increase the percentage of naive cells and decrease the percentage of memory cells in circulation, while natalizumab appears to increase the total number of B cells.

[S30.006] Cerebrospinal Fluid Biomarkers of Multiple Sclerosis Patients in Relapse and Remission
Rotem Orbach, Michael Gurevich, Anat Achiron, Ramat Gan, Israel

CSF samples from subjects with RRMS, CIS, and other neurological diseases (OND) were screened for 43 biomarkers associated with inflammation and neurodegeneration. IL-12p40, which helps regulate the balance between Th1 and Th2 cells, was the best predictor of CIS and RRMS of any biomarker or combination. Most control samples had non-detectable levels of IL-12p40. Another biomarker, pigment epithelial derived factor (a neurotrophic protein), was elevated in CIS subjects compared with RRMS. IL-8 was elevated in subjects in exacerbation compared with those in remission. This cytokine is inflammatory and may recruit monocytes into the CNS. Finally, levels of inflammatory proteins MCP-1 and CRP were correlated with EDSS levels.

An audience member asked whether the OND controls had inflammatory diseases (OIND), because a similar study using OIND controls didn't find any differences. (The answer was yes, OIND controls were included.) Another audience member asked whether the results correlated with MRI findings; Dr. Orbach said that this had not been checked.

[S30.007] Prevalence of Anti-JCV Antibodies in a Cohort of Natalizumab-Treated Multiple Sclerosis Patients from Italy
Lucia Moiola, Francesca Sangalli, Vittorio Martinelli, Milano, Italy, Luigi Maria Grimaldi, Sebastiano Bucello, Cefalù, PA, Italy, Angelo Ghezzi, Arconata, Italy, Damiano Baroncini, Milano, Italy, Amy Pace, Cambridge, MA, Dominick Paes, Zug, Switzerland, Meena Subramanyam, Cambridge, MA, Giancarlo Comi, Milan, Italy

In this study of the leading risk indicator for PML (anti-JC virus antibodies), 378 natalizumab-treated Italian subjects were screened using a 2-step ELISA process. 58% of them tested positive (53% of the females and 68% of the males). Positivity was not associated with age, previous use of immunosuppressants, region (Northern or Southern Italy), or duration of exposure to natalizumab.

Dr. Moiola presented a case of a 24-year old female who tested positive for JCV antibodies and discontinued natalizumab treatment, but still developed PML three months later. Fortunately, hers was a mild case, probably due to having stopped treatment earlier.

S31: Multiple Sclerosis: Visual Outcomes in Multiple Sclerosis (Hollie)

[S31.001] Alemtuzumab Improves Contrast Sensitivity in Relapsing-Remitting Multiple Sclerosis Patients
Laura Balcer, Steven Galetta, Maureen Maguire, Philadelphia, PA, Jeffrey Palmer, David Margolin, Marco Rizzo, Cambridge, MA, On Behalf of the CAMMS223 Study Group, San Antonio, TX

Contrast sensitivity (how well a person can see characters when the printing is light) is a simple but useful method for assessing loss of vision in MS. The CAMMS223 study, which compared alemtuzumab with IFN-beta, included the use of a low-contrast chart (Pelli-Robson) to measure visual functioning. Subjects assigned to the alemtuzumab arm were twice as likely to have sustained improvement over 3 or more months compared with those given IFN-beta. Alemtuzumab users were also 46% less likely to worsen.

[S31.002] Retinal Segmentation of Optical Coherence Tomography Scans Reveals Ganglion Cell Layer Pathology after Acute Optic Neuritis
Stephanie B. Syc, Shiv Saidha, Baltimore, MD, Scott D. Newsome, Nottingham, MD, John N. Ratchford, Lutherville Timonium, MD, Jonathan D. Oakley, Mary K. Durbin, Scott A. Meyer, Dublin, CA, Elliot M. Frohman, Dallas, TX, Laura J. Balcer, Philadelphia, PA, Peter A. Calabresi, Baltimore, MD

A longitudinal study of 20 subjects who had experienced acute optic neuritis used optical coherence tomography (OCT) to assess atrophy of their visual nerves. When the affected eyes was compared with the unaffected eyes, significant losses of the ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thickness were observed 3 and 6 months after the optic neuritis episode. The team also found a loss of GCL thickness in MS subjects with and without a history of optic neuritis compared with controls. GCL thickness correlated with visual acuity better than RNFL thickness. GCL thickness is also useful as an imaging marker at the time of an optic neuritis attack because the GCL does not swell at the time of optic neuritis like the RNFL does.

An audience member asked whether the GCL continues to thin after 6 months. Dr. Syc responded that most of the loss actually appears to occur within the first 3 months.

[S31.003] Pupillary Reflex Metrics in MS: Objective Characterization of the Afferent Pupillary Defect (APD)
Paul Blazek, Erik Burton, Amy Conger, Darrel Conger, Teresa C. Frohman, Steven Vernino, Benjamin Greenberg, Dallas, TX, Peter Calabresi, Baltimore, MD, Laura Balcer, Philadelphia, PA, Scott L. Davis, Elliot M. Frohman, Dallas, TX

This presentation described a new calculation for diagnosing Relative Afferent Pupillary Defect (RAPD), which is a dysfunction in how the pupil dilates/constricts in response to lighting changes. In MS, constriction velocity is decreased in eyes affected by optic neuritis. Coordination of constriction between the two pupils can also be affected.

[S31.004] Retinal Neuronal Loss in Multiple Sclerosis; Extending the Utility of Optical Coherence Tomography with Retinal Segmentation
Shiv Saidha, Stephanie B. Syc, Baltimore, MD, Christopher Eckstein, Cockeysville, MD, Jonathan D. Oakley, Mary K. Durbin, Scott A. Meyer, Dublin, CA, Laura J. Balcer, Philadelphia, PA, Elliot M. Frohman, Dallas, TX, Scott Newsome, Nottingham, MD, John N. Ratchford, Lutherville Timonium, MD, Peter A. Calabresi, Baltimore, MD

This study of MS subjects and healthy controls provided additional support for the use of GCL thickness in monitoring visual effects in MS. GCL thinning correlated better with letter acuity and EDSS than RNFL thinning. GCL thinning occurred in all MS subtypes (RRMS, SPMS, etc.) but was associated with disease duration rather than disease course.

[S31.005] Diffusion Tensor Parameters of the Optic Radiations Are Associated with Visual Acuity and Retinal Nerve Fiber Layer Loss Following Optic Neuritis
Salim E. Abboud, Mark J. Lowe, Blessy Mathew, Ken Sakaie, Stephen E. Jones, Michael D. Phillips, Robert A. Bermel, Cleveland, OH

Diffusion tensor imaging (DTI) is a form of MRI that indicates the structural integrity of tissue that has some type of alignment (such as nerve fibers). In this study, DTI was performed on subjects with unilateral optic neuritis to examine effects on the optic radiations, which are part of the visual pathway in the brain. DTI measurements correlated with visual acuity score and OCT measurements. The research team was able to improve a model that used OCT values to predict visual acuity by adding DTI measurements of longitudinal diffusivity and fractional anisotropy.

[S31.006] Diffusion Tensor Imaging in Acute Optic Neuritis Predicts Axonal Injury and Clinical Outcomes
Robert T. Naismith, Junqian Xu, Samantha Lancia, Nhial T. Tutlam, Kathryn Trinkaus, Sheng-Kwei Song, St. Louis, MO, Anne H. Cross, Saint Louis, MO

This study also used DTI to assess the visual effects of MS. Subjects with optic neuritis were imaged and evaluated at multiple time points over the course of a year. Low axial diffusivity was associated with worse visual outcomes, visual evoked potential scores, and RFNL thickness.

S40: Multiple Sclerosis: Animal Models and Immunology (Evi)

[S40.002] p66SchA Inactivation Is Neuroprotective in a Model of Multiple Sclerosis
Kimmy Su, Gail Marracci, Priya Chaudhary, Xiaolin Yu, Michael Forte, Dennis Bourdette, Portland, OR

A protein called P66SchA contributes to production of reactive oxygen species in the mitochondria. Although these agents help fend off microbial attackers, they can damage a wide variety of cellular molecules and have been implicated in numerous diseases as well as aging. Mice that have been engineered to lack P66SchA resist several experimentally induced diseases and live longer than normal. In this study, described by Kimmy Su from Oregon Health Sciences University, absence of the protein modestly protected the animals from EAE, as indicated by limb paralysis tests and tissue analysis. Spinal cord sections and optic nerve examination revealed that mice without P66SchA harbored significantly less damage than did genetically intact animals. Absence of the protein protected neurons from cell death due to stressors such as nitric oxide that induce production of reactive oxygen species. The results suggest that P66SchA might provide a neuroprotective therapeutic target in MS, although many questions remain about whether loss of this protein triggers serious side effects, including increased susceptibility to microbial pathogens.

After these sessions, we sat in on the “MS Highlights” presentation which was an overview of a few of the posters and presentations given at the meeting. Then we headed out for a group dinner with two of our repository principal investigators (Drs. Ben Greenberg and Peter Riskind), Peter's wife Carolyn, our UT Southwestern study coordinator Stephanie Taylor, and a few others from the UTSW MS clinic.

Thursday 04/14:

S41: Multiple Sclerosis: Trials (Sara)

[S41.001] Ocrelizumab in Relapsing-Remitting Multiple Sclerosis: 48 Week Efficacy and Safety Results of a Phase II Randomized Placebo-Controlled Multicenter Trial
Ludwig Kappos, Basel, Switzerland, David Li, Vancouver, BC, Canada, Peter Calabresi, Baltimore, MD, Paul O'Connor, Toronto, ON, Canada, Amit Bar-Or, Montreal, QC, Canada, Frederik Barkhof, Amsterdam, The Netherlands, Ming Yin, South San Francisco, CA, David Leppert, Robert Glanzman, Jeroen Tinbergen, Basel, Switzerland, Stephen Hauser, San Francisco, CA

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody, an anti-B cell therapy similar to Rituxan (rituximab). In this phase II trial, 220 patients with RRMS were randomized into one of four arms for 24 weeks: 1/4th receiving placebo (A), 1/4th receiving a 600 mg dose of OCR (B), 1/4th receiving 2000 mg of OCR (C), and the final 1/4th receiving interferon-beta 1a (A). For the following 24 weeks, groups A, B, and D received 600mg of OCR and group C, 1000 mg of OCR. The study participants were followed for 72 weeks. Ludwig Kappos presented the study data which indicated effectiveness (as measured by relapse rate and T1-G4 enhancing lesions), showing reduced relapse activity in the subjects receiving OCR and a similar level of relapse activity across all subjects once all were receiving OCR. The rate of adverse events was similar across all groups, with the rate of serious adverse events ranging from 1.9% for the placebo arm to 6% for the IFN-beta 1a arm (later treated with OCR). One subject on the higher dose of OCR did die at week 14 but it was unknown if the death was related to the treatment. One area of concern around treatment with OCR is the possibility of serious infection (a phase III trial of OCR for the treatment of RA and lupus was recently suspended due to several deaths among trial participants). The 72 week data from this trial showed that 8 serious infections had developed but with no clear trend or dose dependence.

[S41.002] Clinical and MRI Outcomes from a Phase III Trial (TEMSO) of Oral Teriflunomide in Multiple Sclerosis with Relapses
Aaron Miller, New York, NY, Paul O'Connor, Toronto, ON, Canada, Jerry S. Wolinsky, Houston, TX, Christian Confavreux, Lyon, France, Giancarlo Comi, Milan, Italy, Ludwig Kappos, Basel, Switzerland, Tomas P. Olsson, Stockholm, Sweden, Hadj Benzerdjeb, Chilly-Mazarin, France, Philippe Truffinet, Antony, France, Lin Wang, Bridgewater, NJ, Mark S. Freedman, Ottawa, ON, Canada

Teriflunomide is an oral drug currently under review for use in treating RRMS. It is a selective inhibitor, reducing the rate of proliferation of both T and B cells. Aaron Miller presented the results of a 108 week phase III trial (TEMSO) which used annualized relapse rate (ARR), MRI changes and EDSS scores to evaluate success. 1,088 participants with EDSS scores <= 5.5 and either 1 relapse in the last year or 2 in the last two years were randomized to receive placebo or one of two doses of teriflunomide (7mg or 14mg). It was reported that teriflunomide reduced ARR by over 31% at both dose levels over placebo. The higher dose also showed statistically significant reduction in progression (the lower dose did not meet statistical significance but trended towards it). There was a slightly increased rate of serious adverse events in the two treatment groups, and no deaths during the course of the study. The side effects most commonly reported included diarrhea, nausea, decreased hair density, and elevated liver enzyme levels.

[S41.003] A Placebo-Controlled Phase III Trial (TEMSO) of Oral Teriflunomide in Multiple Sclerosis with Relapses: Additional Magnetic Resonance Imaging (MRI) Outcomes
Jerry S. Wolinsky, Houston, TX, Paul O'Connor, Toronto, ON, Canada, Christian Confavreux, Lyon, France, Giancarlo Comi, Milan, Italy, Ludwig Kappos, Basel, Switzerland, Tomas P. Olsson, Stockholm, Sweden, Philippe Truffinet, Antony, France, Lin Wang, Bridgewater, NJ, Aaron Miller, New York, NY, Mark S. Freedman, Ottawa, ON, Canada

This presentation provided additional data related to the TEMSO study, focusing on the MRI outcomes. Jerry Wolinsky presented the results of the study which was to evaluate the effect of teriflunomide on a range of MRI parameters. Study participants received MRI scans at baseline, 24, 48, 72 and 108 weeks. A central MRI facility was used for processing and analysis. The key endpoint evaluated was disease burden (total lesion volume) with additional outcomes also studied (including number and volume of Gd-enhancing T1 lesions, volume of T2 lesions, etc.). It was reported that both doses of teriflunomide were superior to placebo over a number of MRI parameters including total lesion volume, number of Gd-enhancing T1 lesions per scan, proportion of patients free from Gd-enhancing T1 lesions, and number of unique active lesions per scan. Teriflunomide did not appear to perform favorably over placebo in terms of brain volume or gray matter volume.

[S41.004] Randomized Placebo Controlled Trial of Ginkgo biloba for Cognitive Impairment in Multiple Sclerosis
Jesus Lovera, New Orleans, LA, Diane Howieson, Katherine Wild, Portland, OR, Mary Fitzpatrick, Kelso, WA, Elizabeth Heriza, Portland, OR, Alicia Sloan, Seattle, WA, Joshua Adams, Portland, OR, Thomas Stover, James Hunziker, Aaron Turner, Seattle, WA, Edward Kim, Portland, OR, Jodie Haselkorn, Seattle, WA, Dennis Bourdette, Portland, OR

In this study, 122 subjects at two centers were randomly assigned to receive either Ginkgo biloba (GB) or a placebo for 12 weeks in an effort to determine if GB would improve the cognitive function in people with MS. Subjects took the four tests that comprise the neuropsychological test battery (NSTB) [Stroop, Paced Auditory Serial Addition Test, the California Verbal Learning Test II, and the Controlled Oral Word Association Test] at week one, had phone interviews monthly and then were retested at week sixteen. There was no significant difference in the test results for either study group, nor was any difference reported in any of the secondary outcome measures (fatigue, depression, etc.). There were no differences in reported adverse events between the groups and no serious adverse events attributed to GB. The study team determined that GB does not appear to be effective for improving cognitive impairment in MS in the short term but did not determine if there are any long term benefits.

[S41.005] Clinical and MRI Assessment of Transdermally Applied Myelin Peptides in MS Patients
Agata Walczak, Malgorzata Siger, Agnieszka Ciach, Lodz, Poland, Marian Szczepanik, Cracow, Poland, Krzysztof Selmaj, Lodz, Poland

In this study, 30 subjects with RRMS were enrolled in one of three groups: one that received 10 mg of three myelin peptides via an adhesive skin patch (MBP 85-99, PLO-139-151 and MOG 35-55), one that received the same three peptides in the same manner but at 1mg dosage, and a placebo group. The concept is that this treatment may be a promising treatment for MS without impacting the entire immune system. Agata Walczak presented the results of the 12-month study which used annualized relapse rate, EDSS, and MRI based assessments as outcome measures. It was reported that ~62% of people in the treatment groups were relapse free compared to 10% of those in the placebo group, and 80% were disability progression free compared with 30% in the placebo group. Similarly positive results were reported as measured by MRI. A caveat to these seemingly promising results is that this study was quite small in number and short in duration. No doubt larger and longer studies will be conducted.

[S41.006] A Double-Blind, Randomized, Placebo-Controlled Trial of Simvastatin as Add-On Therapy to Interferon-Beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis
Per Soelberg Sorensen, Copenhagen, Denmark, Jan Lycke, Gothenberg, Sweden, Juha-Pekka Eralinna, Vantaa, Finland, Astrid Edland, Drammen, Norway, Xingchen Wu, Hvidovre, Denmark, Jette L. Frederiksen, Glostrup, Denmark, Annette Bang Oturai, Copenhagen 0, Denmark, Clas Malmestrom, Goteborg, Denmark, Egon Stenager, Esbjerg, Denmark, Bjorn Sperling, Copenhagen, Denmark

Statins may have immunomodulatory properties and might therefore reduce disease activity in RRMS but there have been conflicting reports on the effect of statins on the effectiveness of interferon beta-1a. One small study reported that atorvastatin reduced the effectiveness of IFN-beta-1a where another suggested beneficial results for the combination. Per Soelberg Sorensen presented the results of a large phase 2 trial designed to evaluate the efficiency and safety of simvastatin as an add on therapy to intramuscular IFN-beta-1a. Thirty four centers participated in this study which used annualized relapse rate as its primary outcome measure and time to 1st relapse, number of new T2 lesions and proportion of subjects free from disease activity as secondary measures. Treatment naïve subjects were all started on IM IFN-beta-1a. At 3 months subjects were randomized to either receive simvastatin in addition to the IM IFN-beta-1a (151 subjects) or placebo as the add on (156 subjects). For the majority of the outcome measures, the results were not statistically significant. Annualized relapse rate, time to first relapse, and mean number of new and/or enlarging T2 lesions were similar for both groups. The report that more subjects receiving placebo were disease activity free (12.5%) compared to those receiving simvastatin (5.6%) was borderline statistically significant. No unexpected adverse events were seen in either group. The study team concluded that there was no beneficial effect found for simvastatin as an add-on therapy to IM IFN-beta-1a. The findings of this study cannot exclude the previous reports that statins may reduce the effectiveness of IFN-beta-1a but the results should not discourage the use of statins in people treated with IFN-beta-1a either.

[S41.007] Pooled Analyses of the Transient and Long-Term Effects of Fingolimod (FTY720) on Cardiovascular Parameters in Phase 3 Studies in Patients with Multiple Sclerosis
John DiMarco, Charlottesville, VA, William Collins, Basel, Gordon Francis, East Hanover, NJ, Lixin Zhang-Auberson, Pascale Burtin, Basel, Switzerland, James Jin, East Hanover, NJ, Ludwig Kappos, Basel, Switzerland, Jeffrey Cohen, Cleveland, OH

One of the concerning potential side effects of fingolimod is the possibility of cardiovascular issues. This study pooled the findings from two phase 3 efficacy studies, the FREEDOMS study (which compared two doses of fingolimod vs. placebo) and the TRANSFORMS study (comparing two doses vs. IFN-beta-1a). John DiMarco presented the pooled safety data from 2,552 patients which evaluated such things as percentage of people discharged at 6 hours without issue, percentage requiring extended hospitalization, percentage needing to be treated for bradycardia, percentage showing an EEG conduction abnormality and percentage showing a 1st degree atrioventricular block. The results showed that initiation of
fingolimod treatment was associated with a dose-dependent decrease in heart rate (HR) that was associated with atrioventricular (AV) conduction slowing. Four subjects receiving fingolimod received medication for bradycardia. The heart rate and atrioventricular changes appeared to stabilize and return to baseline levels by 1 month on treatment. There was also a small increase in blood pressure for the fingolimod groups which responded to standard anti-hypertensive therapy. It's important to note that subjects with moderate to severe cardiac disease were excluded from the FREEDOMS and TRANSFORMS trials so these results would not necessarily be applicable to people with existing heart conditions.

S50: Multiple Sclerosis: Oligodendroglia and Immunology (Hollie)

[S50.001] Haematopoietic Stem Cell Mobilisation and Re-Arrangement of Immune Cell Subsets Following Therapeutic alpha 4-Integrin Blockade in Multiple Sclerosis
Miriam Mattoscio, Richard Nicholas, Omar Malik, Christopher Mc Guigan, Francesco Dazzi, Paolo Muraro, London, United Kingdom

People going on natalizumab for MS often have an increased number of hematopoietic CD34+ stem cells in the bloodstream. This increase may result from more stem cells being mobilized and released from the bone marrow, or it may be due to these cells not being able to migrate into their target organs. Whatever the cause of this phenomenon is, it is unknown whether the increase in these cell numbers is clinically relevant. This research team studied blood samples from MS subjects on natalizumab and found that the increase in CD34+ cells reversed after the first 6 months. They also found that some subjects had large increases but others did not (mobilizers and non-mobilizers). Circulating stem cells were predominantly quiescent. Consistent with a migration-blocking effect, subjects had a transient increase in the percentage of peripheral blood cells that were T cells, and a lasting increase in the percentage of B cells. 3 out of 5 non-mobilizers had a relapse during the study period while none of the mobilizers had one. The non-mobilizers had a longer disease duration on average.

An audience member asked if there was more information about the mechanism of any clinical effect of the stem cell mobilization. The presenter speculated that there might be an “immune system reset” effect at play and that functional studies are being performed to investigate this. Another audience member commented that the increase in stem cells might also just be a marker of treatment efficacy rather than directly contributing to efficacy.

[S50.002] NKG2C and NKG2D: Receptors Acquired by Activated Human CD4 T Cells and Involved in Oligodendrocyte Destruction
Fatma Zaguia, Montreal, QC, Canada, Jack Antel, Westmount, QC, Canada, Philippe Saikali, Nathalie Arbour, Montreal, QC, Canada

Dr. Zaguia described a series of experiments to investigate T cell toxicity towards oligodendrocytes, in particular, which receptors on T cells are responsible for their activation into a toxic form. Natural killer (NK) T cells can express certain receptors (NKG2C and NKG2D) that result in cell activation when they encounter an appropriate ligand. Oligodendrocytes have been shown to express these ligands under inflammatory conditions, so perhaps NKG2C and NKG2D play a role in MS pathology. The experiments involved exposing a culture of oligodendrocytes to activated T cells in the presence of inflammatory cytokines, resulting in oligodendrocyte death. Adding antibodies to NKG2C and NKG2D to the culture did reduce the loss of oligodendrocytes.

[S50.003] Microglia Mediate the Rapid Clearance of Myelin after Oligodendrocytes Apoptosis
Stephen M. Selkirk, Saisho Mangla, Jennifer Dunger, Robert H. Miller, Cleveland, OH

To study the process of remyelination, researchers developed a virus engineered to express a gene toxic only to oligodendrocytes that could be injected into a mouse's brain, thereby creating a focal lesion. Lesions generated in this manner had a robust microglia and astrocyte response, subsequent axonal damage, and scar formation, but low numbers of lymphocytes. When the mice were also given resveratrol (an inhibitor of microglia and astrocytes) on the same day as the virus, the removal of myelin was slower, the number of oligodendrocyte precursor cells (OPCs) in the lesion appeared higher, and the axons were left intact. The research team would like to work with this model further to continue defining the role of microglia in demyelinating lesions.

An audience member asked why Dr. Selkirk had concluded that microglia were critical to the lesion formation process when infiltrating macrophages could also perform the same functions. Dr. Selkirk responded that the rapid response with little influx of T cells suggest that resident CNS cells were primarily involved. Another audience member noted that Robin Franklin's results suggest that myelin clearance is needed for remyelination, so perhaps inhibiting the microglia response could have negative effects on repair.

[S50.004] Comparison of Axonal Ensheathment Capacity by Human Adult Mature and Progenitor Oligodendrocytes
Qiao Ling Cui, Guillermina Almazan, Timothy Kennedy, Montreal, QC, Canada, Jack Antel, Westmount, QC, Canada

Dr. Antel's presentation addressed an interesting question: In MS lesions where oligodendrocytes have been preserved even though the myelin is gone, can those cells participate in remyelination? Or do oligodendrocyte precursor cells (OPCs) do most of the remyelinating? He and his team created cultures using oligodendrocytes and OPCs taken from human surgical specimens, along with rat neurons. The mature oligodendrocytes proved better at surviving in suboptimal culture conditions, but the OPCs were more likely to ensheath the rat neurons. Still to be determined is what is restricting the mature oligodendrocytes from performing their ensheathing duties.

[S50.005] Olesoxime Promotes Oligodendrocyte Maturation and Myelination and Could Be a Promising Complementary Therapy for the Treatment of Multiple Sclerosis
Rebecca M. Pruss, Karine Magalon, Celine Zimmer, Myriam Cayre, Joseph Khaldi, Isabelle Robles, Gwenaelle Tardif, Clarisse Bourbon, Angele Viola, Thierry Bordet, Pascale Durbec, Marseille, France

Dr. Pruss represented a company called Trophos which is developing a compound called olesoxime (TRO19622). It is being tested in motor neuron diseases, but there are reasons to think it may have applications in other neurological diseases such as MS. It promotes neuron survival, crosses the blood-brain barrier, appears to be safe, targets mitochondrial proteins, and promotes microtubule dynamics. In an animal model where the sciatic nerve was crushed, administration of olesoxime promoted remyelination. In culture systems of OPCs and neurons, the drug enhanced myelination, and in cultures of OPCs only, it increased the number of cells expressing myelin basic protein (although it did not increase the number of OPCs).

In an experiment involving the cuprizone model of demyelination, administering olesoxime at the same time as cuprizone resulted in reduced loss of myelin and nerve fibers, and increased numbers of mature oligodendrocytes. The drug also helped to preserve the functional abilities of the animals. Similar results were seen in a different model involving injection of a substance called LPC into the brain. Olesoxime also appears to promote myelination in developing mice and normal adult mice.

[S50.006] Secretory Products of B Cells Are Cytotoxic to Oligodendroglia In Vitro
Robert Lisak, Liljana Nedelkoska, Joyce Benjamins, Jennifer Barger, Detroit, MI, Boli Fan, Nadia Ouamara, Trina Johnson, Sathy Rajasekharan, Amit Bar-Or, Montreal, QC, Canada

In addition to secreting antibodies, B cells also produce other types of factors. This study examined whether any of these factors could be toxic to oligodendrocytes. Dr. Lisak's team created mixed glial cell cultures and exposed them to media from B cell cultures (supernatants) from treatment-negative RRMS and control subjects. The B cells in these cultures were either unstimulated or stimulated using various methods. IgM antibodies were not detected in the supernatants, and IgG was detected only in 7 of 26 cultures.

The supernatants from the MS subjects proved to be more toxic to oligodendrocytes than those from the control subjects, both under stimulated and unstimulated conditions. Astrocytes and microglia in these cultures did not seem to be harmed, although a change was seen in microglia morphology which might indicate activation of these cells. No correlation was observed between oligodendrocyte loss and production of certain cytokines (TNF-alpha, LT-alpha, IL-6, or IL-10). Dr. Lisak noted that future research will involve pinpointing which components are responsible for oligodendrocyte cell death, and determining whether these components come directly from B cells or involve the activity of microglia and astrocytes. Future studies will also include samples from subjects with progressive forms of MS.

[S50.007] Further Histopathologic Evidence for a Primary Lipid Abnormality in Diffusely-Abnormal White Matter in Multiple Sclerosis
G. R. Wayne Moore, Cornelia Laule, Esther Leung, Vladamira Pavlova, Irene Vavasour, Guojun Zhao, David K. B. Li, Anthony L. Traboulsee, Alex L. MacKay, Vancouver, BC, Canada

In addition to normal appearing white matter (NAWM) and lesioned tissue, people with MS also have areas of what is called diffusely abnormal white matter (DAWM). DAWM is characterized by blood-brain barrier breakdown and axonal loss, but myelin basic protein staining is normal. Dr. Moore's study involved obtaining autopsy tissue samples from four MS subjects, performing an MRI scan on each sample, and staining DAWM regions for various molecules such as MBP, CNP, MAG, lipids, and axonal components. In general, samples showed intact MBP and CNP, loss of myelin phospholipids, and loss of axons (though axonal loss was less pronounced than and typically followed lipid abnormalities). The samples did not show an increase in inflammation compared with NAWM. In one sample, extracellular deposition of a type of lipid (ganglioside) was seen in the perivascular space at a DAWM/NAWM interface.

An audience member commented that the abnormalities described were reminiscent of type 2 lesions as classified by Claudia Lucchinetti, and asked whether the samples had been stained for antibodies and complement. Dr. Moore said they haven't looked for that yet, but that it would make sense to do so.

S51: Multiple Sclerosis: Treatment Complications (Hollie)

[S51.001] Effects of Natalizumab Treatment on Vaccination Response in Patients with Multiple Sclerosis
Gabriel Pardo, Oklahoma City, OK, Michael Kaufman, Charlotte, NC, Howard Rossman, Farmington Hills, MI, Marianne Sweetser, Cambridge, MA, Fiona Forrestal, Geneva, Switzerland, Petra Duda, Charlestown, MA

Dr. Pardo presented a research study aimed at learning whether administration of natalizumab could alter how well a vaccine would work in a person with MS. A group of MS subjects were vaccinated against tetanus toxoid as well as another antigen (KLH), either before starting natalizumab or after six months of dosing. Immune responses to both antigens were similar in both groups, indicated that natalizumab did not reduce the effect of these two immunizations.

An audience member noticed from one of the slides that the subjects receiving natalizumab appeared to have an elevated rate of developing anti-natalizumab antibodies after immunization, and wondered whether immunization could increase the chance of these antibodies developing. Dr. Pardo said that the study was too small to draw this conclusion.

[S51.002] Overview of Clinical Outcomes in Cases of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy
Ralf Gold, Bochum, Germany, John Foley, Salt Lake City, UT, Patrick Vermersch, Lille, France, Ludwig Kappos, Basel, Switzerland, Tomas Olsson, Stockholm, Sweden, Diego Cadavid, Bedford, MA, Carmen Bozic, Sandra Richman, Cambridge, MA

Dr. Vermersch gave an update about the people who have developed PML after being treated with natalizumab. 102 cases of PML have been reported through March 4, 2011. Overall, 78,800 people have had at least one dose of the drug; of these, 32,000 have been treated for more than 24 months, and 15,000 have been treated for more than 36 months. Risk of PML is associated with a higher number of infusions. Most of the people who developed PML were treated with plasma exchange and subsequently developed a severe inflammatory response called IRIS, which is treated with steroids.

Of the first 79 natalizumab recipients to be diagnosed with PML, 63 are still alive and have been followed for a median of 10 months. The rest died an average of 2 months after developing PML, probably mostly due to a severe IRIS reaction. Survivors tended to be younger, have a shorter time to diagnosis of PML, show more localized disease on MRI, and have lower JC virus DNA counts in their CSF. Duration of natalizumab treatment and whether a person had had any prior immunosuppressive therapies had no apparent effect on survival. Clinical outcomes were known for 45 of the survivors: 13% had mild residual disability, 50% had moderate disability, and 37% had severe disability. However, their disability levels had not been compared with their levels prior to developing PML, so it's impossible to say what the incremental contribution of PML was. Dr. Vermersch expects that the survival rate of PML will increase over time since there will be better vigilance and faster response when PML is suspected.

[S51.003] Anti-JCV Antibodies Are Consistently Detected Prior to and after PML Diagnosis in Natalizumab-Treated MS Patients
Meena Subramanyam, Tatiana Plavina, Sophia Lee, Moses Njenga, Melissa Berman, Leonid Gorelik, Amy Natarajan, Brian Schlain, Sandra Richman, Cambridge, MA, Susan Goelz, Portland, OR, Carmen Bozic, Alfred Sandrock, Cambridge, MA

Biogen Idec and Elan have developed a 2-step ELISA lab test to detect antibodies to JC virus in serum samples. The ELISA test is being made commercially available this year in Europe and the US. JCV antibodies, along with other risk factors such as length of natalizumab use and prior immunosuppressant use, can help determine a person's risk of developing PML. Analysis of samples from several different MS collections obtained in different countries have revealed that around 55% of people with MS are positive for anti-JCV antibodies. These antibodies have been found in 17/17 (100%) of people developing PML who had samples taken prior to developing PML that were available for analysis. Presumably anyone who tests negative can be considered to have a low risk of PML for the time being.

An audience member asked how often patients on natalizumab should be tested for JCV antibodies. Dr. Subramanyam recommended that those who test negative should be retested annually. It's not necessary to retest anyone who tests positive, because they already have been infected with the virus.

[S51.004] Progressive Escalation of Natalizumab Serum Concentration as a Potential Kinetic Marker for PML Risk Assessment
John F. Foley, Salt Lake City, UT

Dr. Foley presented results from a study investigating why being on natalizumab for more than 2 years increases the risk of PML. He hypothesized that natalizumab concentrations in the body increase with time on the drug. His study collected blood samples from 208 MS subjects who had been on a regular natalizumab infusion schedule (every 28-30 days) for a total of 2 to 49 infusions. Analysis of these samples confirmed clinical trial data showing that natalizumab concentrations in the blood increase with treatment duration. Concentrations also increased with older age (>60 years). Another marker that was analyzed was soluble VCAM, a marker of inflammation. Natalizumab decreases sVCAM levels, and higher natalizumab concentrations in the blood were associated with lower sVCAM levels. sVCAM levels were lower in subjects with a history of herpes zoster, an indicator of reduced antiviral immune activity. Dr. Foley speculated that people with lower sVCAM levels might also be at higher risk of PML, and perhaps dosing/scheduling of natalizumab could be tailored to leave enough residual immune activity without compromising the drug's effectiveness against MS. Checking efficacy and/or MRI data against sVCAM levels could provide additional important input into this question.

Dr. Foley is also looking how at IgG4 levels, as well as CD4+ and CD8+ T cell counts, correlate with natalizumab concentrations. Another phenomenon worth investigating is the drop-off seen in natalizumab levels as someone nears the date of their next infusion.

An audience member asked what happens in people who do not get their infusions on a regular 28-30 day cycle. Dr. Foley responded that their sVCAM levels return to close to normal after about 8 or 9 weeks, and their natalizumab concentrations approach 0 by that point.

[S51.005] Assessment of Baseline Treatment History and Postbaseline Relapses and Serious Adverse Events in MS Patients Treated with Natalizumab
Helmut Butzkueven, Kensington, Australia, Shibeshih Belachew, Diegem, Belgium, Ludwig Kappos, Basel, Switzerland, Fabio Pellegrini, Chieti, Italy, Maria Trojano, Bari, Italy, Heinz Wiendl, Munster, Germany, Annie Zhang, Cambridge, MA, Dominic Paes, Zug, Switzerland, Christophe Hotermans, Weggis, Switzerland

The Tysabri Observational Program (TOP) was set up to track safety and efficacy of natalizumab in Europe, Australia, and Canada. It is designed to follow 3,000 people with MS up to 5 years, and is looking for associations between baseline treatment history and natalizumab safety and efficacy. Almost half of the subjects in this program had only used IFN-b to treat their MS prior to going on natalizumab; the rest were either treatment-naive or had been on one or more other therapies. 64% of the subjects had experienced two or more relapses in the year before beginning natalizumab. 44% have been followed for one or more years; 15% for two or more years.

Annual relapse rate in this cohort was reduced from 1.99 prior to natalizumab to 0.29 after beginning treatment. The greatest reduction in relapse rate was in the treatment-naive group, but natalizumab showed high levels of efficacy in all subgroups. The average EDSS score dipped slightly from the baseline level, and has stayed stable over time. 5 subjects have developed PML. Two of these had previously been on mitoxantrone, and the other three had been on one or more disease-modifying therapies. In addition, 5 subjects developed malignancies. No new safety concerns have emerged in this cohort that had not already been identified.

[S51.006] Subacute Amotivational Syndrome as the Only Symptom of Progressive Multifocal Leukoencephalopathy in a Natalizumab-Treated Multiple Sclerosis Patient
Kristen Babinski, Jonathan Howard, New York, NY, Christopher Gottschalk, New Haven, CT, Joseph Herbert, Fair Lawn, NJ, Ilya Kister, Passaic, NJ

Dr. Babinski described a patient at her clinic who had received a total of 42 natalizumab infusions when his MRI showed an abnormality in the left frontal lobe that indicated possible PML. He didn't exhibit any telltale PML symptoms, but the patient's brother told the clinicians that the patient had recently had a change in personality, becoming demotivated, cynical, and depressed. In addition, the patient's blog postings had also seemed to change in tone over the past 3 months prior to the MRI. The patient was given additional testing which resulted in a PML diagnosis. Natalizumab was discontinued and plasma exchange started, along with mefloquine and steroids to prevent IRIS. The patient now reports better cognitive function and mood, and his MRI is also improving. Dr. Babinski said that this case shows that PML can have an indolent course, and that people at risk of PML may need to have more frequent MRIs (her center now performs them every 6 months).

Awards Plenary Session

This year's recipient of the John Dystel Prize for Multiple Sclerosis was Brian Weinshenker of the Mayo Clinic. He was asked to give a talk about his research, which has contributed significantly to the treatment and understanding of demyelinating diseases, most notably MS and neuromyelitis optica (NMO). Dr. Weinshenker has used some of our NMO genetic samples for his studies, and is incredibly smart and dedicated, so we were excited that he was honored in this way. Congratulations, Brian!

Poster sessions

Here are a few of the posters that we found to be noteworthy:

Obesity, which appears to contribute to many health problems, may also increase the risk of demyelinating disorders in children (P02.163)
By using multiple imaging methods, Peiqing Qian and colleagues showed that T2 lesions that disappear can leave persistent damage. With typical imaging protocols, therefore, physicians might be missing many clinically significant lesions. (P04.203)
An imaging study found evidence that the loss of brain volume that can occur after initiation of certain MS therapies (in this study, IFN-b) may not be due to water leaving the brain as inflammation decreases, as previously supposed, but instead is caused by something else, such as de-activation of immune cells (P04.223)
A review of the records of a major health insurance company (Kaiser Permanente) revealed that MS incidence is actually more common in African-Americans than in Caucasians and other ethnic groups; this goes against previous studies reporting that MS is less common in African-Americans although potentially more severe (P06.032)
A multi-national study confirmed previous findings that the MS gender gap is widening, but this appears to be happening mainly in northern countries and regions, not southern ones (P06.044)
Expanded populations of a T cell subset, Th40, seems to correlate with disease state in humans with MS and these cells can transfer disease in an EAE mouse model (P02.173)
Several posters presented research into biomarkers of treatment response
Another popular topic was the development of new methods for measuring many different effects of MS (cognitive tests, gait/balance tests, composite scores, etc.) -- this research is very welcome since current methods are far from perfect.

Late-breaking news

One talk that we missed because it was scheduled as a last-minute addition to a Friday session was Dr. Giancarlo Comi's presentation of phase III trial results for Teva's new oral MS therapy, laquinimod. The two-year ALLEGRO study compared a 0.6 mg daily dose of laquinimod to placebo. Relapses were reduced by 23% in subjects receiving laquinimod compared with the placebo group; disability progression and brain atrophy were also reduced by 36% and 33%, respectively. No major safety concerns were reported. Another phase III trial comparing laquinimod to IFN-beta and placebo is underway and those results should be reported later this year. You can see the official AAN press release for more information, or better yet read a more detailed report of the ALLEGRO study results at Medscape.

Risk factor round-up: exploring how MS risk factors relate, and launch of new study for MS family members

hollie — Fri, 11 Feb 2011 16:24:29 -0500

Having identified several genetic and environmental factors that appear to affect the risk of MS, scientists are now starting to explore how these factors relate to one another in ways that contribute to the development of MS. Two recently published studies have focused on relationships between various factors that are thought to either increase or decrease the risk of MS. Another study is starting up to further explore this topic, and is reaching out to first-degree relatives of people with MS as potential participants.

The first study was conducted by a team of Swedish researchers, who were interested in whether smoking and immune system genes might interact in determining MS risk. In this study, 843 people with MS and 1209 controls donated DNA samples and completed questionnaires that asked about smoking history, in addition to other topics. The DNA was analyzed for the presence of immune system gene variants HLA-DRB1*15 and HLA-A*02, which have been found to increase and decrease the risk of MS, respectively. The risk of MS was 14 times higher in the group of smokers with DRB1*15 and without A*02 than in non-smokers negative for DRB1*15 and positive for A*02. This increase in risk was greater than if the individual risks for these factors were added together, suggesting that smoking has an especially significant effect on MS in people with certain immune gene variants. The authors suggested that smoking might set off an immune response in the lungs that leads to MS, perhaps involving irritation or infection.

The second study, performed in Australia, sought to clarify the relationship between ultraviolet radiation (UVR) and vitamin D in protecting against MS. Both have been associated with reducing the risk of MS -- but is the association with UVR due only to its vitamin D-producing effect? 216 cases with a first demyelinating event and 395 matched controls were compared in terms of past UV exposure (self-reported exposure and measured sun damage to the skin), and serum vitamin D levels. Increased UVR exposure and higher levels of serum vitamin D were both associated with a reduced risk of MS. However, analysis of the associations showed somewhat independent effects for UVR and vitamin D. This suggests that UVR may provide additional protection against MS via mechanisms that are separate from vitamin D production.

To better understand how various types of risk factors contribute to MS, a team at Brigham & Women's Hospital in Boston MA is launching the "Genes and Environment in Multiple Sclerosis (GEMS) Study." They are enrolling people aged 18-50 who have a parent, child, or sibling who has been diagnosed with MS -- people with MS can also enroll as long as they have a first-degree relative with MS. Subjects will be asked to provide a saliva DNA sample and to complete a 15-minute online survey; some subjects will also be asked for a blood sample and an MRI, but this is optional. Additional surveys will be conducted every 3 years, and the study will run for up to 20 years. The scope (up to 5000 subjects) and long duration of the study mean that lots of data will be collected for MS risk research. One of the goals of the study is to develop an MS "risk score" which could be used to help identify people with the highest risk of MS -- who could then be given up-to-date advice about MS risk reduction. If you're interested in learning more about this study, you can contact the research coordinator, Irene Wood, at 617-264-5980 or at bwhmsstudy@partners.org.

Helminth infections may alleviate MS; treating the infection removes protective effect

hollie — Tue, 01 Feb 2011 16:46:50 -0500

A research team in Argentina has been studying the effect of helminth (worm) infections on MS for several years, reporting that people with these infections appear to have lower levels of MS disease activity and severity. A new study associates antihelminth treatment in people with MS with worsening disease, supporting the idea that certain parasitic infections could have a protective effect on MS.

This study includes twelve people with MS who had been diagnosed with intestinal worm infections of various types. Each was followed for several years, and eventually four of the subjects required anti-parasitic treatment due to symptoms such as fever, abdominal pain, anorexia, diarrhea, etc. The other eight were able to remain untreated. The researchers compared MS relapses, EDSS, and MRI measurements in the treated and untreated subjects, as well as in 12 uninfected MS subjects. Prior to antihelminth treatment, the infected subjects experienced minimal MS exacerbations, EDSS changes, or new MRI lesions. However, in the months following antihelminth treatment, those subjects who had been treated experienced increased clinical and MRI disease activity, with levels of disease activity rising to reach a level similar to that of the uninfected subjects.

Studies of immune system response (secretion of immune factors and number of inflammatory/anti-inflammatory cells) were also performed. These studies compared the treated subjects, untreated subjects, uninfected MS subjects, and healthy controls. Again, the antihelminth treatment was followed by a shift from an anti-inflammatory to a pro-inflammatory profile. Exposing the cells used in the assays to the antihelminth drugs that were used to treat the infections did not affect the results of these assays, suggesting that the worms have a protective effect on MS as opposed to the drugs having a harmful effect on MS.

The authors acknowledged certain limitations of this study, namely the small number of subjects and the fact that the investigators were not blinded as to the infection and treatment status of the subjects. They also caution against using parasitic infections to treat MS, stating that a better approach might be to identify which of the molecules that are produced by helminths are responsible for the therapeutic effect. (However, there are a couple of clinical trials taking place involving helminth infection -- it will be interesting to see the results generated by these studies.)

MS drugs may inhibit new lesion formation in the cortex

hollie — Fri, 14 Jan 2011 18:35:05 -0500

The disease-modifying drugs currently available for MS have well-established effects on relapse rate and white matter lesion development. Whether they also help to protect gray matter has been an open question, primarily due to the difficulties in imaging gray matter lesions. However, since gray matter pathology has been linked with disability and cognitive dysfunction, it is important to learn what effect standard therapies might have in these regions.

A team of scientists in Italy has performed a study on this topic using an MRI technique called double-inversion recovery (DIR), which is capable of imaging lesions in the cortex (the gray matter layer that constitutes the outer edge of the brain). (Click to see the abstract or open-access full text of their paper.) Their study included 165 people with MS randomized to one of three treatments (two forms of interferon-beta and glatiramer acetate). Also included were 50 people with MS who chose not to be treated (due to benign course, needle phobia, pregnancy plans, etc.). Subjects were imaged at baseline and at 12 and 24 months.

At both timepoints, the treated subjects were less likely to have developed new cortical lesions than the untreated subjects (45% vs. 74% at month 12, and 64% vs. 82% at month 24). The number of new cortical lesions was also lower in the treated vs. untreated subjects. Comparing across the different drugs, the largest effects were seen in those subjects taking IFN-b 1a 44 mcg subcutaneous 3x/week, followed by glatiramer acetate, followed by IFN-b 1a 30 mcg intramuscular 1x/week. These differences across drugs were greater at 12 months, and still present but less pronounced at 24 months. The treated subjects also had lower rates of gray matter atrophy compared with untreated subjects (no differences across drugs). As expected, white matter lesion development and relapse rates were also lower in the treated vs. untreated subjects.

This study suggests that the first-line disease-modifying drugs for MS may curb lesion-promoting inflammation in the cortex as well as in the white matter. It is encouraging to think that this critical area of the brain could receive some protection by available MS drugs. Hopefully this line of investigation will be continued, and expanded to include the emerging MS drugs as well.

Boston-area public education event on CCSVI and MS

hollie — Tue, 21 Dec 2010 18:24:55 -0500

The nonprofit group CCSVI Alliance is hosting an educational meeting on the topic of CCSVI at Brandeis University in Waltham, MA on the evening of January 10, 2011. The title of the meeting is "MS and the CCSVI Connection: What do we know? What don't we know? Where do we go from here?" and the speaker will be Dr. Michael Dake, professor of cardiothoracic surgery at Stanford University. Dr. Dake was one of the first doctors to try surgical treatment of CCSVI in people with MS. He placed stents in 35 people but had to stop performing this procedure after one person died following the procedure and another required emergency open-heart surgery to retrieve a dislodged stent.

You can visit this Evite page set up by the CCSVI Alliance for more information and registration (admission is free).

Medscape interviews MS experts about new and future treatments

hollie — Wed, 08 Dec 2010 13:46:01 -0500

The medical information website Medscape recently posted two interviews that people in the MS community might find interesting. In the first, Dr. Andrew Wilner asks Dr. Daniel Kantor for his opinions on the recently approved MS drugs (Tysabri, Gilenya, and Ampyra), including benefits, risks, and monitoring programs. The interview also touches on several MS drugs still in the development pipeline that may become available before long -- including oral drugs and a new interferon-beta formulation that is injected only once per month.

For those who are interested in the longer-term outlook for MS therapies, there's also a panel discussion on the outlook for neuroprotective agents in MS. (You can read the transcript or see the video/slides.) Drs. Omar Khan, Elliot Frohman, Robert Naismith, and Emmanuelle Waubant discuss the opportunities and challenges associated with developing therapies that protect or repair neurons. The need for neuroprotective agents is great, and therefore so is the opportunity to develop these agents, but challenges include a lack of understanding of how/when neurodegeneration occurs in MS as well as a need for new metrics for measuring the efficacy of neuroprotective drugs. According to Dr. Naismith, "This concept of neurodegeneration and neuroprotection or repair will be the focus of the next decade." Hopefully this new focus will produce one or more therapies that can slow, stop, and/or reverse the progression of disability in MS.

Beneficial aspects of the immune system may be impaired in MS

hollie — Wed, 08 Dec 2010 11:45:18 -0500

Much of the immunology research in MS has focused on the immune system's potentially harmful activities and behaviors, such as the role of pro-inflammatory Th17 cells which have been associated with EAE and MS. However, the immune system also has potentially helpful activities and behaviors, and one line of thought is that these beneficial responses are ineffective or muted in MS. Two papers that were recently published support that idea.

The first study reports that T cells from MS subjects produce less of a protein called "noggin" than T cells from unaffected controls. In the brain, noggin has the effect of encouraging neural precursor cells to differentiate into astrocytes, neurons, and oligodendrocytes. Noggin is expressed by cells in the lining of the brain but is also expressed by immune cells. The authors hypothesized that impaired secretion of noggin by immune cells might hold back attempts at remyelination in MS lesions. They studied blood samples from people with MS (either treated with interferon-beta or untreated) and controls. Their analyses indeed showed lower levels of noggin production by T cells in the MS subjects vs. the controls, both under normal conditions and after stimulation with various factors. IFN-beta didn't seem to affect noggin production one way or the other.

The second study focused on the ability of regulatory T cells to migrate within the body and specifically through the blood-brain barrier. Regulatory T cells help to control the inflammatory response and are thus thought of as being helpful in limiting MS disease activity. Compared with other (non-regulatory) T cells, regulatory T cells from mice and healthy humans demonstrated an enhanced ability to migrate and pass through a simulated blood-brain barrier in lab experiments. In fact, these cells have a strong presence in central nervous system tissues of normal mice, indicating that they play a surveillance role there. However, regulatory T cells taken from people with MS had impaired migration abilities under noninflammatory conditions. Perhaps regulatory T cells in people with MS have a harder time entering the central nervous system, which results in a decreased regulatory response at sites of inflammation.

Hollie's notes from ECTRIMS 2010

hollie — Tue, 23 Nov 2010 18:09:54 -0500

Hollie's Notes From the 2010 ECTRIMS Meeting in Gothenburg, Sweden

Each year Accelerated Cure Project attends the ECTRIMS conference. We try to take notes on as many presentations as we can, write them up, and make them available on MSNews for anyone to read.

You can see our notes below. By the way, if you're interested in seeing the abstracts for the posters and presentations from this conference, you can do so here: http://registration.akm.ch/einsicht.php?XNKONGRESS_ID=126&XNSPRACHE_ID=2n

continued...

Mon-Tue 10/11-10/12:

I flew overnight from Boston to Gothenburg via Amsterdam and arrived safely at the Hotel Lorensburg. This is a great little hotel just a short walk from the conference center. One of its nicer features is free cakes/cookies and coffee in the lobby. Highly recommended!

Wed 10/13:

In the morning I attended a teaching session that reviewed what is known so far about the causes/triggers of MS. The causes of MS turned out to be a featured topic at this conference, with many presentations describing the search for genetic and environmental risk factors and interactions between them.

MS genetics and environment or lifestyle factors

The genetics of MS

J. Hillert

Dr. Hillert explained that most of the genes that have been associated with MS to date are involved in the immune system, and many of these act upon the immune "synapse" between HLA-presenting cells and T cells. There could be hundreds or even thousands of MS genes, but even so, together they only explain a small part of MS risk.

Epidemiology supporting the role of environmental factors in MS

G. Ebers

Dr. Ebers reviewed some of the ways in which genes and environmental factors may work together to affect risk of MS. For instance, the expression of the major MS risk gene, HLA-DR15, appears to be affected by vitamin D levels through the involvement of a VDRE (vitamin D response element). Interplay between the HLA region and epigenetic factors and/or month of birth may also affect risk of MS.

Specific lifestyle/environmental factors in MS

A. Ascherio

Many types of evidence point toward the Epstein-Barr virus, and EBV infection after childhood, as an MS risk factor. People tend to be infected with EBV at a younger age in the tropics and other places where MS incidence is lower. Evidence more closely linking EBV with MS comes from a study that analyzed serum samples from military personnel who had not yet been infected with EBV. Of those who later were infected, 10 people developed MS, whereas no cases of MS occurred in those who never became infected. Dr. Ascherio feels that an EBV vaccine could help prevent MS, but not if it only delays infection.

Gene-environment interactions

L. Alfredsson

A group in Sweden is investigating how genetic and environmental factors interact to cause MS by building a large collection of samples and data from people with MS and controls. Their primary focus so far has been on smoking and sun exposure/vitamin D. They have found that smoking increases the risk of MS, and this effect is magnified in people positive for the HLA-DR15 gene or negative for HLA-A2. However, they did not find an interaction between these genetic factors and UV exposure or vitamin D levels.

The epigenetics of neuroinflammation

M. Jagodic

One way in which environmental factors may affect the risk of MS is through altering gene expression. For example, different factors can affect whether a gene region is methylated or not (i.e., has methyl groups attached to it that affect its expression). Dr. Jagodic explained that MS risk may be affected by these types of epigenetic factors, such as methylation changes that alter expression of the FoxP3 gene which is expressed in regulatory T cells.

Satellite Symposium -- European Charcot Foundation: Chronic cerebrospinal venous insufficiency. Relation to multiple sclerosis?

CCSVI: from hypothesis to reality

P. Zamboni

Dr. Zamboni began his talk by addressing his concerns with two recent papers which did not find an association of CCSVI with MS. The paper by Sundstrom, et al, looked for indications of CCSVI using MRI, which has limitations (e.g., it is not good at imaging the azygous vein). The paper from Doepp, et al, reported control data that were very different from control data published by the authors in a previous paper. Also, the internal jugular vein cross-sectional area (CSA) was the same in the MS and control subjects, but the flow was higher in the MS subjects – Dr. Zamboni wondered whether this would indicate a higher back pressure in MS.

He is conducting a new round of tests in which subjects will wear a collar fitted with a strain gauge to measure neck volume differences in the upright and prone positions. This will allow him to measure the time it takes for for blood to drain through the neck in MS vs. control subjects. This technique is called plethysmography and is less operator-dependent than Doppler ultrasound.

Dr. Zamboni also stated his opinion that surgical interventions should not be performed to treat CCSVI outside of clinical trials conducted by well-qualified teams.

CCSVI: relation to multiple sclerosis

R. Zivadinov

Dr. Zivadinov gave an overview of his research results to date. CCSVI has been found more often in MS cases than in people with other neurological diseases, and more often in people with a first MS-like symptom (clinically isolated syndrome or CIS) than in healthy controls. There is no difference in CCSVI frequency in adults vs. children. Based on the available evidence, Dr. Zivadinov feels that CCSVI probably does not play a causative role in MS.

He then presented some work being done to standardize and validate CCSVI investigations using multiple imaging techniques. One imaging technique is MR venography, which in a previous study using a 3T machine detected no significant differences in internal jugular vein morphology between 57 MS and 21 healthy control subjects. Doppler sonography is better than MRV in terms of giving more specific and sensitive CCSVI results; it also can image people in an upright position which MRV cannot. Catheter venography is the gold standard for investigating vein morphology, but it's invasive and also can't be used in people who are sitting upright. A study is being conducted to compared MRV, CT venography, and Doppler sonography with invasive techniques to try to establish standards of CCSVI imaging. CCSVI characteristics also need to be compared with other common MS imaging measurements.

Dr. Zivadinov also mentioned two treatment studies that are underway. The EVTMS trial is studying angioplasty by comparing people who are treated immediately to those whose treatment is delayed. Initial results indicate a possible effect of the treatment on relapse rate and lesions. The PREMISE study will attempt to control for the placebo effect by comparing balloon angioplasty to sham angioplasty. Since the placebo effect is real and can be very strong with invasive procedures, this type of study is necessary to measure the true effect of treating closed or blocked veins in MS.

Doppler sonography of venous outflow of the brain in multiple sclerosis

F. Doepp

Dr. Doepp presented results from a Doppler ultrasound study involving 56 MS and 20 control subjects. The researchers evaluated many veins, both intracranial and extracranial, for blood flow and cross-sectional area. They also examined internal jugular vein valve competence. They found normal venous flow in nearly all of the MS and control subjects. Postural changes also produced similar effects between the groups. No significant differences in CCSVI criteria between MS and control subjects were found.

Questions on CCSVI in multiple sclerosis

O. Khan

Dr. Khan listed some questions/concerns that he believes need to be resolved concerning the biological plausibility of CCSVI's involvement in MS:

If CCSVI causes MS, why would it be more common in women? And how is it related to other MS risk factors such as vitamin D, HLA genes, and Epstein-Barr virus?
Most vascular phenomena increase in frequency with age, but MS diagnosis is less likely in the elderly.
Disorders that are associated with increased cerebral venous pressure have not been demonstrated to increase the risk of MS.
Iron deposition would presumably be involved if CCSVI causes MS, but CCSVI is not found in other disorders involving iron deposition such as Alzheimer's, Parkinson's, etc. Also, no increase in CSF ferritin levels was seen in MS subjects over the course of a three-year study.
Spinal cord venous drainage is complex with extensive protective communicating systems.
Why are features of central venous distention, hypertension and occlusion not seen in pathology studies?

Dr. Khan also noted the need to reconcile the different results from different studies, including differences among studies that report positive results.

Also described in this session was a study conducted by Dr. Wattjes (in press) that used MRV and 3D flow quantification in the upper cervical region and skull of 20 MS and 20 healthy control subjects. Abnormal and normal venous anatomy were present to similar degrees in the two groups, and the venous anatomy was highly variable in both MS subjects and controls. No venous backflow was found in any subject.

There was another presentation concerning the hydrodynamic results from Dr. Doepp. It expanded upon the finding of increased blood flow in the MS subjects through the internal jugular vein despite similar cross-sectional area compared with controls.

The chair of the session, Dr. Comi, summarized an MRV study finding abnormalities in 16% of subjects with "probable MS" and a lower percentage of subjects with transglobal amnesia (see the Baracchini talk below).

An audience member commented on a venography study showing that CCSVI prevalence in MS increases with disease duration, so it is likely to be a result of MS instead of a cause of MS. Another audience member asked whether any pathology studies had investigated CCSVI anomalies in the veins. A panelist answered that no such studies have yet been published comparing MS subjects with controls.

Young Researchers Session I

IRF5 gene variant as biomarker to predict the interferon beta response in multiple sclerosis

S. Vosslamber, L.F. van der Voort, I.J. van der Elskamp, R. Heijmans, C. Aubin, B.M.J. Uitdehaag, J.B.A. Crusius, C.T.M. van der PouwKraan, D. Hafler, P. de Jager, J. Killestein, C.H. Polman, C.L Verweij

One of the hot topics in MS is finding biomarkers that predict a person's response to therapy, which will become more important as more therapies become available. This group looked at genes that affect interferon pathways to see if a potential marker could be found among them, and focused on the IRF-5 (interferon regulatory factor 5) gene. They genotyped MS subjects who were undergoing IFN-b treatment to see whether any variants correlated with outcomes such as MRI lesions or relapses. They did identify one SNP variant in axon 1 of the gene that showed a correlation: subjects with two T alleles had a greater number of new T2 lesions and lower time to first relapse, indicating a possible lack of response to IFN-b.

Regional cortical and basal ganglia atrophy characterises clinically isolated syndrome patients that early convert to MS

M. Calabrese, F. Rinaldi, I. Mattisi, V. Bernardi, A. Favaretto, M. Atzori, M. Puthenparampil, P. Perini, P. Gallo

Studies investigating whether gray matter atrophy is present in CIS subjects have given varying results. The problem may be due to the mix of people in each study who will and won't go on to develop MS. To address this problem, a research team performed MRI scans on a group of 105 CIS and 42 healthy control subjects and then followed them for four years. During this time 59 of the CIS subjects converted to MS. In the baseline scan, no significant difference was seen in global or regional brain volume between the MS subjects, the non-converting CIS subjects, and controls. However, a smaller volume was seen in individual brain areas such as the superior frontal gyrus, thalamus, and cerebellum in the MS subjects compared with the controls and the non-converters.

Brain MRI in a series of NMO-IgG seropositive patients

I. Kister, J. Howard, J. Perumal, J. Herbert

This study characterized the brain MRIs of 21 women with neuromyelitis optica (NMO) who had tested positive for NMO IgG (the antibody to aquaporin-4 that is a biomarker for NMO). NMO lesions are typically concentrated in the spinal cord and optic nerve, but they have also been detected in other brain areas. 19 of the subjects (90%) had small MS-like lesions in the brain. Lesions that were not MS-like were also found, for instance curvilinear lesions that followed ventricular borders. The types of lesions found varied across the subjects.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography

S. Saidha, C. Eckstein, S. Syc, C. Warner, S. Farrell, N. Shiee, P. Bazin, D. Reich, J. Oakley, M. Durbin, S. Meyer, L. Balcer, E. Frohman, J. Rosenzweig, J. Ratchford, P. Calabresi

Studies using optical coherence tomography (OCT) have shown that the retinal nerve fiber layer often gets thinner in people with MS more quickly than is due to the normal aging process. This may simply be the downstream effect of optic nerve damage, but perhaps MS can also affect the retinal nerves independent of optic nerve involvement. To test this hypothesis, a team used OCT to study 50 MS subjects with significant macular thinning but no history of acute optic neuritis. These subjects had a higher MS severity score than average, as well as visual symptoms not typical of optic neuritis, such as photophobia, excessive glare, and photopsia. The OCT exams revealed disproportionate thinning of certain retinal layers in these subjects compared with other MS subjects and controls. The team concluded that MS can involve damage to the retina that is not mediated by optic nerve damage.

Interhemispheric motor inhibition as a marker of callosal disconnection in early relapsing–remitting multiple sclerosis

A. Huebers, M. Wahl, U. Ziemann

This study tested whether subtle damage to the corpus callosum is present in people with early MS even before MRI-detectable lesions appear in that region. 34 early MS subjects and 12 age-matched healthy control subjects were asked to perform a labyrinth test to measure manual coordination. They were also tested for interhemispheric inhibition (a brain function involving the corpus callosum) using transcranial magnetic stimulation. The MS and control subjects performed equally well on the labyrinth test. However, interhemispheric inhibition was decreased in the MS subjects (this was not correlated with EDSS, T2 lesions, or disease duration). Interestingly, the MS subjects with lower interhemispheric inhibition finished the labyrinth test more quickly.

Young Researchers Session II

NMO spectrum disorders associated with myasthenia gravis: a cohort study

E. Coutinho, M.I. Leite, E. Santos, A. Graham, L. Jacobson, C. Buckley, D. Hilton-Jones, A. Vincent, J. Palace

The autoimmune diseases myasthenia gravis (MG) and neuromyelitis optica sometimes occur in the same person. This presentation described eight people with MG who also developed NMO 4 to 41 years later. All were positive for NMO IgG. Questions raised by this comorbidity include: Why does NMO sometimes follow MG? Does immunosuppression given to treat MG delay the onset of NMO? What is the role of the thymus in NMO – does it express aquaporin-4 (the antigenic target in NMO)? (An audience member answered “yes.”) Would a thymectomy performed to treat MG trigger an increase in anti-AQP4 antibodies?

A human commensal antigen protects against CNS demyelinating disease in mice and modulates regulatory T-cell phenotypes in humans

J. Ochoa-Reparaz, Y. Wang, D.W. Mielcarz, S. Begum-Haque, A. Bergeron, J. Channon, D.L. Kasper, L.H. Kasper

Previous work has shown that altering the ecosystem of gut-dwelling bacteria with antibiotics can protect mice against EAE and also reduce IFN-gamma and IL-17 inflammatory responses. This team hypothesized that a certain common commensal bacterium, Bacteroides fragilis, could contribute to this beneficial effect. B. fragilis produces 8 different polysaccharides including PSA. PSA induces production of IL-10 and affects the Th1/Th2 T cell balance; PSA stimulation of CD103+ dendritic cells triggers conversion of T cells to a regulatory phenotype via TLR2 signaling. In addition, oral purified PSA (as well as the bacteria itself) has been shown to protect against EAE and also improve established EAE. To study its possible effect in humans, researchers added PSA to a culture of immune cells from healthy humans. The result was an increase in FoxP3+ regulatory cells and enhanced production of IL-10. Dr. Ochoa-Reparaz wondered whether B. fragilis would be beneficial in MS, since FoxP3 cells suppress pathogenic Th17 cells.

Combined exercise led by a physiotherapist or fitness instructor significantly improves walking distance over six minutes

M. Garrett, N. Hogan, A. Larkin, J. Saunders, S. Coote

313 subjects who needed at most a unilateral support (such as a cane) to walk were enrolled into a study of exercise and walking ability. Four interventions were compared: physical therapist-led exercise, fitness instructor-led exercise, yoga, or control (no intervention). Physical therapist-led exercise included progressive resistance circuit exercise plus independent aerobic exercise. The fitness instructor-led exercise included combined aerobic and progressive resistance exercise. Participants were tested before and after 12 weeks of the program to see how far they could walk in 6 minutes. At the end of the study, the distance increased for the physical therapist- and fitness instructor-led groups, stayed the same for the yoga group, and slightly decreased for the control group.

Dietary vitamin D3 supplements reduces demyelination in the cuprizone model

S. Wergeland, O. Torkildsen, K-M. Myhr, L. Aksnes, S. Mork, L. Bo

Vitamin D has been shown to protect mice against EAE (an autoimmune disease) – can it also protect against demyelination induced by cuprizone (a toxic agent)? Mice were given four different doses of vitamin D, which were administered before and after administration of cuprizone. Demyelination was reduced in the two high-dose groups compared with the low-dose groups. There was no effect of vitamin D dose on oligodendrocyte loss or differentiation, and all groups had similar remyelination after the cuprizone was stopped. Higher doses of vitamin D were correlated with a lower number of activated microglia and macrophages in the corpus callosum. These results suggest that vitamin D might protect against demyelination independent of inflammation, although an audience member suggested that the myelin in the high-dose mice might still have been damaged but just wasn't phagocytosed (removed by macrophages).

Validity of a computerised version of the Symbol Digit Modalities test in patients with multiple sclerosis

N. Akbar, K. Honarmand, N. Kou, A. Feinstein

The Symbol Digit Modalities Test (SDMT) is a cognitive test commonly used in MS. It has been computerized for use in functional MRI studies, but the computerized version has not been validated against the standard paper and pencil test. So 119 MS subjects and 38 healthy controls were given both versions of the test. The computerized version resulted in similar sensitivity and specificity to the written version in terms of distinguishing the MS subjects from control subjects.

Satellite Symposium – sponsored by Merck Serono

The major MS pharmaceutical companies sponsor symposia during the conference to provide information about their drugs to the clinicians who will be prescribing those drugs. I'm not a clinician, but do attend these occasionally because sometimes new information is presented. At this symposium, I was interested to learn about the rules set down by the Australian government for prescribing oral cladribine (trade name Movectro) for treating MS. The treatment can be used for a maximum of two years. Hematological monitoring is required, and monitoring for infections is recommended. This drug is currently being reviewed by the FDA for use in the US – if they approve it, they may similarly specify limits and monitoring for side effects.

Thursday 10/14:

Welcome address and ECTRIMS lecture

I arrived in time for part of the “welcome addresses” and learned about Gothenburg and its university and why I should consider moving there. I do agree that the city is very pleasant, at least what I saw of it!

ECTRIMS lecture: genes and life-style/environmental factors in MS

T. Olsson

This lecture began with an overview of genetic findings in MS. One recently-studied gene, VAV1, increases the severity of EAE. A particular VAV1 variant is associated with MS risk and appears to have a pro-inflammatory effect. A similar role has been been identified for the IL22RA2 gene.

Genome-wide association studies have detected about 20 non-HLA genes that are associated with MS to a high degree of significance. They are all related to immunity -- not to primary neurodegeneration. It is possible that some of these genes are not true MS risk factors themselves but happen to be located near another gene that does affect MS risk. The functional effects of these genes also still need to be explored. Further exploration of the role of immune system genes in MS is taking place through the ImmunoChip project. In this project, 250,000 SNPs representing genes associated with different immunity-related disorders will be used to screen 150,000 subjects with a variety of diseases including MS.

Within the HLA DR15 haplotype, which is the gene variant most strongly associated with MS, it looks like the key MS risk gene is DRB1*1501, although the other genes in the haplotype may contribute additional, smaller effects. Very little is yet known about the functional role of DRB1*1501 in MS – it probably relates to peptide binding but this needs to be explored further. Another HLA gene, HLA*A2 (or something else nearby on the genome) protects against MS and is the second most important MS gene.

Now on to lifestyle and environmental factors. Dr. Olsson described a Swedish study called EIMS (Epidemiological Investigation of Risk Factors in MS) which had also been mentioned by Dr. Alfredsson in the teaching session on Wednesday. This study has enrolled 1500 people newly diagnosed with MS and 2 controls for each case (3000 total) matched on sex, age, and county. Each subject fills out a questionnaire and gives a plasma and DNA sample. One goal of this study is to find interactions between factors that increase the risk of MS in a synergistic way. (For example, synergy would exist if two factors on their own each doubled the risk of MS, but multiplied the risk by 5 when present together.) Finding these interactions is important to fully understand how MS develops in people.

So far, they have found that Epstein-Barr virus (EBV) and HLA-DR15 interact (there is a 10x increased risk of MS in people positive for DR15 and anti-EBNA EBV antibodies compared with people negative for both), but have found no interaction between EBV and HLA A2. The questionnaire asks about sun exposure habits (sunbathing etc.) and samples are analyzed for vitamin D levels. Both UVR exposure and vitamin D levels protect against developing MS, but neither was demonstrated to interact with HLA genes.

Smoking increases the risk of MS, and the greater the smoking habit, the higher the risk. The increased risk persists for at least five years after quitting smoking. The risk is lower if oral tobacco is used, so perhaps the higher risk of smoking is due to lung irritation, inflammation, or chronic infections. The risk of MS associated with smoking is enhanced in people who are HLA DR15-positive and A2-negative. Interestingly, a similar effect has been seen in rheumatoid arthritis, where smoking and HLA DRB1*04 interact to increase the risk of this disease.

MS Genetics

Interactions between HLA and other genes in MS

L. Fugger

The MS-associated HLA genes DR2b (DRB1*1501) and DR2a (DRB5*0101) are usually inherited together. One evolutionary reason for this could be that having both confers a strong advantage in resistance to infections. The basis for their co-inheritance was explored in an animal study. Mice were engineered to express one or both genes, as well as a human T-cell receptor that recognizes both proteins in order to generate an immune response. The mice that had DR2b only developed a spontaneous PPMS-like disease, mice that had DR2a only developed no disease, and mice that had both genes developed a spontaneous RRMS-like disease. DR2a modulated the disease induced by DR2b by promoting the death of autoreactive T cells. This suggests that the reason both genes are often inherited together is because they have complementary functions – DR2b produces an exuberant immune response and DR2a makes sure that the DR2b response doesn't get out of hand. Another humanized mouse model was created that involved the HLA A2 and A3 genes. Autoreactive T cells were stimulated in the mice with A3 but eliminated in those with A2. In mice with both genes, autoreactive cells were still present but there were fewer of them.

The new MS gene list – whole genome association studies in MS

S. Sawcer

Dr. Sawcer reviewed the results of the whole genome studies to date. The initial studies identified 16 genes that have strong associations with MS, and another 10 that are probably associated with MS. A follow-up study funded by the Wellcome Trust has analyzed samples from 14,000 MS cases and 25,000 controls. He was hoping to present the list of associations at this meeting but it wasn't ready yet.

The future: where does MS genetics go from here?

P. De Jager

Much work has been done to find genes that affect MS risk, but much more remains to be done. Dr. De Jager gave a preview of upcoming “to-do” items, beginning with the search for rare genetic variants. Whole genome studies only include fairly common variants, and therefore miss variants that are only present in a small percentage of the population. However, rare variants that play a role in MS have been identified. One example is a rare variant in the SIAE gene which increases the likelihood of getting MS by 8.5 times – and there are probably others out there as well. These gene variants can be found through sequencing, but it may be impossible to find them all, especially those that only increase the risk of MS by a little.

For the gene variants that have been identified, a compelling line of investigation involves finding the biological effect of those variants. Scientists are starting to analyze the biological pathways in which these genes operate and whether the MS-related variants increase or decrease the expression of these genes in a way that affects activation of these pathways.

Another line of investigation involves using known MS-related genes to predict risk of MS. Dr. De Jager is working on a risk model that includes 16 genetic variants plus Epstein-Barr virus titers plus smoking. This model will probably not be useful in evaluating an individual's risk of MS, but might help in selecting subjects at risk of MS (e.g., relatives of people with MS) for studies that would follow people over time to see if, how, and when MS develops. Gene-based models might also be useful for predicting which people with CIS have a higher risk of a second relapse, or which MS subjects would respond to certain drugs. With respect to the latter question, a study that tried to find genes that might influence time to first relapse after starting IFN-b or Copaxone came up empty. The study involved only a few hundred people so a larger sample is needed. Dr. De Jager would like to repeat this investigation by pooling all the data on subjects who were included in a whole-genome study and who also have treatment response data available.

Natural course of MS

MRI and CSF as predictors of time to relapse after CIS in neurological practice

H. Butzkueven, C. Meyniel, T. Spelman, G. Izquierdo, F. Grand'Maison, M. Trojano, C. Zwanikken, C. Oreja-Guevara, A. Lugaresi, T. Petersen, C. Boz, P Grammond, G. Iuliano, P. Duquette, M. Girard, M. Fiol, J. Cabrera-Gomez, R. Hupperts, G. Giuliani, J. Lechner-Scott, F. Verheul, R. Bergamaschi, E. Cristiano, V. Van Pesch, M. Saladino, J. Herbert, T. Petkovska-Boskova, N. Vella, F. Moore, M. Slee, E. Havrdova, M. Paine, C. Young, C. Shaw, M Barnett, C.-A. Sirbu

Many people with a clinically isolated syndrome never go on to have another attack, while others have a second attack fairly quickly. It would be nice to tell someone who has a CIS what they can expect in terms of whether they will develop MS and when. This study included 1,712 CIS subjects who had at least one MRI brain lesion at baseline. 745 of these had another relapse within about two years. Several factors were associated with having a second attack including the presence of spinal cord lesions and oligoclonal bands. Those factors that were most strongly associated with time to second attack were the presence of gadolinium-enhancing lesions and 3 or more T2 lesions. Side note: The MRI feature that was most strongly associated with having oligoclonal bands was spinal cord lesions.

Environmental and life-style contribution in MS

Analysing risk factor interactions in MS

T. Riise

Many MS risk factors have been found, but no one factor can cause MS all by itself. So scientists are trying to learn how risk factors biologically interact with each other in MS. So far there is mixed evidence for an interaction between HLA DR15 and EBV and no apparent association between DR15 and smoking. Evidence is also mixed for an interaction between sun/vitamin D exposure and the vitamin D receptor gene. On the other hand, evidence looks pretty good that the association between EBV and MS is strongest among smokers.

Studying interactions of this type requires large numbers of cases and controls. A multi-country study is underway that has enrolled 1820 MS cases and 3640 controls and has collected 6 pages of epidemiologic data from each. This study has confirmed the MS associations with infectious mononucleosis (caused by EBV), sun exposure and smoking. Interestingly, this data has indicated a negative interaction between mono and smoking, and no significant interactions between mono and sun exposure or sun exposure and smoking.

Vitamin D deficiency as a risk factor

A. Ascherio

Dr. Ascherio noted that different types of evidence support a protective role for vitamin D in MS, but proving this connection would require a large scale trial of hundreds of thousands of people followed for several years. Would vitamin D supplementation reduce progression in people who already have MS? This is unknown, but adding vitamin D may have other health benefits. Dr. Ascherio felt that 2,000 IU/day would probably be safe for most people although long term effects are not known.

HLA-DRB1*15 and vitamin D status at first demyelinating episode are independent risk factors for MS in children

H. Hanwell, S. Magalhaes, L. Verhey, G. Disanto, A. Handel, K. Morrison, S. Ramagopalan, M. McGowan, D. Arnold, R. Vieth, A.D. Sadovnick, G. Ebers, R.A. Marrie, A. Bar-Or, B. Banwell on behalf of the Canadian Pediatric Demyelinating Disease Network

Dr. Hanwell described a study that investigated vitamin D and HLA DR15 in children with a CIS. HLA DR15 gene expression is modulated by vitamin D (along with the expression of over 2,000 other genes) so it makes sense to look for a connection between these two factors. 296 children were enrolled, and were seen at baseline, 3 months, 6 months, 1 year, and yearly thereafter. A full work-up was performed whenever a child had a second demyelinating event. Of the 296 children, 63 were diagnosed with MS (39 because of a second attack, 24 because of new lesions on MRI). The researchers tested the subjects' vitamin D levels (if they were seen within 40 days from onset) and HLA type. They also recorded whether the children had been taking any vitamin D-containing supplements.

The subjects who converted to MS had lower vitamin D levels than those who remained in CIS status. The MS converters also were more likely to be DR15-positive. No interaction was seen between DR15 positivity and vitamin D levels, however. But here's something interesting: Only one of the 29 children who were taking vitamin D supplements converted to MS.

Multiple sclerosis is associated with low previous ultraviolet radiation exposure and low levels of current vitamin D: no interaction with HLA complex genes

M. Bäärnhielm, A. Hedström, I. Kockum, E. Sundqvist, S. Gustafsson, T. Olsson, L. Alfredsson

The Epidemiological Investigation of MS (EIMS) case-control study has reported that vitamin D levels were lower in people recently diagnosed with MS compared with controls matched for age, gender, and place of residence. As in other studies, no interaction was detected between HLA DR15 and UV exposure or vitamin D levels. Strengths of this study include the fact that it's population-based and has good participation from people invited to join it. Limitations include selection bias (people who are more health-conscious would be more likely to participate), recall bias (having a diagnosis of MS might make a person remember past events in a different way), and the possibility that measuring vitamin D after diagnosis might not be relevant in a disease that could have been silently developing for years before onset.

No evidence for a temporal change in disability progression: findings from British Columbia, Canada, 1975-2009

A. Shirani, Y. Zhao, E. Kingwell, P. Rieckmann, H. Tremlett

Have MS disability progression rates changed over the decades, for either better or worse? That is the question that a study from British Columbia sought to answer by analyzing data in the province's clinical MS database. Subjects in the database were divided into five-year groups based on year of symptom onset, starting with 1975. Within each group, the percentage of people who had a sustained and confirmed EDSS score of 6 or greater within 15 years of onset was tabulated. For those with onset during 1975-1979, 28% reached EDSS 6 within 15 years. The percentage for those whose onset happened during 1990-1994 was 22% -- a lower percentage, but not a statistically significant difference. No strong evidence was found for a progression-delaying effect of disease-modifying therapies, which had been used by 23% of the people studied.

Mechanisms and intervention in MS progression

The therapeutic potential of mesenchymal stem cell transplantation as a treatment for multiple sclerosis

A. Uccelli

Mesenchymal stem cells (MSCs) are cells found in bone marrow that can be induced to develop into a variety of different cell types. They are being studied for possible therapeutic potential in MS. Dr. Uccelli described these cells and the research that has been performed with them. MSCs display antioxidant, neuroprotective features and have been shown to induce neural stem cells to differentiate into oligodendrocytes. MSCs can ameliorate EAE by inducing T and B cell tolerance to myelin antigens. Studies in mice showed that MSCs injected either intravenously or into cerebrospinal fluid were able to home into the brain and alter the immune response in the brain. Although they have not been observed to transdifferentiate into neural cells, they do appear to protect axons. They also reduce astrocyte scarring, microglial activation, and microglial production of proinflammatory molecules, while inducing microglia to switch to a neuroprotective form.

MSCs taken from MS patients seem normal upon examination. Dr. Uccelli described a phase I/II study involving 140 MS subjects at different clinical sites. The study is enrolling RRMS or SPMS subjects with active lesions and PPMS subjects with evidence of inflammation. MSCs are being administered one time by IV. Treatment effects will be assessed using MRIs, and the comparison will be made using a randomized cross-over design where part of the group will have a delayed treatment of 6 months.

Satellite Symposium -- Biogen Idec & Elan Pharmaceuticals -- Redefining success in MS: remission and improvement - today and tomorrow

The first part of the symposium reviewed some of the Tysabri trial data, including its effects on the MS Functional Composite score, walking speed, fatigue, and quality of life. I was more interested in the next presentation:

Neuroprotective effects in neuroinflammation via Nrf2 pathway activation

R. Gold

BG-12 (oral fumarate) is an oral drug which is currently going through clinical trials in MS. Dr. Gold outlined its presumed mechanism of action. BG-12 acts upon the Krebs cycle which supplies the energy that lymphocytes need. It also seems to have a neuroprotective, antioxidant effect. When a cell is experiencing oxidative stress, a protein called Nrf2 is released. Nrf2 goes into the nucleus and initiates the upregulation of several detoxication factors. In a culture of astrocytes, fumarate protected the cells from H2O2-related toxicity by activating Nrf2-dependent antioxidation pathways. In mice, fumarate appears to get into the brain at about the same concentrations shown to be neuroprotective in culture. In EAE mice, fumarate upregulates Nrf2 in interneurons, oligodendrocytes, and astrocytes. Nrf2 seems to be involved in the MS neuroprotective response as well – it has been shown to be upregulated in MS spinal cord autopsy tissue. In preliminary clinical trial data, BG-12 reduced MRI “black hole” lesions by 50% in treated subjects compared with placebo-treated subjects. These lesions indicate persistent axonal damage, supporting the case for Nrf2 being neuroprotective. A phase 3 study of BG-12 in MS is concluding soon – it will be interesting to see those results.

Friday 10/15:

Platform presentation of selected abstracts I

A placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis: clinical efficacy and safety outcomes

P. O'Connor, J. Wolinsky, C. Confavreux, G. Comi, L. Kappos, T.P. Olsson, H. Benzerdjeb, B. Wamil, L. Wang, A. Miller, M.S. Freedman for the Teriflunomide Multiple Sclerosis Trial Group

Dr. O'Connor reported the results of a two-year phase III trial of teriflunomide, a new oral drug from Sanofi-Aventis that reduces the proliferation of autoreactive T and B cells. The primary endpoint was annualized relapse rate and secondary endpoints were time to sustained progression and MRI measurements. There were three arms (a 7 mg dose, a 14 mg dose, and placebo), each including around 360 subjects. The drop-out rate was 27% and was similar across all three arms; reasons given for dropping out included adverse events, perceived lack of efficacy and withdrawal of consent. Relapses were lower in the active drug arms: 0.37 relapses per year in treated subjects vs 0.54 in placebo subjects – a 31% reduction in relapse rate. Subjects in the high-dose group were 30% less likely than placebo subjects to have progression sustained for 12 weeks; they also had a reduction of total lesion volume of 67% compared with placebo subjects. No effect was seen for brain atrophy, however.

The risk of adverse effects including serious adverse effects (SAEs) was the same across all groups. Side effects that were more common in those receiving teriflunomide included nausea, diarrhea, mild increase in ALT (a liver function marker), and mild hair thinning. Nobody had a serious opportunistic infection and nobody died. Three placebo subjects and one teriflunomide subject were diagnosed with cancer.

One particular concern with teriflunomide is its effect on developing fetuses. 11 women became pregnant while in the study. Of these pregnancies, 4 were spontaneously aborted, 6 were aborted electively, and 1 went to full-term resulting in a healthy baby. The woman whose pregnancy went to term went through a protocol to wash the drug out of her system to protect the baby.

Based on the efficacy and safety data, Dr. O'Connor suggested that teriflunomide may become another first-line drug for treating MS. The data does seem promising and having more options (particularly those not involving needles) would be a good thing.

Visual pathway axonal loss in benign multiple sclerosis

K.M. Galetta, L.S. Talman, D.J. Lile, S. Syc, A. Conger, G. Remington, P.A. Calabresi, E.M. Frohman, S.L. Galetta, L.J. Balcer

“Benign MS” is a label applied to people who have a low EDSS score despite having had MS for several years. Past studies have shown that people with benign MS have a similar or greater T2 lesion burden than other RRMS subjects, and brain atrophy similar to subjects with SPMS. Reasons why benign subjects are less clinically affected may include sparing of tissue outside lesions, sparing of brain areas directly associated with symptoms, or compensation within the central nervous system that allows functioning despite damage. A group of researchers decided to investigate benign MS by using optical coherence tomography (OCT) to assess the thickness of the retinal nerve fiber layer (RNFL), a collection of axons that can be damaged in MS and optic neuritis. Benign subjects had an EDSS score of 3 or less after 15 years, or an EDSS of 2 or less after 10 years. 51 subjects with typical MS were also included for comparison. Average disease duration was 19 years for the benign group and 5.6 years for the typical MS group. Average baseline RNFL thickness was around 90 microns in both groups. Over 1.5 years of follow-up, both groups had thinning of the RNFL (slightly greater in the benign group) and both had lower visual acuity. However, the benign MS subjects had a lower visual quality of life score and greater history of optic neuritis. This study shows that even though benign MS subjects have a relatively low EDSS, they are still subject to visual impairment and loss of axons involved in vision.

No evidence of chronic cerebrospinal venous insufficiency in clinically isolated syndrome suggestive of multiple sclerosis

C. Baracchini, P. Perini, M. Calabrese, F. Causin, F. Farina, F. Rinaldi, P. Gallo

This study attempted to answer the question of whether CCSVI is a cause or an effect of MS by studying the phenomenon in people at the very earliest stages of MS. 50 CIS subjects with evidence of dissemination in space on MRI (“probable MS”) were followed over a year. 20% converted to MS within this time. 60 subjects with a different neurological condition, transient global amnesia (TGA), were also recruited, as were 110 healthy controls matched by age and gender to the MS and TGA subjects. All subjects had extra-cranial and transcranial Doppler color-coded sonography (EDCS and TDCS) performed to detect CCSVI characteristics. The sonographer performing the analysis was blinded to the subjects' clinical status and used a high-quality sonographic scanner. Subjects were imaged in the upright and supine positions. The Zamboni criteria were used to diagnose CCSVI.

The TDCS findings were normal in all CIS subjects (no reflux, normal volumes). The percentage of subjects with EDCS abnormalities was similar across groups. Eight (16%) of the CIS subjects fulfilled the Zamboni criteria and seven of these underwent venography with normal results. No association was found between the subjects' MS symptoms and their CCSVI type (A-D). Dr. Baracchini concluded that his results do not support a causal role for CCSVI in MS; however, further studies are needed of subjects in later disease stages to provide a full picture.

An audience member asked whether Dr. Baracchini really knew what he was looking for in the venographic images. Dr. Baracchini replied with a summary of his experience and credentials. Another audience member said that his study had obtained similar results but that CCSVI prevalence was higher with a longer disease duration.

Presence and severity of chronic cerebrospinal venous insufficiency is related to lower brain parenchyma venous vasculature visibility on susceptibility-weighted imaging in patients with multiple sclerosis

R. Zivadinov, G. Poloni, C. Schirda, C. Magnano, E. Carl, N. Bergsland, D. Hojnacki, C. Kennedy, F. Parker, M. Dwyer, B. Weinstock-Guttman

The AAN meeting earlier this year included a presentation that showed lower venous vasculature volume in the brains of people with MS compared with controls as measured by a type of MRI called susceptibility weighted imaging (SWI). Lower venous volume might be related to CCSVI-type abnormalities, so Dr. Zivadinov led a study to see whether these two phenomena are linked. The study involved 59 MS subjects and 33 age and sex-matched healthy controls and each was assessed for CCSVI and brain venous volume. 80% of the MS subjects and 18% of the controls met the criteria for CCSVI. As with the previous study, SWI showed reduced venous vasculature in the MS subjects, and these measurements were indeed correlated with the presence of CCSVI.

MS pathology

Revisiting the role of autoimmunity in the progressive phase of MS

H. Wekerle

I missed part of this lecture, but heard Dr. Wekerle describe a hypothesis involving a role in MS for gut-associated lymphatic tissue (immune structures associated with the digestive tract).

Cortical pathology in MS

L. Bö

Dr. Bo provided a recap of what is known about the effects of MS on gray matter in the CNS. Compared with white matter, gray matter until recently was relatively neglected in MS. However, research in the past few years has revealed that the cortex and deep gray matter structures can sustain extensive demyelination and axonal damage as well.

Inflammation versus neurodegeneration in progressive multiple sclerosis

J.M. Frischer, S. Bramow, A. Dal-Bianco, C.F. Lucchinetti, H. Rauschka, M. Schmidbauer, H. Laursen, P. Soelberg Sorensen, H. Lassmann

Dr. Frischer described a pathology study that examined autopsy samples from 67 people with MS and 28 control subjects. MS lesions were classified as active, slowly expanding, or inactive. T cells were the dominant immune presence in lesions while B cells and plasma cells were frequently found in the meninges (the tissue layers surrounding the brain). Inflammation decreased with age in MS subjects but didn't change with age in the controls. Axonal injury also decreased with age in MS subjects but increased with age in controls. Subjects with progressive MS could be divided into two groups: those with active lesions, who had increased inflammation and axonal injury compared with controls, and those with no active lesions, whose levels of inflammation and axonal injury were similar to controls.

Dr. Frischer postulated that there are three general phases of MS:

RRMS: Waves of inflammation, focal lesions, and attempts at remyelination which are vulnerable to inflammatory attacks
SPMS: Compartmentalized (located within the CNS) inflammation, diffuse white matter and cortical pathology
“Burnt-out MS”: Neurodegeneration that is unrelated to MS; remyelination may be possible since there is no longer any active inflammation

The relationship between meningeal inflammation and spinal cord pathology in multiple sclerosis

C. Reali, R. Magliozzi, A. Kirresh, O. W. Howell, R. Reynolds

Research described at a previous ECTRIMS conference revealed that B cell-containing follicles were occasionally present in the meninges of the brain in people with MS. Are these structures also present in the meninges of the spinal cord? Researchers examined post-mortem spinal cord tissues of 14 people with MS with and 14 without follicles in the brain meninges. Similar follicles were found in the spinal meninges of 4 of the people with follicles in the brain meninges. The presence of these follicles was associated with a larger number of CD20+ B cells in the meninges and an increased number of CD4+ T cells (but not CD8+ cells or macrophages) in the meninges and spinal cord tissue. Still undetermined is what causes those follicles to appear where they do.

Risks and benefits of new therapies in MS

Cytotoxic therapeutic agents in MS

G. Edan

Many of the drugs that are being used for MS are toxic to cells – and therefore their efficacy is accompanied by risk of harmful side effects. Dr. Edan provided a review of some of the drugs in this category that are sometimes used in MS.

Mitoxantrone: There is new data that mitoxantrone followed by IFN-b delays disability, especially in people with an EDSS less than 4. However, it comes with an increased risk of heart failure (up to 2% in SPMS patients aged 50+) and asymptomatic cardiac impairment in 5% of patients (which is persistent in 30% of these patients). In addition, mitoxantrone increases the risk of acute leukemia.

Cyclophosphamide and mycophenolate mofetil have been reported in a few studies as potentially useful for people with MS who don't respond to IFN-b.

Cladribine is another example of a cytotoxic drug being studied in MS – this one has undergone large clinical trials and is currently under review by the FDA.

Dr. Edan's conclusions were that there is no evidence that any of these drugs are useful in progressive MS, but there is evidence of benefit over 2-3 years in RRMS. They may be most useful as induction or rescue therapies. We don't know what the effects would be of using them sequentially with other drugs – for example, what would happen if mitoxantrone was followed by natalizumab.

Spingosine 1 phosphate receptor agonists as immunomodulators in MS

C.H. Polman

S1P receptors are expressed on lymphocytes, neural cells and vascular cells. Novartis' new MS drug Gilenia is an nonspecific S1P receptor agonist that traps certain immune cells in lymph nodes while leaving others in circulation to provide immune surveillance. Other drugs are emerging that target particular S1P receptors and therefore may have more fine-tuned effects. For example, Novartis' BAF312 targets S1P1 and S1P5 receptors, and Actelion's ACT-128800 is selective for S1P1 only. Gilenia has been shown to cross the blood-brain barrier and might mediate repair in the central nervous system. A study of this drug in PPMS is underway – the results will be eagerly awaited.

Overview of clinical outcomes in cases of natalizumab-associated progressive multifocal leukoencephalopathy

P. Vermersch, J. Foley, R. Gold, L. Kappos, T. Olsson, C. Bozic, S. Richman

Dr. Vermersch presented a report about PML incidence and outcome in Tysabri users. So far over 26,000 Tysabri users have been treated for more than two years. Average incidence of PML in the post-marketing phase is 0.9 cases per 1,000 people. Looking at incidence by length of time on drug, the highest incidence right now is 1.5/1,000 people in those who have used the drug for 24-36 months. Of the first 35 Tysabri/PML patients, 10 died and the rest survived – a better outcome than in other groups of PML patients. Increased age and higher EDSS were associated with a greater risk of death from PML, but fatality was not associated with duration of Tysabri use or prior immunosuppressant use. Survival was associated with a more localized disease as seen on MRI and with quicker diagnosis (although some fatal cases were diagnosed quickly).

All of the survivors had been treated to rapidly remove the Tysabri from their systems. 91% had a subsequent reaction called IRIS (immune reconstitution inflammatory syndrome). Of those who had been followed for at least six months after diagnosis, approximately 1/3 had mild residual disability, 1/3 had moderate disability, and 1/3 had severe disability – this disability includes effects from MS as well as from PML.

Phase II trial of firategrast shows that oral anti-alpha4 therapy can suppress new MRI lesions in relapsing–remitting multiple sclerosis

D. Miller, T. Weber, X. Montalban, R. Grove, P. Dua, C. Wardell, O. Graff

Oral firategrast is an anti-alpha4 integrin drug, so its mechanism of action is similar to that of Tysabri. Dr. Miller reported on phase II trial results for this drug, which is being developed by Glaxo SmithKline. The trial took place in Europe, Canada, Australia, and New Zealand. Subjects with RRMS were treated for 6 months and followed for 15 months. The primary outcome was new Gd-enhancing lesions and subjects were scanned every month. 350 subjects were divided among four arms: placebo (100 subjects), 150 mg (50 subjects), 600 mg (100 subjects), and 900 or 1200 mg depending on gender (100 subjects). The 900/1200 mg group had lower new lesion accumulation than the other groups (2.69 lesions vs. 4.12-9.51). A trend toward fewer relapses was also seen although this study was not designed to detect a significant relapse effect. Following the end of the treatment period, subjects did have more disease activity but there was no strong “rebound effect.” No significant differences in adverse effects was detected, although there was a trend toward more infections in the treated groups. Nobody developed PML, and nobody had a positive JC virus test result.

Efficacy and safety of ocrelizumab in patients with relapsing–remitting multiple sclerosis: results of a phase II randomised placebo-controlled multicentre trial

L. Kappos, P. Calabresi, P. O'Connor, A. Bar-Or, D. Li, F. Barkhof, M. Yin, R. Glanzman, J. Tinbergen, S. Hauser

Ocrelizumab is a recombinant humanized antibody to CD20 and it targets B cells that express this marker. Because it is more “humanized” than rituximab, another anti-CD20 drug, it may be more powerful and have fewer adverse effects. Dr. Kappos presented results from a phase II study in people with RRMS. Subjects were randomized to four arms: placebo, 600 mg of ocrelizumab, 2000 mg of ocrelizumab, and IFN-b. Ocrelizumab was administered as separate infusions at weeks 0, 2, 24, and 26. An MRI scan was performed at 24 weeks. Ocrelizumab subjects had a lower number of Gd-enhancing lesions at this scan than the other subjects, and were more likely to be free of new lesions. Also, subjects receiving ocrelizumab had significantly fewer relapses than the placebo subjects. At week 24, the placebo and IFN-b subjects were switched to ocrelizumab; by week 48, their relapse rates had declined.

Overall adverse effects were higher in the placebo group. Some ocrelizumab subjects had infusion reactions, but these were mostly absent by the second infusion. There was no significant difference among the groups in terms of infections. However, there was one death in the higher dose ocrelizumab group. The subject died at week 14 of systemic inflammatory response syndrome (SIRS) with disseminated intravascular coagulopathy. He/she developed pneumonia and died of brain edema. Dr. Kappos said that the SIRS was possibly related to ocrelizumab but this could not be confirmed, and that there was no clear safety signal limiting further investigation of this drug. An audience member asked whether it would be advisable for any future studies to use the lower dose. Dr. Kappos replied that the lower dose was well-tolerated and would be appropriate to use if it maintained efficacy.

Biomarkers in MS

Biomarkers as potential tools for monitoring disease activity and treatment efficacy

F. Sellebjerg

This talk described an effort to find pre-treatment factors that would predict treatment response. The study included 39 untreated MS subjects, 24 who were beginning IFN-b treatment, 40 already on IFN-b, and 29 on glatiramer acetate (Copaxone). Each subject had MRI scans, contributed blood samples for gene expression and cellular analyses, and was followed for future relapses.

The number of CD40+ dendritic cells and CD4+ HLA-DR+ T cells independently predicted relapse activity in subjects on IFN-b. The number of CD40+ dendritic cells independently predicted relapses in subjects on Copaxone. IFN-b alters the CD4+ repertoire (but Copaxone doesn't), while Copaxone decreases the number of CD40+ dendritic cells (IFN-b doesn't). Expression of TRAIL/TNFSF10 36-48 hours post-injection also independently predicted relapse risk. However, MRI did not provide an independent predictor of relapse activity.

Unravelling MS pathophysiology through biomarkers

B. Hemmer

Assays to detect antibodies to proteins found on the membranes of cells typically don't reflect “real life” -- for example, they use recombinant proteins or amino acid chains in isolation which don't represent the proteins' true structure in the body. These limitations may account for the mixed results produced by studies of anti-MOG antibodies as predictors of conversion from CIS to MS. A new study used an improved method with a more realistic version of MOG, and found an increased level of anti-MOG in MS subjects vs. controls. This increase was fairly small, but in children with a CIS who were diagnosed with ADEM it was substantial. Anti-MOG levels were also increased in younger children with a CIS who converted to MS. Anti-MOG levels did not predict conversion to MS, however, and were not correlated with anti-EBV levels. Perhaps anti-MOG could be useful as a marker of childhood demyelination.

Exaggerated molecular response to interferon beta predicts disease activity in multiple sclerosis

R. Rudick, S. Rani, Y. Xu, J.-C. Lee, J. Na, J. Schrock, A. Josyula, E. Fisher, R. Ransohoff

Molecular responses to IFN-b treatment vary among patients, but in a given patient, the response seems to remain constant over time. To investigate how molecular responses correlate with disease activity, 85 people beginning IFN-b treatment contributed blood samples for gene expression analysis and were given an MRI scan at six months. A custom gene expression array was used that included genes known to be affected by IFN-b treatment. 15 of the 85 subjects met the criteria for “poor response” which was the appearance of 3+ new or enhancing T2 lesions. The subjects who turned out to be poor responders had an exaggerated upregulation or downregulation of certain IFN-influenced genes compared with the good responders. This is kind of counterintuitive – normally you might expect that poor drug response would be associated with a lackluster biological response to that drug. Results from this study need to be confirmed, but perhaps this gene expression test could be used to guide treatment decisions in the future.

Satellite Symposium – sanofi-aventis -- Emerging therapeutic solutions for MS patients: TEMSO phase III results

Introducing teriflunomide: a far-reaching programme for the future and long-term experience to date

C. Confavreux

Dr. Confavreux reported results from the extension phase of a teriflunomide clinical trial that has recorded up to eight years of total follow-up for trial subjects. For those who have remained available for follow-up, disease activity has been low and disability has been stable. No new safety issues have been reported, including no increased risk of cancer or opportunistic infections.

Optimising disease-modifying therapy in MS: spotlight on teriflunomide in adjunctive therapy

M. Freedman

In addition to treating MS by itself, teriflunomide may also have potential as an add-on option for first-line drugs IFN-b and glatiramer acetate. Dr. Freedman reviewed the results of a preliminary study evaluating teriflunomide in conjunction with IFN-b. Subjects who were stably treated on IFN-b were given either placebo or 7 or 14 mg doses of teriflunomide as an add-on. No safety issues were identified. About half of the IFN+placebo subjects had Gd-enhancing lesions at 24 and 48 months; however, very few of the subjects receiving teriflunomide had these lesions. There was a trend toward a reduced relapse rate in the teriflunomide subjects. Sanofi-Aventis is now sponsoring a phase III study (TERACLES) with teriflunomide as an add-on to IFN-b in subjects having breakthrough disease.

Satellite Symposium -- Novartis Pharma AG -- Multiple sclerosis: emerging evidence for the role of fingolimod

I picked up a couple of tidbits at this symposium. First, fingolimod (Gilenia) may work by sequestering Th17 cells, a type of T cell recently discovered to have particularly aggressive inflammatory qualities. And second, after treatment with fingolimod is stopped, immune cell levels are restored in around 1-2 months.

Saturday 10/16:

Late breaking news

No beneficial effect of simvastatin as add-on therapy to interferon-beta-1a for the treatment of relapsing-remitting multiple sclerosis: results of a large double blind, randomised, placebo-controlled trial

P. Soelberg Sorensen, J. Lycke, J.-P. Erälinna, A. Edland, X. Wu, J. Frederiksen, A. Oturai, C. Malmeström, E. Stenager, B. Sperling

The title kind of says it all (although I don't know if I would call a ~300 person trial “large” necessarily – maybe medium-sized?). Newly diagnosed subjects with RRMS were put on IFN-b, and then after three months were randomized to add-on placebo or simvastatin (40 mg initially, going up to 80 mg) for an additional 12 months. Outcomes included relapse rate, disability sustained for three months, and MRI measurements. Adverse events were equivalent between the two groups. However, the placebo group did slightly better than the simvastatin group in terms of relapses and remaining disease-free. So, it appears that combining IFN-b and statins does not make for an effective MS treatment.

Benefit of early treatment with glatiramer acetate (COPAXONE): results from the 5-year prospectively planned follow up in patients with clinically isolated syndrome from the PreCISe study

G. Comi, V. Martinelli, M. Rodegher, L. Moiola, O. Bajenaru, A. Carra, I. Elovaara, F. Fazekas, H.-P. Hartung, J. Hillert, J. King, S. Komoly, C. Lubetzki, X. Montalban, K.M. Myhr, M. Ravnborg, P. Rieckmann, D. Wynn, C. Young, M. Filippi for the PreCISe study group

Dr. Comi presented some follow-up data from the PreCISe study of Copaxone in people with CIS. The main study was designed to run for three years and included a treatment group and a placebo group. Placebo recipients were switched to Copaxone after converting to MS but some were switched early after efficacy had been demonstrated. An additional two years of follow-up data have been collected with subjects having the option to continue treatment on an open-label basis. Of the original 481 participants, 409 stayed in for the follow-up, but 120 of these terminated follow-up early.

After a total of 1497 days, 33% of the group originally assigned to Copaxone had converted to clinically definite MS vs. around 50% of the subjects assigned to placebo. Annual relapse rate, MRI lesions and brain atrophy measurements also provided results in favor of early treatment. However, the percentage of people with confirmed EDSS progression was the same in both groups, around 20%. Dr. Comi stated that these results were at least as good as those produced by similar early treatment IFN-b studies.

Magnetic resonance imaging (MRI) efficacy of ofatumumab in relapsing-remitting multiple sclerosis (RRMS) – 24-week results of a phase II study

P. Soelberg Sorensen, J. Drulovic, E. Havrdova, S. Lisby, O. Graff, S. Shackelford

Ofatumumab is another new antibody-based therapy that targets CD20 and depletes B cells. Dr. Sorenson presented the results from an early-stage clinical trial in RRMS subjects. Three stages were conducted with different doses (100, 300 and 700 mg), starting with the 100 mg dose. Each stage had 4 placebo recipients and 8 active treatment recipients. The average EDSS of the subjects was 2.5 and average disease duration was 6.9 years. The number of new MRI lesions appearing between weeks 8 and 24 were counted. Most placebo subjects had new Gd+ lesions whereas only one ofatumumab subject had any. Similar results were found for new or enlarging T2 lesions. Overall, 88-99% relative reductions in MRI measures were achieved by ofatumumab compared with placebo. Over 24 weeks, 3 placebo subjects had relapses, compared with 2 100-mg subjects, 3 300-mg subjects, and 0 700-mg subjects. Dr. Sorenson was a little surprised at the lack of relapse efficacy, but this was a very small study, and he felt that the MRI results warranted further investigation of this drug. No major safety issues were seen and administration of ofatumumab did deplete CD19+ B cells as expected.

Antibody suspension bead arrays with multi-parallel CSF profiling for biomarker discovery

A. Häggmark, B. Ayoglu , U. Igel , J. Ottervald , M. Khademi, T. Olsson, M. Uhlen , J. Schwenk , P. Nilsson

A collaborative effort called the Human Protein Atlas project is systematically generating antibodies against a wide variety of human proteins. So far, the participating scientists have generated and verified 23,000 antibodies using this approach, and are using these antibodies to screen samples for the presence of the relevant proteins. Dr. Haggmark described a project to analyze plasma/serum and CSF samples from MS cases and controls using a number of antibodies that were implemented in an experimental array. After screening samples from a few hundred subjects, they have come up with 6 top candidate proteins that seem to distinguish people with MS from control subjects. The identity of these proteins were not revealed though.

Factors associated with anti-JCV antibody prevalence in a large cohort of natalizumab-treated MS patients

M. Subramanyam, T. Plavina, K. Simon, E. Wilson, M. Berman, B. Schlain, A. Pace, S. Richman, L. Cristiano, C. Bozic

Dr. Al Sandrock presented data sponsored by Biogen Idec to identify in advance who might be at risk of developing PML. Researchers have developed a two-step assay to detect anti-JCV antibodies in serum. This assay was used to screen a large number of serum samples that had been collected through various Tysabri studies. Anti-JCV antibodies were present in 48-60% of the samples from these studies. Prevalence of anti-JCV is lower in women and increases with age, but is not affected by either prior immunosuppressant use or Tysabri exposure. Researchers also tested all available samples from the Tysabri users who had developed PML (the samples had been taken prior to PML development) and found anti-JCV in all of them. Dr. Sandrock gave an estimate that 3 cases of PML would develop in every 1000 patients who were positive for JCV antibodies and had been treated for 18+ months. 0 cases of PML would be expected to develop in patients negative for JCV antibodies. The ultimate goal of this research program is to stratify people for PML risk; more work needs to be done to generate data that can be acted upon in a clinical setting.

An audience member asked whether risk of PML goes up with age – Dr. Sandrock has not personally seen this correlation. Another person asked about the conversion rate from anti-JCV negative to positive. Dr. Sandrock replied that this was being studied.

Repair of selective astrocyte depletion in the rodent brain

C. Wrzos, S. Nessler, B. Hemmer, W. Brück, C. Stadelmann, J. Bennett

This talk described an animal model study of neuromyelitis optica (NMO), a demyelinating disease that involves astrocyte death. Researchers injected antibodies to aquaporin-4 (an astrocytic protein targeted in NMO) into rodents. The animals developed NMO-like lesions in white and gray matter that featured depletion of astrocytes and mature oligodendrocytes. Oligodendrocyte precursor cells were also lost, but axons were preserved. Astrocyte death preceded oligo death, and oligo death occurred via apoptosis (programmed cell death). After one week, the lesions were almost completely repopulated with astrocytes, but there was little oligodendrocyte repopulation or myelin repair.

Plenary Session 2 -- Adult CNS regeneration; Highlights and awards

Generation of neurons and glial cells in the intact and injured adult central nervous system

J. Frisén

Dr. Frisen described some of the current research being performed in the area of neural regeneration. He has been studying ependymal cells, which are glial cells that line the surface of ventricles in the brain and the central canal in the spinal cord. Under normal conditions, they renew themselves but don't do much else (no migration, no differentiation). However, when the brain or spinal cord is injured, they migrate to the site of injury and stay there, whereupon they divide to make new cells and may differentiate into astrocytes or oligodendrocytes. Dr. Frisen wondered whether a way could be found to induce ependmyal cells responding to injury to become oligodendrocytes instead of scar-forming astrocytes.

Another active research topic concerns using carbon 14 to determine how old cells are, and thus get an idea of the regenerative activity in a particular tissue or structure. Environmental levels of C14 change over time – for instance, during the Cold War, nuclear bomb tests released large spikes of C14 into the environment that have since declined. When a cell divides, its DNA takes up the carbon that is present in the environment, so you can tell how old a cell is by measuring its C14 level. Dr. Frisen has been isolating cells and carbon dating them. He has found that neurons typically date to when a person was born – meaning that neurogenesis happens very slowly. Other cell types may date to later years. There are some exceptions; for instance, neurons in the hippocampus have a greater rate of turnover than other neurons. Hippocampus turnover is greater in young people – e.g., 10% per year in young adults – and declines with age. Dr. Frisen is now working on oligodendrocyte dating.

ECTRIMS 2010: trials highlights

J.A. Cohen

The Highlights presentations are the “speed round” of ECTRIMS – quick snapshots of some of the more compelling presentations and posters from the conference. Dr. Cohen reviewed the things that caught his attention in the category of clinical trials.

Results from trials of emerging drugs (teriflunomide, firategrast, ocrelizumab, ofatumumab) plus the SIMCOMBIN trial (simvastatin & IFN-b)
New data from previously reported trials of alemtuzumab, Copaxone, Tysabri, cladribine, dalfampridine that contributed information about efficacy, subgroup analyses, and longer-term safety records
Study design and progress reports from studies of BG12, Tysabri in PPMS subjects, more selective S1P receptor modulators, etc.
Rehabilitation and symptomatic therapy trials using, for example, cognitive behavioral therapy, mindfulness training, and balance boards
New CCSVI data that present mixed results; indications that CCSVI correlates with disease progression suggest that CCSVI is not causative of MS but may be a co-morbidity

ECTRIMS 2010: scientific highlights

C. Lubetzki

And here are the scientific highlights, according to Dr. Lubetzki:

Epidemiology and genetics:

A new gene list generated from the largest GWAS study to date
Interactions between DR15 and both EBV and smoking
New evidence regarding vitamin D and sun exposure in MS
An increasing female/male ratio which has been reported mostly in countries with higher latitudes but with some exceptions (e.g., Canada)
The fact that MS in Japan is “Westernizing” (shifting from opticospinal MS to conventional MS), particularly in northern areas

Immunology and lesion formation:

The influence of VEGF-A in blood-brain barrier disruption
A T-cell trafficking study using biphoton photoscopy
Dr. Wekerle's presentation on inflammation -- it comes first (with the gut playing a role), is present in all stages of MS but lessens with age, and is associated with axonal injury
A study of the different types of macrophage activation (classical and alternative), with classical activation predominating in MS lesions
B and T cell meningeal infiltrates involved in spinal cord pathology
Two new autoantigens: neurofascin, which is present at the node of Ranvier, and contactin-2, which is targeted by T cells and mediates gray matter damage
Oligodendrocyte damage in NMO potentially mediated by astrocyte release of glutamate

Repair:

Grafting strategies: neural stem cells, neural crest cells, mesenchymal stem cells
Inhibitors of endogenous repair: chondroitin sulfate proteoglycans which are part of the extracellular matrix and appear to impede remyelination

Markers of disease evolution:

Microparticles shed from microglia (found in the CSF of people with MS and Alzheimer's disease)
Light chain neurofilaments in CSF
Micro RNAs – several posters reported on these as a potential distinguisher of people with MS vs. controls or an indication of disease course

Imaging:

7T MRI detects more small lesions than lower strength scans
9.4T MRI can differentiate between demyelinating and remyelinating lesions (in post-mortem brain tissue)
PET imaging quantified early neuronal damage in RRMS, even before atrophy was apparent
DIR imaging shows 240% more intracortical lesions than FLAIR

And that was it for the conference! Overall, it seems that steady progress is being made in several areas. I'm encouraged to learn that different groups are investigating the interactions between factors that trigger MS -- this will provide a fuller view of the origins of MS and increase the chances of curing and/or preventing MS. It is interesting to watch how the search for MS genes has evolved, becoming both more powerful and more sophisticated. The clinical trial results that were reported also provide hope that, until cures are developed, people with MS will at least have an increasing variety of options to minimize disease activity. In particular, it was good to hear about a few trials involving progressive forms of MS. Scientists are continuing to study and learn about the pathology of MS in brain and spinal cord tissue, which is where the action is after all. And while the CCSVI picture isn't entirely clear yet, many different types of investigations are generating results which will soon fill in this picture, and scientists are working to standardize their methods so that future results can be compared more readily.

Oral drug Gilenya approved by the FDA for use in MS

hollie — Wed, 22 Sep 2010 16:15:32 -0400

Big news today in the world of MS therapies -- the FDA has approved the use of Novartis' oral drug Gilenya as a disease-modifying therapy for relapsing forms of MS. (Gilenya is the drug formerly known as fingolimod and FTY720.) People with MS now have the option of taking a daily pill rather than giving themselves injections -- surely a welcome development for many! In clinical trials, Gilenya was shown to reduce relapse rates and slow progression in people with MS. It is not on pharmacy shelves just yet, but will be soon.

The FDA decided that Gilenya could be prescribed as a first-line drug, as opposed to being only recommended for people who had already tried another drug. There was some question about this because Gilenya is a new type of drug that works by keeping immune cells in the lymph nodes and out of circulation, and it doesn't have a lengthy track record. However, the safety data generated by the clinical trials was apparently sufficient to make the FDA feel comfortable with having it used more widely.

As with any drug, Gilenya has been associated with various side effects. Some of the more serious effects include slowed heart rate, increased risk of infection, an eye disorder called macular edema, shortness of breath, and liver problems. Some of the more common side effects include headache, diarrhea, back pain, flu, and cough. Those who decide to go on Gilenya may need to have blood and eye tests as well as an ECG (heart test), depending on their risk factors for these side effects.

For more information, click on the following links:
* The official press release from the FDA
* The press release from Novartis concerning Gilenya's approval
* A medication guide from Novartis that describes the possible side effects of the drug
* The prescribing information written by Novartis for doctors prescribing this drug -- it describes the potential adverse effects in more detail and also summarizes the results of the clinical trials

Also, the National MS Society has put together an information page that includes a list of frequently asked questions at the end.

It's always great to have a new option to treat MS, and the fact that this one comes in pill form is definitely a bonus. Other oral drugs are also in the wings, such as oral cladribine from EMD Serono which is currently being considered by the FDA for approval. Until MS has been cured, the next best thing is to have several different drugs available so that people have a greater chance of finding one that helps with their disease. The availability of Gilenya represents significant new progress toward that goal.