Art and Hollie's Notes From the 2007 AAN Meeting in Boston
American Academy of Neurology meeting 4/30/07 - 5/3/07 Boston, MA
This year the AAN was held in our backyard. This was good because that meant we didn't have to travel, but it also meant we couldn't dedicate our every waking moment to the conference as our regular lives were able to intrude.
Nevertheless, we managed to attend the talks and take notes as usual. Below you will find our opinions of what we saw and heard. By the way, if you are interested in reading for yourself the abstracts of the posters and presentations, you can find them here (just click the box under Option 1 and hit "submit").
Art and Julie drove into Boston, parked, and carted our stuff over to registration and picked up our badges. We met with the folks from Praxeon who would be helping us show off their new search engine CurbSide.MD, that focuses on searching for medical information in neurology.
We set up our booth, found someone to install the electricity we ordered, and then left. We returned that evening for the exhibit hall opening event.
During this time, Art went over to try out the Biogen Idec attraction: an MS Simulator booth. In an attempt to give neurologists a taste of what it can be like to have MS, Biogen Idec had a company build 4 booths that provide a 4 minute interactive "ride" as a person with MS. I expected it to be totally bogus, but I don't think they could have done much better given the constraints of it being safe and short.
The user dons gloves that have vibrators in all the fingers to give a sense of numbness and tingling. The video walks you through a typical day from hell for someone with MS, along with blurry vision, problems with balance (done via an interesting treadmill), and fumble fingers with a rigged coffee cup that pops out of your hands when you try to pick it up. I was just glad they didn't simulate loss of bladder control! I was interviewed for the Boston Globe about it; you can see the article here.
Afterward, Melissa and Art joined some folks from an Ohio MS clinic and from Teva Neuroscience for dinner.
Tuesday morning Hollie and Art attended the poster sessions where researchers create big posters of their work (like a science fair, but without the cool dioramas) and stand by them so you can ask them questions.
During this time (and a bit later) we ran into several of our Scientific Advisors including Peter Riskind, Amit Bar-Or, Mike Racke, Judy Abdalla, Rip Kinkel, David Simon, Ruth Ann Marrie, and Ben Greenberg.
The first MS scientific session of the conference was:
Clinical Trials I (Art & Hollie)
Phase I Rituximab in RRMS
Rituximab is a mouse/human chimeric monoclonal antibody for CD20 that depletes B-cells. It has been used to treat B-cell lymphomas since 1997. This study had 26 MS subjects who were given rituximab infusions at weeks 0, 2, 24, and 26, and then monitored after that. Adverse events were 80% mild to moderate and 20% severe (mostly after the first infusion).
In this trial rituximab was found to dramatically reduce gadolinium enhancing lesions and T2 lesions, and there were a total of 3 relapses in the treated group during the whole trial (compared with at least one per subject in the year before the trial). CD19+ B cells were nearly depleted but plasma B cells which pump out antibodies were not affected. This means that rituximab probably works through some other mechanism than inhibiting antibody production -- perhaps its effect has to do with eliminating the antigen-presenting function of B cells. You can read more about this drug in the write up of the Phase II trial below.
Effect of Two Doses of Laquinimod on MRI in RRMS
Laquinimod is an oral immunomodulatory drug. This trial compared 0.3mg to 0.6mg to placebo in ~100 people per arm for 36 weeks. The 0.3mg dose showed no significant difference compared with placebo but the 0.6mg group had a 51% reduction in cumulative gadolinium enhancing lesions. There was a trend (researcher speak for "it looks like something but isn't really") in relapse reduction for the high dose only. Side effects were minimal.
Glatiramer Acetate and Minocycline
This proof of concept study looked at combining glatiramer acetate (Copaxone) and minocycline (a common oral antibiotic, often use to treat acne). It was a 9 month study in 44 subjects. The minocycline was taken twice daily at 100mg. The results did not show any significant improvement over glatiramer acetate alone, although the presenter did her best to make us believe there was something there.
Immediate vs. Delayed initiation of Betaseron Treatment in CIS
The BENEFIT trial looked at what happened to people with CIS (clinically isolated syndrome - basically a single episode indicating demyelination, but not enough evidence to call it MS) when they took Betaseron at diagnosis, compared to waiting 24 months or for a second episode resulting in a diagnosis of MS. In this trial, the subjects in the placebo arm were offered Betaseron when they had a second episode or at the end of the 24 months, whichever came first. The investigators are continuing to follow the subjects after the 24 month point, even though there is no longer a group of people on placebo.
The results presented were from year 3 (one year into the follow-up phase) of what will be a five year trial. There were around 300 subjects and the investigators found a 50% risk reduction of a second attack in the immediate treatment group. A similar difference was seen in EDSS progression (a measure of physical disability) with only 16% of those in the immediate treatment group progressing vs 24% of the delayed group. There did not seem to be a difference in relapse rate at year 3, however.
None of this was a big surprise as we've seen this type of data with other interferon drugs.
Daclizumab in MS (RRMS & SPMS)
Daclizumab is a monoclonal antibody that blocks the IL-2 receptor expressed on activated T cells and limits T cell expansion while promoting natural killer cell expansion. It is currently used to prevent rejection in kidney transplants but some physicians are using it to treat MS as well. The data in this presentation came from reviewing medical charts of 55 people with MS who had used daclizumab monthly via IV for 6 or more months. After an average of 15 months, 71% of the participants had EDSS scores that remained the same or had improved, 63% had activity-free MRIs, and 71% had no relapses. The presenter attributed this to the treatment, but without a control group we're not sure that you can really make this claim. They did try to get a baseline on the subjects (to use them as their own controls), but it was only two points so none of the results were significant. There seemed to be a series of side effects, including one person who came down with psoriasis.
Phase I Trial of Pioglitazone in RRMS
Pioglitazone (trade name Actos) is an oral diabetes drug, taken daily, that is a PPARgamma agonist and has anti-inflammatory as well as neuroprotective activity. This trial evaluated this drug's performance in combination with Avonex in 22 subjects (11 on Actos plus Avonex, 11 on Avonex alone). After a year, no difference between the two arms was found in terms of Gd-enhancing lesions, T1 lesion volume, or EDSS (although changes in EDSS were not likely to be seen after only one year). It did show some effect for up to five months in improving the MS Functional Composite (or MSFC, another measure of disability that includes manual dexterity and cognitive processing), as well as a significant reduction in brain atrophy and FLAIR lesion volume. The MSFC improvement was almost entirely in the PASAT (a cognitive test). The drug was well tolerated. Seems like there may be some promise with this one.
Clinical Trials II (Art & Hollie)
Presentation of Dystel Prize
The Dystel Prize is an award given out jointly by the AAN and the NMSS. It seems to be like a lifetime achievement award. The winner gets some money as well as bragging rights, and gets to give a talk on the work they do. This year the winner was Howard Weiner, who gave a review of the things his lab has been working on, such as looking for biomarkers of MS. He also described having examined John Dystel, the namesake of the award, several years ago.
Rituximab in RRMS Phase II
This was the follow-on to the previously mentioned Phase I study. It was 48 weeks long and included 104 subjects, 69 who received the drug and 35 who received placebo. At the 24-week point, the treated group had a 91% reduction in cumulative Gd-enhancing lesions and a 58% reduction in the number of people who had relapses, compared with the placebo group. Other significant differences were seen in T2 lesion volumes and in the number of subjects with new Gd+ lesions. There were some serious adverse events (although most adverse events were mild to moderate and due to the initial infusion only). Infection-associated adverse events were similar across both groups. At week 48, 33% of the treated group had anti-rituximab antibodies although no effect of these was seen on the drug's efficacy or safety.
Alemtuzumab In Treatment Naive RRMS
Alemtuzumab is better known as Campath, a monoclonal antibody that targets CD52 on white blood cells. In this study Campath was compared to Rebif with approximately 110 people in each of 3 groups: Rebif, 24mg Campath, 12mg Campath.
Campath was planned to be dosed via IV for 5 days, then after 12 months for another 3 days, then at 24 months for another 3 days. However, dosing was halted during the second year because one of the subjects developed immunogenic thrombocytopenic purpura (ITP) as a result of the drug and died.
Although the death of the subject was tragic, the results of this trial were pretty exciting. Investigators reported an 87% decrease in the number of relapses in the Campath vs. Rebif recipients, and an 88% decrease in risk of increase in disability. They actually saw an average improvement of .6 points on the EDSS scale (this came from over 50% of the subjects on Campath)! Lesion load was also reduced in the Campath group compared with the Rebif group.
Adverse events were seen, largely after the first infusion, including five others who developed ITP but were treated in time. A monitoring plan has since been developed to detect the first signs of ITP and avoid serious consequences. The Campath group also showed an increase in thyroid autoimmunity compared with the Rebif group.
This may be the first drug that has shown a significant improvement in EDSS - indicating that it may be allowing the nervous system to repair itself. Plans are now underway for additional Phase 3 studies to further evaluate Campath in MS.
Avonex Combination Trial
This was a huge study (72 sites with 313 subjects) conducted over a year to compare adding another treatment to Avonex in people who had breakthrough disease on Avonex. There were four arms: Avonex alone, with methotrexate, with IV steroids, and with both methotrexate and IV steroids. Unfortunately, all that effort resulted in no significant improvement seen for either of the add-on drugs.
Before the talks started, Art, Hollie, and Melissa went to lunch with Robert Glanzman. Robert is the US Medical Director of Novartis in charge of FTY-720, their new oral MS drug that is in Phase III trials. Novartis isn't presenting any human clinical data on FTY at this conference, but did have posters describing animal studies (including results that indicate that the drug has neuroprotective as well as immunologic effects). They will have additional data at ECTRIMS this fall. We got to hear a bit about the fungally-derived drug and what seem to be pretty amazing results. It won't be on the market until 2010 by the earliest, but it looks like a very promising therapy.
We also saw some interesting posters in the poster sessions. One used clinical trial data to show that people who appear to progress according to clinical trial standards (sustained progression over 90 days) often improve back to baseline later, so unless a trial is four years long or so, it can't really prove that a therapy has an effect on sustained progression. There were also two posters concerning small cohorts of people for whom MS was "accidentally" discovered through lesions found on MRIs administered for reasons such as headache. These cohorts are being followed to see which ones go on to have MS symptoms.
Clinical Outcomes (Art)
HLA-DRB1*1501 Influences Longitudinal PASAT-3 in Early MS
HLA-DRB1*1501 is a genetic region that has been associated with MS in many studies. This group enrolled 480 subjects, genotyped them, gave them 3T (1.5T is standard strength) MRIs, and had them perform the MS Functional Composite (MFSC, a series of 3 tests to measure disability). Surprisingly, almost exactly half of the people were 1501 positive. They found that 1501+ subjects were more likely to show cognitive decline as measured by PASAT (one of the 3 components of MSFC) over a year and were more likely to have a worse initial MRI.
Sustained Disability Progression Using MSFC
This talk was hindered by a malfunctioning speaker (the electronic kind as well as the human kind - he mumbled something awful) and so I wasn't able to understand a single word he said. This is from reading his slides.
This came from one of the Tysabri studies with 942 subjects, randomized 2:1 (Tysabri:Placebo) for 120 weeks. The investigators found 11% of Tysabri subjects showed sustained progression vs. 23% on placebo. The question was how to use the MSFC to measure this -- in other words, what is considered "improvement" on the 3 tasks that make up the MSFC (25 foot timed walk, 9 hole peg test, paced auditory serial addition test).
They concluded that a 15% improvement in each component would be the right amount, although it appears they thought that because it would make their results look good. They pointed out that a previous paper showed that you could see up to a 20% daily variation in test results from a single subject.
I think I lost something in my inability to understand this speaker.
Novel Methods for Monitoring Fatigue and Physical Activity in MS
Currently fatigue is measured using something called the Fatigue Severity Scale (FSS). They wanted something that was more precise and so tried out a couple of devices - Actiwatch (attached to wrist) and Actical (attached to waist) - in 17 subjects for 3 weeks in a trial looking at ginseng and fatigue. They feel these devices are as accurate as the FSS and more precise (more measurements per day and more data, such as caloric expenditure).
Criteria for Dissemination in Space in CIS
This study looked at different ways to assess CIS patients for conversion to MS. They found that presence of oligoclonal IgG bands (OCGB) in the spinal fluid (using a ultra-sensitive test) along with 2 MRI lesions was highly specific and sensitive for predicting conversion to MS. This appears to be an improvement over existing methods.
Evaluation of 2005 and 2001 McDonald Criteria for Diagnosis of MS in CIS Patients
This study found you could alter the criteria for diagnosing MS in patients presenting with CIS using what they are calling "New Criteria" that are simpler and as specific and accurate.
All these attempts to create complex definitions to diagnose MS really beg the question - what causes it? We need to have a lab test.
BENEFIT Study: Characteristics of Placebo Treated Patients With CIS Who Did Not Show Further Disease Activity Over 2 Years
The BENEFIT study looked at treating people presenting with CIS with Betaseron immediately compared to placebo. In this study they had 7.2% of their placebo treated subjects remain stable (compared to 20% of the treated). The question is, was there anything about these untreated subjects that could predict a benign course? The quick answer is "No," but that group tended to be older, CSF-, have fewer T2 lesions, and no Gd enhancing lesions at baseline.
Immunology I (Hollie)
Loss of Aquaporin-4 in Active Perivascular Lesions in NMO
A tissue study of spinal cord and brain sections from six MS and 12 NMO subjects examined differences in the presence of aquaporin-4 and other factors between the two diseases. NMO spinal lesions were often marked by the absence of AQP-4, the absence of the astrocytic marker GFAP, the presence of complement, and the presence of MBP. AQP4 was also lost in the periventricular brain sections. In MS plaques, however, AQP4 and GFAP were upregulated. The conclusion was that NMO is a disease of astrocytic impairment associated with autoimmunity to AQP4.
Pattern Specific Loss of Aquaporin 4 Immunoreactivity Distinguishes Neuromyelitis Optica from Multiple Sclerosis
This presentation also looked at tissue samples from NMO and MS subjects as well as from other controls. Whereas all NMO lesions examined demonstrated loss of AQP4, AQP4 was only absent in MS lesions that were inactive or cavitary and it was upregulated in periplaque MS white matter as well as in reactive astrocytes. Loss of AQP4 in MS lesions seems to be stage-dependent and not dependent on which of the four previously-described histological patterns the lesion fits. Also seen in the NMO samples were areas where the AQP4 was gone but the myelin was intact -- perhaps these are sites that are about to become lesions?
Autoantibodies to Myelin Oligodendrocyte Glycoprotein in Human Demyelinating Diseases
A new technique for detecting anti-MOG antibodies has been developed that may help resolve conflicting results about the presence of these antibodies that have been produced in the past. This technique found antibodies to folded MOG in 19% of ADEM samples but in only a few adult MS samples and one pediatric MS sample.
Immunoglobulin Heavy Chain Repertoire Bias and the Risk of Demyelinating Disease Following a Clinically Isolated Syndrome
This presentation concerned a new method for predicting which people with a clinically isolated syndrome will go on to have a second clinical attack and be diagnosed with MS. In this method, single plasma cells (antibody-producing B cells) from the CSF are analyzed to see which heavy-chain variable gene sequence they have (VH1, VH2, etc.). This method was used to analyze CSF samples from 10 CIS subjects. The seven subjects who had an overabundance of cells with VH2 or VH4 genes all went on to develop MS over the follow-up period. The three who didn't have this bias have not yet converted to MS. Questions remaining include how does this bias develop, and can it also predict progression in MS?
Soluble Nogo-A Product, an Inhibitor of Axonal Regeneration, as a Biomarker for Multiple Sclerosis
An analysis of CSF samples from 125 MS/CIS subjects and over 150 controls with other neurological diseases identified a particular NogoA protein fragment (NogoA 20kDA) in in almost all of the MS/CIS samples but none of the controls. This fragment was also found in MS brain samples but not control samples. This indicates that NogoA 20kDA is soluble and is generated in/around MS lesions. NogoA is expressed by oligodendrocytes to inhibit axonal growth, so perhaps NogoA 20kDA is released from damaged oligos and inhibits axonal regeneration. It may wind up being a good biomarker for MS but its presence doesn't seem to correlate with other factors such as EDSS.
Lower Motor Neuron Loss in Multiple Sclerosis and EAE
An autopsy study of 9 MS subjects and 9 controls showed that 50%+ of the gray matter neurons in MS subjects' lumbar spinal cords had been lost. The affected neurons are motor neurons and this loss leads to a reduction in muscle action potentials. Why motor neurons and not sensory neurons are targeted is not known.
Clinical Trials III (Art & Hollie)
Rituximab in NMO
This two-year study includes 20 subjects with neuromyelitis optica (NMO, a demyelinating disease that affects the spine and optic nerve). Dr. Genain presented one-year interim results for 10 subjects who had been given two courses of Rituximab (RTX, two infusions two weeks apart = one course) at 0, 12, and 36 weeks. They averaged four relapses per year prior to treatment.
After treatment they averaged 0.6 relapses per year. There was a trend toward EDSS stabilization or improvement. Six of the relapses that occurred on treatment (in three subjects) required hospitalization however. 7/10 of the subjects were NMO IgG+ (a biomarker for NMO). Side effects were similar to those seen in other RTX studies.
Small study, promising results, more needed.
Retrospective Analysis of Rituximab Treatment of 25 Cases of NMO
Dr. Jacob and colleagues looked at the medical records of 25 NMO or relapsing myelitis patients treated with rituximab in the past (even if they had taken other treatments also). They found a reduction in relapse rate (0.7 on RTX vs 2.2 when not). EDSS in all but two subjects was stable or improved. Adverse events were similar to other studies, including increased infections. They mentioned that RTX costs about $12,000 per course (2 infusions).
Phase III Oral Fampridine in MS
We've reported on this previously, but this is the formal presentation of the data on oral fampridine, a potassium channel blocker being tested by Accorda. It was a 14 week study with 229 MS subjects on fampridine and 72 on placebo, 10mg twice daily with 5 off-drug visits (for baseline) and 4 on-drug visits (to monitor progress).
The drug was hoped to help with walking difficulty. They defined response as having a walking speed greater than any of the 5 off-drug visits at 3 out of 4 of the on-drug visits. 35% of the Fampridine subjects responded vs. 8% of placebo subjects (a statistically significant difference) with approximately a 20% improvement in speed. They also noticed some improvement in leg strength (or as they say "lower extremities") and improvement of MS symptoms in general. Adverse events included insomnia, fatigue, back pain, balance problems, one seizure, and anxiety. No factors were found that could predict which subjects would respond to this drug.
Seems like a small number of people will benefit (and you can tell if you do or don't), but for those who do, it could be quite useful.
ITP Following Treatment of MS with Alemtuzumab
This talk was a detailed review of the one fatal case of ITP (see above) and the five non-fatal cases seen in the Campath trial. The one fatality occurred in a subject who was experiencing serious side effects for more than two weeks, yet did not seek medical attention.
ITP is an autoimmune disorder associated with antibodies against platelets. It reduces a person's blood-clotting ability and generally starts with a rash. ITP can occur long after Campath clears from your system. To combat this possible side effect, they have put in place a risk management plan that involves investigator and patient education, and monitoring for ITP (apparently you can see it coming via blood tests). This plan led to the diagnosis of three additional cases (developing 12-16 months after the last dose) after the inital three. All people in the trials are undergoing a five-year followup. All subsequent cases have fully recovered.
Atorvastatin + Rebif in MS (Safety Trial)
This nine-month trial looked at combining statins with Rebif. It had 3 arms: Rebif + placebo, Rebif + 40mg statins, and Rebif + 80mg statins daily for 6 months. The trial included 29 subjects who had each been stable on Rebif for at least six months. Five subjects dropped out either before or during treatment, one due to muscle pain (a known problem with statins). Unfortunately, 67% of the people on combined Rebif plus statins wound up having a clinical event or a new MRI lesion during the trial, compared with 11% on placebo (statistically significant). The study investigators speculate that statins may block interferon signalling, and conclude that it is probably not safe to take statins with interferons.
Genentech/Biogen Idec Reception
Hollie, Melissa, and Art were invited to a reception held by Genentech and Biogen to meet with MS Advocacy groups. There we sipped wine, ate tasty tidbits, and hob-nobbed with other from the NMSS, MSF, and MSAA.
Thursday poster sessions
There were a few items of interest, namely:
Neither Art nor Hollie attended this section. Until there is an animal model that we feel is truly relevant to human MS, we probably won't be spending too much time on this area of research.
Imaging (Art & Hollie)
Benign MS Characterized by a Lower Rate of Brain Atrophy as Compared to Early MS
This presentation reviewed data from Howard Weiner's CLIMB study (in which Art is a subject). They looked at 75 people who fit their definition of "benign" MS:
(1) 10-14 years since first symptom and EDSS 1.5 or less, or (2) 15+ years since first symptom and EDSS 2.0 or less
and compared them to 70 people with early MS (disease duration <=5 years). They found that people with benign MS had lower rates of brain atrophy than those with early MS (0.16%/yr vs. 0.51%/yr). Total T2 lesion volume and brain parenchymal volume (a measure of cumulative brain atrophy) were similar in both groups. The conclusion was that people with benign MS have a less destructive type of disease (which doesn't seem very surprising).
MS White Matter Lesion Topography Defines White Matter Tracks Involved in Verbal Memory
A group of scientists is studying which white matter tracks are used in memory storage and retrieval by giving verbal memory tests to people with MS and comparing their results with where their lesions are. Using this method, they found a number of white and gray matter pathways that seem to be involved in memory storage and retrieval.
Regional Hippocampal Atrophy in RR and SPMS
[Most of these imaging talks spent a fair amount of time discussing how the imaging was done, details which we are leaving out for the most part.]
Dr. Sicotte and colleagues measured the volume of the hippocampal area of the brain and looked for correlations with a variety of tasks. They found that people with RRMS had disproportionately more atrophy in this area than in the brain overall and that this correlated with a more difficult time learning unrelated word pairs.
20 Year MRI & Clinical Follow-up of Patients with CIS
A group of 137 people who presented with CIS back in '84-87 were continually followed by researchers over the course of 20 years. After 20 years the researchers were still in touch with 107. They found that 87% of the CIS subjects who had an abnormal MRI at baseline had converted to MS compared to 21% with a normal MRI. The number of lesions seen on MRI did not correlate with conversion, but a moderate effect of T2 lesion volume on severity could be seen even early on. 39% of those subjects who converted to MS could be classified as having benign MS and an equal amount as having major disability.
Comparison of Betaseron and Copaxone on Newly Enhancing Lesions
This is a sub-study of a big study comparing Betaseron to Copaxone. In this study the investigators looked at 3 Tesla MRIs (usual strength is 1.5T) with triple dose Gad over 15 months and found no difference in the rate of newly enhancing lesions in either group. They did observe that a newly enhancing lesion can remain enhancing for as long as 7 months.
Regression to the Mean Affects Gad Enhancing Lesions in RRMS
Many MS drug trials recruit subjects based on having recent disease activity in the form of Gad enhancing lesions. This study looked at the placebo group from the PRISMS trial (Rebif) and saw a 40% decrease in Gd+ lesions over the course of nine months. They also saw that the majority of people with no activity at baseline developed activity during the study period. This regression to the mean implies that studies that use a cross-over design may not be valid since they could be easily biased to show positive results (cross-over studies measure disease activity prior to administering the drug and use that measurement as the basis for comparison, rather than using a placebo or other form of therapy for comparison).
In-Vivo MRI of MS at 7 Tesla
This study demonstrated the safety and results of using an MRI that is WAY stronger than any MRI in common use today. It provides 20-25 times the resolution. The pictures were amazing - rather than a fuzzy image of a brain, it looked like photographs of autopsy slides. You can clearly see many more lesions in the same subject. The contrast between white and gray matter was much sharper, and even cortical lesions were visible (these are generally undetectable on regular MRI).
Hopefully this sort of technology will become widely available soon.
Controlled Study of Acute Effect of Immunoablation and Autologous Hematopoetic Stem Cell Transplantation on Changes in Brain Volume, Axonal Integrity, Myelin, and Parenchymal Water in MS
The presenter had to speak quickly since there was only a couple minutes left after reading the title of the study. :-)
A procedure sometimes used to "reboot" the immune system in various diseases (including MS) is immunoablation (chemo) followed by BMT (bone marrow transplant). We see significant brain atrophy after this procedure and nobody knows why.
This study first confirmed that the atrophy was occurring, and found that people undergoing this procedures lost on average 2.9% of their brain volume in the year following treatment compared with 0.7% in similar people who didn't undergo the procedure. Most of this treatment-related atrophy occurred in the first two to three months following the procedure.
Using imaging techniques, the researchers were able to demonstrate that the atrophy was not due to a decrease in water (edema) or inflammation in the brain, nor a loss of axons, but they did see a loss of myelin. Since axons aren't lost, it may be that the myelin that is lost has been cleared from already damaged axons.
Immunology II (Hollie)
2-Year Longitudinal PBMC Gene Expression Profiling Results of MS Patients Receiving Interferon Beta 1b Predict Therapy Outcome
This presentation described attempts to find gene expression profiles using a decision tree model that would predict who would or would not respond well to interferon beta therapy. A set of genes were found (many of which were interferon-related, as expected) that seemed promising if evaluated one month into therapy.
Validation of the HLA C05 Association with Multiple Sclerosis Susceptibility and Exploration of Its Effect on Clinical and MRI Phenotypes
Philip de Jager
Analysis of 1000 families from the US and UK has detected a genetic variant (HLA C05) that appears to be less frequently found in people with MS than controls. More work is being done to confirm and better understand this association, and to see if it is also found in other diseases.
Effects of Long Term Fingolimod (FTY720) Therapy on Circulating Mononuclear Cell Populations in Multiple Sclerosis
This study evaluated the effect of FTY720 on specific types of cells in the bloodstream. FTY720 binds to S1P receptors on T cells and prevents them from leaving the lymph node; it also inhibits the function of B cells. The subjects discussed in this presentation participated in a Phase 2 study of the drug and then in an extension phase, and had been using the drug daily for >=18 months. Analysis of their blood samples compared with controls showed an approximately 80% depletion of all mononuclear cells, a ~90% depletion of CD4 and B cells, and a ~50% depletion of CD8 cells. Monocytes and natural killer cells were unaffected.
Platelet Activating Factor Receptor Is a Novel Th17 Cell Marker Coexpressed with IL-17, Upregulated by IL-23 and Increased in Peripheral Blood of MS Patients
Platelet activity factor receptor (PAFR) was found to be upregulated in the peripheral blood of MS subjects compared with controls. PAFR is stimulated by IL-17 and vice versa, creating an inflammatory self-amplification loop.
Statins Block Interferon Signaling in Human Immune Cells: Potential Loss of the Therapeutic Effect of IFN-β in Multiple Sclerosis
This presentation described research into how statins might modify the effects of interferons. Several different cell lines were activated with either IFN-beta or IFN-gamma, resulting in an increase of STAT-1 expression. When statins were added, this expression decreased. These results might explain the decrease in efficacy seen in the Rebif + statins combination trial described above. (I wonder how much testing of this type was conducted before the clinical trial began?)
Outcomes/Optic Neuritis (ON) (Art)
Recurrent ON: Clinical & Demographic Features Stratified by NMO IgG Seropositivity
A while back, the folks at the Mayo found a biomarker (NMO IgG) that seems to be unique to NMO. When working with this disease people are now testing for this biomarker to see what they can learn about its use as a diagnostic tool.
This study looked at samples from 34 subjects who had ON, 20 of whom were IgG- and 14 of whom were IgG+. The negative group only had one person convert to MS and the positive group had 6 convert to NMO.
They found that the positive group was more likely to be non-Caucasian, more likely to have a more severe course of ON (temporary legal blindness), and older.
Low-Contrast Visual Acuity Test Increases Sensitivity of the MSFC to Disease Progression in RRMS
This was another sub-study from the Tysabri trial. The investigators used a low-contrast visual acuity test (gray letters on a white background) and found that its results reflected axonal loss as measured by Optical Coherence Tomography (OCT, a tool that measures the thickness of the retinal nerve fiber layer). A worsening by 2 lines (like an eye chart) indicated clinical relevance.
They did a bunch of statistical manipulations to show that adding this test to the MSFC (or replacing the PASAT with it) improved the outcome of the test, for this study at least.
Retinal Nerve Fiber Layer Changes in Progressive MS
This presentation confused me as the presenter came to the opposite conclusion than what was in the AAN book describing the talk. The basic gist was that they used OCT to measure retinal thickness and found that controls had thicker layers than people with MS.
Basically, there are a lot of people looking at this technology as (hopefully) a quick and safe way to gauge atrophy in the brain by only looking in the eyes.
Fundoscopic and OCT Findings in NMO vs MS
Looking in the eyes of people with NMO and MS showed that a fair number with NMO had arteriolar changes (not seen in people with MS), and that people with NMO had much lower retinal nerve fiber layer thickness.
OCT as a Biomarker in MS
They looked at 163 people with MS and 43 controls using OCT and after a lot of slicing and dicing and sub-grouping I think the only conclusion that could really be made was that controls had thicker retinal nerve fiber layers than people with MS.
The talks portion of the conference was now over. We packed up the booth, took a look at the last posters, and left.