Wednesday, 17 September 2014

MS Day Waterworks in MS

Dr Jalesh Panicker: Q&A

Why do you use tablets or certain type of tablets when people have cognitive problems?

Blood brain barrier separates brain from the rest of the body. These tablets can cross the blood brain barrier and they can go to different parts of the brain and proteins that are there. This is why these tablets can cause memory problems. Not everyone experiences this problem. However If there is an issue, then we will just use the tablets that do not cross the blood brain barrier such as trospium chloride.
Can you tell us if there is a role for sacral nerve stimulation (SNS) in MS patients?
To tell you about SNS, it’s a treatment involving stimulating one of the  sacral nerve roots with a device akin to a pacemaker, which is surgically implanted.  It has been shown to help with urinary urgency, frequency and incontinence, as well as with retention.  The evidence base for its use in MS is limited though.  Though it might be useful in the short term, it’s less clear whether it continues to work when bladder dysfunction worsens with MS progression.  This becomes relevant considering that it is an expensive device with costs approaching £8000. Moreover, the commonly used devices are not compatible with MRI, though newer MR-compatible devices are becoming available. 

Too much salt appears to be bad

Farez MF, Fiol MP, Gaitán MI, Quintana FJ, Correale J.
Sodium intake is associated with increased disease activity in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014. pii: jnnp-2014-307928. doi: 10.1136/jnnp-2014-307928. [Epub ahead of print

BACKGROUND:Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS.
METHODS: We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated. We then replicated our findings in a separate group of 52 patients with MS.
RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group.
CONCLUSIONS:Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

It was suggested in animals that too much salt was not a good thing for EAE. Should we take this with a pince of salt or take notice. 

This study looked at salt intake and disease activity and found that MSers having lots of salt in their diet was associated with a 3 fold higher relapse rate  "western Diets" can have high salt, fat, sugar etc. Is this a reason to MS going up. High salt consumption has been associated with a number of health issue. Another study presented at ACTRIMS/ECTRIMS 2014 also pointed a finger at salt and enhanced immune response arguing that in blood the salt level is lower than tissues and by enhancing salt levels you make the immune cells behave like they are in tissues and have enhanced immune reactivity but we will diiscuss this when it is published.

Whilst we need to see replication salt intake is something that is in your control. ProfG may comment on this further

CoI : None  
Anti-SEMA4D antibody: targeting the MS disease (ECTRIMS 2014 abstract)

Semaphorin 4D (SEMA4D/CD100) is expressed on neural and immune cells, and its high affinity receptor, Plexin B1 (PLXNB1), is expressed on neural, endothelial, and dendritic cells. SEMA4D signaling through PLXNB1 has been shown to modulate glial cell activation, inhibit differentiation and migration of oligodendrocyte precursor cells (OPCs), disrupt CNS endothelial tight junctions, and induce neuronal process collapse. Multiple sclerosis (MS) is characterized by CNS immune cell infiltration, blood-brain barrier (BBB) breakdown, myelin destruction, and neuronal degeneration. Antibody neutralization of SEMA4D could, therefore, ameliorate multiple sclerosis through multiple mechanisms. Blocking SEMA4D could promote survival, migration and differentiation of oligodendrocyte precursors and remyelination.
In addition, preventing SEMA4D-mediated breakdown of the blood brain barrier (BBB) may suppress immune cell infiltration into the CNS and reduce inflammation and secondary immune responses to CNS antigens. We generated a monoclonal antibody that binds with high affinity to mouse, rat, monkey, and human SEMA4D and blocks the binding of Sema4D to its cognate receptors. Anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation in vitro, and promotes migration of OPC to the sites of demyelinating lesions in vivo. Anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination. In a transgenic model of Huntington’s disease, anti-SEMAD can be shown to prevent loss of brain volume and to restore behavioral deficits. This model may be better aligned to progressive neurodegenerative disease than is EAE. Collectively, these data suggest that antibody-mediated neutralization of SEMA4D represents a viable therapeutic strategy for multiple sclerosis. To this end, a randomized, placebo-controlled, double blind, single ascending dose Phase 1 study in MS patients using a humanized anti-SEMA4D antibody (VX15/2503 ) was initiated and will soon be completed.

Anti-SEMA4D reduces EAE clinical scores:
 Anti-SEMA4D preserves brain volume...

...and improves cognition in Huntington's disease mice

This was a poster presented at this years ECTRIMS (to see the poster follow this link: Anti-SEMA4D antibody appears to be both anti-inflammatory (the EAE figure) and neuroprotective (the Huntington's model) - a rare combination. Importantly, SEMA4D is an axon guidance molecule and its primary role is to inhibit axonal growth (similar to LINGO1 - which is currently in clinical trial); it is plausible that the observed improvement in atrophy and cognition/memory is the result of new axonal growth and synapse/neuronal connections. I assume Vaccinex (the company) will be selling the product on to 'Big Pharma' once the Phase I safety study is 'safely' completed (their collaborating partners are Teva, GSK, Biocon and Bayer!).

ECTRIMS 2014: Daclizumab results

Daclizumab was my number 1 ECTRIMS highlight: what is it telling us about MS? #MSBlog #MSResearch

"My number one ECTRIMS highlight is the MRI daclizumab results, which shows that daclizumab reduces brain atrophy compared to Avonex in both year 1 and year 2. Why? This is telling us that daclizumab is having an effect on end-organ damage in MS and supports its positioning as a highly-effective therapy in MS. Big deal you may say? The reason why this is so interesting is  that daclizumab challenges most of the immunological dogmas about MS. Here is a drug that is not overtly immunosuppressive and has little impact on the effector function of B cells, CD4+ and CD8+ T cells. Please note these cells are meant to be key players in MS. Daclizumab also reduces T-regulatory or T-reg cell numbers and function; aren't T regs cells also meant to be a major players in MS?"

"What daclizumab does is it expands a population of cells called CD56-bright NK cells. These so called natural killer cells are part of the so called innate immune system and play a role in anti-viral responses. Daclizumab is therefore the one DMT with a mode of action  that seriously challenges the autoimmune MS dogma and possibly supports an alternative view of MS. We simply can't ignore Daclizumab's putative mode of action; it is telling us something very important about MS."

'The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.' Thomas Huxley

Arnold et al. Brain MRI results of DECIDE: a randomized, double-blind trial of DAC HYP vs. IFN β-1a in RRMS patients. ECTRIMS 2014.
  1. DAC HYP substantially reduced the burden of T2 hyperintense, Gd+,  and T1 hypointense lesions (black holes) compared to IFN beta-1a.
  2. Improvements in MRI parameters could be seen as early as Week 24  and were sustained over 96 weeks.
  3. DAC HYP reduced brain atrophy compared to IFN beta-1a over 2 years of treatment.
CoI: multiple