Tuesday, 31 January 2017

Not so Silent Lesions. Will the Real Progressive MS stand Up.

Wundes A, Bowen JD, Kraft GH, Maravilla KR, McLaughlin B, von Geldern G, Georges G, Nash RA, Lu JQ. Brain pathology of a patient 7 years after autologous hematopoietic stem cell transplantation for multiple sclerosis. J Neurol Sci. 2017 ;373:339-341. 

Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.

A myelin B Macrophages C Tcells, D CD4 T cells, E, CD8 T cells F Damaged Nerves. G Grey matter lesion, H altered cellularity I Preserved nerves J macrophages/microglial,  K Rare T cell, L Damaged axons

Here is a person with progressive MS, who had stem cell therapy. There disease continued to worsen over the next 4 years and sadly they died. 

This is a timely reminder that HSCT is not the solution for everyone. The data indicates that people with active relapsing Disease respond best.

What did the lesions look like?

See Above

Is this new....not really.

This study predisposes us to the thought that T cells are the problem. However they are not. As the MDs showed in EAE in 2005 (Pryce et al. 2005. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis), you can have disease worsening without T cell activity, based on histology as used here, therefore this study should come as no surprise. 

Furthermore, if we suggest that T cells are not the real problem then, this should surprise us even less.

Based on response to therapy there is little evidence to support this view. T cell immunotherapy has consistently failed in progressive MS. Is it not time that we ditch the dogma that T cells do every thing in MS? 

It simply is not true

However even if T cells are the problem, how many cells are needed?

It is clear that T cells are not the end mechanism that damages the nerves. This is likely to be a problem of glia. The histology shows us this the imaging shows us this the response to therapy shows us this...yet we still hear "T cells, T cells, T cells", that shackle many people in to trying approaches that are doomed before they start. 

What happened to the B cell...so T cell focused, I guess we can't be bothered with B cells

We need a different solution to effectively deal with increasing disability, getting rid of the trigger is important.

The glial cells can be activated from a far by things such as cytokines and also antibodies. They can bind to the Fc receptors on microglia and activate them, this could be from B cell follicles elsewhere in the CNS. So a T or B does not need to be anywhere near the lesion, or the section looked at.

What triggers these degenerative events and how long do they remain self-sustaining?  In animals, the inflammatory ( T cell cell mediated) events that trigger the generation of the neurodegeneration lasts a few days, but the worsening lasts months and months and moths. Why not years and years as a human is a many more times as big as a mouse to damage the nerve tracts and synapses as tall as a human is going to take years.  The fuse has been lit and it is going to burn and burn and burn until the nerve tract is gone. As it goes it snips off the synapses that branch off and give some compensation capacity, compounding the worsening.

The question is are there still big demyelinated lesions or is there evidence of remyelination if there is remyelination then says you don't need remyelination therapies just time. Let's ask the authors

The silent MS lesions

Exp Ther Med. 2017 Jan;13(1):91-96. doi: 10.3892/etm.2016.3950. Epub 2016 Dec 2.

Magnetic resonance diffusion tensor imaging for occult lesion detection in multiple sclerosis.

Chen J, Zhou C, Zhu L, Yan X, Wang Y, Chen X, Fang S.


It remains challenging to locate occult lesions in patients with multiple sclerosis (MS). Diffusion tensor imaging (DTI) has been demonstrated to have the potential to identify occult changes in MS lesions. The present study used 3.0T magnetic resonance DTI to investigate the characteristics of different stages of MS lesions. DTI parameters, fractional anisotropy (FA), mean diffusivity (MD), λ// and λ┴ values of lesions were compared at the different stages of 10 patients with MS with 10 normal controls. The results demonstrated that FA and λ// values of MS silent and subacute lesions are decreased and MD and λ┴ values are increased, as compared with those of normal appearing white matter (NAWM) and normal controls. NAWM FA values were lower, and MD, λ//, and λ┴ values were higher than those of normal controls. It was also indicated that MS lesions had reduced color signals compared with the controls, and the lesion area appeared larger using DTI as compared with diffusion-weighted imaging. Furthermore, fiber abnormalities were detected in MS lesions using DTT, with fewer fibers connected to the lesion side, as compared with the contralateral side. FA, MD, λ// and λ┴ values in the thalamus were increased, as compared with those of normal controls (P<0.05); whereas MD, λ// and λ┴ values were significantly increased and FA values significantly decreased in the caudate nucleus and deep brain gray matter (DBGM) of patients with MS, as compared with the controls (P<0.05). λ// and λ┴ values were also significantly increased in the DBGM of patients with MS as compared with normal controls (P<0.05). The present findings demonstrate that DTI may be useful in the characterization of MS lesions.

These are the known knowns - MS lesions visible to the naked eye in eloquent areas lead to a neurological deficit; there are known unknowns - not all MS relapses correspond to a visible lesion on MRI. This is the quandary which is the silent MS. Chen and colleagues suggest diffusion tensor imaging (DTI), a particular MRI sequence can help identify these silent MS lesions.

"MS lesions can be identified by conventional magnetic resonance imaging (MRI); however, it remains challenging to detect lesions in early stage or occult MS lesions. Because of this, clinicians are unable to connect all clinical symptoms with the findings on MRI".

DTI uses the flow of water in neurones to outline their structure and thereby their loss using parameters such as fractional anisotropy (FA) and mean diffusivity λ┴ and λ//. They demonstrate a case example of this in a 27 year old who developed slurred speech for 1 week (see figure below).

Figure A: Abnormal signal in the right corona radiata (the whitish hyperintensity next to the ventricles which is the back H-shape in the center), B: FA showing loss of signal at the lesion, C: Colour-map showing reduced signal at the lesion, D and E: The neuronal fiber bundles showing interruption and fewer fibers on the affected side.

Therefore DTI maybe able to overcome the limitations of conventional MRI in identifying silent MS lesions. In particular, FA and λ// were lower in these lesions i.e. the directionality of the diffusion (secondary to axonal damage and loss of myelin) and diffusion parallel to the nerve fibers are affected (secondary to axonal degeneration). Clearly, what DTI provides is an image of broken nerve fibers and disintegration of fibers distal to lesions. It reveals a story greater than the sum of its part. If were are to repair this, we would have to become sophisticated structural designers. Or we let the brain do it; the unknown unknowns - I wouldn't mind being a fly on the wall to watch that process. 

Monday, 30 January 2017

#ClinicSpeak: weekend warrior survey results

How is your self-loathing and guilt? #ClinicSpeak #BrainHealth #WeekendWarrior

The following are the headline results of last week's survey. I am impressed; those who responded are more active than I expected.  

#ResearchSpeak: asymptomatic MS in siblings of MSers

How common is asymptomatic MS in siblings of MSers? #ResearchSpeak #MSBlog

The study below confirms that siblings of people with MS have a high incidence of sub-clinical, or asymptomatic, MS. Almost 1 in 10 siblings of pwMS have MRI features of MS. This confirms the findings of an earlier Sardinian study and other studies demonstrating that siblings of pwMS have early markers of MS. The NIH study only looked women, which will slightly bias the results as MS is commoner on women. 

We did a pilot study similar to this but had too few study subjects to pick-up a definite signal. What do we do with this information? We could use the information to power a prevention study in people at high-risk of MS. But what intervention would we use? Vitamin D? Anti-EBV drugs, for example rituximab or an small molecule antiviral? Should we be screening all siblings of people with MS and diagnosing them in the asymptomatic phase of the disease so we can intervene early with treatments? The latter is problematic as we don't have any evidence that intervening at the asymptomatic phase of the disease alters the long-term prognosis, but I suspect it will based on scientific principles underpinning treat-early and effectively. In addition, the current diagnostic criteria for MS don't allow neurologists to diagnose MS in the asymptomatic phase of the disease. This is important as payers, such as the NHS and health insurance companies, can't pay for treatments for a non-disease. I suspect it is only a matter of time until we extend the diagnostic criteria of MS into the asymptomatic phase. Once we do this we could then start clinical trials in the hope of preventing symptomatic disease later on (1st attack) and further damage.

Please note that if you are a sibling of someone with MS, or you have siblings, who are at high risk of MS you should probably be encouraging them to do what they can to lower  their risk of developing MS. At the moment this advice includes telling them not to smoke and to keep themselves vD replete.

Xia et al. Assessment of Early Evidence of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members. JAMA Neurol. 2017 Jan 17.

IMPORTANCE: Subclinical inflammatory demyelination and neurodegeneration often precede symptom onset in multiple sclerosis (MS).

OBJECTIVE: To investigate the prevalence of brain magnetic resonance imaging (MRI) and subclinical abnormalities among asymptomatic individuals at risk for MS.

DESIGN, SETTING, AND PARTICIPANTS: The Genes and Environment in Multiple Sclerosis (GEMS) project is a prospective cohort study of first-degree relatives of people with MS. Each participant's risk for MS was assessed using a weighted score (Genetic and Environmental Risk Score for Multiple Sclerosis Susceptibility [GERSMS]) comprising an individual's genetic burden and environmental exposures. The study dates were August 2012 to July 2015.

MAIN OUTCOMES AND MEASURES: Participants in the top and bottom 10% of the risk distribution underwent standard and quantitative neurological examination, including disability status, visual, cognitive, motor, and sensory testing, as well as qualitative and quantitative neuroimaging with 3-T brain MRI and optical coherence tomography.

RESULTS: This study included 100 participants at risk for MS, with 41 at higher risk (40 women [98%]) and 59 at lower risk (25 women [42%]), at a mean (SD) age of 35.1 (8.7) years. Given the unequal sex distribution between the 2 groups, the analyses were restricted to women (n = 65). When considering all measured outcomes, higher-risk women differed from lower-risk women (P = .01 by omnibus test). Detailed testing with a vibration sensitivity testing device in a subgroup of 47 women showed that higher-risk women exhibited significantly poorer vibration perception in the distal lower extremities (P = .008, adjusting for age, height, and testing date). Furthermore, 5 of 65 women (8%) (4 at higher risk and 1 at lower risk) met the primary neuroimaging outcome of having T2-weighted hyperintense brain lesions consistent with the 2010 McDonald MRI criteria for dissemination in space. A subset of participants harbor many different neuroimaging features associated with MS, including perivenous T2-weighted hyperintense lesions and focal leptomeningeal enhancement, consistent with the hypothesis that these individuals are at higher risk of developing clinical symptoms of MS than the general population.

CONCLUSIONS AND RELEVANCE: Higher-risk asymptomatic family members of patients with MS are more likely to have early subclinical manifestations of MS. These findings underscore the importance of early detection in high-risk individuals.

Rebound? What causes the emergence of disease after alemtuzumab

#MS Research #Clinical Speak

There was a report of severe disease activity that occured within 6 months of the first infusion of alemtuzumab.This responded to B cell depletion.


The first suggestion was this could be a novel CNS autoimmunity, as could occur as discussed by Profg yesterday


However could it be disease reactivation?

This created some contradicting ideas (see post and comments) from TeamG, were we fighting online?

(a) DrK suggested neutralizing antibodies may have blunted the depletion of alemtzumab allowing disease to re-appear
(b) ProfG suggested, however that it could be a return of disease activity after rapid reconstitution.
(c) I also suggested it could be fluke occrance of natural course of alemtuzumab, on which the case reports are based.

Without knowing the depletion in the individuals, it could have been any of the above. Why?

This data from a EMA report from the phase III trials may show us why.

So it is not fighting, but independent thinking aloud.

We don't always agree, but are prepared to listen and modify our thoughts. Are you?

I have added some boxes/circles around some data from individuals to highlight some points. This shows the white blood cell level in pwMS at various times after alemtuzumab in people with (blue) and without (red) anti-drug antibodies

(1) Alemtuzumab does not deplete cells in everyone, so disease could carry on regardless, because there are non-depletors (top left dot). 

CD52 is a highly glycosylated (loads of carbohydrates) 12 amino acid long oligopeptide anchored into the membrane by a glycosylphosphatidylinositol (GPI) anchor. Two single-nucleotidepolymorphisms of CD52 were described,rs1071849 (A119G) andrs17645 (A123G).CD52 polymorphism may affect the efficiency of GPI anchor formation and thus may indirectly alter the response to anti-CD52 agents (This needs to be formally shown).

(2) ProfG hinted that as problem occurred after first infusion an influence of neutralizing antibodies, which have not been reported to occur, would be less likely to influnce treatment. 

However, following the first infusion of alemtuzmab a whopping 56% (n=486) of people injected with alemtuzumab develop neutralizing antibodies within the first month of treatment.  This is amazing given it is a humanised antibody and that alemtuzumab kills T and B cells.

Whilst the injected antibody is all but gone from the circulation within 15-20 days after first infusion, as it only takes about 6 days to produce an antibody response, at least in mice, hypothectically a neutralizing antibody response (although those found are of low titre=strength), could be generated shortly after the last infusion of the first courtse done over 5 days. This could blunt depletion and allowing rapid repopulation (e.g. see poor depleters with anti-drug antibodies above). They are unlikely to stop depletion altogether as some depletion would occur before antibodies could be formed. This could be more of a problem for the second, third, etc infusions.

(3) There are people who do not produce anti-alemtuzumab antibodies, who have high levels of cells, 2-4 months after infusion. These could be rapid repopulators (alternative was these people were poor depletors and remained poor depletors when assayed  months later. 

You have to do some detective work to find this information..Why?

Sunday, 29 January 2017

#ClinicSpeak & #NeuroSpeak: not everything that looks like MS is MS

How sure are you that you have MS? #ClinicSpeak #NeuroSpeak #MSBlog

Not everything that looks like MS is MS. Did you know that about 1 person in 20 with MS does not have the disease? This won't come as a surprise to you if you are a regular reader of this blog; I have posted on this issue several times in the past. Today's post by the MouseDoctor on two patients getting worse with alemtuzumab raises questions about whether or not they had MS to begin with versus the suggestion they developed a second disease on top of MS. 

We have know for some time that patients with NMO (neuromyelitis optica) spectrum disorder do very badly on alemtuzumab. Of the 4 cases written up below, 3 of them died post-alemtuzumab from catastrophic ongoing relapses. The one case that did well was subsequently treated with rituximab. These cases of catastrophic relapses post-alemtuzumab raises the question of how good we really are at diagnosing MS? Clearly there many more MS mimics out there that need to identified, defined and treated differently to MS. 

Cases 1 to 3: 

Azzopardi et al. Alemtuzumab use in neuromyelitis optica spectrum disorders: a brief case series. J Neurol. 2016 Jan;263(1):25-9.

Alemtuzumab is an anti-CD52 monoclonal antibody recently licensed for use in relapsing-remitting multiple sclerosis. Here, we report our experience of its use in neuromyelitis optica (NMO) spectrum disorders. A retrospective case review of patients treated with alemtuzumab in Cambridge, UK, was conducted to identify those who fulfil the criteria for NMO spectrum disorder. Three cases were identified. Case 1, 9-year-old female, presented with transverse myelitis and bilateral optic neuritis,with one lower medullary and several longitudinally extensive cord lesions. Despite immunosuppression including two courses of alemtuzumab, she continued to relapse, was wheelchair bound and registered blind by age 12, and died at age 18. Case 2, 41-year-old female, presented with bilateral optic neuritis and transverse myelitis with longitudinally extensive cervical cord lesions. Despite three courses of alemtuzumab, she had five relapses with visual impairment and new cord lesions. She later developed tumefactive white matter lesions and died aged 51.Case 3, 31-year-old female, presented with transverse myelitis with longitudinally extensive cervical cord lesions and positive aquaporin-4 antibody. After one course of alemtuzumab, she relapsed with 4 episodes of myelitis with new enhancing lesions and accumulating disability. She became relapse free after rituximab and mycophenolate mofetil. From this case series, we conclude that alemtuzumab failed to prevent disabling relapses and poor outcome in NMO. We hypothesise that rituximab is more effective, as in case 3, because it causes much more prolonged B lymphocyte depletion than alemtuzumab. We therefore caution against the use of alemtuzumab in NMO.

Case 4: 

Gelfand et al. Massive CNS monocytic infiltration at autopsy in an alemtuzumab-treated patient with NMO. Neurol Neuroimmunol Neuroinflamm. 2014 Oct 9;1(3):e34.

OBJECTIVES: To describe the clinical course and neuropathology at autopsy of a patient with neuromyelitis optica (NMO) treated with alemtuzumab.

METHODS: Case report.

RESULTS: A 61-year-old woman with aquaporin-4 immunoglobulin G antibody seropositive NMO had 10 clinical relapses in 4 years despite treatment with multiple immunosuppressive therapies. Alemtuzumab was administered and was redosed 15 months later. For the first 19 months after the initial alemtuzumab infusion, the patient did not experience discrete clinical relapses or have evidence of abnormally enhancing lesions on brain or spinal cord MRI. However, she experienced insidiously progressive nausea, vomiting, and vision loss, and her brain MRI revealed marked extension of cortical, subcortical, and brainstem T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities. She died 20 months after the initial alemtuzumab infusion. Acute, subacute, and chronic demyelinating lesions were found at autopsy. Many of the lesions showed marked macrophage infiltration with a paucity of lymphocytes.

CONCLUSIONS: Following alemtuzumab treatment, there appeared to be ongoing innate immune activation associated with tissue destruction that correlated with nonenhancing T2/FLAIR hyperintensities on MRI. We interpret the cessation of clinical relapses, absence of contrast-enhancing lesions, and scarcity of lymphocytes at autopsy to be indicative of suppression of adaptive immunity by alemtuzumab. This case illustrates that progressive worsening in NMO can occur as a consequence of tissue injury associated with monocytic infiltration. This observation may be relevant to multiple sclerosis (MS) as well as NMO and might explain why in previous studies of secondary progressive MS alemtuzumab did not seem to inhibit disability progression despite a dramatic decline in contrast-enhancing lesions.

CoI: multiple

Worsening after alemtuzumab

#MSresearch #Clinicspeak

Haghikia A, Dendrou CA, Schneider R, Grüter T, Postert T, Matzke M, Stephanik H, Fugger L, Gold R. Severe B-cell-mediated CNS disease secondary to alemtuzumab therapy. Lancet Neurol. 2017;16: 104-106.

We have recently had reports suggesting that people taking alemtuzumab after fingolimod may be at increased risk of treatment failure. Bad news for alemtuzumab

In these case (two) reports presented the inference is that some people may not respond well. In this study the suggestion was made that alemtuzumab did not treat MS and instead generated a severe, antibody mediated CNS condition within a few months. 

Both pwMS responded to plasmaphersis (which is removing antibodies from the blood). Indicating that alemtuzumab had allowed the generation of autoreactive antibodies. We know that this happens, as alemtuzumab is associated with a variety of B cell mediated autoimmunities. Is this (1) augmentation of MS, (2) generating a new autoimmunity targeting the CNS, or (3) a fluke of disease reactivation? 

In both cases, they were treated with B cell depletion thereapy using rituximab. This does not cause immediate plasma cell depletion and disease was controlled.

I believe that B cell autoimmunity is an inherent problem of using alemtuzumab, due to its depletion characteristics (more on this later), but without more info, it is all speculation. However (2) is a possibility but this could be part of (1) also.

CoI: Currently non-relevant

Saturday, 28 January 2017

#ThinkSpeak: unrelated comments as a forum for change

The best way to treat your pet troll is to be kind and patient; at Barts-MS we like to think that we are both kind and patient. #ThinkSpeak

Do you use, and read, unrelated comments? This is a useful feature of our blog that we added many years ago to improve our offering. It is important to let the blog evolve over time, which explains why we have expanded our readership over the years. The idea of the unrelated comments is to ask questions and start a conversation about a topic that is unrelated to a specific post. Yesterday one commentator asked a string of questions. I will try and answer these over the next few days. Three of the questions are all related to alemtuzumab.

Prof G do you claim alemtuzumab to be curative in MS? 

Incorrect. I have never claimed alemtuzumab is a cure for MS. I have always taken the position that based on the autoimmune hypothesis that PIRTs (pulsed immune reconstitution therapies) of which alemtuzumab is one may offer a potential cure. This is the underlying therapeutic principle that underpins PIRTs; in addition to alemtuzumab cladribine and HSCT can also be classified as PIRTs. I have also discussed many times what a potential cure would look like in MS and we are not there yet in terms of follow-up. I have always maintained that this is a 15-20 year experiment

Could something cure MS even though no-one knows why MS happens?

Yes, something could cure MS even if no-one knows why MS happens. This is called an empirical observation and it has happened many times in medicine, particularly in relation to environmental exposures. We didn't know how alcohol caused caused acute liver damage, but abstinence was the empirical cure. I don't agree with the comment that 'no-one knows why MS happens'. MS is a complex disease due to an interaction between genetic susceptibility and the environment. The main environmental factors are low vitamin D or low UV sun exposure, EBV and smoking. I am convinced that EBV is causal based on strong epidemiological data. We are working on a study design for an EBV vaccination study, that should answer the question whether or not  EBV is the cause of MS. What we don't know is how EBV triggers or drives MS once someone develops the disease. We have many ongoing research projects that are looking into this. We have discussed most of these projects on the blog under the 'Charcot Project' an initiative that brings all this research together. The Charcot Project is not one study but a many studies that look into the viral hypothesis of MS. 

Why do some patients who go onto alemtuzumab continue to progress?

This is has been discussed endlessly under the so called asynchronous progressive MS hypothesis and length-dependent axonopathy hypothesis. Unfortunately, progression is often primed by previous damage and switching off inflammation now with alemtuzumab is unable to repair the previous damage that has primed neurons and axons to die off over time. This is why we recommend early effective treatment to prevent damage. Another factor that plays out in so called 'progressive disease' is premature ageing. Life is a sexually-transmitted neurodegenerative disease. If we all live long-enough we will see the effects of ageing on the nervous system (poor memory, unsteadiness of gait, poor balance, reduced hearing, etc.). What protects us from age-related neurodegeneration is brain and cognitive reserve. Unfortunately, MS reduces both brain and cognitive reserve and brings ageing forward in time. Alemtuzumab like all other DMTs that have been licensed to treat MS have not been shown to impact on ageing of the nervous system. This is why some pwMS will continue to progress despite being rendered NEDA by alemtuzumab. Finally, the dreaded intrathecal plasma cell. One of the hypotheses that we are exploring is that the long-lived plasma cell, which makes immunoglobulin with the brain and spinal cord, may be responsible for delayed progression. We have shown that alemtuzumab does not impact on these cells and hence this is another reason why pwMS may continue to progress despite being treated with alemtuzumab. 

Our Pet Troll

I must point out that if this particular commentator had taken the time and effort to read the blog they would have had all their questions answered. This explains why we repeat ourselves. Most readers dip in and out of the blog and only read current posts, by repeating ourselves we hope the messages get through. We also need to curate the blog. Blogging software is not ideal for navigation. I have been working on creating a curation site with links to important posts to make it easier for you to find information and to help navigate the blog. This is part of evolving our site to make it more user-friendly; we really don't want the blog to be stuck in time. 

CoI: multiple

All Antibodies are the same- think again!

New anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoid malignancies.Robak T, Robak E. BioDrugs. 2011;25:13-25.

Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells.

The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region.

Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for haematological malignancies and autoimmune diseases.

Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells.

Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities (strength of binding to the target of individual Fab is the avidity...strength of the binding of the two Fab in the antibody molecule is the affinity) and a stronger effect on CDC compared with rituximab.

Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor.

The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab.

PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab.

GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies.

TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs.

This week we have had a worry about the capacity to work following fingolimod treatment. The inference is that alemtuzumab does not kill white blood cells in the lymph glands because it kills by antibody dependent cellular cytotoxicity (ADCC) requiring phagocytes to bind to the Fc region via Fc receptors and release their products to kill the target. This is compared to complement fixation, which is activation of a cascade of blood/tissue pro-enzymes that are activated to punch holes in the target and to kill them.
The bioengineers can change an antibody to have different properties ,such that it depletes or does not deplete their targets and it can change the way they deplete.

The cells required for ADCC occur at low levels in the lymph glands. so Alemtuzumab does not kill the target cells in the lymph glands compared to killing them in the blood. If you can engineer alemtuzumab to kill in the lymph glands then maybe fingolimod would not stop alemtuzumab working.

There are second generation alemtuzumab antibodies being developed but those relating to anti-CD20 B cell depleting agents are more developed.

You may have heard of rituximab which is part human and part (the Fab regions) mouse. Oreclizumab is largely human except for the target binding region called the complementarity determining region. Ofatumumab is totally human. This means the human immune system is less likely to reject the antibody as it can recognise the mouse bits as being foreign to the body.

Theorectically ocrelizumab could have the same issues as alemtuzumab treatment after fingolimod because it depletes or perhaps doesn't deplete in the same way as alemtuzumab (However I would like to see the data on the use of ocrelizumab in human CD20 transgenic mouse to see how it depletes in lymph glands and bone marrow...prod, prod).

But you can see you can betterer and betterer depleting antibodies than rituximab or ocrelizumab. expect to see some of them appear once ocrelizumab gets licenced.

Friday, 27 January 2017

The Dre Approach to treating RR MS

Sawad AB, Seoane-Vazquez E, Rodriguez-Monguio R, Turkistani F. Cost-effectiveness of different strategies for treatment relapsing-remitting multiple sclerosis. J Comp Eff Res. 2017 . doi: 10.2217/cer-2016-0056. [Epub ahead of print]

AIM:To compare the cost-effectiveness of different disease-modifying therapies' strategies for treatment of relapsing-remitting multiple sclerosis.
METHODS:A Markov model was developed to assess the cost-effectiveness and incremental cost-effectiveness ratios for different strategies of using disease-modifying therapies from a US third-party payer perspective. All costs were converted to 2014 US$.
RESULTS: Over 20 years, the total costs per patient were estimated at US$161,136.60 for Strategy 1 (symptom management [SM] alone), US$551,650.66 for Strategy 2 (SM and IFN-β-1a), US$703,463.60 for Strategy 3 (SM and natalizumab) and US$670,985.24 for Strategy 4 (SM and alemtuzumab). The accumulated quality-adjusted life years were 10.49, 10.66, 10.69 and 10.71 for each of the four Strategies 1-4, respectively. The resulting incremental cost-effectiveness ratios were 2,297,141.53 comparing Strategy 2 to Strategy 1, and -1,623,918.00 comparing Strategy 4 to Strategy 3.
CONCLUSION: Strategy 1 was the cost-effective strategy for treatment of relapsing-remitting multiple sclerosis when compared with other strategies.

I am not sure that I can explain this one in terms of how cost-effectiveness was assessed but I think it says that in comparison to giving alemtuzumab, natalizumab, beta interferon or nothing (except symptom management) then nothing is the most-cost effective. Hardly surprising as the symptom control drugs cost "peanuts" and the other DMT cost "an arm and a leg". 

This study panders to the "Lazy Neuro" approach  recently renamed the "DreApproach (see comments from Yesterday). Apparantly you just rap "There....there, we'll get you a nice wheelchair...... Bruv!

I don't buy this, do nothing approach. It shows a real lack of ambition to make a change, We need to think about maintaining Brain Health for All. 

#ThinkSpeak: alternative facts and multiple sclerosis

Therapeutic nihilism vs. masterly inactivity vs. active treatment: damned if you do damned if you don't! #ThinkSpeak

I haven't done a #ThinkSpeak post for sometime. It is amazing how trends start, evolve and spread like wildfire. The latest trend to hit MS is the 'alternative fact'. Some commentators are actively trying to peddle a different, or alternative, view about MS and its treatments.

'Alternative facts' is the phrase used by Kellyanne Conway, one of Donald Trump's aides, during a Meet the Press interview, in which she defended White House Press Secretary Sean Spicer's incorrect statements about the attendance at Donald Trump's inauguration as President of the United States. The term is clearly very sticky.

There are some people with MS, or not, who think the treatment paradigm that we have been promoting of treating MS early and effectively is wrong. In other words people with MS should just accept their lot in life and get on with it as best they can. We researchers should pack up shop and not try and prevent MS or modify the course of MS. This form of extreme therapeutic nihilism makes neurologists who favour 'watchful waiting' or 'masterly inactivity' look active in their approach to treating MS.

I have embedded my old infographic, which has now been viewed ~2.5 million times, as a reminder of what untreated MS looks like.

CoI: multiple

Thursday, 26 January 2017

Biogen Skinned by a Patent Troll

Pharma don't always get their way and when there is money to be made the vultures are out.

It is reported (click) that Biogen has agreed to pay $1.25 billion in cash to Forward Pharma a Copenhagen-based firm that has no approved products.

The legal battle centers on Biogen's multiple sclerosis treatment Tecfidera, which raked in $4 billion in 2016 sales.

Forward Pharma has been arguing that its patents on dimethyl fumarate (DMF), the active ingredient in Tecfidera, were filed before Biogen's and that the firm therefore has royalty rights to the drug. These are suits still going through the courts

Under the deal, Biogen would also pay Forward 10% royalties from Tecfidera sales between 2021 and 2028, and a 20% royalty thereafter (if Forward is able to secure the patents on its Tecfidera competitor). The deal would end once one of the drugs' patents lapse.

I am led to believe that the Danish person found an university patent and picked it up,  and had the financial clout to take on big pharma.

A few years ago someone came to me to ask if I would do some work on a compound in EAE, which is in phase II now, as they had picked up the patent rights via trawling the Japanese patent database. (If you don't have a translation and you don't read Japanese, stuff can get missed). So  maybe someone else will also get a shock in the future if the clinical development is successful. Sorry I can't tell you what it was.

Did you know that it costs over £10,000 to get a patent translated from English into Japanese....this patent stuff is a real cash cow mainly to lawyers who never lose out.

Patents are essential to developing treatments and without protection of a patent drugs don't get developed. This is one of the reasons why rituximab was dropped in favour of ocrelizumab


However this action is not victimless and whilst the fat cats get rich, you will pay for this. 

Has this anything to do with the 8% Price Hike of Biogen Drugs reported earlier this week (click)? 

This will give Biogen about an extra $400,000,000 (based on $4 billions sales) from the sale of tecfidera, then add the extra revenue from avonex, plegridy, natalizumab and the patent troll is being paid.

#ClinicSpeak: are you a ISCer?

If you are an ISCer choose your catheter wisely, that's assuming you are given a choice. #ClinicSpeak #ThinkHand

ISCer = somebody who intermittently self-catheterises 

Bladder problems in pwMS are almost the norm. Why? The neuronal system that supplies innervation to the bladder is long, has little functional reserve and is quite complicated in how it functions. This all makes bladder dysfunction in MS very common and in my experience a poor prognostic sign. PwMS with early bladder problems tended to do badly. Please note that I am using the past tense as we need to update our prognostic information with what happens to pwMS in the DMT era. I predict the prognosis will have improved substantially even if you do have bladder problems and are your MS is being treated actively and effectively. 

The systematic review below looks at outcomes of based on different approaches to ISC (intermittent self-catheterisation). The authors' found advantages to the use of so called hydrophilic-coated catheters in decreasing the incidence of UTI (urinary tract infections) and urethral trauma as well as improving ISCer satisfaction. The review also found that prelubricated catheters to be superior to conventional older catheters. As always with systematic reviews it concluded that randomised controlled trials are needed to assess the cost-effectiveness of hydrophilic and prelubricated catheters to see if they justify their price. 

From a personal perspective finding the right catheter makes an enormous difference to ISCers and cost is usually not the major issue. Preventing UTIs and the associated extra visits to the doctors and hospital admissions that result from UTIs will almost certianly justify the extra costs.  I would be interested to hear your thoughts on this issue. I am sure many of you have your own catheter nightmare and catheter bliss stories to tell. 

On reflection wouldn't it be nice if we could prevent bladder dysfunction in pwMS in the first place?

One last point I wanted to make is that the ability to self-catheterise is one of upper limb, or hand, functions that was highlighted over and over again by many of you as part of our #ThinkHand campaign. Maintaining the ability to self-catheterise is something we need to incorporate into our new ABILHAND PROM for pwMS. 

Shamout et al. Outcome comparison of different approaches to self-intermittent catheterization in neurogenic patients: a systematic review. Spinal Cord. 2017 Jan 24. doi: 10.1038/sc.2016.192.

STUDY DESIGN: Systematic review (Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA); http://www.prisma-statement.org).

OBJECTIVES: Different types of catheters and techniques have been described in the past three decades to identify the best self-intermittent catheterization method. Our aim is to review systematically the literature on the most appropriate material and technique to perform self-intermittent catheterization in the adult neurogenic population.

METHODS: A systematic review search was performed through PubMed/Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases to study all types of self-intermittent catheters, and analyzing their impact on urinary tract infections (UTIs), urethral trauma, cost-effectiveness, quality of life and patient's satisfaction. We used the following keywords: 'intermittent catheterization/catheterisation', 'neurogenic', 'urinary catheters for intermittent use' and 'urethral catheterization/catheterisation' published by November 2015.

RESULTS: After screening 3768 articles, 31 were included in the final synthesis (level of evidence 1b to 2b). The 2188 trial participants were mainly spinal cord injury adults and women with multiple sclerosis. Hydrophilic-coated catheters tended to decrease the incidence of UTI as well as urethral trauma and improve patient's satisfaction when compared with non-hydrophilic-coated catheters. Similarly, prelubricated catheters were associated with better results in terms of patient satisfaction. Sterile technique seemed to decrease the incidence of recurrent UTI; however, these results are counter-balanced by significantly increasing cost compared with clean catheterization.

CONCLUSIONS: The present review demonstrated advantages of hydrophilic-coated catheters in decreasing risk of UTI and urethral trauma as well as improving patient's satisfaction. Prelubricated catheters has been shown to be superior to conventional polyvinyl chloride catheters. Randomized controlled trials comparing hydrophilic and prelubricated catheters must be conducted to assess possible superiority and cost-effectiveness.Spinal Cord advance online publication, 24 January 2017; doi:10.1038/sc.2016.192.

Cholesterol makes myelin...should we be eating bad fat.

Berghoff SA, Gerndt N, Winchenbach J, Stumpf SK, Hosang L, Odoardi F, Ruhwedel T, Böhler C, Barrette B, Stassart R, Liebetanz D, Dibaj P, Möbius W, Edgar JM, Saher G. Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.
Nat Commun. 2017 Jan 24;8:14241. doi: 10.1038/ncomms14241.

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes.

The message of the paper is that dietary cholesterol may be useful in myelin repair and as myelin is largely fat, is it surprising that there could be some influence on myelination. The implications are clear, but before you start diving into that plate of cheese, there needs to be some balance.
                                New MS Treatment for Repair

Whilst the inference of the mouse study is that increasing cholesterol will promote remyelination, however there is even more evidence that elevated cholesterol levels are risk factors for a large number of conditions, including cardio-vascular disease. 

To deal with this, statins have become a main agent to treat the effects of dietary cholesterol. 

The ARRIVE guidelines of reporting animal studies suggest that you discuss the work within the context of previous studies and also to discuss the implications for translation into humans. 

This manuscript is lacking, in an adequate discussion that encompasses the substantial literature surrounding the cholesterol pathway and the use of statins.  I guess to acknowledege the exsistence of such limits the novelty of the approach, so the contents of reference 43 were never discussed. 

Dietary cholesterol did not inhibit or augment EAE as shown here, but we and others have shown that blocking cholesterol does not inhibit or augment EAE. The effect of statins in EAE appears to be upstream of cholesterol and they can inhibit EAE. More importantly are the reports that statins can inhibit remyelination. Which supports the claims here and again asks what's new here?

Miron VE, Zehntner SP, Kuhlmann T, Ludwin SK, Owens T, Kennedy TE, Bedell BJ, Antel JP. Statin therapy inhibits remyelination in the central nervous system. Am J Pathol. 2009; 174:1880-90.

Although there is some confusion. 

Paintlia AS, Paintlia MK, Khan M, Vollmer T, Singh AK, Singh I. HMG-CoA reductase inhibitor augments survival and differentiation of oligodendrocyte progenitors in animal model of multiple sclerosis. FASEB J. 2005 19(11):1407-21 is right

There are obvious implications from this for the use of statins in MS. This current study would imply that statins would have a negative impact on MS.

However, there is a suggestion that simvastatin slowed the worsening associated with secondary progressive MS in a phase II trial. Therefore, on balance the data would imply the any adverse influence on remyelination is negated.

Six years after the publication of the MS-STAT phase II trial, could a phase III come to the table?.

This would raise some questions that may or may not have answers:

1. In light of this study should a neuroprotection trial be done? Do we ignore the animal data(...so what's new there?) and carry-on?.

2. Do the statin investigators have a plausible mechanism to under-pin the basis of the trial?  A trial with a rationale mechanism surely has more chance of success than a stab in the dark. Is it another look-see punt in the dark? or should I say punt in the dusk, as the phase II trial was the shot in the dark. 

The original mechanism was that statins influenced either the cytokine balance or white cell migration, which had their targets firmly in relapsing MS. Statins didn't fair sufficiently well for relapsing MS but the logic of trying statins in secondary progressive MS, was never really expanded upon or clear to me.

Given the link of Alzheimer’s, progressive EAE and the cholestrerol pathway one can construct one, but surely this is a job for the Investigators.

3. What will the trial be like?…will they go cheap and fail you by only testing the high-dose used in the phase II trial. 

A normal dose is needed to show the added risks of the high-dose are warranted. Dose response is what academics/regulators have made pharma do, so I really hope this is done. But it will add to the costs.

Would a phase III study be adequately powered, as academic trials often over-state the likely treatment effect to reduce the numbers, to detect change, to reduce costs.

4. Would they determine where the statins are working. Is it neuroprotection by affecting nerves within the brain, or are they simply affecting a co-morbidity, which could be done by comparing a CNS penetrant verses a non-CNS penetrant statin.

I suspect too much science for a trial.

5. Is it a drug-lite trial of only statin verses placebo, as the biology indicates that it would best be done on top of an anti-inflammatory, immune-modulator.

6. What is the plan post trial?.  Is the hope, that if positive, neuros will just use it. But will they? Will pharma be annoyed that they have to do two properly powered trials and spend millions getting drugs approved. If one ploughs on and people don't adopt it will be 5 years wasted, or is the PR of doing a trial more important that success.

Importantly, what happens once pharma gets something approved eg ocrelizumab or siponimod, which may happen before the trial is finished. What will neuros do.

Maybe, I have it all wrong and the rumors are just rumors 

Wednesday, 25 January 2017

#ClinicSpeak: a low EDSS hides a lot

Don't be lulled into a false sense of security with a low EDSS. #ClinicSpeak #MSBlog

Every now and then you get a reminder of how debilitating MS can be and how crude, or crap, the EDSS really is in capturing the impact of MS.  

The study below analysed gait in adolescents with MS (~15 years of age) with average disease duration of less than 2 years, in other words early MS, and a low EDSS 1.7 (no discernible or outwardly visible disability). The remarkable finding in this study is that despite low disability as measured by the EDSS the results show that adolescents MSers walked slower with a wider base of support compared with age-matched healthy control subjects. You may say big deal these changes are too subtle to matter, but scale this up to other neuronal systems including cognition and you can imagine the impact, or potential impact, this would have on these MSers functioning. Adolescents are at a stage in their lives were they need to function at school and on the sports field. Being able to compete and fitting in is important for their development. These adolescent MSers are unlikely to be excel on the sports field, which is brutal when it comes to natural selection. Hopefully, the classroom will allow them some comfort. 

All this makes me realise that we are disadvantaging so many young people with this disease. The possibility that MS may be preventable makes me angry. Why haven't we started prevention studies? Why does science take so long to get going and achieve things? 

If I was a parent with a child with MS I would find this piece of research frightening. All I can say to reassure you is that with the emergence of highly effective treatments and a change in our treatment paradigm to treat-2-target of NEDA we will hopefully save your children from the full brunt of the disease. 

Kalron et al. Gait Characteristics in Adolescents With Multiple Sclerosis. Pediatr Neurol. 2016 Dec 22. pii: S0887-8994(16)30723-8.

BACKGROUND: Multiple sclerosis is a progressive autoimmune disease of the central nervous system. A presentation of multiple sclerosis before age 18 years has traditionally been thought to be rare. However, during the past decade, more cases have been reported.

PATIENT DESCRIPTION: We examined gait characteristics in 24 adolescents with multiple sclerosis (12 girls, 12 boys). Mean disease duration was 20.4 (S.D. = 24.9) months and mean age was 15.5 (S.D. = 1.1) years. The mean expanded disability status scale score was 1.7 (S.D. = 0.7) indicating minimal disability. Outcomes were compared with gait and the gait variability index value of healthy age-matched adolescents.

RESULTS: Adolescents with multiple sclerosis walked slower with a wider base of support compared with age-matched healthy control subjects. Moreover, the gait variability index was lower in the multiple sclerosis group compared with the values in the healthy adolescents: 85.4 (S.D. = 8.1) vs 96.5 (S.D. = 7.4).

CONCLUSIONS: We present gait parameters of adolescents with multiple sclerosis. From a clinical standpoint, our data could improve management of walking dysfunction in this relatively young population.

Is ProfG making us go fishing?

ProfG's highlight of the month in MSARDS
               was EAE in Zebra fish (click here for a free copy)

I thought I would add more    
       There's a video of EAE in fish....not for the faint hearted 

The fish will die, so one needs to put in endpoints,before the paralysis

Why a highlight
Is prof G trying to get rid of Me?
He even asked if I have got the fish tanks yet:-(

Should we be investing in this area? 
Can I afford it?, Can I afford to Ignore it?                  
I guess the Home Orifice 
is getting their wellies out, ready to make the mousers
go fishing.
What do you think?........Dr. Doox?

Will it be Fish & Mice...an add-on or an instead of?

Angry Astrocytes kill nerves and probably contribute to progressive MS

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA.Neurotoxic reactive astrocytes are induced by activated microglia.Nature. 2017. doi: 10.1038/nature21029.

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.
  • Inflammation activates microglia
  • Activated microglia produced a gliotic astrocyte to be produced
  • These gliotic A1 astrocytes block oligodendrocyte formation
  • These gliotic A1 astrocytes are neurotoxic and make toxic elements to kill nerves
  • Blocking A1 astrocytes may slow nerve loss
  • Progressive MS is likely to involve glial inflammation 
Astrocytes are an underated cell, but we know they support the function of the brain and control the tightness of the blood brain barrier, they control neurotransmitter levels, support the energy and growth factor requirements of nerves and other cells and cause problems, when they are targeted for damage in neuromyelitis optica. 

They are also the major scar forming cell in the demyelinated lesion and so contribute to lack of remyelination. When astrocytes are activated some people call them "reactive astrocytes" other people including me would call them "gliotic" where they put out more proteins including glial fibrillary acidi proteiin ( a hall mark of astrocytes) and many years ago I showed that they contain lots of IL-6 at least in the mouse. In this study term an reactive astrocyte subset and call it A1. However this should not be confused if you read about type I and type II astrocyttes.

This study shows that activated microglial produce some inflammatory mediators and this helps create the astrocytes. These are a complement component and interleukin-1 and tumor necrosis factor, which are well known pro-inflammatory mediators produced by inflammatory such as microglia and other cells....the other cells may relate to why blocking TNF can lead to demyelinating disease and MS worsening.

A1 astrocytes, which are present in diseases associated with neurodegeneration, lose the ability to promote neuronal survival, nerve outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. 

A1 astrocytes loose the ability to promote nerve survival and induce the death of nerves and oligodendrocytes. So this allows you to have nerve damage without needing a T or a B cell anywhere near the system. Importantly if you cut/transect the axon to simulate damage then the death of axotomized CNS neurons is prevented when the formation of A1 astrocytes is blocked,

Therefore, targeting this process may slow the processes of neurodegeneration, but is the the T and B cell theory intact.

Sure it it is because you have to ask what makes them microglia angry and what causes the transections (cutting of the axon). We know that active inflammation causes 11,000 transections/mm2. 

What made the microglial activated then this is where T and B cells will come in, they trigger/create the environment to activate microglial and make astrocytes gliotic, 

However, this is where there are aspects of progression that do not respond to certain anti-inflammatory drugs. That astrocytes contribute to nerve survival is well known and they do such things as control the lactate that impinges on energy levels of the nerve and its survival

We have been saying for some time that you have to control the glial inflammation to control progression. There is a toxic factor. What is it? This is a new part of a jigsaw, but this does not change my world view. 

If it thrusts the astrocyte into the limelight... great...it is an underestimated cell.

This aspect that was targeted in the Progressive Alliance by a group in Harvard. We know that astrocytes control the glutamate-glutamine cycle and we know how important this may be in glutamate excitotixicity killing nerves. In this case they produce toxic factors that did not support nerve survival and also they block the proliferation of oligodedrocytes and so would inhibit remyelination. It has been known for some time that astrocytes block remyelination

In this study they found that caspase (cell death effectors) inhibitors blocked death caused  by the astrocyte derived factors. We showed this a few years ago to block  nerve loss. 

Neuroprotection in a novel mouse model of multiple sclerosis.
Lidster K, Jackson SJ, Ahmed Z, Munro P, Coffey P, Giovannoni G, Baker MD, Baker D. PLoS One. 2013;8(11):e79188.

However, we could not get the company interested producing the treatment agent to try the approach in MS, and we never got any funding to develop this, so it is interesting that pharmacological inhibitors are becoming available at least for experimental use...However, they may have all sorts of problems if used globally. 

Likewise there is perhaps issues with the statement that there are FDA approved inhibitors of the molecules. Whilst these A1 cells are  formed by TNF, blocking this in MS is a no-no. It makes MS worse or causes demyelinating disease.

Interleukin-1, blockade of this may be interesting but as it is a globally used cytokine involved in the generation of all sorts of cells, it will not come without side effects.

Is this enough to treat progression?

Comabella M, Julià E, Tintoré M, Brieva L, Téllez N, Río J, López C, Rovira A, Montalban X. Induction of serum soluble tumor necrosis factor receptor II (sTNF-RII) and interleukin-1 receptor antagonist (IL-1ra) by interferon beta-1b in patients with progressive multiple sclerosis. J Neurol. 2008; 255:1136-41.

Soluble receptor blocks TNF and IL-1Ra blocks IL-1, but is beta interferon great for progression...not really.

However, the plus side it gives a focus on astrocytes..on the bad side we will now see a sea of uninterpretable acute EAE experiments with astrocyte conditional knockout mice that are not particularly directly relevant to astrocyte activity in progressive MS:-)