Saturday, 25 March 2017

MS lymphocytes making new myelin

El Behi M, Sanson C, Bachelin C, Guillot-Noël L, Fransson J, Stankoff B, Maillart E, Sarrazin N, Guillemot V, Abdi H, Cournu-Rebeix I, Fontaine B, Zujovic V.
Brain. 2017. doi: 10.1093/brain/awx008. [Epub ahead of print]

One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. 

Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. 

Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. 

Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. 

Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.


Last week we had the story that Treg cells produced a molecule that promoted remyelination and this week we have something similar but they take human cells and inject them into a nude mouse.



A nude mouse is a mutant mouse that does not make hair, but they also do not make T cells and so they can't reject human cells that are transplanted into the mouse. They injected a toxin to make demyelinated lesion as the toxin kills oligodendrocytes.

They then inject human cells, which they have activated,into the mice and find that they promote repair. As the mice were not genetically engineered e.g. to be MHC compatible, the T cells would not be able to talk to the lymphocytes. They go a test bleed from the eye by putting a needle into the retro-orbital sinus, which was banned (as their are alternatives) in the UK about 25 years ago, to check the cells are still present. They find there is variability in the repair potential, They found that MS blood cells demonstrate that multiple sclerosis lymphocytes did not interfere with OPC recruitment, but impeded OPC differentiation. This had an effect of via microglial cells and when they looked at 72 secreted molecule they found differences in three IL-7 and IL-20 which are immune growth factors and CCL-19 which is a protein that attracts cells called a chemokine. The latter was lower from people with MS. 
Taking advantage of our innovative in vivo model to study the role of human lymphocytes in remyelination, we demonstrated a strong implication of adaptive immune cells in this repair process. In particular, multiple sclerosis patient lymphocytes induce detrimental environment for the repair process notably by directing MIGs toward a pro-inflammatory M1 phenotype. Strikingly, the molecular cues needed for a successful remyelination were different when considering multiple sclerosis patient and healthy donor lymphocytes

Friday, 24 March 2017

#PoliticalSpeak: impact or lack of impact

Why has academia become so bureaucratic? #PoliticalSpeak #MSBlog

Life as an academic is becoming increasingly complicated and frustrating; I spend an extraordinary amount of time doing administration. We have been asked to start preparing for the next REF, which is likely to be in 2020, and need your help. 



In the UK academic institutions are assessed every 6-7 years as part of the Research Excellence Framework exercise or REF. As part of this assessment we have to provide 'impact case studies' demonstrating the impact of our research on wider society. Impact is defined as ‘an effect on, change or benefit to the economy, society, culture, public policy or services, health, the environment or quality of life, beyond academia’.

We had an informal discussion yesterday about what academic activities we are engaged in have impact and how can we show impact. If we have to submit an impact statement next REF we will need to be able to demonstrate how we are having impact with the relevant metrics, etc. As you are quite close to our activities you could help us prioritise our efforts so that we can focus on the academic activities that are most likely to succeed. This exercise will also help focus our minds as a group. Thank you. 



CoI: multiple

More on B cells.We don't all have the same ideas. Who is right?

We don't normally report on reviews. But we have a couple of recent ones

Nguyen AL, Gresle M, Marshall T, Butzkueven H, Field J. "Monoclonal antibodies in the treatment of MS: emergence of B-cell targeted therapies". Br J Pharmacol. 2017 Mar 20. doi: 10.1111/bph.13780. [Epub ahead of print]

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease modifying therapies have rapidly emerged, including monoclonal antibodies (mAbs) that have provided highly targeted therapies with superior efficacy compared to platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials, and renewed interest in the mechanism of B-cell depleting therapies to ameliorate relapse activity and progression in MS. In this manuscript, we will review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B-cell targeted therapies


We did the same but came to very different conclusion.
Here it is all to do with B cell regulatory function rather 
than B memory function.

If you work in percentages if one goes down (Memory B cell subsets) the others (Regulatory B cells) must go up.

However in some cases because we have tried to work with absolute numbers we know that B memory cells go down

We have recently published 
our first part of the original series of papers written 
just before Christmas.
The last part of the originally submitted studies 
actually surfaced first

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.
EBioMedicine. 2017 Feb;16:41-50. doi: 10.1016/j.ebiom.2017.01.042

This has gained some Interest on the Blog as it becomes evident that this subset of Bcells is infected by Epstein Barr Virus.

Maybe there are alternative explanations to the view that B cells help T cells do it all.


Following dogma can lead us down a garden path, as we will see as the next part of the equation eventually surfaces.

However, this thought does not even occur on some people's radar
So here is a standard view

Ocrelizumab in multiple sclerosis: markers and mechanisms.
Hohlfeld R, Meinl E. Lancet Neurol. 2017;16(4):259-261.

They say

"Anti-CD20 therapy acutely depletes CD20+ cells in the periphery, but only causes a delayed and modest decline of circulating antibodies.CSF studies with rituximab revealed decreased T-cell and B-cell counts, whereas intrathecal IgG production was relatively spared. For these reasons, depletion of pathogenic antibodies might not be the dominant mechanism of action of ocrelizumab in multiple sclerosis, although this cannot be totally excluded". 


"Overall, it seems plausible that anti-CD20 therapy partly acts by eliminating the potent antigen-presenting function of B cells, a view supported by animal experiments. Furthermore, B cells produce many pro-inflammatory and anti-inflammatory cytokines. Profound B-cell depletion might therefore lead to changes in the cytokine network, dampening pathogenic T-cell responses and thereby contributing to the beneficial effect of anti-CD20 therapy in multiple sclerosis".

"Lastly, it should be noted that anti-CD20 therapy is not entirely specific for B cells, as it also depletes CD20+ T cells, which are about 5% of blood T cells".

Whilst our review accommodates all these views, it gives an opinion and then it puts the focus in a very different direction. As memory B cells are not really mentioned. However, again we see that animal studies again tell us how MS drugs work. 

Although I am aware that the animal studies support such a mechanism, I personally think the data from treatment of animals with anti-CD20 is weak. 

Should we do a critique of the animal data? 

If the animal data is on shaky ground, where does it leave the hypothesis?



Do Mice Have Paws? What have they got?

We have been requesting access to data from pharma relating to B cells and disease activity.  As we told you, we got kicked back by some of the Companies, 

This prompted ProfG to start a petition to ask 

Ely Lilly to release their anti-B cell in MS trial data 
(Click here to sign)

One of the bloggers to say the least was very angry at this and wrote "MD. I've a few old uni friends work for pharma (lovely people) but I've taken this a bit personally. I sincerely hope you get your paws (do mice have paws?) on this eventually. Keep writing the papers! And thanks for sharing them with us, ignore any criticisms I love your posts - they usually make me laugh too" 

Do mice have paws?

The answer is yes, and we already have or paws on something.

Why have we started writing about B cells?  

Check out the acknowledgement in our B cell paper

Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis :-)


FYI. We have moved up the command chain to by-pass Roadblock#1. 

It was poetry world day this week so

Whilst mice have paws ferrets have locking jaws:-)

Thursday, 23 March 2017

Natural Killer cells and MS

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia.Caruana P, Lemmert K, Ribbons K, Lea R, Lechner-Scott J. Mult Scler. 2016:1352458516679267. doi: 10.1177/1352458516679267

To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity.


METHODS: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to 'No Evidence of Disease Activity' (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression.


RESULTS: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment ( p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects ( p < 0.05).


CONCLUSION: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.



So a suggestion that NKbright cells that are expanded by daclizumab in this study they suggest high levels are associated with stable disease...Is this a sign that its not B cells?

#PoliticalSpeak & #OffLabel: it is okay to use off-label DMTs

Off-label prescribing; how do we get it adopted? #PoliticalSpeak #MSBlog #OffLabel
My number one book from my homeland, South Africa. 

'Who knows for what we live, and struggle, and die? Wise men write many books, in words too hard to understand. But this, the purpose of our lives, the end of all our struggle, is beyond all human wisdom.'

'You ask yourself not if this or that is expedient, but if it is right.'

'There is only one way in which one can endure man's inhumanity to man and that is to try, in one's own life, to exemplify man's humanity to man.'

'I envision someday a great, peaceful South Africa in which the world will take pride, a nation in which each of many different groups will be making its own creative contribution.'

'To give up the task of reforming society is to give up one's responsibility as a free man.'

'Cry, the beloved country, for the unborn child that is the inheritor of our fear. Let him not love the earth too deeply... For fear will rob him of all if he gives too much.'

Alan Paton

One of the most important issues we have tried to address on this blog in access to effective DMTs for pwMS in resource-poor settings. I had a Skype call with a young neurologist from South Africa yesterday and she informs me that she has not been able to get permission to start any of her patients on a licensed DMT in the last 18 months. In addition, she is unable to offer these patients off-label subcutaneous generic cladribine or leflunomide as these drugs are not licensed in South Africa for MS. This is a true Catch-22! 

These and other experiences of what it is like to be a pwMS living in a resource-poor country remains our primary motivator for this policy initiative. We will continue to promote the use of off-label, cheaper, alternative DMTs to treat MS. What we need is some action. I wish politicians would read this blog and meet pwMS face-to-face. May be it should be them who say you can't have drug x, or drug y, and explain to them why.

The following is our essential off-label DMT list (click on each drug for more information):


Comments from the survey (updated 20h15, 23-Mar-3017):

I suspect I would be in a very dark place today without ldn being prescribed (since 2004), for my PPMS.

I have had SPMS since optic neuritis in 1985 at age 27. No relapses since that episode. Have slowly, steadily progressed since then. MRI shows spinal cord but not brain atrophy, with few lesions. I am now taking simvastatin, since nothing approved and progression has been constant. Drug is cheap, downside of use is low and we are monitoring liver health.

Trials and expensive drugs are a much trickier problem. Govt. needed to fund these things. Clinical research is so expensive.

I live in a different country each year for work. In a disease like MS which is so variable, off label uses of existing drugs offers some flexibility to deal with symptoms and syndromes that affect some msers but not others. And as for off label use in tx attempts (eg LDN), if the safety profile of the drug is known, and their are no contraindications, I see no harm in trying. In fact, it would be borderline negligent not to try everything possible to ease the symptoms at least. Providing the pt accepts responsibility for their decision to take the drugs.

If the drug is considered safe and not likely to react badly with concurrent medication, exacerbate symptoms or reduce quality of life with intense side effects, it's a sound way to find out if the drug has any disease-altering or symptom-modifying capability in MS. Funding RCTs to find out the results is expensive and time-consuming, so retrospective analysis of case studies - properly documented and analysed, seems a good use of resources, as long as organizations such as NICE don't block on the grounds of medication costs.

Full process for getting commercialization approval takes 12 years, Phase IIa should be enough for open label prescription, for a neurodegenerative illness like MS.

My son had his first dose of Campath 2 years ago. Since then no relapses and  no new MRI activity. If he hadn't had a neurologist willing to prescribe off licence, he'd be in a dire state by now, as it is likely it will be another 2 years before it may be licensed, and he would have missed his window of therapeutic opportunity.

I would like to comment, although I think I mostly agree with what Prof G has laid out on the blog, As an MSer, I would like to think that a mechanism can be made to do this more effectively, and also give a return to the drugs companies, everyone is happy then.

Surely some consent for off labelling between practitioner and patient with a really good explanation of the risks would stop law suits (from potentially being proved!)

I'm just not well enough informed to comment properly I feel, but understand the basics of the market and legal sphere.

I support off label prescribing so long as the drugs do not contain poisons such as antifreeze, etc. 


I'm currently taking Modafinil for fatigue issues. My insurance won't cover the cost ($564 USD), so I wait until my max out of pocket expenses are exhausted, and only then does my co-pay drop to 10 bucks. Modafinil has been a Godsend for me, and without it, I'm not sure I could continue to work. It may be off-label, but so essential to PwMS!

I support it as long as the patient is fully informed of the status of the drug.

I am taking LDN and it is helping me like nothing else has, I fully support it being prescribed.

Yes as long as it works the same as the name brand stuff.

I'm currently taking 40 mg simvastatin bid. SPMS since 1985 -not taking dmds.

For me I've had Provigil prescribed off-label. It's a very helpful drug for me for energy but I am concerned that it is not tested in people with MS. Maybe it worsens the disease or allows neurons to incur damage that wouldn't be done if the patient was respecting their fatigue. It should be tested so we know it's safe. But I don't want it taken away either. Dilemma. That's why I answered 'Maybe.'

In general, it's a bit difficult to comment intelligently on this, clearly if there are drugs that look like they might work in MS for relapses and/or morre importantly progression, we need to find this out. This clearly needs a different mechanism so that we get our drugs and pharma get their coin....
Its the only way I could get Rituxan (Copaxone, Avonex, Betaseron, and Tysabri all failed to stop progression on my MRI).

I have secondary ms and would have no options without off label treatment.


In the experience and opinion of the commentator, it would seem as if off-label prescribing is an exception, not the rule. This is understandable and expected from the perspective of the use of established standards for initial, mid and long-term therapies for "non-orphan" types of disease. Unfortunately, if low (clinical, measurable, qualitative) efficacy of these standards is an issue for the patient, physicians appear particularly sensitive to the potential legal liability of other forms of treatment, even following discussions with the patient releasing the physician from such liability. Again understandable if secondary therapies exist. However, in the absence of such, or at the request of the patient for other reasons, (low efficacy, side effects) this sensitivity, ultimately, may deprive the patient of avenues of treatment that might otherwise provide relief both clinically and from the standpoint of an improved quality of life. Further, this commentator has concluded that the importance of quality of (the patient's) life has, over time, been de-emphasized in the medical community as part of, and as a result of the above and would suggest that views similar to those offered here will be dismissed by this same community.

Great initiative!

There´s a large amount of people here on Rituximab, let´s see what happens when Ocrelizumab gets to the market...

As a physician as well as MS patient I would pursue these DMTs and repurposed drugs like statins if required ; but I am fortunate to have gone straight to Gilenya 3 yrs ago, NEDA since.

Why has Mitoxantrone to be prescribed off-label in the UK?

It is important to make many resources available in countries that do not have access.

The cost of MS drugs is prohibitive. Prescribing off labels drugs will surely force Pharma to reduce their price to the consumer.

My doctor does significant off-label prescribing and it works. Every second infusion I get to sit across from someone that looks like my mother - it's very hard. This lady has been receiving off-label treatment since '89 - my mother died after a long untreated illness in 2003.

The path I am currently going down... Tysabri ,Gilenya now rituxan.

I have no chance to get Rituximab instead of Alemtuzumab

If the drug a exists and can help in the treatment of MS I find it highly unethical to not let those suffering have access to it. people in powerful positions seem to have forgotten they exist to help the patients. how does the old expression go? 'one day a rain will come and wash the streets clean'
I think you're right in your quest. As long there is data showing good results, then off-label should definitely be considered, in both resource-rich and poorer countries. Thank you for this effort. Have a Happy New Year!


I think you're right in your quest. As long there is data showing good results, then off-label should definitely be considered, in both resource-rich and poorer countries. Thank you for this effort. Have a Happy New Year!

Whatever it takes to keep us with MS on our feet and in the best shape as possible.

Please God, let this happen.


Prescribing limited by NICE, off-label may be necessary to obtain best drug for patient.

Great initiative.

It is important to try a possible treatment, having weighed the pros and cons. We all react to treatments differently.

I support all use of medication to try to find a cure.

As an MS sufferer diagnosed with a mild form of RRMS in 2011 with symptoms progressing now I have had little or no support from my neuro because I don't meet criteria for drug intervention. The options are too limited. Aged 38 I now face an uncertain future.

Interesting.

We're lucky in Australia most of the prescribed MS drugs are on our PBS (free and available) but with our right wing government who knows what the future holds...


Dear All, in Kosovo are 1200 people with MS and only 80 get free treatment. It would be great if any Neurologist will visit Kosovo and explain to our MD s for other alternatives of the treatment in cheaper way.

To benefit those without access to on-label drugs.


Off label in no way means untried / unknown / ineffective / risky. Let physician and informed patient decide if appropriate - especially where alternative is inadequate or even nonexistent treatment.

My son got alemtuzumab earlier than he would have in the UK- time is brain- due to the bravery and conviction based on evidence of a UK neurologist.

If it helps people why not.

We should have the right to use all tools at our disposal.

My yes is for resource poor countries. I think I have understood from the blog that pharma companies need to make money in rich countries or disaster strikes.

People will look back and wonder why?

I don't actually trust Barts' opinions on this issue - too many conflicts of interests, far too much bias.

I am concerned about the lack of affordable treatments in developing countries, and the lack of any treatments anywhere, so far, for people with PPMS.

I support early treatment, and this among many other initiatives you have tried to overcome inertia and complacency among medics. I also support any attempt to mitigate the iniquitous lottery of health care provision both within UK and globally.

It's legal here as long as you can afford cost of the meds.

I work in the pharmaceutical industry and see first hand the aversion to off-label prescribing! On the flip side if there is an opportunity to obtain an additional indication on a license and extend a drugs patent they will provide all the necessary resource!

Access to medications and/or other generic treatments are as important in MS as any other condition.

Pharma and tort laws here won't let it happen. Sad.


When an off-label drug costs less, gives a better overall quality of life, and saves hospitalization from relapse costs, it should no longer be off-label.

Off label Rituxan and Imuran (in combo with interferon in 2004) has been useful to me.

Providing access to resources allowing a better quality of life for people diagnosed with MS seems logical & compassionate. This issue should not be about putting obstacles in the way of providing assistance to people in need or maximizing profits but helping people who need the help.

If effective treatments exist, PwMS should always have access to them. Political and commercial obstacles should be pushed aside.

I think Big Pharma only wants to earn money. They do not care about the MS patients.
Generic copy of rituximab is expected to come on the market here summer '17, or is it still too expensive for SA?

Since 2004 I have taken ldn to treat PPMS and suspect I would be in a very dark place today without it.

If there are no licenced alternatives available (or alternatives are too expensive / contraindicated) then it is morally right to prescribe off-label. 


Eg resource poor countries (all forms MS) or people categorised as ppms / spms in US, UK etc.


My understanding of 'off-label is that the drug has been tested with positive results but not yet authorized for prescription. Equally important the drug is significantly cheaper than many other drugs that are available. In this world where there is a shortage of money for treatment it strikes me that not allowing a less expensive but effective medical solution is inexcusable. Even in the UK there are excellent drugs available to help people with MS that have not been authorized by NICE.


I am so confused by DMTs and the differing messages. Certainly in countries where the newer and more expensive drugs are not allowed or are far too expensive then the use of these off label drugs should be allowed. They are widely used for other illnesses and at least their side effects and interactions are understood. But how effective are they? Or is anything that is moderately safe better than nothing at all. What a poor choice for so many people in this world.

I think it essential that there is off-label prescribing because the cost of new drugs is not affordable in much of the world.

No brainer.


Obtaining an off-label prescription is very difficult. You have to be very persuasive, and your local neurologist is more likely to refer you to a London teaching hospital than prescribe the drug himself. 


Entirely agree that the politicians and civil servants responsible for decisions to deny license or allocation should not be allowed to remain faceless and nameless, and should publicly take responsibility for their decisions.



CoI: multiple

Wednesday, 22 March 2017

ClinicSpeak; gardening post-alemtuzumab

Another opportunistic infection associated with alemtuzumab use in a person with MS. #MSBlog #ClinicSpeak

Question: "I am day 12 day after last alemtuzumab dose and probably have lymphopenia/leukopenia at the moment. Should I avoid the garden this spring :-(?"

Answer: Yes, you are putting yourself at risk of Nocardial infection. Nocardia species live in the soil. There have been cases described post alemtuzumab (see below). 


The first case below presented with a 3-week history of cough, shortness of breath, and a high fever 8 weeks after the first cycle of alemtuzumab treatment. Nocardia are aerobic gram-positive bacteria found in soil and water.  Nocardia is an opportunistic infection and needs to be taken very seriously. At the moment nocardial infections are rare and I am not sure what the risk is post-alemtuzumab. However, whilst you are neutropaenic and lymphopaenic I would advise avoiding soil exposure. 

Nocardia in the brain at autopsy; image from Wikipedia

Sheikh-Taha & Corman. Pulmonary Nocardia beijingensis infection associated with the use of alemtuzumab in a patient with multiple sclerosis. Mult Scler. 2017 Feb 1:1352458517694431.

Nocardia is a Gram-positive aerobic pathogen that usually affects immunocompromised patients. We report a case of pulmonary infection caused by a rare Nocardia species, Nocardia beijingensis, in a 50-year-old woman who had received alemtuzumab for the treatment of her multiple sclerosis. The invasive pulmonary infection was successfully treated with meropenem.

Penkert et al. Fulminant Central Nervous System Nocardiosis in a Patient Treated With Alemtuzumab for Relapsing-Remitting Multiple Sclerosis. JAMA Neurol. 2016 Jun 1;73(6):757-9.

#ClinicSpeak & #Neurospeak: low platelets with alemtuzumab

Not all low platelet counts post-alemtuzumab are due to ITP. #ClinicSpeak #NeuroSpeak #MSBlog

I received a query from a colleague a few months ago about a low platelet count in one their patients treated with alemtuzumab. The low platelet count was in the first week, it was transient and was not due to ITP. We became aware of this a few years ago and dropped Professor Coles an email about the observation. He sent us this picture from his thesis (below) and reassured us that the low platelet count will be transient and it was. The explanation he provided is that platelets stick to blood vessels due to adhesion molecule expression secondary to the cytokine release that occurs with alemtuzumab. In his experience, and our experience, this is nothing to worry about. I hope this helps. 



Background: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported.


Objective: We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab.

Results and conclusion: In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

CoI: multiple

Imaging hot microglia.

Datta G, Colasanti A, Kalk N, Owen DR, Scott G, Rabiner EI, Gunn R, Lingford-Hughes A, Malik O, Ciccarelli O, Nicholas R, Nie L, Battaglini M, De Stefano N, Matthews P.
[11C]PBR28 or [18F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis.J Nucl Med. 2017. pii: jnumed.116.187161. doi: 10.2967/jnumed.116.187161. [Epub ahead of print]
Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). 
Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands (11C-PBR28 or 18F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). 
Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. 
Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. 

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain.

TSPO has been proposed to interact with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. It has been suggested to be a marker of microglial activation. 

In this study they reported more activity in MS and found lesions in relapsing and SPMS and the lesions were more active in relapsing rather than SPMS, but still there are active lesions. So as we have been saying, RRMS and SPMS are not distinct. 

However, it gives an indication of the presence of hot microglia, it  seems increasingly evident that there is a broader activity than just microglia so we have to interpret the data more cautiously

#GuestPost & #NeuroSpeak: Neuro-Compass

How useful is Neuro-Compass as a tool to help manage MS? #GuestPost #Neurospeak

The following is a guest post from Professor David Bates explaining the aims of Neuro-Compass. This is a follow-up post on yesterdays guest post from Dr Overell on the DMT Toolbox. 

Professor Bates has agreed to answer questions on the post for the next 7 days; so please keep him busy (very busy).


CoI: multiple, Neuro-Compass is sponsored by an unrestricted grant from Biogen

Tuesday, 21 March 2017

#DigestingScience at Great Ormond Street hospital

On Saturday we were at Great Ormond Street to take part in their educational day for families affected by demyelinating conditions.

Although the Digesting Science activities were originally designed to teach children aged 6 - 12 about their parents MS, they can also teach children about their own condition. The morning was really inspiring and we met some amazing young people with a good turn out of under-13's and teenagers.


There were lots of questions about genetics, treatments and simple things like how to manage fatigue. One teenager had a brilliant outlook on life. He was experimenting with different ways to manage his fatigue so he could still go to the gym with friends and work out, without completely wearing himself out.


Mouse Dr took over the treatment activity with Dr Sara Simeoni from UCLH on walking. 


If your interested in coming along to a Digesting Science event, the next London date is Saturday the 13th May in Whitechapel which you can book onto via eventbrite: https://www.eventbrite.co.uk/e/digesting-science-tickets-27674603484

If your not based around London, we've been supporting teams to run Digesting Science events for their families in Dorset, Gosport and Norwich with three events for young carers happening over the next two months across Surrey. There's a kit going Wales with the MS Society and some of the activities have been used in Sheffield with the MS Research team there. If you would like to run an event in your area - please get in touch!

#GuestPost & #NeuroSpeak: Dr James Overell describes the DMT toolbox

New digital tools for MS clinical practice available on Neuro-Compass. #GuestPost #Neurospeak

I hope you are enjoying our flurry of guest posts? We are deliberately trying to increase the number; we know that you are bored of hearing the same-old stuff from us over-and-over again. 

A few week's ago I was introduced to Neuro-Compass a web-portal for HCPs working in the MS space. I was particularly impressed with the DMT Toolbox to help decision-making around DMTs in clinical practice. I have always wanted to create a tool like this for pwMS, but have not had the time. James Overell a colleague of mine, who works in Glasgow, led on the development of this particular feature of the portal. When I saw him at the UK MS Debating Society meeting a few weeks ago I extracted a guest post out of him for the blog. 

James produced, or his team at Neuro-Compass, produced a fully formatted post with pictures, etc. in the form of a word document. To save time I have embedded the post as a PDF. If I had to reformat this using HTML, on blogger, it would have taken at least 30 minutes and probably longer. If you don't mind reading guest posts as embedded documents we could use this format more often and increase the number of posts. I have also asked Professor David Bates, the chairman of the Neuro-Compass site to do a guest post as well to explain the aim of the site. 

Please let us know what you think of the portal? Dr Overell has agreed to answer questions on the post for the next 7 days; so please keep him busy. 



CoI: multiple

Don't write off a write-off: a reassessment of Teriflunomide

Mult Scler. 2017 Mar 1:1352458517695468. doi: 10.1177/1352458517695468. [Epub ahead of print]

The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies.

Freedman MS, Wolinsky JS, Comi G, Kappos L, Olsson TP, Miller AE, Thangavelu K, Benamor M, Truffinet P, O'Connor PW; TEMSO and TOWER Study Groups.

Abstract

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Figure:   (a) ARR by prior treatment; (b) Disability worsening by prior treatment. Teriflunomide shows a trend towards improvement, including those who have received prior DMT, but the effect is not statistically significant.

Teriflunomide (Aubagio), a first-line oral MS therapy has an Achilles heel, and that is its side-effects; particularly irksome are liver problems (requiring frequent blood tests), diarrhoea, and hair thinning/loss. They occur often enough that they overshadow it's selling point as an alternative to dimethyl fumerate (Tecfidera), which has the PML risk. Teriflunomide blocks rapidly dividing cells and this includes activated T cells by inhibiting pyrimidine (building blocks of genes) synthesis.

Here the TEMSO and TOWER study groups (these were the two of the clinical trials performed prior to licensing of teriflunomide) reanalyse the pooled data by dividing those into ones who received disease-modifying therapies (DMT) before and those who had not, i.e. DMT naïve. Most included in the analysis were DMT naïve with ~30% having used one or more DMT (so this is a 2:1 analysis so to speak). The most frequently used other DMT was interferon beta (IFNβ). Overall, there is a numerical reduction in relapse rate and risk of disability progression with teriflunomide 14mg compared to all the subgroups analysed (see Figure above). The differences, however, are not significant and should be born in mind. The authors point out that this may be due to the small size of the groups analysed but I feel the numbers were sufficient even if it's a post-hoc analysis. Interestingly, they also noted that those who had prior DMTs also had greater MRI activity with more enhancing lesions and relapse rates compared to the treatment-naïve group, which is concerning (those who participated had to be off their DMTs for 3-6 months prior to inclusion) and implies rebound after coming off treatment. The latter is a practical lesson to learn for clinicians swapping treatments.

Overall, despite the less than impressive data, teriflunomide in my books will remain a first-line contender by simply not following the paths trodden by others. It does not pretend to achieve the excellence of the second generation DMTs, nor does it imitate those who are most excellent, and as such, will remain a prudent man's/woman's choice.

Monday, 20 March 2017

What Did the B Cell Video Miss?

Many Years (1994) Ago, 
I made an (immortalised) B cell Line. 
Here are the Pictures (low power on left).  
On cell surface (on the right) there are little blobs. 
What were they?
They were Budding Virus Particles

So Maybe the New B cell Video
didn't miss a trick. 
Here's the B cell containing Little blobs too.
They get infected with Virus in Humans, notably in MS


A Black Swan Idea


Anti-CD20 kills Immature to Memory Cells, 
Alemtuzumab (anti-CD52) really kills the memory B cells
           
Maybe B cell Depletion Kills the Virus

Maybe that is why they work?

Maybe Not a T cell Issue...Food For Thought

#NeuroSpeak: blast from the past cladribine MOA

Telling complicated stories through slick Pharma-funded movies. #NeuroSpeak #MSBlog

Whilst we on the topic of critiquing slick videos on the modes of action of DMTs it may be a good idea to review the oral cladribine MOA video from 6 years ago; yes, it has been 6 years since oral cladribine was launched in Australia. 

The oral cladribine video is much longer than the Roche-funded anti-CD20 video you may have seen this weekend. Cladribine is a smart drug that uses very clever biochemistry to target T and B cells. Does the video do the job of communicating this or do we need to something simpler?


CoI: multiple and this video was funded by Merck

Predicting MS Activity

Håkansson I, Tisell A, Cassel P, Blennow K, Zetterberg H, Lundberg P, Dahle C, Vrethem M, Ernerudh J.Eur J Neurol. 2017 . doi: 10.1111/ene.13274. [Epub ahead of print]

BACKGROUND AND PURPOSE:

Improved biomarkers are needed to facilitate clinical decision-making and as surrogate endpoints in clinical trials in multiple sclerosis (MS). We assessed whether neurodegenerative and neuroinflammatory markers in cerebrospinal fluid (CSF) at initial sampling could predict disease activity during 2 years of follow-up in patients with clinically isolated syndrome (CIS) and relapsing-remitting MS.

METHODS:

Using multiplex bead array and enzyme-linked immunosorbent assay, CXCL1, CXCL8, CXCL10, CXCL13, CCL20, CCL22, neurofilament light chain (NFL), neurofilament heavy chain, glial fibrillary acidic protein, chitinase-3-like-1, matrix metalloproteinase-9 and osteopontin were analysed in CSF from 41 patients with CIS or relapsing-remitting MS and 22 healthy controls. Disease activity (relapses, magnetic resonance imaging activity or disability worsening) in patients was recorded during 2 years of follow-up in this prospective longitudinal cohort study.

RESULTS:

In a logistic regression analysis model, NFL in CSF at baseline emerged as the best predictive marker, correctly classifying 93% of patients who showed evidence of disease activity during 2 years of follow-up and 67% of patients who did not, with an overall proportion of 85% (33 of 39 patients) correctly classified. Combining NFL with either neurofilament heavy chain or osteopontin resulted in 87% overall correctly classified patients, whereas combining NFL with a chemokine did not improve results.

CONCLUSIONS:

This study demonstrates the potential prognostic value of NFL in baseline CSF in CIS and relapsing-remitting MS and supports its use as a predictive biomarker of disease activity.

Neurofilaments in spinal fluid is a reasonable predictor of disease activity. We have said this many times

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.

Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.Paroni M, Maltese V, De Simone M, Ranzani V, Larghi P, Fenoglio C, Pietroboni AM, De Riz MA, Crosti MC, Maglie S, Moro M, Caprioli F, Rossi R, Rossetti G, Galimberti D, Pagani M, Scarpini E, Abrignani S, Geginat J. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.
J Allergy Clin Immunol. 2017. pii: S0091-6749(17)30043-X. doi: 10.1016/j.jaci.2016.11.045. [Epub ahead of print]

BACKGROUND:Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated.
OBJECTIVE:We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS.
METHODS:We analyzed CD4+ helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS.
RESULTS: TH1/TH17 central memory (TH1/TH17CM) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. TH1/TH17CM cells were closely related to conventional TH17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing TH1 and TH1/TH17 subsets. However, while TH1 cells responded consistently to viruses, TH1/TH17CM cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive TH1/TH17CM cells but also blocked virus-specific TH1 cells.
CONCLUSIONS: We propose that autoreactive TH1/TH17CM cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas TH1 cells perform immune surveillance. Thus the selective targeting of TH1/TH17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis


We have been tooing and frowing between T cells and B cells and this swings back to T cells

Sunday, 19 March 2017

Viral Infections can be a problem

Clerico M, De Mercanti S, Artusi CA, Durelli L, Naismith RT. Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab. Mult Scler. 2017 Feb 1:1352458516688350. doi: 10.1177/1352458516688350. [Epub ahead of print]
Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.

So there you are warned. CMV is a common virus in humans and is a problem if you are immunosuppressed. It appears it can be a problem in mice too

Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice.Milovanovic J, Popovic B, Milovanovic M, Kvestak D, Arsenijevic A, Stojanovic B, Tanaskovic I, Krmpotic A, Arsenijevic N, Jonjic S, Lukic ML.Front Immunol. 2017;8:192. doi: 10.3389/fimmu.2017.00192.

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35-55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35-55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35-55.

How times change when I first started with EAE, we had the SJL and the PL mouse and BALB/c and notably C57BL/6 were classed as the most genetically resistant mouse strains on the planet. 

This is becuase people were using myelin basic protein or proteolipid protein to induce EAE. We first showed that myelinoligodendrocyte glycoprotein (MOG) in mice.

Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D. Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice.J Immunol. 1994;153:4349-56.

Then it was shown shortly after that C57BL/6 mice could get MOG induced EAE, using the MOG35-55 that we showed induced disease in ABH (H-2g7= Kd, Ag7, E-, Dq transplantation antigen type that determines which peptides they respond to) mice.
This opened up the use of knockout mice which were typically made on the C57BL/6 (H-2b) or 129 (H-2b) mouse background.

We showed also that the MOG35-55 peptide commonly used may not have been the best peptide in C57BL/6 (H-2Ab) mice
Delarasse C, Smith P, Baker D, Amor S.Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunology. 2013;140(4):456-64. doi: 10.1111/imm.12155.

This was repeated a year later, by a group from West Coast USA that forgot not to acknowledge the existence of the early discovery (Bad Science)-
 I'm not bitter:-)

This is great and bad because C57BL/6 is still a weak susceptibility background and shows gene related differences that disappear as unimportant once you do the same experiment in a high susceptibility strain

Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis.
Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, Selwood DL, Giovannoni G, Baker D.PLoS One. 2013 Oct 9;8(10):e76907. 

We also showed that BALB/c mice were other low susceptiblity strain can be induced to develop disease.

Croxford JL, O'Neill JK, Baker D.Polygenic control of experimental allergic encephalomyelitis in Biozzi ABH and BALB/c mice.J Neuroimmunol. 1997;74(1-2):205-11

So in this study they find that infection of BALB/c (H-2d) mice with CMV makes them susceptible to EAE with MOG35-55.
They get alot of CD8 to respond ,so that will be by Kd or Dd molecule by which they are restricted, and it is interesting in ABH mice (Kd, dq) get disease and we have noticed more CD8 cells in the CNS when mice are immunised with this peptide. 

It also induced monophasic chronic disease that becomes progressive from first attack in ABH and C57BL/6 mice whereas MOG8-22 (residues 8-22 in the MOG molecule) get relapsing disease. So saying that genetics does not necessarily dictate disease course.

It also says that viral infection can influence susceptibility, which is known too and this was how PL/J were found to EAE susceptible after infection with mouse hepatitis virus.

Cross AH, McCarron R, McFarlin DE, Raine CS.Adoptively transferred acute and chronic relapsing autoimmune encephalomyelitis in the PL/J mouse and observations on altered pathology by intercurrent virus infection. Lab Invest. 1987; 57:499-512.