Saturday, 29 April 2017

The Young Ones: Bringing Digesting Science to young carers

#DigestingScience #Youngcarers #MS #multiplesclerosis

Digesting Science is an event where 6-12 year olds engage in fun activities, to learn more about MS. It’s aimed at children who have a parent (or parents, or carers) with MS. Over half a day, families complete games and challenges to learn more about the risk factors, symptoms, treatments and science behind the condition. The activities were created by designer Alison Thomson and the Barts MS team. It was made into a kit and the event format was developed with the expert help of mum, drama teacher and MSer Harriet Smith. The kits have since travelled the country and are soon to travel the globe!

Thus far, events have been put on by a local MS charity branch or part of a health service team (MS nurses or other health workers). But excitingly, we have recently started to work with young carers charities.

It’s hard to get an accurate figure of how many young carers there are in the UK. Carers Trust say they “know there are 170,000 young carers in England and Wales” but that a BBC estimate (done seven years ago in 2010) put the number at 700,000. How many of these care for a parent with MS? We don’t know. But after being approached by a young carers charity in Surrey to do an event, we sent an email to young carers charities nationwide, through the Children’s Society’s Include project. The response has been really positive already, and our first Digesting Science events for young carers have been taking place across Surrey.

It’s exciting because it’s a new direction for the project, but also because we feel we have found a way to help families who are perhaps not accessing as much support as they need from their health service.

If you're interested in have a Digesting Science event in your area then please contact and we can support you all the way! We are on Twitter (@DigestingSci), Facebook (including a closed group called Digesting Science Families), and will shortly be launching a newsletter, that you can subscribe to, with Plain English research news, tips and information relevant to families affected by MS and those who support them.


Mosquitos leads us to more evidence for the memory B cells at centre stage for the causal pathway to MS.

In the week that began with a bit of Fake News about the cause of MS, and it ends with something that is perhaps related to the cause, 

but two "Cause" stories in a Week are not going to make it in the News. 

Why do I say cause, because this is Genetics and this is the predisposition of Risk.

So what have B cells got to do with Mosquitos?
Read on

Overexpression of the Cytokine BAFF and Autoimmunity Risk.
Steri M et al.N Engl J Med. 2017;376(17):1615-1626.

BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.
METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.
RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.

CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. 

Although MS is usually less common the further south you go in the Northern Hemisphere, Sardinia in Italy is unusual. 

It has an unusually high incidence of multiple sclerosis and also autoimmune diabetes is common. The Sardinians have some genes in their MS that are more associated with arthritis/diabetes, but this new study identifies a susceptibility gene. It tells us B cells are likely to be involved because the gene is B cell activating factor (CLICK). BAFF). This gene is also found in people with Lupus (SLE) an antibody mediated autoimmune disease that be controlled by CD20-B cell (rituximab) depletion

The genetic variant in MS was associated with increased BAFF levels, this will support growth of mature B cells and plasma cells making antibodies. Is this the issue?

They showed the BAFF-var dramatically augmented levels of soluble BAFF, which we know are elevated in MS
                                            Kannel et al. 2015

They showed that BAFF-var dominated the association with circulating B cells levles (B-cell counts, P=4.23×10−12; B-cell percentage with respect to lymphocytes, P=9.36×10−23) 

Furthermore to refine the target-cell type, they carried out deeper profiling of six B-cell subtypes. Rather than any particular subtype explaining the overall B-cell association, several subtypes were affected, with CD24+CD27+ (comprising unswitched and switched memory) B cells being most strongly associated.

They then showed that the presence of the gene variant was positively selected in the Sardinian population meaning that there was some advantage in having the gene.
BAFF over expression can protect mice from lethality due to malaria infection and malaria was present in Sardinia until the 1950s so BAFF may confer protection against Malaria, hence the mosquito

We can see how protection against Malaria can select genetics. This is the Sickle cell issue. If you have no DNA copies of the sickle cell gene. You are at risk from malaria and this kills millions of African Children each year. If you have two copies of the sickle cell gene you get sickle cell anemia and this can kill the children, but if you are heterozygous then it give you some protection.

The genetic variant was common in Sardinia (26.5%) but in the UK 1.8% in the United Kingdom and Sweden), so it may not a reason why people in UK get MS, however, perhaps if we look genetic pathways leading to memory cell formation other genese may do the same thing.

Our immune genes variants are there to protect us from infection, and it is likely that the MS genes are perfectly normal variants that we use to fight infection. These would keep us alive until we can have babies. If we have certain combinations of these normal genes they may make such a good immune response that in a small percentage of people they may attack their one body.

This would be acceptable from the view of maintaining the human race, just like the human species would tolerate the sickle cell mutation, and so the genes that lead to MS would not be selected against particularly because most people historically would have had their children before MS strikes. So these genes remain.

Now the question we all want to know is does this cause lead to a cure and the quick answer is No definitely not and in fact the opposite is the case. 

Importantly we should definitely not listen to the authors of this paper who have not done their reading.

They say "we infer that the increased risk of multiple sclerosis and SLE associated with BAFF over-expression mainly involves humoral immunity, consistent with the efficacy of B-cell–depleting therapies"

However, the B cell depleting therapies are not antibody depleting therapies and blockade of BAFF is an antibody-depleting therapy and it did nothing or made MS worse.

Then they say:

"A pertinent one, to be assessed in further studies, would be that patients stratified according to BAFF-var status might show a differential benefit from anti-BAFF therapies. One might also anticipate that patients carrying BAFF-var would have a weaker response to B-cell–depleting therapies owing to a faster resurgence of memory B cells"


The first mistake here is to assume that the influence of the gene is relevant after disease onset (it is a risk factor!). It is much more likely to influence disease before it develops to increase risk. It would make mature cells develop is a certain way and these down the line could become memory B cells.

The second mistake is to assume that anti-BAFF is protective it may not be. BAFF can also have an inhibitory role in the development of B differentiation and block BAFF and the number of memory cells can increase and MS can worse.

However, memory B cells may not respond well to blockade of BAFF and it may actually increase MS. We have seen this with atacicept, which blocks BAFF and APRIL B cell growth factors.

It is now very clear that we as a community really need to see the data that Ely Lilly is holding.

They have done a trial of blocking only BAFF with tabalumab. This has not been developed for SLE, and thus is unlikely to be used in MS, but Belimumab is available for SLE and somebody unaware of the tabalumab trial could try it with disastrous consequences. Maybe it was the APRIL that was the problem 

Did the tabalumab do nothing or did it make MS worse?

Please Read the link below

Therefore blockade of BAFF is perhaps the last thing you want to do without some thought. Maybe we should do the opposite.

Although not realized by the authors, in conclusion we have yet more evidence for the memory B cells as a pivotal cells in the MS pathway: genetics, aetiology infection, pathology and - importantly - response to therapy.... the evidence mounts!

Are there other genes involved in the cause?

Of course there are, over 150 have been implicated and there are a few hundred more to find, so more millions down the science plug-hole:-). Each of these caries a very small increase in the risk of MS. No genetic variant is absolutely necessary. The main region is the major histocompatibility complex (MHC), which controls what you recognize as an invader/infection. Number 2 gene was the interleukin 7 receptor, which has been confirmed in another study.

Liu H, Huang J, Dou M, Liu Y, Xiao B, Liu X, Huang Z.
Variants in the IL7RA gene confer susceptibility to multiple sclerosis in Caucasians: evidence based on 9734 cases and 10436 controls. Sci Rep. 2017;7(1):1207. doi: 10.1038/s41598-017-01345-8.
Recently, numerous genome wide association studies (GWAS) and other case-control association studies examining the relationship between interleukin-7 receptor α chain (IL7RA) gene rs3194051, rs987107, rs11567686, and rs11567685 variants and multiple sclerosis (MS) risk have been conducted, but the conclusions have been inconsistent. The main objective of this meta-analysis was to more precisely explore the association of these four IL7RA variants with MS development. Twenty-seven eligible studies involving 9734 cases and 10436 controls were included in the present meta-analysis. Power calculation, publication bias, sensitivity analysis and cumulative meta-analysis were performed to derive a reliable conclusion. Our study indicated three IL7RA loci were significantly associated with increasing MS risk (rs3194051: recessive model: OR = 1.22, 95% CI 1.08-1.38; rs987107: recessive model: OR = 1.44, 95% CI 1.22-1.69; and rs11567686: dominant model: OR = 1.18, 95% CI 1.01-1.37). Additionally, IL7RA rs11567685 variants might not be related to MS development. In all, IL7RA locus polymorphisms could play an important role in the predisposition to MS, which could contribute to a better understanding the pathogenesis of multiple sclerosis.

MS is now a Kidney Disease :-)

Zhou X, Packialakshmi B, Xiao Y, Nurmukhambetova S, Lees JR. Progression of experimental autoimmune encephalomyelitis is associated with up-regulation of major sodium transporters in the mouse kidney cortex under a normal salt diet.Cell Immunol. 2017 Apr 18. pii: S0008-8749(17)30062-X. 

Recent demonstrations of exacerbation of experimental autoimmune encephalomyelitis (EAE) by high salt diets prompted us to study whether EAE stimulated Na absorption by the renal cortex, a primary regulatory site for Na balance, even under a normal NaCl diet. We found that as EAE progressed from mild to severe symptoms, there were parallel increases in the protein abundance of NHE3 and αENaC and the Na,K-ATPase activity with an affiliated elevation of its β1-subunit protein. These effects are associated with increases in the protein levels of the well-known regulators SGK1 and scaffold NHERF2, and phosphorylation of ERK1/2. These effects of EAE could not be explained by reduction in water or food intake. We conclude that EAE progression is associated with up-regulation of major Na transporters, which is most likely driven by increased expression of SGK1 and NHERF2 and activation of ERK1/2. These data suggest that EAE progression increases Na absorption by the renal cortex.
We have heard how some people think that salt (sodium chloride) is a driver of autoimmunity and so as the saga carries on people are now looking at sodium balance and in this study and shows that the kidneys can influence salt balance. I don't have time to explain this one but it shows were ideas can get you. Is disease activity related to kidney function?

Friday, 28 April 2017

#ThinkSpeak & #ClinicSpeak: blog links

Can you please let us know which web links you want us to support? #ThinkSpeak #ClinicSpeak

During the AAN a neurologist from the US came up to me and thanked me for our blog and said that it had become his go to resource for information and that he used our landing page for all other MS resources. He specifically asked me to put back our PML infographic and other web links. Do others feel this way? If yes, which other web resources should we support and are there any other MS-related resources out there that you would recommend we link to? Please note we don't want the list to be overly long and nor do we want to support sites that are commercial. 

Cause of multiple sclerosis

As all is quiet on the MS News and twitter front, so I will not rush a post out today.

You can have it tomorrow.

However, whilst MS awareness week started with a media-bang of the “Discovery of the cause of MS”, science emerged yesterday of something that actually contributes to the cause of MS, but has gone largely un-noticed by the media so far. 

Two stories on the cause of MS in a week…unlikely. 

This points the finger at our subject of the week…Yep the B cell.

The first turned out to be a bit of Fake News and the results reported was information that turned out to be a consequence. What had been found helps us understand damage a better but does not get us to a cause.

However, yesterday science news emerged which does speak to the cause of MS. This cause is suggested to be because of a………….

I’ll explain tomorrow. Does it lead us to the cure?....Far from it.

AAN2017. B cells and Disease Activity

348  Relationship between MRI Lesion Count and B Cell Count Reduction under Ofatumumab Treatment  M. Savelieva (Novartis Pharma AG, Basel, Switzerland), J. Kahn (Novartis Pharma AG, Basel, Switzerland), E. Wallstroem (Novartis Pharma AG, Basel, Switzerland), D. Leppert (Novartis Pharma AG, Basel, Switzerland). 

Objective: To characterize the relationship of B cell depletion with gadolinium enhanced (Gd+ ) magnetic resonance imaging lesion counts under ofatumumab treatment. 
Background: Ofatumumab is a fully human anti-CD20 monoclonal antibody that depletes circulating peripheral B cells and has shown significant efficacy in multiple sclerosis (MS) patients in Phase 2 studies. The efficacy of anti-CD20 therapy, including the reduction of lesion formation, is hypothesized to be directly related to the extent of peripheral B cell depletion. However, ofatumumab is the first anti-CD20 antibody where this hypothesis has been tested in a full-scale dose finding study (MIRROR). 
Design/Methods: In the Phase 2 MIRROR study, a total of 231 relapsing-remitting MS (RRMS) patients were randomized (2:1:1:1:2) to placebo or ofatumumab 3, 30, 60 mg for every 12 weeks, or 60 mg every 4 weeks. Patients received treatment for 24 weeks and were followed up for an additional 24 weeks. B cell counts and Gd+ lesion counts were assessed at screening and every 4 weeks until the end of the study. A quasi-Poisson regression model was developed relating new Gd+ lesion counts to the average B cell levels at weeks 4 to 20, the number of lesions at baseline, and the treatment group. 
Results: The model showed that depletion of B cell counts is significantly associated with superior control of Gd+ lesions. Efficacy of any ofatumumab treatment regimen in controlling Gd+ lesions was explained solely by the extent of B cell depletion caused by the different dosing regimen. 
Conclusions: The model indicated that low B cell counts over time, achieved and consistently maintained under ofatumumab treatment, are essential for efficacious control of lesion counts.
Recently we proposed that memory B cell numbers are important indicators of whether treatments work. If this is the case on may hope that their numbers correlate with disease activity. In this study they look at efficacy and B cell numbers and conclude that there is a link between efficacy and CD19 B cell depletion. People with lower B cell levels had less accumulation of  MRI lesions. Those below 8 CD19 B cells per microlitre of blood did the best. This would equate to about 2-4 memory B cells. It would have been nice to see that memory T cell levels didn't have any influence However this suggests that we may be on the right track 

Dimethyl fumarate is it CD8 T cells?

We have made a suggestion that most if not all MS drugs work by targeting a memory B cell subset. So we should attempt to disprove this, which is the science method. 

The paper today says Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS.

Therefore is the idea disproved already. When we came up with the B cell idea it was based at looking at highest-efficacy drugs. Dimethyl fumarate was not as clear cut, but its efficacy on relapse rate is reported to be less than some of the more effective agents.

The CD4 hypothesis of MS has been challenged by the fact that depletion of CD4 T cells with CD4-specific antibody, did not inhibit MS yet depleted CD4 T cells by 70%, so people switched their attention to CD8 T cells that are more common in MS lesions.

So what would the effect of depleting CD8 T cells, be? 
Does it inhibit? Do nothing? Or make MS worse?

Alemtuzumab depletes CD8 very well, for at least for 6-12 months, but ocrelizumab is not that good at depleting CD8 T cells so they can't work in the same way, can they?

In the latest report the suggestion is Dimethyl fumarate (DMF) depletes CD8 T cells and their level of depletion controls MS. Their contribution has not been investigated before....really?

Fleischer V, Friedrich M, Rezk A, Bühler U, Witsch E, Uphaus T, Bittner S, Groppa S, Tackenberg B, Bar-Or A, Zipp F, Luessi F.
Treatment response to dimethyl fumarate is characterized by disproportionate CD8+ T cell reduction in MS. Mult Scler. 2017 Apr 1:1352458517703799. doi: 10.1177/1352458517703799. [Epub ahead of print]

BACKGROUND: The effect of dimethyl fumarate (DMF) on circulating lymphocyte subsets and their contribution as predictors of clinical efficacy have not yet been investigated in multiple sclerosis (MS).
OBJECTIVE: To evaluate lymphocytes and lymphocyte subsets (analyzed 6 months after DMF start) in MS patients with and without disease activity after 1 year of treatment in a retrospective study.
METHODS: Peripheral blood lymphocyte subsets were analyzed by flow cytometry. Untreated MS patients ( n = 40) were compared to those 6 months after onset of DMF treatment ( n = 51). Clinical and magnetic resonance imaging (MRI) disease activity of DMF-treated patients were assessed in the first year under treatment.
RESULTS: Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment. Furthermore, an increased CD4/CD8 ratio ( p < 0.025) in stable patients indicated a disproportionate reduction of CD8+ T cells relative to CD4+ T cells. Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year.
CONCLUSION: DMF treatment response is reflected by lower circulating lymphocytes and specific lymphocyte subsets. Changes in the cellular immune profiles under DMF treatment are clinically relevant and might serve as a surrogate marker of treatment response.

It was published on April the first, so is this a joke?

Well nope, the same group said the same thing in March that DMF kills CD8 T cells.

Ghadiri M, Rezk A, Li R, Evans A, Luessi F, Zipp F, Giacomini PS, Antel J, Bar-Or A. Neurol Neuroimmunol Neuroinflamm. 2017 Mar 23;4(3):e340.Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis.

or  yes, it preferentially kills CD8 T cells

Khatri BO, Garland J, Berger J, Kramer J, Sershon L, Olapo T, Sesing J, Dukic M, Rehn E. The effect of dimethyl fumarate (Tecfidera™) on lymphocyte counts: A potential contributor to progressive multifocal leukoencephalopathy risk. Mult Scler Relat Disord. 2015; 4(4):377-9.

yes it really does kills CD8 T cells very well

Spencer CM, Crabtree-Hartman EC, Lehmann-Horn K, Cree BA, Zamvil SS.Reduction of CD8(+) T lymphocytes in multiple sclerosis patients treated with dimethyl fumarate.mNeurol Neuroimmunol Neuroinflamm. 2015 ;2(3):e76.

So now it is all CD8's. 

Are you confused?  I am . If you work in the one lab you really must be confused, CD8 one month and in the same month we are back to good old CD4 Th17 as the culprit:-).

Bühler U, Fleischer V, Luessi F, Rezk A, Belikan P, Graetz C, Gollan R, Wolf C, Lutz J, Bar-Or A, Siffrin V, Zipp F. Role of IL-17-producing lymphocytes in severity of multiple sclerosis upon natalizumab treatment.Mult Scler. 2017 Apr;23(567-576

OBJECTIVE: Natalizumab is known to prevent T-helper cells entering the central nervous system (CNS). We hypothesize that more pathogenic T-helper cells are present outside the CNS and a possible relationship to disease severity.
METHODS: Characterization and enrichment of human CD4+IL-17+ cells were performed ex vivo using peripheral blood mononuclear cells from natalizumab-treated relapsing-remitting multiple sclerosis (RRMS) patients ( n = 33), untreated RRMS patients ( n = 13), and healthy controls ( n = 33). Magnetic resonance imaging (MRI) scans were performed routinely for patients.
RESULTS: Lymphocytes were elevated in peripheral blood of natalizumab-treated patients compared to untreated patients and healthy controls. Whereas group comparison for CD4+IL-17+ numbers also differed, CD4+IFN-γ+ and CD4+IL-22+ counts were not increased. CD4+IL-17+ cells not only expressed but also secreted IL-17. In natalizumab-treated patients, IL-17+ cell frequency was found to correlate with T1-hypointense lesions, but was not an indicator for rebound activity after treatment discontinuation, except in one patient who experienced a fulminant rebound, and interestingly, in whom the highest IL-17+ cell levels were observed.
CONCLUSION: Increased lymphocytes and CD4+IL-17+ cells in the blood of RRMS patients receiving natalizumab corroborate the drug's mechanism of action, that is, blocking transmigration to CNS. Correlation between IL-17-expressing lymphocytes and T1-hypointense lesions underlines the important role of these cells in the disease pathology.

So is this a case of the Emporers New Clothes. We are so busy maintaining the Th17 mantra that no one dares say anything and if we are only looking for Th17, is it surprising we only see Th17 cells? What else changed in the rebounders to link to disease.

"The Emperor's New Clothes" is a short tale written by Danish author Hans Christian Andersen, about two weavers (immunologists) who promise the emperor (Science guru) a new suit of clothes (new mechanism of disease) that they say is invisible (yep invisible... after all cells are microscopic).to those who are unfit for their positions, stupid, or incompetent. When the Emperor parades before his subjects (scientists) in his new clothes, no one dares to say that they don't see any suit of clothes on him for fear that they will be seen as "unfit for their positions, stupid, or incompetent". Finally, a child (me) cries out, "But he isn't wearing anything at all!" (It ain't CD4 T cells)

But now back to the story

Ghadiri et al. 2017 says. Within the CD3+ T-cell population, CD8+ counts decreased from an average of 0.47 × 10*9 cells/L pretreatment to 0.11 × 10*9 cells/L at 12 months, representing a 77% decrease (p = 0.0498), whereas CD4+ counts decreased by only 44%, from 1.02 to 0.57 × 10*9 cells/L (p = 0.0028).

Looking at the P value p=0.0498 just about P<0.5 then there must be massive variation going on. Is this why efficacy of DMF is variable, but I digress. 

However, the first study suggests that DMF acts by depleting CD8 T cells. It would say that cladribine is not a very good immune modulator and ocrelizumab would not be a very good immune modulator if there was a common mechanism of action between the three drugs. However, the latter have equal or better efficacy to DMF and so the argument falls apart. So they have different mechanisms.

So if you have less CD8 are you going to be less good at getting rid of viruses, like JC virus, and EBV? So is the idea of getting rid of this virus flawed? If MS was caused by a virus kept in check by the CD8 T cells then surely DMF should make MS worse. 

Is doesn't, so does that say the accumulation of CD8 cells in the CNS is not because there is a virus in there but because the CD8 T cells are autoimmune. It also suggests that there isn't much CD8 T regulation in MS, as this would make MS worse too. 

In this study at the top they report that the level of control of MS, is associated with the level of CD8 depletion. For alemtuzumab, this is not reported to be the case,

Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J. Neurology. 2014 Jun 17;82(24):2158-64.

But is the elephant in the room in Fleischer et al. 2017 B cells. "Stable patients showed significantly lower lymphocytes, CD4+ and CD8+ T cells as well as CD19+ B cells compared to active patients under DMF treatment.


"Reduced lymphocytes, CD8+ T cells, and CD19+ B cells 6 months after DMF start allowed prediction of the treatment response in the first year,

In most reports such as with alemtuzumab above CD19 levels did not associate with disease activity, the question is do memory B cells correlate levels correlate with disease activity? 

Why were they not investigated too? Maybe an oppertunity missed?  Disease activity linking to memory CD8 T cells and not memory B cells could kill the hypothesis, but it isn't dead just yet. 

In fact the point of this post is to discuss

Poster 380. Interim Results of an Open-Label Study to Assess the Effects of Delayed-release Dimethyl Fumarate on Lymphocyte Subsets and Immunoglobulins in Patients with Relapsing-remitting Multiple Sclerosis Christian Von Hehn , Devangi Mehta, Claudia Prada, Lili Yang, Shifang Liu, Soma Ray, Sarah Sheikh 

Objective: Given the immunomodulatory properties of delayed-release dimethyl fumarate (DMF) and its observed effects on lymphocytes, further research evaluating these effects is needed. We are conducting this study to comprehensively characterize the effects of DMF on circulating lymphocyte subsets and immunoglobulin levels within the first year of treatment and beyond. 
Background: DMF is an approved oral disease-modifying therapy (DMT) to treat RRMS. DMF has putative immunomodulatory properties through activation of the Nrf2-dependent and NRF2-independent pathways. A mean ALC decrease by ~30% during the first year of treatment has been observed in pivotal trials and in realworld settings; however, a detailed and comprehensive analysis of the impact and time course of changes in circulating lymphocyte subsets has not been described. 
Design/Methods: In this ongoing, open-label, multicenter study, 218 patients aged 18-65 years with RRMS were enrolled and treated with DMF 240mg twice daily. Blood samples were taken at baseline, and at Weeks 4, 8, 12, 24, 36, and 48. Lymphocyte subset changes were monitored by flow cytometry using a comprehensive panel of surface markers and intracellular cytokines. 
Results: This interim analysis includes ~165 patients from 6 different countries with ≥6 months follow-up or who discontinued the study earlier. The overall safety results and the changes in ALC and detailed lymphocyte subset counts, including phenotypic characterization of CD4+ T-cell, CD8+ T-cell, B-cell, and natural killer cell subsets, based on a comprehensive panel of surface markers and intracellular cytokines will be presented. Conclusions: The results will provide insight into the effects of DMF on a comprehensive panel of immune cell subsets and their correlation with changes in ALC within the first 6 months of treatment initiation and may help to understand treatment-related changes in immune cell function. 
Study Supported by: Biogen 

On face value not one to get your juices going but when you see the poster ...Ace.  (You can see the poster by going to the AAN2017, click on the search abtracts. see comments how to find it) . This study looks at 163 people and tests to see what cells are depleted over 6 months of DMF. Yes we can indeed see that CD8 cells are depleted, but they have done an amazing panel of different cell types and TH17 are not that down,  so where do you look. I look at Memory B cells and they are depleted, and within the CD19 population they are the major subset affected, if only this study can link depletion to disease activity it could another major key in understanding of MS. 

It shows you all the problems of data interpretation of flow cytometry (How you make the Emporers clothes). If you look at the percentage changes you can see that the natural killer cells CD56 bright increased by daclizumab are up and T regs are up so here's an alternative mechansim for DMF, but when look at the absolute numbers there is no change....The numbers of the T regs appear to go up because other cells do down. Check it out I would bet on closer inspection of many papers, we will find this fudge and mis-interpretation of the result.

Thursday, 27 April 2017

AAN2017. B cells remain in the brain after rituximab treatment

341 Persistent B lymphocytes in multiple sclerosis plaques after rituximab treatment S. esfandi (University of Colorado), S. Salimian (U of Colorado School of Medicine), J. Corboy (U of Colorado School of Medicine), E. Alvarez (University of Colorado).

To describe the persistence of inflammation lymphocytic infiltrates in plaques from a postmortem case of aggressive multiple sclerosis (MS) after treatment with Rituximab.

Background: B-cells are believed to be strong autoimmune effector cells in the pathogenesis of MS. Rituximab depletes B-cells in the peripheral blood and is an effective treatment for MS. However, this effect may not extend to the CNS as effectively. Spinal fluid analysis from multiple studies has shown the persistent presence of B-cells after rituximab treatment, despite elimination from peripheral blood. 

Design/Methods: Case report. Results: 30 year old man with aggressive multiple sclerosis was diagnosed in 2010 and presented to University of Colorado in 10/2013 in a wheelchair. He was treated with Tysabri from 10/2013 until 8/2014. He was JCV+ and was then treated with 1 gram of rituximab in 9/29/14. He was showing gradual improvement and was beginning to ambulate with a walker (leg strength went from 2/5 to 4/5) when he died on 1 November15. He had received two additional 500mg doses with the last dose on 15 September. His peripheral CD19/20 counts stayed undetectable. His last MRI Brain on 3 July 2015 was stable. 

CNS autopsy verified severe multifocal brainstem and cerebral periventricular white matter plaque burden. Microscopically, several plaques manifested conspicuous perivascular lymphocytic cuffs, predominantly CD3+ T cells (mixed CD4/8) and macrophages, but individual CD20+ cells could still be identified within the parenchyma and perivascular cuffs. 

Conclusions: This case underscores the fact that lymphocytic inflammation in plaques, including B-cells, is not completely abrogated following treatment with Rituximab, even with undetectable peripheral CD20+ B cell counts.

It is clear in arthritis that some people with arthritis relapse despite depletion of B cells in the blood and this case shows that the same is the case in MS, however it also shows us that these systemically adminsitered agents do not effectively deplete cells from the brain. 

#ClinicSpeak & #AAN2017: cognition and MS

Is it not time to start measuring cognition in routine clinical practice? #ClinicSpeak #AAN2017

As promised to several people who have come up to me at the AAN; the following are my slides from the satellite symposium on MS and cognition. In my talk, and slides, I make a strong case for measuring cognition in routine clinical practice. If you don't measure and monitor it how can you address it in clinical practice? 

To help I have also asked Biogen to make available their iPad based Processing Speed Test (PST), which is a 2 minute version of the SDMT (single digit modality test), which is rapidly becoming the mainstay of cognitive testing in MS. This could be the game changer we need. 

One commentator made the point that if you measure cognition and its getting worse what can you do about it? Several things; firstly you can assess whether or not it is related to MS disease activity, which may require starting or switching therapy. Secondly, it may be related to some reversible factor, for example a concomitant medications that affects cognition, e.g. anti-cholinergics, or even a cognitive relapse. Thirdly, if you do detect worsening cognition you can also counsel patients and offer them help, for example cognitive rehabilitation. People with MS who have worsening cognition may factor in this information into certain life choices, for example, whether or not to register for a particular educational course or not to apply for a specific job. Some patients may use the knowledge to change their work and life status. 

I also made the point that why should we treat cognition differently to other MS outcomes, for example the EDSS and walking speed. PwMS know that they are physically deteriorating, why shouldn't they have the option of knowing that their cognition is deteriorating? To make the latter point an Italian colleague of mine sent me the following quotes:

'Omnia metire quaecumque licet et immensa ad mensuram tempestive redige' or 'measure what is measurable and render measurable what is not', which has been attributed to Galileo. The phrase is the motto of Franz Halberg, the father of modern Chronobiology and sounds very similar to Lord Kelvin’s: 'When you can measure what you are speaking about, and express it in numbers, you know something about it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind; it may be the beginning of knowledge, but you have scarcely, in your thoughts advanced to the stage of science'

CoI: multiple

#PoliticalSpeak & #BrainHealth: can we shame MEPs?

The European Parliament sucks! #PoliticalSpeak #BrainHealth #MSBlog

The following is the EMSP report from our recent meeting at the European Parliament. The meeting was hosted by Cristian Busoi, an MEP from Romania, who was the only, and I really mean the only, MEP to attend. No other MEPs bothered to attend despite them being aware of the meeting and having many constituents in their countries with the disease. I wish we could name and shame them.

The report: 

My presentation:

The peogramme:

Wednesday, 26 April 2017

AAN Targeting EBV with CD8 specific T cells

Symptomatic and Objective Clinical Improvement in Progressive Multiple Sclerosis Patients Treated with Autologous Epstein-Barr Virus-specific T Cell Therapy: Interim Results of a Phase I Trial

Michael Pender, MD, PhD; Peter Csurhes; Corey Smith; Nanette Douglas; Michelle Neller, PhD; Leone Beagley, PhD; Sweera Rehan, PhD; Tracey Hopkins, PhD; Kate Thompson, PhD; Stefan Blum, MD; Kerryn Green, MBBS; Zara Ioannides, MD; Alan Coulthard, PhD; Kaye Hooper, PhD; Scott Burrows, PhD; Rajiv Khanna, PhD

Objective: To determine the safety of treating progressive multiple sclerosis (MS) patients with autologous Epstein–Barr virus (EBV)-specific T cells. Background: Mounting evidence indicates a role for EBV in MS pathogenesis. EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T-cell immunity.
Design/Methods: In this trial we administer autologous EBV-specific T cells to patients with progressive MS (EDSS 5.0–8.0). Each patient receives their own T cells stimulated ex vivo to enhance reactivity to EBV nuclear antigen-1, latent membrane protein 1 (LMP1) and LMP2A, and is followed through 26 weeks. Four escalating dose infusions are administered biweekly.
Results: To date, four SPMS patients and one PPMS patient have been treated. No significant adverse events have been observed. Three patients experienced symptomatic and objective clinical improvement, which commenced 2–8 weeks after the first infusion and was most marked in the two patients receiving T cells with the highest EBV reactivity. Striking improvement occurred in one SPMS patient, with normalization of lower extremity tone and plantar (Babinski) responses for the first time in 16 years, increased walking distance with walker from 100 metres at baseline and for the previous 5 years to 1200 metres, marked reduction in fatigue, increased manual dexterity, and improvements in lower extremity power, reflexes and sensation. A second SPMS patient had reduced fatigue, increased productivity and improved balance. The third responder (PPMS) had improved colour vision, visual acuity and manual dexterity and reduced fatigue, lower extremity spasms and urinary urgency. These data are consistent with prior data from the first patient ever treated (SPMS compassionate use) who experienced reduced fatigue and lower extremity spasms, and improved cognition, hand function and productivity.
Conclusions: This is the first report of clinical improvement in a prospective trial of autologous EBV-specific T cells to treat progressive MS patients. Further studies are planned.

Study Supported By: Multiple Sclerosis Society of Queensland, Multiple Sclerosis Research Australia and Perpetual Trustee Company Limited

This isa safety study designed to test whether vaccination against EBV could impact on MS. They have made viral reactive CD8 T cells and transfer them in to kill the EBV infected (B) cells. This will be of interest, so maybe ProfG may have time to tweet or report on the presentation.

In the AAN press release it said the trial was designed to look at ten people and have found it should have been five with PPMS and five with SPMS. In the trial, the volunteers received four escalating doses of cytotoxic CD8 T cells over six weeks and were followed for an additional twenty weeks after the last dose. 

Here the abstract above it says five people were looked but in the press release from the AAN, it says six. These results are encouraging, but the study is seemingly unblinded and is reporting symptomatic improvements and this is not what a trial in progression may go for. But being a phase I it is designed to say it is safe. 

This study used autologous cells, so they were generated from the same people who they were later received the cells back after they were expanded. 

However, this data is now being reported as company data. It appears the company has got some rights from the University in Queensland. 

Anyway according to the company website. They are planning to use their product as allogenic cells, i.e. made in one person to be used in another person. Whilst this will help in production of a standardised cell this, without more data on the technology, makes little immunological sense as to get proper engagement of cells you need your antigen presenting cells to present to your own T cells.

An allogenic cell may not recognize the B cells infected with EBV in another person, but they can recognize a large percentage of other peoples major histocompatibility complexes (transplantation antigens) as a target, so you could be injecting cells that that can potential kill every cell in the recipient. I hope not. 

More likely the injected cells will last about 5 days and then the recipient will destroy them as being invaders.  

#NeuroSpeak & #ClinicSpeak: fingolimod rebound is a yellow-carder

Another thing for HCPs to lookout for: rebound post-fingolimod. #ClinicSpeak #NeuroSpeak 

An emerging and very important differentiator in the MS space is rebound activity that occurs when stopping a therapy. The MHRA have now made this a reportable, or yellow-card, event. It is good to see the regulators taking such a keen interest in such an important issue. Maybe they are begging to flex their muscles before the EMA departs after Brexit. 

MHRA: Multiple sclerosis therapies: signal of rebound effect after stopping or switching therapy. April 2017.

Healthcare professionals should report any suspected adverse effects relating to fingolimod (Gilenya▼) or other treatments for multiple sclerosis, including suspected adverse effects occurring after discontinuation, via the Yellow Card Scheme.

We are aware of two recently published articles1 2 describing a suspected rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected for that patient prior to discontinuation or treatment change) in patients with multiple sclerosis after treatment with fingolimod (Gilenya▼) was stopped, some of whom were switched to other treatments.

In conjunction with other European national regulatory authorities and the European Medicines Agency, we are evaluating all available evidence on this safety signal. Further information on the outcome of the review and any relevant new guidance will be issued as soon as it is available.

Healthcare professionals are reminded to be vigilant for such events and report any suspected adverse effects relating to fingolimod or other treatments for multiple sclerosis via the Yellow Card Scheme.

For any reports of suspected rebound effect, please provide as much detail as possible. This could include any clinical, imaging and other test details; along with a description of disease activity prior to and during therapy.

Article citation: Drug Safety Update volume 10, issue 9, April 2017: 3.

Hatcher SE et al. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol 2016; 73: 790–94.

Willis M et al. An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2017; 4: e320. 

CoI: multiple

Tuesday, 25 April 2017

#ThinkSpeak & #AAN2017: burnout

Did you know neurologists are the specialists that are most likely to suffer burnout? #ThinkSpeak #AAN2017

I went to the opening, or plenary, session of the AAN meeting and heard Terrence Cascino, the President of the AAN, present the data from a national survey of US neurologists on well-being, burnout and career satisfaction. It was flabbergasted to hear that neurology is the speciality most likely to be affected by burnout and that ~60% of  respondents had at least one symptom of burnout. As this impacts negatively on their work, I wonder how it is affecting the management of their patients with MS?

When Terrence Cascino presented the list of symptoms of burnout I realised that I, and a lot of my colleagues, suffer from burnout; i.e. emotional exhaustion, feelings of cynicism and detachment (depersonalization), and a sense of ineffectiveness at work (low personal accomplishment). I realise that I need to do something about it, but what?   

Busis et al. Burnout, career satisfaction, and well-being among US neurologists in 2016. Neurology. 2017 Feb 21;88(8):797-808.

OBJECTIVE: To study prevalence of and factors that contribute to burnout, career satisfaction, and well-being in US neurologists.

METHODS: A total of 4,127 US American Academy of Neurology member neurologists who had finished training were surveyed using validated measures of burnout, career satisfaction, and well-being from January 19 to March 21, 2016.

RESULTS: Response rate was 40.5% (1,671 of 4,127). Average age of participants was 51 years, with 65.3% male and nearly equal representation across US geographic regions. Approximately 60% of respondents had at least one symptom of burnout. Hours worked/week, nights on call/week, number of outpatients seen/week, and amount of clerical work were associated with greater burnout risk. Effective support staff, job autonomy, meaningful work, age, and subspecializing in epilepsy were associated with lower risk. Academic practice (AP) neurologists had a lower burnout rate and higher rates of career satisfaction and quality of life than clinical practice (CP) neurologists. Some factors contributing to burnout were shared between AP and CP, but some risks were unique to practice setting. Factors independently associated with profession satisfaction included meaningfulness of work, job autonomy, effectiveness of support staff, age, practicing sleep medicine (inverse relationship), and percent time in clinical practice (inverse relationship). Burnout was strongly associated with decreased career satisfaction.

CONCLUSIONS: Burnout is common in all neurology practice settings and subspecialties. The largest driver of career satisfaction is the meaning neurologists find in their work. The results from this survey will inform approaches needed to reduce burnout and promote career satisfaction and well-being in US neurologists.

AAN Siponimod Phase III positive in Secondary Progressive MS

Safety and Tolerability of Siponimod in Patients with Secondary Progressive Multiple Sclerosis: Robert Fox , Ludwig Kappos , Amit Bar-Or , Bruce Cree , Gavin Giovannoni , Ralf Gold, Patrick Vermersch , Harold Pohlmann, Christian Wolf , Frank Dahlke , Erik Wallström , Tatiana Sidorenko

Objective: To present safety and tolerability results of the randomized, double-blind, placebo-controlled, Phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate (S1P) receptor-1/-5 modulator with peripheral and central effects was investigated in SPMS, a condition driven by neurodegeneration and inflammation in the central nervous system, where treatment options are limited. Efficacy results are reported separately. 
Design/Methods: In EXPAND siponimod significantly reduced the risk of 3-month confirmed disability progression. Safety and tolerability based on the safety analysis set for the double blind treatment period are reported. Patients were randomized (2:1) to receive once-daily siponimod 2mg or placebo (with a 6-day initial dose titration). 
Results: Of 1651 randomized patients, 1645 comprised the safety population (siponimod, N=1099; placebo, N=546). Mean age was 48 years (SD 7.87), median EDSS 6.0. At least one treatment-emergent adverse event (TEAE) was reported for 88.7% and 81.5% of siponimod and placebo patients; in 7.6% and 5.1% of patients, these led to treatment discontinuation. Most common TEAEs (>10% in any group) were headache, nasopharyngitis, urinary tract infection, falls and hypertension. Serious TEAEs were reported in 17.9% and 15.2%, including four deaths in each treatment group (0.4% and 0.7%). Incidence of infections and malignancies were similar (49.0% vs. 49.1%, 1.9% vs. 2.6%, respectively). Lymphopenia below 0.2x10˄9/uL was observed in 2.7% vs. 0.2% of patients and Liver Function Test elevations ≥3xULN – in 5.6% vs. 1.5%. The incidence of other AEs of interest were: bradyarrhythmias, 3.5% vs. 2.4%; hypertension, 12.6% vs. 9.3%; and macular oedema, 1.8% vs. 0.2%, respectively. With dose titration (during treatment initiation) there were only few bradyarrhythmic events. No cases of Mobitz II or higher degree AV-blocks were reported. Conclusions: The safety profile of siponimod appears to be in line with other S1P receptor modulators. 

Efficacy of Siponimod in Secondary Progressive Multiple Sclerosis: Results of the Phase 3 Study Ludwig Kappos , Amit Bar-Or , Bruce Cree , Robert Fox , Gavin Giovannoni , Ralf Gold , Patrick Vermersch , Sophie Arnould , Tatiana Sidorenko , Christian Wolf , Erik Wallström , Frank Dahlke

Objective: To present the efficacy results of the randomized, double-blind, placebo-controlled, phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate receptor-1 and -5 modulator with peripheral and central effects was investigated in SPMS, a condition for which treatment options are limited. 
Design/Methods: Patients were randomized (2:1) to once-daily siponimod 2mg or placebo. The primary endpoint of this event- and exposure-driven study was time to 3-month confirmed disability progression (CDP), assessed by the Expanded Disability Status Scale (EDSS). Key secondary endpoints were time to confirmed worsening of ≥20% from baseline in the Timed 25-Foot Walk test (T25FW) and T2 lesion volume (T2LV) change from baseline. Other secondary endpoints were 6-month CDP, annualized relapse rate (ARR), 12-item Multiple Sclerosis Walking Scale (MSWS-12), number of T1-Gd+ and T2 lesions and percent brain volume change (PBVC). For other secondary endpoints p-values are nominal (not corrected for multiplicity). Safety and tolerability are presented separately. 
Results: Overall, 1651 patients were randomized. Siponimod reduced the risk of 3-month CDP by 21% versus placebo (HR [95% CI]: 0.79 [0.65, 0.95]; p=0.013). Point estimates in favor of siponimod were consistently observed across predefined subgroups, including patients with no relapses in the 2 years prior to study and those without gadolinium-enhancing lesions at baseline. The risk reduction observed for T25FW was 6.2% and not statistically significant (p=0.440). Siponimod reduced the risk of 6-month CDP by 26% (p=0.006), ARR by 55.5% (p<0.0001), T1 Gd+ lesion number by 86.6% (p<0.0001), and new T2 lesion number by 81% (p<0.0001). Relative difference in change from baseline in T2LV, MSWS-12 and PBVC were 79.1% (p<0.0001), 39.7% (p=0.057) and 23.4% (p=0.0002), respectively, versus placebo. 
Conclusions: Siponimod had a robust positive effect on disability progression and other relevant outcomes in SPMS. 
So good news for secondary progressive MS. At last a **imod that does something so why did fingolimod not work in primary progressive. It is clear that it blocks the same targets. Points in favour was found in people without relapses or gadolinium enhancing diseased. ProfG is a co-author so can fill you in on that score

CoI Multiple