Saturday, 31 March 2018

The MS Establishment

The recent commentary by Alasdair Coles and riposte by Jack Antel has sparked a prickly debate about the role of a relatively small number of academic neurologists, who are also known as KOLs (key opinion leaders), in relation to MS clinical trials and their subsequent publications. 

Friday, 30 March 2018

Thursday, 29 March 2018

Guest post: Alasdair Coles on An Instinct for Kindness

Prof G asked me to listen to An Instinct for Kindness and offer some comments. As I was mulling over what I might say, I read the posts about the play on this blog: some appreciative, some angry, some disturbed. 


Wednesday, 28 March 2018

NEDA after ocrelizumab

No-evidence of disease activity (NEDA) means 
  • No Clinical Relapse
  • No New Lesion activity
  • No progression of EDSS
ProfG works some magic with Oreclizumab to make it better than any other chemical DMT.

What's he done?

Monday, 26 March 2018

Trying to emulate the Cleveland Clinic at Barts-MS

I have just spent two days attending the 2018 or third Cleveland Clinic Neurological Institute MS Summit on 'MS Treatment Strategies'. I had to give a talk on composite outcomes in trials and clinical practice. I am not sure why I was asked to cover this topic as I would not rate myself as being an expert on MS-related outcome measures.



As promised I have made my slides available.


News Update: positive GNbAC1 phase 2 results

Has the black swan arrived? Could MS be due to a viral infection? Is the #CharcotProject alive and kicking?

Sunday, 25 March 2018

B regulatory cells promote remyelination

First we had T regulatory cells promoting remyelination. 

In this report it is the turn of the B regulatory cells to do the same thing

Saturday, 24 March 2018

Estimating the future Prognosis

If you live in the UK, If you haven't done this yet, why not sign up to the UK MS register.


Friday, 23 March 2018

Is MOG the important autantigen in MS, like it is in EAE

MS is an autoimmune disease...isn't it.

Where is the proof?  

There is plenty of circumstantial evidence and there is clearly autoimmunity in MS, but is it the chief problem

"Of course it is" I hear many of my colleagues say.

Look at EAE, that is autoimmunity and that's MS isn't it.

Thursday, 22 March 2018

The Phoenix has risen: the era of disease modification in progressive MS has truly arrived

The EXPAND study is the first positive study in people with secondary progressive MS and marks a new landmark in the treatment of MS.


Please note that I am a co-author on this paper and I sit on the trial steering committee. I am clearly conflicted and therefore you may not want to read or hear what I have to say about the trial's findings. 

Fingolimod inducing low white blood cell levels but saving brain

What are the consequences of having a low lymphocyte count when starting fingolimod?



If we #Thinkhand we would have another treatment for Progressive MS.

Another DMT for progressive MS bites the dust! Yet another poorly designed progressive trial. If only it had been designed better it would have transformed the management of SPMS. Have we learnt from our mistakes?



Wednesday, 21 March 2018

Is it not time to extend the diagnosis of MS into the asymptomatic phase?

At a continuing medical education (CME) meeting I co-chaired in Vienna, a concept emerged that is silently gnawing away at my consciousness and has changed my thinking.

The concept concerns how we deal with the problem of the radiologically isolated syndrome (RIS) or asymptomatic MS.




Monday, 19 March 2018

Cladribine selectively depletes B cells and induces long term depletion of memory B cells

Last year we suggested that all agents that currently are used to inhibit MS, all target memory B cells.

The agents that are highly-effective deplete memory B cells well and those that are not highly-effective don't.

We didn't have the data on whether cladribine depletes memory B cells, but as cladribine is highly effective in treating relapsing MS.
It suggests that they should be depleted.

The hypothesis can be tested, as we have been using cladribine off-label.

If you want to know the answer...read on

MS in the News HSCT poster doing the rounds

"Game changing" HSCT data is being reported in the media.

This is in response to data being presented at a meeting, which we commented on a few weeks ago.. I saw Roumen Balabanov last week and he wasn't aware that the abstract below was published.

We made a post where the authors had complained about Social media as inaccurate, but I made the point that the authors are happy to take the benefits of Social Media.


This story is being circulated by Social Media.
If you want to read the abstract

Sunday, 18 March 2018

#Thinkhand - Natalizumab preserves upper limb function in advanced disease

Most people with MS will have discrete episodes of disability - relapses - from which they get better. Unfortunately over time, many people gradually accumulate disability and stop having clear relapses. This shift is often labelled as a shift from 'relapsing' to 'progressive' disease, and once in the second phase people are often given the label 'secondary progressive MS'. While this label may not necessarily be that helpful - it make be more useful just to distinguish early from advanced MS - it is still widely in use. 

Saturday, 17 March 2018

Charcot 3: does an anti-viral inhibit MS?

Does an anti-viral inhibit MS? Charcot 1 is still not published (nudge, nudge) but it didn't work but that didn't surprise me as the treatment agent prevented virus integrating into the DNA, which was targeting a virus that had already integrated.

However there was anecdote of disease remission after taking the drug. It has happened again:

Friday, 16 March 2018

Guest Authors: The alternative view

Earlier this week a piece was published in the Annals of Neurology reporting how certain authors are on clinical trials and implying that they could be "guest authors"; celebrated “key opinion leaders” who do not contribute to trial design or execution, or manuscript drafting, but whose name lends gravitas to the study.

Today Prof A gives a response to this.

Thursday, 15 March 2018

Can interleukin-4 save nerve cells?

Untreated inflammation is bad for the brain. Over time, repeated bouts of inflammation predispose to the gradual loss of nerve cells from the brain and spinal cord. This gradual degenerative process is what we can quantify with brain atrophy and measurements of neurofilament. Loss of nerve projections (axons) begins very early in the inflammatory process, occurs both within and distant from lesions, and is probably the main driver of disability. 

Wednesday, 14 March 2018

Off-Label Use. Is it bad for business? Should it be allowed?

Should we have off-label use of MS treatments, if it competes with pharma interest?

There are many that would not contemplate this view. 

What do you think? 

Tuesday, 13 March 2018

More on endogenous retroviruses in MS

Int J Mol Sci. 2018 Mar 9;19(3). pii: E786. doi: 10.3390/ijms19030786.

Genetic Determinants of Antibody Levels in Cerebrospinal Fluid in Multiple Sclerosis: Possible Links to Endogenous Retroviruses.

Emmer A, Brütting C, Kornhuber M, Staege MS.

Abstract


The pathogenesis of multiple sclerosis (MS) has not been clarified. In addition to environmental factors; genetic determinants have been implicated in the pathogenesis of MS. Furthermore, endogenous retroviruses (ERV) might play a role in MS. The presence of oligoclonal immunoglobulin in cerebrospinal fluid (CSF) is a typical feature of MS. Recently, genetic polymorphisms in loci on human chromosomes 6, 14 and 18 have been identified as major determinants of CSF antibody levels in MS. The functional relevance of these single nucleotide polymorphisms (SNPs) remains unclear and none of them is located in an open reading frame. In previous studies, we identified ERV sequences in the vicinity of MS associated SNPs. Here, we describe the identification of ERV sequences in the neighborhood of SNPs associated with CSF antibody levels. All of the identified SNPs are located in the vicinity of ERV sequences. One of these sequences has very high homology to a sequence derived from the so-called MS-associated retrovirus (MSRV). Another cluster of three ERV sequences from the immunoglobulin heavy chain locus has retained the typical organization of retroviral genomes. These observations might shed new light on a possible association between ERVs and MS pathogenesis.

Figure: MS associated SNPs are located in the vicinity of ERV sequences

I've been reading a lot of poetry of late, so here goes nothing!!!

Viruses are hot to trot,
Hot off the press,
Hot on the heals of EBV,
Undisputably not full of hot air.

Anyway, back to the topic at hand...

Oligoclonal bands are a sign of immune response and the presence of antibodies in the spinal space. Genetic variations (or single nucleotide polymorphisms, SNPs) have been reported on chromosomes 6, 14 and 18 in regions involved in antibody production in MS. Endogenous retrovirus elements (are virus sequences in the human genome that are thought to be derived from retroviruses; viruses often insert a copy of their DNA into their host genome during their replication cycle, and once there are inherited through successive generations) have been also found in the human genome and may influence the expression of our own genes. Here, the authors put forward the theory that these ERV loci could drive the production of antibodies (the oligoclonal bands) in MS.

They note that surrounding the genetic polymorphisms is the presence of various ERV sequences. Particularly, surrounding the polymorphism rs9807334 on chromosome 18, the open reading frame that encodes a protease and reverse transcriptase, is highly similar to a sequence in MSRV (which has been strongly linked to MS) suggesting that ERV activity may influence antibody levels. Similarly, polymorphisms on chromosome 14 (which generates part of the antibody, specifically the heavy chain) and chromosome 6 (the Major Histocompatability Complex, a group of proteins by which foreign antigen recognition by the immune system occurs) that are more directly involved in antibody synthesis also contained in their vicinity retrovirus-like open reading frames.

It is therefore possible that during inflammation there may also be synthesis of proteins from these retroviral elements, which may generate a B cell response. Although, this needs to be investigated in greater detail.

Monday, 12 March 2018

Is Prof G a guest author or trial junkie?

Has Prof Rev C from Cambridge gone rogue and decided that he doesn’t like the MS World much, as he points the finger at Ten  Neurology Trial Junkies (known by letters of the alphabet)? 

This study looks at trial reports and concludes that certain people appear all too often. Is Prof G one of them?

Do not read if you easily get offended.

Sunday, 11 March 2018

Is it the B-cell and/or the T-cell? Prof G eats his hat.

At Barts-MS we have been pushing the B-cell hypothesis based on circumstantial evidence when a lot of genomic, and other data, make it clear that T-cells are also involved in the pathogenesis of MS. Now that the first non-depleting BTKi (Bruton Tyrosine Kinase Inhibitor) is effective in MS does this change our central hypothesis? 


Yes, I am eating my hat. I predicted that unless a BTKi was depleting it would not work in MS. Why? 

Education: Whats BTK

Bruton's tyrosine kinase (abbreviated to BTK) also known as tyrosine-protein kinase BTK is an enzyme that plays a crucial role in B-cell development.

However, whilst ProfG has been munching on his chapeau, I've been doing some reading and am not ready to let the T cell boys and girls off the hook. More B cell magic....

Saturday, 10 March 2018

Guest post: #ThinkHand Campaign for Advanced Multiple Sclerosis

I attended the launch of the #ThinkHand campaign for advanced MS by Barts MS Health at the Bankside Gallery in Southwark on Thursday 22 February.

My MS
I can still walk, but it is a very slow walk and I must use a rollator or walker. I have lost the ability to walk independently. If you fall into this category of disability then there is no drug available from the NHS to slow down the inevitable  progression of MS.

The ability to use my hands and arms is now very important for a multitude of reasons. Without them I could not use a rollator or walker.

A bit of history
All the drug therapies approved by NICE can only be prescribed for early-stage MS known as RRMS. There was a time when I could run, hop, skip and jump but that was a long time ago. It was a terrible shock when I discovered in 2001 I could not even walk in a straight line. In 2004 I was no longer able walk the dog. Now I definitely had SPMS. My consultant who I was seeing once or twice a year was powerless to do anything that might help me.

#ThinkHand Campaign for Advanced MS
The Barts MS Health team are dragging treatment for advanced MS into the 21 st  century. Here are some objectives of their #ThinkHand campaign:

  • Use the 9 Hole Peg Test (9-HPT) as a primary outcome measure in clinical trials to assesses hand function.
  • Give MS patients who cannot walk access to clinical trials
  • Perform a clinical trial for MS wheelchair users. The Chariot-MS Study that uses Cladribine has been proposed.
  • Provide an environmentally friendly 9-HPT so people with advanced MS can monitor their arm and hand function.
     
  • The pharmaceutical industry needs to design clinical trials that are inclusive for people with advanced MS

Awareness
Multiple sclerosis is an incurable disease. There are quite a few drugs that can be given to people to slow down the progress of MS. When the consultant decides that your MS is not the Relapsing Remitting type then you are not eligible for any drug modifying therapy. Just think about that for a moment.

How good is your mobility?
Quality of walking is an indication of the severity of the MS. Long before I needed a walking stick I knew that I was unable to walk along a painted line. I could still run
but my balance was definitely squiffy. If anyone implied that I might end up in a wheelchair then I was selectively deaf. 

Today I can’t walk unaided but also I don’t need to use a wheelchair yet.

Other problems
Now my writing is almost illegible, I can’t type instead I use dictation software.  I have no feeling in my fingertips and it is very difficult to do up buttons. Is my MS better or worse than someone who has to use a wheelchair?

There are too many things you take for granted that I cannot do. The #ThinkHand campaign for advanced MS wants to make people more aware of the impact of advanced multiple sclerosis. Hope and quality of life are important for
everyone.

by Patrick Burke



Patrick was diagnosed with RRMS in 1995 but believes his symptoms started in 1972. The disease turned into SPMS in about 1999/2000. He was forced to take medical retirement in 2012 and set up the website Aid4Disabled in the same year. The website is the story of his MS since retirement and it describes a wide range of objects that are readily available for disabled people to improve their quality of life. Patrick is also a member of the Barts MS Advisory Group.

Friday, 9 March 2018

Guest Post: Extending natalizumab dosing interval may reduce the risk of PML

Natalizumab extended interval dosing (EID) is associated with a significant reduction in PML risk compared with standard interval dosing (SID) in the TOUCH® Prescribing Program.

Thursday, 8 March 2018

2018 Research Day news

We are excited to announce that this year Barts-MS will be teaming up with neurologists from Glasgow and presenting a research day in Stornoway on the Isle of Lewis.


Wednesday, 7 March 2018

Reflections on 'An Instinct for Kindness'

The BBC Radio 4 dramatisation on the assisted suicide of a person with advanced SPMS has generated some heated exchanges. I have now listened to the dramatisation and have reflected on the story. It is a very touching story and I would recommend it to all people with an interest in MS. 

Tuesday, 6 March 2018

News: British & Irish MSologists are spoilt for choice

The following are two MS-related meetings happening this week. If you had a choice which one would you choose to attend?



Complementary medicine in MS

Are you a complementary or alternative medicine person? This post is about the usage of complementary and alternative medicine by people with MS.


Monday, 5 March 2018

Blogs can't see wheat from chaff...should we defend our position?

Blogs cannot separate wheat from chaff.
Burt RK, Snowden JA, Burman J, Oliveira MC, Sharrack B.
Science. 2017 Nov 3;358(6363):602.


Should we accept this claim or defend our position?

Sunday, 4 March 2018

Help ProfG become Peter Pan

 Does Prof. G suffer from the Peter Pan Syndrome*?



Ask Barts-MS - March 2018

Want to ask a question or make a point unrelated to the threads?


This is the place for you

Saturday, 3 March 2018

ACTRIMS 2018: Rituximab does not affect MRI detected meningeal lesions

Intrathecal rituximab is worth exploring as a treatment option? Can it eliminate the B-cells driving progressive disease?


Blast from the past: something the new readers don't know

You asked does Ocrelizumab need to be dosed so often?

I repost this from last year about the 4 year old data and ask why it has not been published?

We need a study to address the question, is there induction therapy potential. 

Friday, 2 March 2018

Urgent News Update: daclizumab is withdrawn from the market

The EMA has just announced that Biogen and Abbvie are pulling daclizumab from the market. Why?



Atraumatic Needles: times are changing but we need to do more

Are you about to have a lumbar puncture? If yes, what needle is your neurology team going to use to perform the lumbar puncture? If you want a simple guide to LPs please visit our LP web app.