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 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.


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.