Saturday, 15 December 2018

Real Life Use of CD20 depletion

Yamout BI, El-Ayoubi NK, Nicolas J, El Kouzi Y, Khoury SJ, Zeineddine MM. J. Immunol Res 2018:9084759

OBJECTIVE: To evaluate the efficacy and safety of rituximab in multiple sclerosis in a clinical practice setting.


Clinical data for all adult patients with multiple sclerosis (MS) treated with off-label rituximab at a single MS center in Lebanon between March 2008 and April 2017 were retrospectively collected from medical charts. The main efficacy outcomes assessed were annualized relapse rate (ARR) and proportion of patients free from relapses, disability progression, or magnetic resonance imaging (MRI) activity.


A total of 89 rituximab-treated patients were included: 59 relapsing-remitting MS (RRMS) and 30 progressive MS (PMS). Patients were treated with 1000 or 2000 mg rituximab IV every 6-12 months for a mean duration of 22.2 ± 24.8 months. The subjects were 65.2% females with a mean age of 40.5 ± 12.3 years and a mean disease duration of 7.9 ± 6.2 years. During treatment, the ARR decreased from 1.07 at baseline to 0.11 in RRMS (p < 0.0001) and from 0.25 to 0.16 in PMS patients (p = 0.593). The mean Expanded Disability Status Scale (EDSS) remained unchanged in both RRMS and PMS patients. Between baseline and the last follow-up, the percent of patients free from any new MRI lesions increased from 18.6% to 92.6% in the RRMS group and from 43.3% to 82% in the PMS group. No evidence of disease activity (NEDA) was achieved in 74% of patients at 1 year of treatment. A total of 64 adverse events (AEs) (71.9%) were recorded with the most common being infusion-related reactions in 25.8% of patients, all mild in nature. Two of our rituximab-treated patients experienced serious AEs requiring surgical interventions: pyoderma gangrenosum vaginalis and an increase in the size of a meningioma. No case of progressive multifocal leukoencephalopathy (PML) was detected.


In our real-world cohort, rituximab was well-tolerated and effective in reducing relapse rate and disability progression in relapsing-remitting and progressive MS patients.

This is real-life use of rituximab, a B cell depleting drug, which is like ocrelizumab, only cheaper...OK it is what we call chimeric, part animal (mouse) and a large part human. Ocelizumab is humanised, a tiny part animal and vast majority human and ofatumumab which is human.

Ocrelizumab binds to CD20 better than rituximab and it is a more effective B cell killer than rituximab.

The main side effect is infusion reactions which was similar to the about 30% infusion reactions in people treated with ocrelizumab.

The main adverse events was a meningioma a type of slow growing brain cancer  and a form of Pyroderma gangrenosum . This is an unpleasent ulcering condtion thought to a problem with neutrophils, which are the most common type of white blood cell type.

WARNING: Dont view this whilst you are having your breakfast! 
It looks unpleasent and it is not even the vaginalis variant.

Prof G what is therapeutic lag?

Worsening disability in someone with progressive MS over the next 2 years is primed by inflammation from years ago. Suppressing inflammation today, therefore, will have little, or potentially no, impact on worsening disability over the next one to two years as the damage priming progression over this time has already occurred. Therefore, all anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

Friday, 14 December 2018

Blood lipids and disease activity are they related?

The headline is "How Lipid Level Tests Can Help People with Multiple Sclerosis"

We have been striving to understand how statins can work in MS.
These are cholesterol-lowering drugs.

Altered lipid metabolism is a feature of chronic inflammatory disorders. Increased plasma lipids and lipoproteins have been associated with multiple sclerosis (MS) disease activity. Our objective was to characterise the specific lipids and associated plasma lipoproteins increased in MS and to test for an association with disability. Plasma samples were collected from 27 RRMS patients (median EDSS, 1.5, range 1–7) and 31 healthy controls. Concentrations of lipids within lipoprotein sub-classes were determined. Plasma cytokines were measured. Differences between the patient and volunteer groups were found for lipids within very low density lipoprotein (VLDL) and  high density lipids (HDL) lipoprotein sub-fractions (p < 0.05). Multivariate regression demonstrated a high correlation between lipids within VLDL sub-classes and the Expanded Disability Status Scale (EDSS) (p < 0.05). An optimal model for EDSS included free cholesterol carried by VLDL-2, gender and age (R2 = 0.38, p < 0.05). Free cholesterol carried by VLDL-2 was highly correlated with plasma cytokines CCL-17 and IL-7 (R2 = 0.78, p < 0.0001). These results highlight relationships between disability, inflammatory responses and systemic lipid metabolism in RRMS. Altered lipid metabolism with systemic inflammation may contribute to immune activation.

You can read the abstract but sorry to break the bubble, as an R2=0.38  is not a high correlation. 

R2 is the coefficient of determination and pronounced "R squared", is the proportion of the variance in the dependent variable that is predictable from the independent variable(s).

Time and time again we see correlations but the problem is that whilst VLDL may correlate with movement problems (is this cause or perhaps effect), there is no real predictive value for the individual and so will having a test tell you anything for the that you don't know already. It cannot tell you your future accureately Maybe Ari will do a "Guest post" and you can get it from the horse's mouth.

The VLDL (carries triglycerides, a type of fat, to your tissues also known as Bad Cholesterol) are associated with the detection of CCL17 a chemokine (a protein that your cells migrate towards) expressed notably on dendritic cells and interleukin 7 (IL-7) a T cell cytokine which is implicated in MS Susceptibility which is also produced by dendritic cells. 


Did you know that  oxidised low density lipid promotes dendritic cell formation form monocytes?. No neither did I until I read this. Apparently these dendritic cells produce IL-12 (cytokine)...Oh no...does this mean it promotes pro-inflammatory Th1 cells? VLDL receptor can influence dendritic cells function too...Is this the link? I've no idea its not my project.

Thursday, 13 December 2018

Alemtuzumab autoimmune problems, this time it is a brain problem

As I said we will be back with more news of of alemtuzumab.

This time the person recieving alemtuzumab, developed a brain disease.  They have not found the causative antibody but the person responded to plasma exchange and was the third autoimmunity that the person had:-( 


  • This case describes the first reported case of autoimmune encephalitis as a secondary autoimmune complication of Alemtuzumab therapy.
  • Despite the absence of an identifiable antibody the patient responded well to immunotherapy including plasma exchange.


Secondary autoimmune disorders are a recognised complication of alemtuzumab treatment for multiple sclerosis. We report a case of autoimmune encephalitis manifesting as a polymorphic epilepsia partialis continua / status epilepticus seven months after the second course of alemtuzumab in a patient with previous autoimmune hypothyroidism and immune thrombocytopenic purpura. An MRI revealed multifocal cortical abnormalities and neuronal loss was evident on biopsy. Although testing for anti-neuronal antibodies was negative, the patient responded well to immunotherapy including plasma exchange. This is the first reported presentation of an autoimmune encephalopathy secondary to alemtuzumab therapy.

Wednesday, 12 December 2018

Explaining why you get worse despite being NEDA

In my MS clinic, I have to continually work on a narrative to explain to pwMS why they are getting worse despite having no evidence of disease activity. The following is a draft of a paper I am working on. Does it make sense? Is it too complicated? Does it need pictures? Thanks. 

Glial cells involved in progressive MS

We all know that the glial response may be involved in progressive MS

Do you want more evidence

Tuesday, 11 December 2018

Pregnancy in MS

Mult Scler. 2018 Dec 3:1352458518816614. doi: 10.1177/1352458518816614. [Epub ahead of print]

Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria.

Bsteh G, Algrang L, Hegen H, Auer M, Wurth S, Di Pauli F, Deisenhammer F, Berger T.



Multiple sclerosis (MS) predominantly affects women of child-bearing potential. Pregnancy in MS is still a controversial issue lacking standardized treatment recommendations.


To examine the reciprocal effects of pregnancy, MS, and disease-modifying treatment (DMT).


We analyzed 387 pregnancies in 239 women with relapsing remitting multiple sclerosis (RRMS) and ⩾1 pregnancy, establishment of diagnosis >1 year before conception, and ⩾2 years of follow-up after delivery. Relapse rates and Expanded Disability Status Scale (EDSS) scores were compared in the year before conception, during pregnancy, and 2 years postpartum. Binary logistic regression was used to investigate predictors of risk for relapses and disability progression during pregnancy and postpartum.

Monday, 10 December 2018

#ThinkSocial: survey results

Thank you and Thank you! 

Guest post: New study - Are people living with MS in the UK vitamin D deficient?

Help us spread the word, we have a new study open to people living with MS in the UK! This study is looking at vitamin D levels in the MS population and we know that vitamin D research is one of the top research priorities for people living with MS. This strong interest in vitamin D research has been demonstrated by the overwhelming response we have had to this study - but we still need more participants! 

Sunday, 9 December 2018

An interview with myself: secondary progressive MS

I did a post-ECTRIMS interview with a Portuguese health magazine last week. The interview has helped me reflect and formalise some of my many ideas about secondary progressive MS that have been fermenting in my cortex for some months. I have therefore put pen to paper using a new format the self-interview.

Are Neuros Conspiring to Avoid Treatments for Progressive MS

Of course not they want a treatment option, just as you do, but I feel we have been shooting ourselves in the foot and unfortunately this mistake means a bullet to your brain.
The question is can we learn from these mistakes?

Saturday, 8 December 2018

If you have to switch make sure it is effective

Treatment escalation leads to fewer relapses compared with switching to another moderately effective therapy. Chalmer TA, Kalincik T, Laursen B, Sorensen PS, Magyari M; Members of Danish Multiple Sclerosis Group.J Neurol. 2018. doi: 10.1007/s00415-018-9126-y.

BACKGROUND Patients with multiple sclerosis who experience disease breakthrough often switch disease-modifying therapy (DMT).
OBJECTIVE: To compare treatment effectiveness of switch to highly effective DMT (heDMT) with switch to moderately effective DMT (meDMT) for patients who switch due to disease breakthrough defined as at least one relapse within 12 months of their treatment switch.
METHODS:We retrieved data from The Danish Multiple Sclerosis Registry on all relapsing-remitting MS patients with expanded disability status scale (EDSS) less than 6 who experienced disease breakthrough. We used propensity score matching to compare annualized relapse rates (ARRs), time to first confirmed relapse, time to first confirmed EDSS worsening and time to first confirmed EDSS improvement.
RESULTS: Each matched group comprised 404 patients. Median follow-up time was 3.2 years [interquartile range (IQR) 1.7-5.8]. ARRs were 0.22 (0.19-0.27) with heDMT and 0.32 (IQR 0.28-0.37) with meDMT; relapse rate ratio was 0.70 (95% CI 0.56-0.86; p = 0.001). Escalation to heDMT reduced the hazard of reaching a first relapse (HR 0.65; 95% CI 0.53-0.80; p < 0.001). We found no evidence of delayed disability worsening (HR 0.83; 95% CI 0.62-1.10; p = 0.20) and weak evidence of disability improvement (HR 1.33; 95% CI 1.00-1.76; p = 0.05) with heDMT.
CONCLUSION: Switching to heDMT is associated with reduced ARR and delay of first relapse compared with switching to meDMT. Patients on DMT who experience relapses should escalate therapy to heDMT.Patients with multiple sclerosis who experience disease breakthrough often switch disease-modifying therapy (DMT).

This study says if you are switching make sure you switch to a higher efficacy alternative, Simple. Going to low efficacy drug

Friday, 7 December 2018

Side effects and MS drugs

Another report on the drug that just keeps giving....A shame it is giving us extra autoimmunities to be aware of.

Pisa M, Della Valle P, Coluccia A, Martinelli V, Comi G, D'Angelo A, Moiola L. Acquired haemophilia A as a secondary autoimmune disease after alemtuzumab treatment in multiple sclerosis: A case report. Mult Scler Relat Disord. 2018;27:403-405.

Alemtuzumab is a highly effective monoclonal antibody for the treatment of multiple sclerosis (MS). During the immune reconstitution following the use of this treatment severe secondary autoimmune diseases (SADs) can develop. We present the case of a patient affected by active MS who failed to achieve disease control with several disease-modifying drugs and was thereafter successfully treated with alemtuzumab, obtaining no evidence of disease activity and a high quality of life. Twenty months after the first infusion of alemtuzumab the patient developed acquired haemophilia A (AHA), a treatable but potentially life-threatening condition that should be considered a possible SADs associated to this drug. In order to allow an early diagnosis and to prevent possible complications of AHA, routine coagulation tests (prothrombin time and activated partial thromboplastin time) should be included in the laboratory serological monitoring of patients treated with alemtuzumab.

Hemophilia A, also called factor VIII (FVIII) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene.

Thursday, 6 December 2018

Alemtuzumab as a cause of stroke

How does alemtuzumab cause stroke? It is unlikely to be due to secondary autoimmune disease as it occurs too soon after administration. Could it be due to a mechanism that triggers thrombotic mechanisms, for example via platelet activation? Alemtuzumab causes an early and transient low platelet count (thrombocytopenia), which may be related to thrombosis. 

Wednesday, 5 December 2018

More Mice in Nature

Knier B, Hiltensperger M, Sie C, Aly L, Lepennetier G, Engleitner T, Garg G, Muschaweckh A, Mitsdörffer M, Koedel U, Höchst B, Knolle P, Gunzer M, Hemmer B, Rad R, Merkler D, Korn T. Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity. Nat Immunol. 2018. doi: 10.1038/s41590-018-0237-5. [Epub ahead of print]

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) have been characterized in the context of malignancies. Here we show that PMN-MDSCs can restrain B cell accumulation during central nervous system (CNS) autoimmunity. Ly6G+ cells were recruited to the CNS during experimental autoimmune encephalomyelitis (EAE), interacted with B cells that produced the cytokines GM-CSF and interleukin-6 (IL-6), and acquired properties of PMN-MDSCs in the CNS in a manner dependent on the signal transducer STAT3. Depletion of Ly6G+ cells or dysfunction of Ly6G+ cells through conditional ablation of STAT3 led to the selective accumulation of GM-CSF-producing B cells in the CNS compartment, which in turn promoted an activated microglial phenotype and lack of recovery from EAE. The frequency of CD138+ B cells (plasma cells) in the cerebrospinal fluid (CSF) of human subjects with multiple sclerosis was negatively correlated with the frequency of PMN-MDSCs in the CSF. Thus PMN-MDSCs might selectively control the accumulation and cytokine secretion of B cells in the inflamed CNS.

As mouse EAE has been found to contain neutrophils and MS has B cells, some people are making the case that MS is a problem of neutrophils although if you look in MS, or non-mouse EAE they are vanishingly rare. Here they report that a cell enters the CNS and becomes a neutrophil with suppressor cell function after interaction with B cells. If they depleted them more B cells accumulated in the CNS and activated microglia So may that is the function of activate microglia.

Warts after Fingo

I had the pleasure of meeting Dr Reddel last week at recent "At the Limits meeting". He is following in his Father's footsteps and likes doing risk assessments.

His dad as a test pilot in Australia and Dr Reddel, a Neuro with a real sense of humour. He gave a neuro from the shires a bit of a ticking off for not testing their pwMS for tuberculosis prior to giving certain DMT. As surely they are not too snobbby to travel or have visitors and catch something that remains undiagnosed.

Dr Reddel has developed Apps to monitor alemtuzumab risks but today he has commented on fingolimod 

Triplett J, Kermode AG, Corbett A, Reddel SW. Warts and all: Fingolimod and unusual HPV-associated lesions.Mult Scler. 2018 Nov 14:1352458518807088

BACKGROUND:Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster.
METHODS:We present five cases of chronic and treatment refractory warts associated with fingolimod therapy.
RESULTS:Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod.
CONCLUSION:Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

I am not a clinician and so am not making any recommenedations however it is something you should be aware of . Where is ProfG? 

Other docs commented "Although chronic warts have not previously been reported, it is conceivable they have escaped collection, and by publishing this series we may draw attention to the HPV associated risks of fingolimod. While further data is collected, clinicians should consider obtaining a history of HPV infections and vaccination history in females arranging a gynaecological exam and Pap smear to assess for dysplastic lesions and/or direct cervical screening for HPV. The newly available nine-strain HPV vaccination is effective against the most commonly oncogenic genital HPV strains and should be considered in unvaccinated patients prior to commencing fingolimod". 

"It is not clear if increased frequency of cervical cancer screening would be useful or even cost-effective in female patients on fingolimod, but clinician awareness around these cases is important".

Tuesday, 4 December 2018

Prescribing habits in the UK

Factors influencing multiple sclerosis disease-modifying treatment prescribing decisions in the United Kingdom: A qualitative interview study.

Cameron E, Rog D, McDonnell G, Overell J, Pearson O, French DP.

Mult Scler Relat Disord. 2018 Nov 22;27:378-382. doi: 10.1016/j.msard.2018.11.023. [Epub ahead of print]

Disease-modifying therapies (DMTs) reduce the rate of relapse in relapsing-remitting multiple sclerosis (RRMS) (Oh and O'Connor, 2015), and can therefore improve quality of life and lessen the need for relapse management interventions (e.g. steroids, hospitalisation, neuro-rehabilitation). Accordingly, the Association of British Neurologists (ABN) recommends that DMTs should be considered promptly for all individuals with active RRMS (Scolding et al., 2015). Despite this, people with RRMS in the United Kingdom (UK) are prescribed DMTs considerably less frequently than patients in other European countries.

Monday, 3 December 2018

Social prescribing survey

I have been taken to task and chastised for neglecting the blog and my patients. I realise that the blog is part of our #ThinkSocial campaign. To help understand the need for social prescribing I would appreciate it if you could please complete the following survey. 

Thank you. 

Advent 3

On the third day of December my true MD gave to not a partridge in a pear tree but.....
Three memory B cells
Two GA reactive Th2 T cells
and a myelin basic protein sending us up a dead-end tree.

T cells are not all bad

Choi EH, Xu Y, Medynets M, Monaco MCG, Major EO, Nath A, Wang T. Activated T cells induce proliferation of oligodendrocyte progenitor cells via release of vascular endothelial cell growth factor-A. Glia. 2018; 66:2503-2513

Neuroinflammatory diseases such as multiple sclerosis are characterized by infiltration of lymphocytes into the central nervous system followed by demyelination and axonal degeneration. While evidence suggests that activated T lymphocytes induce neurotoxicity and impair function of neural stem cells, the effect of T cells on oligodendrocyte progenitor cells (OPCs) is still uncertain, partly due to the difficulty in obtaining human OPCs. Here we studied the effect of activated T cells on OPCs using OPCs derived from human hematopoietic stem cells or from human fetal brain. OPCs were exposed to supernatants (sups) from activated T cells. Cell proliferation was determined by EdU incorporation and CellQuanti-Blue assays. Surprisingly, we found that sups from activated T cells induced OPC proliferation by regulating cell cycle progression. Vascular endothelial growth factor A (VEGF-A) transcripts were increased in T cells after activation. Immunodepletion of VEGF-A from activated T cell sups significantly attenuated its effect on OPC proliferation. Furthermore, VEGF receptor 2 (VEGFR2) was expressed on OPCs and its inhibition also attenuated activated T cell-induced OPC proliferation. Thus, activated T cells have a trophic role by promoting OPC proliferation via the VEGFR2 pathway.

T regs have been reported to promote remyelination this study indicates a molecular mechanism of how T cells can do this

Sunday, 2 December 2018

Social Medicine and Social Prescribing

We are launching a new campaign called #ThinkSocial. Why?

The issue of alemtuzumab

More on the problems of alemtuzumab and the additional autoimmunities that occur following treatment in MS. and how ideas to stop them have passed.

And if that wasn't bad news for alemtuzumab, there is more on the way.

The warnings of alemtuzumab just grow and grow....tick tock, tick tock. This time is the risk of stroke shortly after infusion. 
The FDA has issued a warning

Advent 2

A favourite mechanism of action(MOA) of the inventors was that Glatiramer acetate induced a GA reactive Th2 response.. 

Aharoni R, Teitelbaum D, Sela M, Arnon R.Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis.
Proc Natl Acad Sci U S A. 1997;94:10821-6

Sure enough this was found in MS, by the immunology big guns.
Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA. Glatiramer acetate (Copaxone) induces degenerate, Th2-polarized immune responses in patients with multiple sclerosis. J Clin Invest. 2000 Apr;105(7):967-76.

Qin Y, Zhang DQ, Prat A, Pouly S, Antel J. Characterization of T cell lines derived from glatiramer-acetate-treated multiple sclerosis patients. J Neuroimmunol. 2000 Aug 1;108(1-2):201-6
Neuhaus O, Farina C, Yassouridis A, Wiendl H, Then Bergh F, Dose T, Wekerle H, Hohlfeld R. Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells.
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7452-7

Chen M, Gran B, Costello K, Johnson K, Martin R, Dhib-Jalbut S. Glatiramer acetate induces a Th2-biased response and crossreactivity with myelin basic protein in patients with MS.Mult Scler. 2001;7(4):209-19.
This MOA was of course before T regulatory cells came along and kind of says the Th2 idea was rather rubbish.


"Response to therapy" I answer. 

If GA produces a Th2 response, then as GA is only modestly effective  then it says the influence of driving a Th2 response is only going to be modest. You can't have it both ways.

Jee Y, Liu R, Bai XF, Campagnolo DI, Shi FD, Vollmer TL. Do Th2 cells mediate the effects of glatiramer acetate in experimental autoimmune encephalomyelitis?Int Immunol. 2006 Apr;18(4):537-44.

Then there are the studies in mice that lacks IL-4 and IL-10 and so don't make Th2 cells but GA still has activity in the beasties. So is it really Th2?

Saturday, 1 December 2018

Advent calendar 1

Glaterimer acetate was based on the idea that autoimmunity to myelin basic protein (MBP) is the cause of multiple sclerosis. They took a random mix of the the amino acids found in myelin basic protein and made a mixture that reflects the the amino acid composition of myelin basic protein. This was done in the hope that they could use it to induce disease in animals and this failed miserably. However, they found that it could stop disease from developing (perhaps more on that later) but the rest is history. The world biggest selling drug.  Why?  I scratch my head on this I'm afraid?

I don't know. It can't be because of efficacy, as it is not a high efficacy agent and perhaps has one of the lowest levels of efficacy based on relapse rate. I guess it is based on low side effects. 

However, as to the logic that this agent mimics myelin basic protein, I am not sure I buy this. I guess first up although autoimmunity occurs in MS, there is no definite evidence that autoimmunity is the primary problem.

There are only twenty amino acids and GA contains four of them. These four amino peptides will be found in hundreds of proteins and so why MBP? 

The answer is simple I think..... Lazy T cell immunologists. 

As soon as EAE came along and the thought that MS was autoimmune, you are looking for an autoantigen and so let's choose the one we can make and work with. 

MBP is a common protein in the CNS and it dissolves in water and so is easy to work with and you can find T cells that respond to it and it they do you can get EAE, or if you are a rabbit you can get EAE and EAN. EAE = experimental autoimmune encephalomyelitis and so a disease of the brain and spinal cord, but EAN = neuritis and a disease of the peripheral nerve and so it is expressed in peripheral nerves and this is the second problem with the molecule. This means that if MS was targeted to this molecule there would be a lot of poly-neuropathy with disease of the brain and the spinal cord and the peripheral nerves. However MS is largely targeted to the central nervous system. This casts some doubt on the MBP story.

However, some animals do get CNS restricted disease when they become sensitised to it , but not the beasty I prefer to work with, the response to MBP is pants and they respond to proteolipid protein which is the major protein in the central nervous system but being a proteolipid it is not water soluble and is like brick dust in that it doesn't dissolve in water and in fact it is so lipid soluble it will stick itself into cell membranes and can become toxic to lymphocytes and so it is no good for doing T cell work.....Phew. I never grew up loving Th1 Th2 or Th17 for this reason and so was not wedded to any single, simple idea that I had to follow like a lemming. 

Anyway back to MS and MBP. There have been numerous trials in an attempt to tolerise the immune response aginst MBP in the hope that MS would go away. They all failed, over and over and over again trial after trial. Now, I could say that these failures show that MS has nothing to do with MBP.

Whilst this may be true the trials were in my opinion doomed to fail because the ideas on which the trials were based were flawed. The trial design was definitely flawed. I remember saying to the people doing an intravenous MBP study in MS that they were wasting their time and their money. The company is now on the rubbish heap. MBP a bad choice, but that's not it, they decided to do their trials in SPMS. Removing the immune system does not stop SPMS at least quickly so the trial was doomed. 

Next up to get intravenous tolerance to work properly in my opinion, you have to first deplete the immune cells and tolerise them as they repopulate. Not done and another reason for a trial failure. Unpersuaded other companies are doing the same thing and again failures will appear, I suspect. 

Then there are other companies sticking MBP into the skin as we speak. Immunology tells us this is a sensitizing route not a tolerogenic route, I wonder what will happen. I will keep an open mind but I have serious doubts. 

Then there was the MBP altered peptides aimed at making a TH1 into a TH2 cell and what happened? Disaster two trials failed. Nature paper for the trial failure report and then a Nature paper for the reason why the trial failed as it caused allergy. So they did a two year trial rather than a three week EAE experiment to get that result em:-( However the other trial didn't fail for the allergy it failed because it made MS worse. You don't want Th1 or Th2 they are both bad news.

Anyway this is the only bit of info that really links MBP to be an autoantigen in MS. Put an MBP under the skin (a sensitizing route) and you get worse MS. However some of the people got polyneuropathy...yep because MBP is found in the central and peripheral nervous system. Worse of all the idea was that the TH1 to Th2 switch was based on expression of a molecule called DR2. The people in the trial were not screened and some of the people I think were DR4 and rather than a Th1 to Th2 switch you got stimulation of TH1 so a paper for that explanation too. Is this the evidence that MBP is a problem for MS.

Anyway now I have pulled the rug under the MBP story, what of GA? Well we had it working in a system that doesn't respond to MBP and other people showed it worked in non-MBP EAE  too and them some people report that it does its stuff in non-MS conditions so out goes the idea of MBP in my mind. Would it work to stop other autoimmune conditions...

How does it work, I don't idea.

COI Multiple but not relevant

Unrelated Comments & Questions - December 2018

Sometimes you want to say something unrelated to the thread or ask a clinical question or some other MS-related question that has not been answered in past. This is the place for you.

Friday, 30 November 2018

Advent Calender 2018

It's december again, but the "House of Mouse" has closed its doors again (for 2019)
So how can we fill 25 days for an advent calender for some Christmas Fun. After a bit of head scratching....I thought
Maybe we could look at the World's best selling drug.

This is glatiramer acetate..... but how does it work?

The Regulators say it "Targets the mechansism associated with multiple sclerosis"

So that is it....This is why we get a new mechanism for GA, as it has to work by the new 25 mechanisms...Easy peasy.

The logic of GA

Eskyte I, Manzano A, Pepper G, Pavitt S, Ford H, Bekker H, Chataway J, Schmierer K, Meads D, Webb E, Potrata B.
Understanding treatment decisions from the perspective of people with relapsing remitting multiple Sclerosis: A critical interpretive synthesis.Mult Scler Relat Disord. 2018 Nov 17;27:370-377. doi: 10.1016/j.msard.2018.11.016.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system that mainly affects young adults. While there is no cure for MS, disease modifying treatments (DMTs) reduce the relapse rate and partial accrual of disability. More effective DMTs may have higher risks including life-threatening infections or secondary autoimmunity. The complexity and novelty of available treatments cause challenges for clinicians when prescribing treatments and for people with MS (PwMS) when deciding what trade-offs they are willing and ready to make.
OBJECTIVE: To explore the experience of people with relapsing remitting MS (PwRRMS) and their perspectives in choosing treatments.
METHODS: Critical interpretive synthesis was employed to review and synthesis the published literature. Eighty-three publications were selected in a multi-step systematic process.
RESULTS: Findings are presented in four interrelated areas: the influence of the clinical evidence-base in decision making; the meaning of DMT efficacy for PwRRMS; the influence of models of decision-making and information acquisition practices in PwRRMS; and the importance of psychosocial dimensions in DMT decision making. Synthesis of the findings revealed that alongside medical and individual reasoning, contextual circumstances play an important role in making treatment decisions.
CONCLUSION: This review identifies and explains the importance of diverse contextual circumstances (clinical, social, psychological) that are important for PwRRMS when making treatment decisions. The findings demonstrate the importance of eliciting, understanding and addressing such contextual factors.

I am from Yorkshire and must speak a different form of English as I just have no clue what this abstract really means. I disagree with the tennet that there is no cure, because if people are disease free as some people have been with the immune reconstitution therapies then maybe the c-word is here. Time will tell.

However, in making decisions on glatiramer acetate it must be limited side effects and perhaps lazy neurologists who don't want to do any monitoring that are all important. Otherwise the glateriods would not be the number one best seller.

It can't be based on efficacy, as they are probably the least efficacious group of treatments.

It can't be because of convenience as you have to inject every day
It can't be based on logic and mechanism as these were designed on a (in my opinion) false idea that myelin basic protein is the autoantigenic cause of MS, using data of dubious translational value, where it only really works well in animals when you mix the stuff with the adjuvants used to induce disease.

The regulators says "The mechanism(s) by which glatiramer acetate exerts its effects in patients with MS is (are) not fully elucidated. However, it is thought to act by modifying immune processes that are currently believed to be responsible for the pathogenesis of MS"


Is this why GA has a "mechanism a month" ?

Because as each new mechanism comes along GA has to work via it.  

Thursday, 29 November 2018

Lipoic Acid in SPMS

Loy BD, Fling BW, Horak FB, Bourdette DN, Spain RI.
Complement Ther Med. 2018;41:169-174.Effects of lipoic acid on walking performance, gait, and balance in secondary progressive multiple sclerosis.

BACKGROUND: Gait and balance impairment is common in secondary progressive multiple sclerosis (SPMS). Lipoic acid (LA), an over-the-counter antioxidant, is effective in MS animal models and may improve walking speed, but effects on mobility are unreported.
OBJECTIVE: Examine the effects of 1200 mg daily oral dose of LA versus placebo (PLA) on gait and balance in a 2-year, randomized, double-blind pilot study.
METHODS:134 participants were screened for eligibility before assignment to LA (n = 28) or PLA (n = 26). Included here were, 21 participants with SPMS who took LA (N = 11) or PLA (N = 10) capsules for 2 years (enrolled May 2, 2011 - August 14, 2015) and completed all tasks without the use of an assistive device. Participants completed the Timed Up and Go (TUG) and quiet standing tasks every 6 months while wearing inertial sensors (APDM Opals) to quantify mobility.
RESULTS: LA had a medium effect on time to complete TUG at 2 years (g = 0.51; 95% CI = -0.35, 1.38). In a subset of 18 participants with less disability (EDSS < 6, no use of ambulatory device), turning time was significantly shorter with LA (p =  0.048, Δ= 0.48 s). No differences in balance metrics were found between groups.
CONCLUSIONS: LA had an effect on walking performance in people with SPMS, particularly in those with lower baseline disability.

So a small study of lipoic acid. For the trial the primary outcome stated on clinical is brain atrophy with 25 foot walk as a secondary. Not sure why this study report is so limited as the results were posted and published in 2017.

Change in brain atrophy on Lipoic acid was -0.4 + 0.7 verses -1.3 + 1.1 and change in 25 foot walk effect was 1 second less (-1.0 +2.8s) compared to 0.1 + 20 worsening.

Advent Calendar 2018

Wednesday, 28 November 2018

Symptomatic drugs may slow your progression

Drugs that  control MS symtoms have been reported to be neuroprotective in models of MS and so they should slow progression.
I say NSS this is what we have been saying for a long time,

Tuesday, 27 November 2018

A sneak peak at the blog's makeover. What do you think?

The Bart-MS blog is getting a brand new makeover. And we want to hear your thoughts about it.

Have a heart

Acta Neurol Belg. 2018 Nov 23. doi: 10.1007/s13760-018-1051-4. [Epub ahead of print]

Adrenergic hyperactivity: a missing link between multiple sclerosis and cardiovascular comorbidities?

Habek M, Mutak T, Nevajdić B, Pucić D, Crnošija L, Krbot Skorić M.


The aim of the study is to investigate differences in non-standard adrenergic baroreflex sensitivity (BRS) indices in patients with different phenotypes of multiple sclerosis (pwMS) and healthy controls (HC). Retrospective analysis of types of systolic blood pressure (BP) curves during Valsalva maneuver (VM) [balanced (BAR), augmented (AAR) and suppressed (SAR) autonomic responses] and adrenergic baroreflex sensitivity (BRSa) measured with BRSa1, α-BRSa and β-BRSa in patients with clinically isolated syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), progressive multiple sclerosis (PMS) and HC. We also investigated correlations between BRSa1, α-BRSa, β-BRSa and resting catecholamine levels. pwMS had higher α-BRSa compared to HC (p = 0.02). There was no difference in BRSa1, s and β-BRSa between patients with CIS, RRMS and PMS. There was no association between pwMS and HC, and the type of sBP curve [χ2 = 4.332, p = 0.114]. pwMS and BAR or AAR had higher supine systolic and diastolic BP compared to pwMS and SAR. There was a significant correlation between α-BRSa and upright systolic BP (rp =0.194, p = 0.017), α-BRSa and norepinephrine (rs =0.228, p = 0.021), and BRSa1 and epinephrine (rs = 0.226, p = 0.040). pwMS and HC exhibit different alpha-adrenergic response to Valsalva maneuver. These results may explain the connection between MS and increased cardiovascular risk.

'When sorrows come, they come not single spies.
But in Battalions'
-William Shakespeare

Monday, 26 November 2018

Make time for learning

I would like to thank all our readers for persevering. Tomorrow is the launch of the first triMS-online virtual conference. The ideas underpinning this meeting arose from suggestions on this blog.

The driving principles underlying triMS-online are:

The complexity of the Microglia Uncovered..Nine different good, it was published twice.

I seldom read a paper and think wow.....This study from Harvard reveals the signature of microglia as mice age and they look at over 76,000 individual cells and get their whole transcriptomes........M1 and M2 are out of the window here comes M1-M9

Sunday, 25 November 2018

Learning about the effects of B cell depletion

B cell depletion in other conditions, can it tells us how things work

Saturday, 24 November 2018

S1P2 receptor as a target for remyelination

People have desperately being trying to show that fingolimod promotes remyelination and it has been have notably suggested that it can target glial cells via sphingosine -1-phosphate 5 receptor (S1P-5) adding to the effects on modulation of S1P1 to blcok lymphocyte migration.

Fingolimod blocks activity of S1P1, S1P3, S1P4 and S1P5, is the missing activity on S1P2 a probablem...

Maybe so.

Friday, 23 November 2018

Watch out when you finish fingo

Anyone who reads the blog will know about this already, but just in case it stipped your mind...When you decide to start a new treatment, you need to think how you will tcome off it, if it doesn't work.

The big problem comes with the immune-migration inhibitors and they cause rebound if disease is not effectiviely controlled

Thursday, 22 November 2018

Now Dogs are a Risk factor for MS

Cats influencing MS is the number one post read on the blog

T cells back in the pack

Helper CD4 T cells expressing granzyme B cause glial fibrillary acidic protein fragmentation in astrocytes in an MHCII-independent manner. Stopnicki B, Blain M, Cui QL, Kennedy TE, Antel JP, Healy LM, Darlington PJ. Glia. 2018 Nov 16. doi: 10.1002/glia.23503. [Epub ahead of print]

During inflammatory processes of the central nervous system, helper T cells have the capacity to cross the blood-brain barrier and injure or kill neural cells through cytotoxic mechanisms. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein that is part of the astrocyte cytoskeleton that can become fragmented in neuroinflammatory conditions. The mechanism of action by which helper T cells with cytotoxic properties injure astrocytes is not completely understood. Primary human astrocytes were obtained from foetal brain tissue. Human helper (CD4+ ) T cells were isolated from peripheral blood mononuclear cells and activated with the superantigen staphylococcal enterotoxin E (SEE). 

Granzyme B was detected by enzyme linked immunosorbent assay and intracellular flow cytometry. GFAP fragmentation was monitored by western blotting. Cell death was monitored by lactic acid dehydrogenase release and terminal biotin-dUTP nick labeling (TUNEL). Astrocyte migration was monitored by scratch assay. Adult human oligodendrocytes were cultured with sublethally injured astrocytes to determine support function. Helper T cells activated with SEE expressed granzyme B but not perforin. Helper T cells released granzyme B upon contact with astrocytes and caused GFAP fragmentation in a caspase-dependent, MHCII-independent manner. Sublethally injured astrocytes were not apoptotic; however, their processes were thin and elongated, their migration was attenuated, and their ability to support oligodendrocytes was reduced in vitro. Helper T cells can release granzyme B causing sublethal injury to astrocytes, which compromises the supportive functions of astrocytes. Blocking these pathways may lead to improved resolution of neuroinflammatory lesions.

CD4 T cells are usually activated by antigen and MHC class by antibegn presenting cells  in conjunction with co-stimulatory molecules.  In this stuy they used a superantigen which can trigger cells expressing certain T cell receptors and makes the T cell activated. In this study these cells release a molecule that can kill astrocytes. Would these cells kill astrocytes in MS and is this process relevant to MS,

Wednesday, 21 November 2018

Chief Energy Officer, or not

The MS Academy held our first #MSVariance meeting on 1st and 2nd of November in Birmingham. We were oversubscribed, which would indicate that there is an appetite for change in the way we practice MSology in the UK. I learnt a lot from the meeting and had several of my assumptions challenged.

Switching from Natalizumab

Pfeuffer S, Schmidt R, Straeten FA, Pul R, Kleinschnitz C, Wieshuber M, Lee DH, Linker RA, Doerck S, Straeten V, Windhagen S, Pawlitzki M, Aufenberg C, Lang M, Eienbroeker C, Tackenberg B, Limmroth V, Wildemann B, Haas J, Klotz L, Wiendl H, Ruck T, Meuth SG. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation.J Neurol. 2018 Nov 16. doi: 10.1007/s00415-018-9117-z.

BACKGROUND:Natalizumab (NTZ) was the first approved monoclonal antibody for the treatment of relapsing-remitting multiple sclerosis(RRMS). Despite proven and sustained efficacy, its use is limited by the risk of progressive multifocal leukoencephalopathy (PML). Moreover, some patients show ongoing disease activity under NTZ, requiring a switch to another disease-modifying treatment (DMT). However, evidence regarding the optimal DMT for treatment of active RRMS after NTZ-cessation is still scarce.
OBJECTIVE:To evaluate efficacy and safety outcomes of ALEM vs FTY treatment after cessation of NTZ.
METHODS:We retrospectively identified patients at 12 German neurology centers and analyzed risks for disease activity, adverse events, disability progression, and treatment discontinuation.
RESULTS:195 patients were identified and 144 underwent final analysis (FTY: 101; ALEM: 42). The hazard ratio for clinical relapses was 2.24 favoring ALEM (95% CI 1.12-4.50; p = 0.015). The hazard ratio for adverse events was 7.78 (95% CI 1.04-57.95; p = 0.006) and 2.41 for MRI progression (95% CI 1.26-4.60; p = 0.004). The odds ratio for disability progression after 12 months was 4.84 (95% CI 1.74-13.47, p = 0.003). Differences remained after adjusting for possible confounders (e.g., age, sex, baseline disability, NTZ treatment duration, washout time).
CONCLUSION:Our findings indicated particular advantages of ALEM compared to FTY in patients stopping NTZ.

COI: Multiple. I do not need to comment, You cant read.

Tuesday, 20 November 2018

Drugs that harm toddlers

Clin Drug Investig. 2018 Nov 15. doi: 10.1007/s40261-018-0726-1. [Epub ahead of print]

Drugs that Can Kill a Toddler with One Tablet or Teaspoonful: A 2018 Updated List.

Monday, 19 November 2018

Oligodendrocytes become antigen presenting cells

Now we have Th1 and Th2, then came M1 and M2 for macrophages, then we got A1 and A2 for astrocytes as the lab wanted some naming-fame and now we have different oligodendrocytes. Is this O1 and O2 for Good and the bad guys?

Sunday, 18 November 2018

EBV Immunotherapy Works in MS

Perhaps this is what we have been hoping for, but come on I say, look at the result. It is hardly the end of MS.

Saturday, 17 November 2018

How does HSCT work?

I have been asking myself about the non-myeablative HSCT and wondering how does it work?

It is often a combination of cyclophophamide and anti-thymocyte globulin.

Friday, 16 November 2018

Alternatives to Cladribine tablets appears

DrK has been beavering away and has now started to disclose his experience

Thursday, 15 November 2018

HSCT after natalizumab

Mariottini A, Innocenti C, Forci B, Magnani E, Mechi C, Barilaro A, Nistri R, Fani A, Saccardi R, Massacesi L, Repice AM. Safety and efficacy of autologous hematopoietic stem cell transplantation following natalizumab discontinuation in aggressive Multiple Sclerosis. Eur J Neurol. 2018 Nov 10. doi: 10.1111/ene.13866. [Epub ahead of print]

BACKGROUND: Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting multiple sclerosis (RRMS), but its withdrawal is often followed by disease reactivation or rebound, even if other disease-modifying treatments (DMTs) are administered. In this study, for the first time, safety and efficacy of autologous hematopoietic stem cell transplantation (aHSCT) performed following NTZ discontinuation was retrospectively compared with conventional DMTs.
METHODS: Patients with RRMS treated with NTZ and who discontinued the drug after at least six administrations and with at least six months of follow-up were included. Patients underwent aHSCT after a minimum period of six months following NTZ withdrawal, receiving in the meanwhile cyclophosphamide or corticosteroids, or received other DMTs approved for MS (control group) after an adequate wash-out period. Both haematological and neurological follow-up were assessed according to standard policies.
RESULTS: Fifty-two patients were included, 11 who received aHSCT and 41 DMTs. Baseline clinical and demographic characteristics were similar between the two groups. No fatality or life-threatening complications, including Progressive Multifocal Leukoencephalopathy, were observed. At three years following NTZ discontinuation no evidence of disease activity was reported in 54.5% of the patients in the aHSCT group compared to 11.5% of those in the DMT group (p=0.0212); disease reactivation in the aHSCT patients was observed only during wash-out/bridging therapy and after aHSCT 100% of the cases were free from disease activity.
CONCLUSION: These data suggest that an aggressive therapy should be established after NTZ with the shortest possible wash-out period. AHSCT after six months from NTZ withdrawal seems safe.

If you are not having a sub clinical infection of JC virus, conversion to a depleting antibody is safe. However there have been cases of fatality after alemtuzumab, where there was carry over infection. So the risks for HSCT are similar so ensure you don't have sub clinical PML before starting