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 MSers 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.