Sunday, 30 September 2018

Engaging the wider MS community: MS Ireland & South Devon 2018

An important and often neglected part of being an academic is public engagement or PPI (patient-public involvement). The aim of these activities is to try and communicate the science of MS in a way that is understandable to people and to involve them in MS Research. 

Over the last two weekends, I presented at the MS Ireland annual meeting in Athlone and the South Devon MS Meeting in Torquay.

For the slides and more.....

Saturday, 29 September 2018

DMF inhibiting B cells numbers

Times are a changing folks. 
Not a year ago the same type of phenotpying data was reported in the blood of people treated with DMF. 
The focus has now changed, guess where.

Friday, 28 September 2018

Treating Fatigue with Stem Cells

Fatigue is the symptom which has been high on the agenda for research into its cause and cure.

Thursday, 27 September 2018

ECTRIMS 2018... here we go again!

In little over 2 weeks' time, the MS professional community will travel to Berlin for the 34th ECTRIMS meeting. It's the largest European conference focusing on MS research and treatment, and is attended by MS healthcare professionals, companies, researchers and charities.

Similar to previous years, the Barts-MS team are keen to get some of this new research out to you as quickly as we can, and also provide opportunities for you to get involved. 

Wednesday, 26 September 2018

Guest Post: The Real, Real Deal with Exercising and MS

Oh no. No, no, no, you’re thinking. Not another Barts MS Blog lecture on the importance of exercising when you have multiple sclerosis. Especially a guest blog from that Dave guy who runs and who thinks he is funny and has no professional medical or physical fitness credentials—just a dude who runs a blog, ruffles feathers like Gavin, and works out.

Tuesday, 25 September 2018

And the risk-sharing scheme results...

J Neurol Neurosurg Psychiatry. 2018 Sep 21. pii: jnnp-2018-318360. doi: 10.1136/jnnp-2018-318360. [Epub ahead of print]

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme.

Palace J, Duddy M, Lawton M, Bregenzer T, Zhu F, Boggild M, Piske B, Robertson NP, Oger J, Tremlett H, Tilling K, Ben-Shlomo Y, Lilford R, Dobson C.



Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue.


The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model.


4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores.


This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study.
Figure: Time to sustained EDSS 6.0 (requiring a single stick) in RSS (risk-sharing scheme) treated groups and in the untreated comparative control group.

Finally ladies and gentleman, the UK risk-sharing scheme 10y data is ready for prime-time; with me sound asleep at my desk none the wiser that it has been published. For those of you who haven't heard of the UK risk-sharing scheme before, this post gives you a good overview:

You might ask what's the big deal? The scheme targets an era in RRMS that has now been superseded by better and faster acting MS treatments. It has also been heavily criticized for it's non-randomized comparisons introducing bias into the assessment, the lack of power calculations to determine the number needed to treat, and last but not least despite including drugs it's main purpose is not to determine their clinical effectiveness but establish long-term cost effectiveness. But, the powers of B need their pound of flesh, and a promise is a promise...

Armed with the uncertainty of long-term benefits of DMTs (Disease Modifying Therapies), the risk-sharing scheme authors 10y on ask how sustainable are their treatment effects? More importantly could their early treatment effect have long-term impacts on disability?

The study recruited ~ 5000 participants on interferons-betas (IFNBs) and glatiramer acetate between 2002 and 2005, and followed them up for 10y. Their efficacy was compared with natural history data of untreated individuals. The analysis of interest were two fold: 1) what was the effect of time on the outcome and 2) what was the effect of treatment on time to loss of unaided ambulation?

Two methadologies of assessing efficacy were used; one was the Markov model, which uses the annual probabilities of moving between EDSS (a measure of disability) scores (or remaining on the same score) from the values derived from the untreated individuals, and the second was the multilevel model (MLM), which uses the average trajectory for the whole population that is then applied to the baseline data of participants in the RSS to predict their EDSS progression if they had been without treatment. The latter is then compared with the observed values to estimate the absolute treatment effect.

Surprisingly, or unsuprisingly the 10y-treatment effect was a 0.61 reduction using MLM and 0.12 reduction using the Markov model in mean EDSS scores. The corresponding relative reduction in progression was 28% using MLM and 7% using the Markov model. The average time to sustained EDSS 6.0 was 12.5y vs 8.4y for untreated individuals, i.e. a delay by 4y in reaching the requirement for a walking stick (see figure above). A greater impact of treatment was observed in those with a lower disability level at the start, a shorter time from disease onset, women rather than men, those on treatment throughout rather than those who came off treatment in between, and those recruited later on in the scheme (probably because more in the early course of the disease were recruited as the study went on). Last but not least, there was treatment effect throughout the study, but it became progressively smaller as the study went on.

Around 17% of those included initially switched to highly active drugs and therefore left the study and 18% discontinued treatment, effectively excluding those on a worse disease projection from the overall analysis. Moreover, this paper doesn't include any data on how the individual DMTs fared, which is disappointing. However, having said this the study sets the precedent for future works of this ilk and teaches us something about lessons that can only be learned the hard way.

Monday, 24 September 2018

Old but good news: children and adolescents get their first licensed DMT in Europe

I personally want to thank all those involved in getting fingolimod licensed as the first disease-modifying therapy for children and adolescents with MS. Getting this trial done was a 'mission impossible'. Novartis, the steering committee, investigators and all study participants must be congratulated on getting past the finish line. History will judge this as an important milestone for MSers and the wider MS community.

Sunday, 23 September 2018

A quick summary of Prof G's Twitter activity (17-23 Sept 2018)

Papers during the week

Here are some papers you may or may not find interesting

Saturday, 22 September 2018

Is EAE a valid tool if studing MS

Mouse EAEers currently use myelin oligodendrocyte glycoprotein to induce disease, with which to study MS.

However, do people with MS respond to this protein

Friday, 21 September 2018

The Scottish MS Register Annual Report - 2018

The Scottish MS Register (SMSR) has been collecting data on everyone with a confirmed diagnosis of MS in Scotland since the year 2010. Unfortunately, Scotland has one of the highest rates of MS in the world. The Scottish MS register was set up to count people newly diagnosed with MS, to help monitor service quality and to plan future services for people with MS.

Thursday, 20 September 2018

CCSVI2..Don't Do it.

Messing about with suspected blocked blood vessels led to the CCSVI movement, that was discredited by science, 

So yesterday we had the media suggesting that you should block a different vessel in the brain to get rid of MS. 

One of the readers asked whether this is the beginning of CCSVI2

 It was claimed that a "Team identifies brain's lymphatic vessels as new avenue to treat multiple sclerosis" in the headline from Medical express..."

What do they actually say?

Wednesday, 19 September 2018

Copaxone, why is is not so effective?

I think Glatiramer acetate (at the population level) is a low efficacy treatment.

What supports this?

Shame on Barts Health NHS Trust

In our patch of East London if you have MS and live in Newham you get a very poor service; for example, you are 3-4 times more likely to require an emergency or non-elective hospital admission compared to if you live in Tower Hamlets or Hackney (our local London boroughs).


Tuesday, 18 September 2018

Real-world experience on first line oral therapies DMF and teriflunomide

Comparable efficacy and safety of dimethyl fumarate and teriflunomide treatment in Relapsing-Remitting Multiple Sclerosis: an Italian real-word multicenter experience

E D’Amico, A Zanghì, G Callari, G Borriello, A Gallo, G Graziano, P Valentino, M Buccafusca, S Cottone, G Salemi, P Ragonese, R B Bossio, R Docimo, L M E Grimaldi, C Pozzilli, G Tedeschi, M Zappia, F Patti

Ther Adv Neurol Disord. 2018; 11: 1756286418796404. Published online 2018 Sep 10.


The aim of the study was to evaluate the achievement of ‘no evidence of disease activity’ (NEDA) over a 12-month period in a large multicenter population with relapsing remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) and teriflunomide (TRF) using a propensity-score adjustment.


A time-to-event method was used to determine the percentages of patients with RRMS (pwRRMS) in both groups achieving NEDA 3 (no relapses, no 12-week confirmed disability progression, and no new T2/gadolinium-enhancing brain lesions). We described the safety profile of the investigated drugs.


Of the 587 pwRRMS treated with DMF and the 316 pwRRMS treated with TRF, 468 pwRRMS were successfully paired by propensity score: 234 on DMF and 234 on TRF. The percentages of pwRRMS who achieved NEDA 3 were 80.3% in the DMF group and 77.2% in the TRF group. Serious adverse events occurred in four (1.9%) pwRRMS on DMF and in three (1.3%) pwRRMS on TRF.


DMF and TRF significantly impacted RRMS disease activity in our study. Serious safety concerns were recorded in less than 2% of the studied population.

Figure: Frequency of adverse events on tecfidera (DMF) and aubagio (teriflunomide)

Last week I looked at a paper comparing the highly active monoclonals, and this week it's the turn of first line oral therapies: dimethyl fumarate (tecfidera) and teriflunomide (aubagio) in RRMS. This study proves something that I've suspected for some time now, which is that aubagio is not half-bad.

At the time of its advent it was probably the least likely to be prescribed of the two; firstly it's unpopular two weekly liver function blood monitoring over a 6 month period, and then there is its unattractive elimination procedure. But, over the years I've come to the realization that tecfidera itself is not straightforward as directed on the packet. The management of lymphopenia on tecfidera, particularly the grade 3 lymphopenias is not an easy task (<500-200m^3 or 0.5-0.2x10^9), and in my practice has directly resulted in a number of lateral swaps to using aubagio instead (some of you reading this are probably nodding your head). I may even go as so far as to say that aubagio is the tortoise in this saga; and we all know how that one ended.

D'Amico and colleagues findings of a head-to-head performance of the two drugs is therefore not surprising. After one year of treatment, NEDA (no evidence of disease activity, based on clinical and MRI parameters) was 80.3% on tecfidera and 77.2% for aubagio. Furthermore, there was no difference in the time to 1st relapse after starting treatment. Among those who discontinued treatment it was 4.3% on tecfidera and 3% on teriflunomide (6 on tecfidera due to lack of efficacy vs. 2 on aubagio - not statistically significant). Those on tecfidera were more likely to have not been on an MS drug before as opposed to aubagio, suggesting that the latter has good efficacy. Adverse events (detailed above) were 26.5% on tecfidera was 12% on teriflunomide (p<0.001), but serious adverse events were similar in both treatments (severe lymphopenia and diarrhoea with tecfidera, and severe vomiting and two cancers with teriflunomide).

Whether the long-term outlook of both drugs is the same is unanswered by this work. Real-life practice is messy, but for the time being looking at short-term objectives is a start.

Monday, 17 September 2018

MSexism take two: The Mystery of the Missing Authors

Recently this blog featured an eye-opening article written by our guest blogger Rachel, about gender inequality in the world of multiple sclerosis, from a patient’s point of view. It’s well worth a read. She also outlines just how few women feature on academic panels. And this investigation has now been taken further, with an analysis of authors on academic papers.

Rachel Horne interviews ProfG to ascertain why the Department of Health and NICE have said no to ocrelizumab for treating people with PPMS. 

Sunday, 16 September 2018

Socks make Myelin

More on experimental myelination

Benign MS. How common is it?

Benign MS is MS is something that I guess you hope for, if you get an MS diagnosis. Likewise if you are a neurologist, benign MS may mean that you don't  commit to treatment.

But how common is this in the UK?

Saturday, 15 September 2018

Fingo Coming of Age

Fingolimod is better than interferon beta in adults so what happens in children.

Yep you got it.

Diagnosis MS.Saving 3 years

The McDonald criteria are diagnostic criteria for multiple sclerosis (MS).They have undergone revisions in 2005, 2010 and 2017

Has this made a difference?

Friday, 14 September 2018

Wakey-wakey people. Read this and it all becomes clear. MS gets simpler

If you are a regular reader of the blog, you may think this work is old hat. This is because you have been watching these ideas evolve over the past year.

Hopefully for others who have not been following us, this could be a day of revelation and the Penny may finally Drop (The penny dropped is a casual idiom outside the United States used to mean a person has belatedly put two and two together or understood something).

If you are a nurse or a neurologist or Junior Doctor, and only read one paper (Click on link below for full paper) a year give this one a read. It may help you conceptualise MS and its treatment better as "MS therapy just got easier".  

Send this post to your friends. Ask them for holes in the arguments.

If you are a person with MS, give it a read and ask questions if you don't understand. It may make your descisions of treatment easier.

However, for all you young-researchers (meaning mentally young even if old in body) out there...the old-ones are probably a lost cause as they are unlikely to want change their ways and will simply ignore this:-(.....Give this a read, spot the holes and the inconsistencies, but maybe look at your research in a different way. Try and disprove the ideas. 

Depletion of CD20 B cells increases active B cells...killing our idea...Maybe not.

To continue on with today’s subject

Are you interested in what happens in mice following CD20 depletion?

Read the paper below and I think it says we have got the "B memory cell idea" all wrong.
However, read the data (and the literatureL) and perhaps we can make some other conclusions. 

Suggesting mouse is not more ways than one


Thursday, 13 September 2018

Will we ever learn? Just need to Read and Assimilate. Is it too much to Ask?

Results of a mycopheylate study in PPMS

Looks like mycophenolate is down the tube as far as progressive MS goes?

I wonder are Neuros doing their upmost to ensure that we don't deliver treatment options

Wednesday, 12 September 2018

Guest post: The meaning of exercise and physical activity in community-dwelling people with MS

It is well established that exercise and physical activity is beneficial for people with MS. However, we also know that people with MS report lower levels of physical
activity and lead sedentary lifestyles. Finding ways to increase physical activity in people with MS remains a challenge for both people with MS and health professionals.
Nevertheless, getting this right is crucial because of the increased risk associated with the secondary complications associated with inactivity. These include, but are not limited to, type 2 diabetes, stroke and cardiovascular conditions.

Tuesday, 11 September 2018

ProfG and his cry for Action

ProfG says he is fuming and on the warpath.

Looks like the MS Society is too.

They want access to treatment for people with PPMS

If you do, Sign Up (CLICK HERE) Now and Speak Up

COI: None Relevant

The leader of the pack

Mult Scler Relat Disord. 2018 Aug 29;25:322-328. doi: 10.1016/j.msard.2018.08.026. [Epub ahead of print]

Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis.

Xu X, Chi S, Wang Q, Li C, Xu B, Zhang J, Chen X.


Several monoclonal antibodies have been licensed for relapsing remitting multiple sclerosis (RRMS). It is still unclear which treatment regimen should be recommended due to the lack of head-to-head randomized controlled trials (RCTs). This study aims to investigate the relative efficacy and safety of existing monoclonal antibody therapies in treating RRMS.


We searched PubMed, Embase, and the Cochrane Library for RCTs of monoclonal antibodies for treatment of RRMS. We performed a network meta-analysis to identify evidence comparing monoclonal antibodies with one another, interferon beta-1a (INFβ-1a), or placebo in adult patients with RRMS. The primary efficacy outcome was annualized relapse rate and the primary safety outcome was incidence rate of serious adverse events.


A total of 14 eligible studies containing 9412 patients treated with 7 regimens were analyzed. INFβ-1a was the most common comparison treatment and showed an annualized relapse rate of 45.3%. All monoclonal antibody regimens, including natalizumab, natalizumab plus INFβ-1a, alemtuzumab, daclizumab, and ocrelizumab, were associated with significant reduction in annualized relapse rate and similar risks of serious adverse events. Cluster analysis showed that natalizumab plus INFβ-1a and alemtuzumab performed best in terms of high efficacy and safety. Natalizumab and daclizumab were characterized by high efficacy but relatively high risk of serious adverse events. Ocrelizumab was differentiated by high safety but relatively poor efficacy.


This network meta-analysis provided a comprehensive summary of efficacy and safety of monoclonal antibodies for RRMS, which might provide a reference for treatment. More direct comparison studies are warranted.

Figure: Network meta-analysis of monoclonal antibodies compared with INFβ-1a for primary efficacy and safety outcomes. (a) Annualized relapse rate, (b) incidence rate of sever adverse events, (c) cluster rank plot of ranking estimation for reducing annualized relapse and serious adverse events. Mean with 95% CI represent the risk ratio and its 95% confidence interval of annualized relapse rate and serious adverse events. The dashed lines represent the different quadrants of the ranking estimation. ALE = alemtuzumab; DAC = daclizumab; NAT = natalizumab; OCR = ocrelizumab; PBO = placebo.

If I'm asking you a question, chances are I already know the answer...How you might add? My reply would be that you get answers only when you ask the correct questions. Pause for a moment and think about it.

RRMS therapeutics is a smorgasbord of the new and the old, but the question on everyone's lips is who is the leader of the pack? There is then the annoying concept of  how to sequence these treatments in order to avoid short and long-term complications. Whilst the pharmaceutical industry brings out the latest kid on the block, neurologists and regulatory authorities watch agog at the runaway horse, whilst at the same time trying to bring back some semblance of order. The regular neurologist is content to follow the pack (nothing wrong with this), but its the 'experts' who will be deciding on which questions we should all be asking. It is a race to the finish line. And, the guidance you end up following is very much dependent upon which corner of the world you currently inhabit.

Here is an interesting attempt by Xu and colleagues to make our life a bit easier by telling us which treatments are best for RRMS in terms of efficacy and safety (note daclizumab has been withdrawn owing to safety issues). The monoclonals of course seem to be the obvious choice (natalizumab, alemtuzumab, ocrelizumab, dacalizumab), all know to be superior to interferon-beta 1a - but which one is the best? The issue remains that there are no head-to-head studies, but with some statistical jiggery anything is possible (for those who're interested, its a network meta-analysis using a consistency model by frequentist approaches with interferon as the comparator). Luckily interferon hasn't changed much!

They found that natalizumab, natalizumab plus INFβ-1a, alemtuzumab, daclizumab, and ocrelizumab were associated with a significantly lowered risk of annualized relapse rate compared with INFβ-1a (RR 0.14 [95% CI 0.11–0.19] for natalizumab plus INFβ-1a, 0.31 [0.24–0.39] for alemtuzumab, 0.41 [0.26–0.64] for natalizumab, 0.45 [0.37–0.55] for daclizumab, and 0.45 [0.36–0.56] for ocrelizumab). Ranking according to relapse rates the best treatments were: natalizumab plus interferon > alemtuzumab > natalizumab > daclizumab (withdrawn) > ocrelizumab. All biologicals had a similar incidence of serious adverse events. If you combined relapse rate reduction to serious adverse events, natalizumab plus interferon beta-1a was associated with the best outcome. Whilst, in terms of a single drug alemtuzumab was the leader of the pack, and ocrelizumab at the bottom of the monoclonals (see figure above).

Without stepping on anybody's toes, this study confirms what we already know, which is that monoclonals offer the best option for a person with RRMS.

Monday, 10 September 2018

News: Prof G is fuming, why?

I am considering giving up working for the NHS. How can I face my patients with active PPMS and tell them we can't treat their disease because the Department of Health/NHS won't come to the table with a deal that involves differential pricing of ocrelizumab?

NICE has just said no to ocrelizumab for treating active PPMS on the NHS. Why? The problem is that the price of ocrelizumab has been set for RRMS and this is too expensive for the NHS; i.e. it is not cost-effective for the treatment of PPMS based on its efficacy in PPMS and the fact that ocrelizumab has to be compared to best supportive care (no treatment) for PPMS. In comparison, in RRMS ocrelizumab was compared to all the other DMTs. To address these issues I have been told that Roche agreed to lower the price for ocrelizumab for the PPMS indication so that it would be cost-effective. This would mean that ocrelizumab would need two prices on the NHS books; a more expensive price to treat RRMS and a cheaper price for PPMS. Apparently, the Department of Health is not prepared to go there. Why not? In short, they don't give a toss about PPMSers. For the DoH and the NHS, this is just another can of worms they want to be kicked into the long grass. 

This decision creates inequity; those PPMSer lucky enough to be wealthy and have money will get ocrelizumab privately, those lucky enough to have been in clinical trials will get it from Roche as part of the extension study and those lucky enough to live in another EU country will be on it via their healthcare system. There is a chance the Scottish NHS may say yes, then we would end up with the situation that Scotthish PPMSers will have access to ocrelizumab, but not English PPMSers.  

What can we do about it? I think we need to launch a protest campaign that includes the following:
  1. An open petition; we will need 100,000 signatories to trigger a debate in the house of commons.
  2. A passive email/letter campaign; each and every one of you who cares about the treatment of PPMS needs to write to your MP to ask for an explanation.
  3. Street protests; we need to organise a protest and march on the DoH. Do you think they will respond to a 1,000s of MSers, their families and friends outside the DoH's HQ in Whitehall? We could block Whitehall with wheelchair users. 
  4. We need to media behind the campaign; article after article and TV programmes about the issues raised by this perverse decision. We need the broader public to know about the issues. The implications of the ocrelizumab rejection go far beyond the treatment of a small group of PPMSers. 
If any of you want to help please contact me. I need ideas as well. 

If this decision was about breast cancer or HIV there would be national protests. The pink and red ribbon brigades would be out in force. Let's make it an orange ribbon day. 

CoI: multiple; I sat on the steering committee for the ORATORIO (ocrelizumab in PPMS) trial and I am the principal investigator of the ORATORIO-HAND trial (ocrelizumab in advanced PPMS). I am conflicted up to my eyeballs, but I am also an advocate for my patients. They need me to stick my head above the parapet and fight for them, which is what I am going to do. 

B cells against brain proteins during active MS

These papers were from a  fews years back but I have decided to post them as this paper looks for B cells that react to proteins within the brain. Not myelin proteins in particular. They simply look at a brain mush and find that the majority of people with MS make B cells that can recongnise the brain. These represent plasma cells/plasma blasts making antibody at the time of assays and the memory B cells are detected by activating the memory B cell pool to produce plsma cells/plasma blasts. These are increase in active disease and people who are negative can become positive as  people relapse. This suggests that there are brain reactive  B cells occuring in active MS

Identification of a B cell-dependent subpopulation of multiple sclerosis by measurements of brain-reactive B cells in the blood.
Kuerten S, Pommerschein G, Barth SK, Hohmann C, Milles B, Sammer FW, Duffy CE, Wunsch M, Rovituso DM, Schroeter M, Addicks K, Kaiser CC, Lehmann PV.Clin Immunol. 2014 May-Jun;152(1-2):20-4.

B cells are increasingly coming into play in the pathogenesis of multiple sclerosis (MS). Here, we screened peripheral blood mononuclear cells (PBMC) from patients with clinically isolated syndrome (CIS), MS, other non-inflammatory neurological, inflammatory neurological or autoimmune diseases, and healthy donors for their B cell reactivity to CNS antigen using the enzyme-linked immunospot technique (ELISPOT) after 96 h of polyclonal stimulation. Our data show that nine of 15 patients with CIS (60.0%) and 53 of 67 patients with definite MS (79.1%) displayed CNS-reactive B cells, compared to none of the control donors. The presence of CNS-reactive B cells in the blood of the majority of patients with MS or at risk to develop MS along with their absence in control subjects suggests that they might be indicative of a B cell-dependent subpopulation of the disease.

Categorization of multiple sclerosis relapse subtypes by B cell profiling in the blood.Hohmann C, Milles B, Schinke M, Schroeter M, Ulzheimer J, Kraft P, Kleinschnitz C, Lehmann PV, Kuerten S.
Acta Neuropathol Commun. 2014 Sep 16;2:138.
INTRODUCTION:B cells are attracting increasing attention in the pathogenesis of multiple sclerosis (MS). B cell-targeted therapies with monoclonal antibodies or plasmapheresis have been shown to be successful in a subset of patients. Here, patients with either relapsing-remitting (n = 24) or secondary progressive (n = 6) MS presenting with an acute clinical relapse were screened for their B cell reactivity to brain antigens and were re-tested three to nine months later. Enzyme-linked immunospot technique (ELISPOT) was used to identify brain-reactive B cells in peripheral blood mononuclear cells (PBMC) directly ex vivo and after 96 h of polyclonal stimulation. Clinical severity of symptoms was determined using the Expanded Disability Status Scale (EDSS).
RESULTS:Nine patients displayed B cells in the blood producing brain-specific antibodies directly ex vivo. Six patients were classified as B cell positive donors only after polyclonal B cell stimulation. In 15 patients a B cell response to brain antigens was absent. Based on the autoreactive B cell response we categorized MS relapses into three different patterns. Patients who displayed brain-reactive B cell responses both directly ex vivo and after polyclonal stimulation (pattern I) were significantly younger than patients in whom only memory B cell responses were detectable or entirely absent (patterns II and III; p = 0.003). In one patient a conversion to a positive B cell response as measured directly ex vivo and subsequently also after polyclonal stimulation was associated with the development of a clinical relapse. The evaluation of the predictive value of a brain antigen-specific B cell response showed that seven of eight patients (87.5%) with a pattern I response encountered a clinical relapse during the observation period of 10 months, compared to two of five patients (40%) with a pattern II and three of 14 patients (21.4%) with a pattern III response (p = 0.0005; hazard ratio 6.08 (95% confidence interval 1.87-19.77).
CONCLUSIONS:Our data indicate actively ongoing B cell-mediated immunity against brain antigens in a subset of MS patients that may be causative of clinical relapses and provide new diagnostic and therapeutic options for a subset of patients.

Sunday, 9 September 2018

A beta interferon me-too is just as good as the original

We have been talking about the differences between the original and generic variants. This study looks at the effect of Cinnovex and Avonex and finds no difference.

Pakdaman H, Abbasi M, Gharagozli K, Ashrafi F, Delavar Kasmaei H, Amini Harandi A. A randomized double-blind trial of comparative efficacy and safety of Avonex and CinnoVex for treatment of relapsing-remitting multiple sclerosis.Neurol Sci. 2018. doi: 10.1007/s10072-018-3550-8. [Epub ahead of print]

BACKGROUND AND AIM: Interferon beta is currently the first line treatment of relapsing-remitting multiple sclerosis (RRMS). Different formulations of interferon beta are available. Avonex and CinnoVex are two interferon beta-1a being prescribed by neurologists in Iran. The aim of this study was to compare the four and half year outcome of Avonex and CinnoVex in patients with RRMS.
METHODS:A total 186 of patients with definite RRMS diagnosis were followed for four and half years. Patients were randomly assigned to receive either Avonex or CinnoVex. Patients were subsequently visited every 6 months, and MRI was also undertaken prior each visit. The efficacy end points were to compare mean scores of expanded disability status scale (EDSS) and the proportion of patients with MRI and clinical activity in follow-up visits between Avonex and CinnoVex. Safety end point was to compare the percentage of adverse events between two groups.
RESULTS:One hundred and eighty-two patients completed the study. The population of study experienced a steady increase in EDSS during follow-up with a mean increase of 1.03. Repeated measures ANOVA revealed no statistically significant difference between Avonex and CinnoVex (p = 0.78). The most common adverse events were headache, myalgia, fatigue, fever, flu symptoms, injection site pain, and depression. Direct comparison of each adverse events revealed no meaningful difference between two groups except for only a few adverse events. There was no statistically significant difference in MRI activity and clinical activity between two groups.
CONCLUSION:Avonex and CinnoVex showed similar efficacy and safety outcome in patients with RRMS.

You may not have heard of Cinnovex, that is unless you live in Iran. If you live in Iran this may give you comfort that your home grown variant is as good as the American alternative.

Iran is a hot bed of MS, but it has been an international pyriah for many years. Many things were embargoed by the West, notably the USA. 

A few years ago American Journals were banned from accepting Iranian Scientist's work, if they were government sponsored:-(.

However, if you are seen as the "Worlds' bad lads" and you are banned from getting Western Goods, you can either do nothing for your population or you can say "Stuff the Global Patent System" and make your own drugs. 

This is what Iran does "allegedly" and Cinnovex is one example of this. 

It is good that Iranian Neurologists have done a formal trial to show that their generic is as good as the original version. 

The beta interferon patents have now expired so maybe they feel OK reporting this. However I have heard that Iran has produced their own Iranian fingolimod and cladribine. So good news for people with MS in Iran as I guess they have treatment options.

Saturday, 8 September 2018

T cells: a paper on Nur77

Interested in T cells?

The Good, The Bad and the Beautiful

Macrophages can be the Good guys  (Phagocytes are molecularly adapted for clearance of tissue debris and the support of CNS repair often termed M2 phagocytes) and also the bad guys (phagocytes with a proinflammatory polarization = classically activated or [M1 phagocytes] release high levels of toxic mediators, including reactive species, and contribute to CNS damage). But what makes these differences. In this beautiful study we find that it is environment within the CNS that dictates the path they choose.

Friday, 7 September 2018

Prognosis of fampridine Responsiveness

Fampridine helps you walk faster but it doesn't work for everyone.
Your baseline walking speed may predict if it will work for you.

Fampridine is a potassium channel modulator, which helps your nerves fire faster, allowing to walk faster.

Tuesday, 4 September 2018

Evidence from Iran that wealth is unrelated to MS

Mult Scler Relat Disord. 2018 Aug 23;25:292-296. doi: 10.1016/j.msard.2018.08.019. [Epub ahead of print]

No association between socioeconomic status and risk of multiple sclerosis: A population-based incident case-control study in a developing country.

Abdollahpour I, Nedjat S, Salimi Y, Moradzadeh R, Mansournia MA, Sahraian MA, Shokoohi M.


Evidence on the association between socioeconomic status (SES) and multiple sclerosis (MS) is inconsistent. We examined the association of several indicators of SES with MS in an Iranian population.


We conducted a population-based incident case-control study with 547 incident cases and 1057 general population controls in Iran, 2015. Data was collected using telephone interviews and indicators of SES i.e. parental education, and household SES during adolescence using asset variables. Adjusted odds ratios (AORs) were estimated using multiple logistic regression model.


Parental education levels were not significantly associated with MS development. Household SES during adolescence was insignificantly associated with an increased risk of MS diagnosis (P = 0.575).


We did not identify an association between household SES during adolescence, parental education levels, and a subsequent risk of developing MS in an Iranian population.

In Iran the rates of MS have been sky rocketing. In the capital city, Tehran, between 1989 and 2005 the yearly diagnoses of MS rose from 0.68 per 100,000 to 4.58 per 100,000. By 2009, the incidence rose even further to 9.1 per 100,000 with a prevalence of 73 per 100,000; approaching figures quoted for the UK. Who knows what has led to this sudden change? First and foremost cultural changes need to be factored in. Not being privy to the Iranian lifestyle I must admit that overlaying Western cultural risk factors may not be the correct way to go. But, it goes without saying that over the over the last two decades, like most Eastern nations, Iran has witnessed a dramatic rise in the wealth of the typical worker more in line with Global wealth, and possibly even adoption of certain Western lifestyles.

Socioeconomic status (SES) has received consistent attention as a risk factor for MS, in particular a higher levels of SES have been associated with a greater risk of developing MS, i.e. MS is more prevalent in higher income countries. Although this hasn't been a consistent finding, and in fact the complete opposite has been suggested in more recent studies. Studies which have used educational level as a proxy for SES have found the exact opposite; wherein individuals with a higher educational level were 39% less likely to get MS (Bjørnevik et al., 2016).

Here, Abdollahpour et al. investigate whether SES can be playing a role in the risk of MS in a developing nation, such as Iran. They conducted a population-based case-control study in the capital city Tehran, the most populated region in Iran. Using the Iranian MS Society registry they were able to contact 1057 of PwMS in the registry. They studied parental educational level, assets, participants educational level, and potential confounders (substance abuse and smoking history).

Although, they found that risk of MS was greater in those with illiterate parents and lower in those with University educated parents, this risk was not statistically significant (odds ratio/measure of an association between exposure and outcome was 1.03, CI 0.99-1.07). But, looking at asset values there was an increased but not significant risk in the higher asset groups compared to low asset groups.

In summary, this study did not show that SES was associated with an increased risk of multiple sclerosis. Such studies are often difficult to perform at a population level, in particular owing to lack of full information and the contextual nature of wealth which is forever changing. You might even argue that educational level is not the same as liquidable assets.

Monday, 3 September 2018

Should Prof G do less blogging and more walking the talk?

Did you know that approximately 25% of people diagnosed with a radiologically-isolated syndrome (RIS), or asymptomatic MS, already cognitive impairment and smaller brains? This indicates that even before MS has been diagnosed the disease processes are already causing subclinical damage to brains of people destined to develop full-blown MS in the future. The reason you are not aware of this is that the brain has spare capacity, reserve or some redundancy to allows you to compensate for this early damage.

What about hand function (#ThinkHand)?

Sunday, 2 September 2018

Tweet of the Week

Sorry Experiment failed, I can't keep up with the tweet monster.
Follow ProfG on twitter if you want to see his tweets,

Sign up or visit the web page

I've other things to do at the moment

How soon would you like your MS diagnosed?

The MS prodrome; how real is it? 

Saturday, 1 September 2018

Memory B cells are there to help CD4 T cells

Memory B Cells present antigen to CD4 T cells in multiple sclerosis, so T cells are on top of the pile and B cells are there to help the baddie T cells. Therefore, the status quo is maintained and everything is super.

However, has the latest autoantigen in MS been found?

Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic-, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as “autoproliferation” of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in an HLA-DR dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells.

In MS there are cells that are spontaneously proliferating in the blood. These can be found in the brain of people with MS. The cells that are proliferating are mainly memory T cells and they respond via a mechanism involving MHC class II and they produce interferon gamma (TH1) cells.

The B cells (Switched memory and to some extent non-switched) upregulate HLA-DR and drive the auto proliferation by T cells.

This is proliferation is not blocked by targeting CD40 on the B cells perhaps not surprising if EBV creates CD40 mimicks. However it could be blocked by bruton tyrosine kinase inhibitors. So maybe a mechanism of action of BTK inhibitors. 

They looked at cells found in CNS lesions and this consisted of T cells where it seems that the CD8 cells present are abundant in the periphery also suggesting that they were trafficking in perhaps by a bystander mechanisms. However, there were CD4 clones that may have expanded in the CNS. This study elegantly examined the recognition target of the cells and they recognised nucelotide exchange factors (RASGRPs), notabtly RAS guanyl-releasing protein 2. Other people recognised this target too. Is this the cause of autoimmunity in MS?

A nice piece of work that I have yet to adequately digest but I have my doubts.

Based on Message the target is expressed by nerves but it is is also found in other tissues, including lymphocytes. Is this why there is autoproliferation? 

Anyway a trial is now planned to block the immune response to this antigen. 

Q & A September

Not ready for Winter yet?

If you have a question unrelated to the thread this is the place for you