Saturday, 20 October 2018

Cladribine is getting rid of oligoclonal bands

Off-label Cladribine use has been championed by DrK and this in part led to the re-emergence of the oral variant, which remerged after a 6 year holiday.

During this time we have generated a large cohort  (See Stephanias ECTRIMS work below) of people taking this drug and we have defined a new working mechanism for cladribine .


Whilst memory B cell targeting is not uniqure to Cladribine, it has one potential advantage over other highly effective MS drugs.


This is that it enters (about 25% the blood level) and can be active within the CNS (Finglomido enters the brain but its main mechanism is in the lymph glands) . Therefore it can target elements of disease that are relevant to progressive MS.


However, the center of off-label cladribine was not the East-End of London, it was the East-End of Europe. Indeed our friends in Poland have been using of-label cladribine for years and they have asked what happens to the oligoclonal bands.


Interested read on.

Friday, 19 October 2018

Whats Lost is Lost, Why CRAB can sometimes mean CRAP

This German studies shows real life data that dimethyl fumarate is better than the CRAB drugs plus teriflunomide......So why are we still using them?

Thursday, 18 October 2018

Why is Prof G dissatisfied?

I have been espousing the message that time is Brain in the treatment of MS, but the NHS makes it difficult to practice what you preach. MS services in the NHS are not configured at present to react quickly in terms of new referrals and as a result, MSers pay the price. In the last few months, two MSers have lost brain and spinal cord because of how long it has taken them to get into the Barts-MS system. This upsets me and leaves me feeling very dissatisfied with my NHS practice. 



Guest Post: DrMaria from Spain explains about relapses

Hello everybody

First of all, I would like to introduce myself. I am Maria Mateo, I am a Neurology registrar from Spain and I have the pleasure of spending three months at Barts-MS to learn about MS.
As a part of my stay here, I have been attending MS clinics. As we know, MS patients can experience a broad variety of symptoms during their disease that can be difficult to explain. Thus, I have noticed that some MS patients have difficulties interpreting whether their symptoms are due to a new relapse or not, or if their symptoms are related to something else. Therefore, I have thought that it would be useful to clarify some main concepts around MS relapses.




Wednesday, 17 October 2018

ECTRIMS2018 Time is Your Brain,

There is no doubt that some people do OK on CRAB (copaxone, rebif, avonex and betaferon) drugs, but many do not and there are a number of more effective agents out there. 

However there are consequences of not getting disease under control as shown at ECTRIMS 2018

Guest post: A different MS Chariot

I have been encouraged by ProfG to write a post about my “MS Chariot” experience. It's a good example of an activity that those with limited leg function can enjoy, but for which it is important to preserve upper body function.



Monday, 15 October 2018

triMS-online: helping female academics

Another development at ECTRIMS 2018, which I heard about via the ECTRIMS grapevine, is that female academics are mobilising and have formed a group to demand gender equality at the top table of MS academia. Good!




Sunday, 14 October 2018

Early reflections on ECTRIMS 2018

I am writing this post on the flight back to London from Berlin. Being trapped in a tin tube at over 10,000m above sea level is always a good time to think.

under&over - ProfG's #1 non-scientific highlight at #ECTRIMS2018


Guess what my #1_scientific_highlight was at #ECTRIMS2018?

Rixtuximab in the brain trial...Why?

As the MS community reels from the news of the MS-SMART trial, there have been some comments on the blog chastising the science community for their role in another failure a MS SMART seems not so SMART.


Saturday, 13 October 2018

Is it time to reunify MS as one disease?

I am just about to leave Berlin tired but content that the MS world is finally beginning to acknowledge that #MS_is_1_and_not_2_or_3_diseases. We have covered this topic extensively over the last 4-5 years and I did so again in my talk as part of the Roche satellite symposium.


I have also uploaded all my other ECTRIMS-related slides and posters to my new SlideShare site for download.

CoI: multiple

Friday, 12 October 2018

Late Breaking Bad News from ECTRIMS

We have the top-line results of the MS SMART trial.

This trial compared the effects of riluzole, amiloride and fluoxetine and placebo in secondary progressive MS in a phase II trial. 

This indicates that ....

Broadcasting from ECTRIMS 2018

Mouse Dr and Neuro Doc Gnanapavan will broadcast from the ECTRIMS meeting currently happening in Berlin. The will cover data and results presented in paper presentations, keynotes and posters from the past few days.


The broadcast is now over but you can view the video here. Viewers commented and tweeted questions to us while it was on live. 



Pre-broadcast revision

ECTRIMS2018. Relapses with B cells present

Disease activity with ocrelizumab in the absence of B cells
Should we start panicing about the B cell hypothesis?

Thursday, 11 October 2018

ECTRIMS2018.La La La La, Alemtuzumab neutralizing antibodies are not important

As Greg Winter from Cambridge got the Nobel Prize for his part in the making of antibodies, notably humanizing antibodies, we can celebrate his work on the production of the world's first humanised antibodies (CAMPATH-1H) that was designed to stop anti-antibody responses , which were common when rodent antibodies were used.

Although it achieved its aim somewhat....It is in fact probably one of the Worlds worse antibodies for inducing an anti-drug response.
Did these stop the drug working?

ECTRIMS 2018. A Trial too Far...Spasticity study outcome reported

You have been asking “When will I be making the millions?” as you have been following our 17 year adventure into pharma-land as we try to develop a new treatment for spasticity in MS.

Today, you have the answer as the trial results in MS are made public at ECTRIMS 2018.

Wednesday, 10 October 2018

ECTRIMS2018. Hot Topics

Is there a new MS subtype. Nerve loss without Demyelination

Myelocortical multiple sclerosis: cortical neuronal loss in the absence of cerebral white matter demyelination B. Trapp, Cleveland, US
Background: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis (MS). Brain magnetic resonance imaging (MRI) studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. The purpose of this study was to investigate whether post-mortem MS brains show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination. 
Methods: Visual examination of centimeter-thick slices from 97 postmortem MS brains identified 12 without evidence of cerebral white-matter demyelination. Demyelination was quantified histologically in cerebral white matter, cerebral cortex, and spinal cord and compared with demyelination in 12 cases of MS with cerebral white-matter lesions. Atrophy, MRI metrics, cortical neuronal densities, and pathological correlates of MRI abnormalities were compared. 
Results: Cases without cerebral macroscopic lesions had demyelination in spinal cord and cortex, but a paucity of histologic cerebral white-matter demyelination. Despite the lack of cerebral white-matter demyelination, cortical neuronal loss, cortical thinning, and cerebral white-matter MRI abnormalities were significantly increased compared to brains from healthy controls and were similar to those in MS brains with cerebral white-matter demyelination. In the 12 brains without cerebral white-matter demyelination, swollen myelinated axons were the pathological correlate of white-matter regions with MRI abnormalities.
Conclusions: A subtype of MS, which we call myelocortical multiple sclerosis (MCMS), is characterized by demyelination of spinal cord and cerebral cortex, but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and is therefore an independent pathological event in MCMS.

It has been suggested that there is an MS subtype that displays nerve loss without significant demyelination in the outside of the brain, in people with demyelination in the spinal cord.


ClinicSpeak stand at ECTRIMS - What’s new this year?


For the past couple of years we’ve worked hard to put on a stand in the exhibition hall at ECTRIMS. The exhibition hall is where companies, other research projects and charities showcase their work to conference delegates. The main purpose of our stand is to share our #ClinicSpeak resources with others working in MS research and care.




Tuesday, 9 October 2018

ECTRIMS 2018: will MS become one again?

I arrived in Berlin yesterday and already I am seeing ECTRIMS 2018 turning into a battle between the lumpers and splitters, i.e. is MS one, two or three diseases. 


Making Berlin one again

Cannabis as good as copaxone in animals: Two wrongs don't make a right

Avidekel Cannabis extracts and cannabidiol are as efficient as Copaxone in suppressing EAE in SJL/J mice.Gallily R, Yekhtin Z.Inflammopharmacology. 2018 Oct 5. doi: 10.1007/s10787-018-0536-3. [Epub ahead of print]
Multiple sclerosis (MS) is an autoimmune disease leading to the destruction of myelin with consequent axonal degeneration and severe physical debilitation. The disease can be treated with immunosuppressive drugs that alleviate the symptoms and retard disease aggravation. One such drug in clinical use is glatiramer acetate (Copaxone). The non-psychotropic immunosuppressive cannabinoid compound cannabidiol (CBD) has recently been shown to have beneficial effects on experimental autoimmune encephalomyelitis (EAE). The aim of our study was to compare the efficacy of CBD and standardized extracts from a CBD-rich, ∆9-THClow Cannabis indica subspecies (Avidekel) with that of Copaxone. Our data show that CBD and purified Avidekel extracts are as efficient as Copaxone to alleviate the symptoms of proteolipid protein (PLP)-induced EAE in SJL/J mice. No synergistic effect was observed by combining CBD or Avidekel extracts with Copaxone. Our data support the use of Avidekel extracts in the treatment of MS symptoms.

This is not something I would be boasting about, because although Copaxone is number one treatent for MS, the animal data that supports this use is pretty pants . 

Therefore to suggest that cannabidiol is just as good..actually says that cannabidiol is pants too. 

Of course we can get copaxone to work  but not in the way it is used in humans. 

However, we know that cannaidiol is rubbish already and we had shown it does very, very little as an immunosuppressive to inhibit EAE. Shame that others maintain the opposite. 

Either we are rubbish in how we do experiments, or they are . There is not inbetween. We tried to get cannabidiol to do something for years. Therefore Time will tell and I predict the human trials will show that it is indeed rubbish.

Tetrahydrocannabinol can induce immuomodulation in animals, but only when they are so out-of-it that we think it is meaningless for human use. However you can believe this if you want

Does contrast need to be given for MRI scans?

AJNR Am J Neuroradiol. 2018 Oct 4. doi: 10.3174/ajnr.A5828. [Epub ahead of print]

Do All Patients with Multiple Sclerosis Benefit from the Use of Contrast on Serial Follow-Up MR Imaging? A Retrospective Analysis.

Mattay RR, Davtyan K, Bilello M, Mamourian AC.

Abstract
BACKGROUND AND PURPOSE:

Patients with multiple sclerosis routinely have MR imaging with contrast every 6-12 months to assess response to medication. Multiple recent studies provide evidence of tissue deposition of MR imaging contrast agents, questioning the long-term safety of these agents. The goal of this retrospective image-analysis study was to determine whether contrast could be reserved for only those patients who show new MS lesions on follow-up examinations.

Monday, 8 October 2018

ProfG's MS-related Twitter activity: week 1st-7th October 2018


Measuring progression a blast fromm the past

This study measures markers in the blood to monitor disease activity. Astrocyte proteins can be found

Sunday, 7 October 2018

Infection risk after alemtuzumab drops with time

Alemtuzumab is the a sledgehammer drug that depresses the immune system such that your T and B cells, monocytes and sometime neutrophils drop, leaving you open to infection. However, the cells rapidly recover  and the infection risk will drop.

The 6 year follow up of the alemtuzumab trials says

Saturday, 6 October 2018

PPMS v RRMS what's the difference?

PPMS v RRMS what's the difference?

Besides cost effectiveness of treatment and the fact of loads of treatments for RRMS and only 1 (maybe depending where you live) for PPMS


Friday, 5 October 2018

Q & A October


Dock Tarn Lake District photo by MD2

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

Mouse and Man..when does it become unethical

Uyttenhove C, Gaignage M, Donckers D, Nasr Z, Cheou P, van Snick J, D'Auria L, van Pesch V. Prophylactic treatment against GM-CSF, but not IL-17, abolishes relapses in a chronic murine model of multiple sclerosis. Eur J Immunol. 2018. doi: 10.1002/eji.201847580. [Epub ahead of print]

The pathogenic role of IL-17 and GM-CSF has been unravelled in experimental autoimmune encephalomyelitis (EAE), a murine (mouse or rat) model of multiple sclerosis (MS). However, in most models (Meaning C57BL/6 mice, Lewis rat and marmoset) , EAE is characterised by a monophasic attack which is not representative of the relapsing nature nor the chronicity displayed in MS. Here, we used proteolipid protein peptide (PLP139-151 ) to trigger EAE-relapses (EAE-II) in SJL mice that had recovered from a primary-EAE episode (EAE-I). This procedure resulted in severe and irreversible disease that, unlike EAE-I, was not abolished by anti-IL-17-mAb (In virtually all papers published anti-IL17 ameliroates but does not abolish disease) . In contrast, prophylactic anti-GM-CSF-mAb treatment prevented EAE-I and -II. Strikingly, the expression of T-cell transcription factors and cytokines/chemokines in mice treated with anti-GM-CSF during both EAE episodes was silenced. Anti-GM-CSF-mAb treatment administered only during EAE-II did not completely prevent relapses (Therefore it will probably fail in MS) but mice ultimately reached full recovery. (I doubt it, we can always see residual deficits if you look) Anti-GM-CSF treatment also strongly impaired and ultimately resolved monophasic MOG35-55 -induced EAE in C57Bl/6 mice. In such protected mice, anti-GM-CSF treatment also prevented a further relapse induced by MOG-revaccination. These results underscore the critical role of GM-CSF on pro-inflammatory mediator production. Furthermore, we observed a strong preventive and curative effect of anti-GM-CSF neutralisation in two EAE models, relapsing and chronic. Altogether these findings are relevant for further MS research. (How?)

So where are we on this one?

Thursday, 4 October 2018

ProfG are you walking-your-talk or just huffing-and-puffing?

I was asked after my 'ProfG is fuming' blog post from a few weeks ago, if I was walking-my-talk and doing something about NICE's decision about ocrelizumab for PPMS? Or was I just huffing-and-puffing and doing nothing about it? 




My response was yes; I am walking-my-talk. The following is a summary of some of my activities.

ECTRIMS 2018 - Burning Debate


On Wednesday 10th October at ECTRIMS 2018, we will be running another Burning Debate. Like previous years, the aim of this session is to encourage MS clinicians and researchers to use social media (specifically Twitter) to discuss topical issues in MS research and treatment. 

The topic this year is: The new McDonald diagnostic criteria are controversial, making them difficult to use in clinical practice.




(Image: The 2016 debate got slightly inflated)

Wednesday, 3 October 2018

EAE: Dendritic cells starting the Immune response or are they

It sounds like it is time for me to eat some more humble pie as I said "I don't think that the CNS is the right environment to initiate immune responses"

Dendritic cells are reported to be present in the CNS and they are critical for autoimmunity according to a new report

or are they?

CCSVI..the last nail?

People with chronic diseases that are not adequately controlled, often turn to alternative medicines.

This is not a surprising response, but few of these alternative treatments have generated so much polarisation of opinion as the CCSVI phenomenon.

MS was caused by blocked veins...a bit of venoplasty to open the vessel and a wonder cure was born. 

Even better you didn't have to deal with neuros as you could get the treatment, at a price, by non-neurologists. Social media, unchallenged by neuros until it was too late, propelled this into the public eye.

Canda and Italy were CCSVI-central and the MS Socieites there felt compelled to use their research budgets on validating the presence of blocked veins and the value of venoplasty.

It all came to nothing

Is this the final nail?

Tuesday, 2 October 2018

Optic neuritis in MS

J Neuroimmunol. 2018 Sep 22;324:115-118. doi: 10.1016/j.jneuroim.2018.09.010. [Epub ahead of print]

Recurrent optic neuritis - Different patterns in multiple sclerosis, neuromyelitis optica spectrum disorders and MOG-antibody disease.

Lotan I, Hellmann MA, Benninger F, Stiebel-Kalish H, Steiner I.

Abstract
BACKGROUND:

Optic neuritis is a frequent finding in multiple sclerosis (MS) and in neuromyelitis optica spectrum disorder (NMOSD), as well as in Myelin-Oligodendrocyte Glycoprotein (MOG) -positive disease. While both NMOSD and MOG-antibody disease are known to be associated with a humoral, antibody-mediated attack against a specific antigen, much less is known about the etiology and pathogenesis of MS. The aim of this study was to determine if the localization of recurrent episodes of ON follows the same pattern in MS as in NMOSD and in MOG-positive recurrent ON.

METHODS:

We retrospectively reviewed our database to identify patients with recurrent ON. The eye affected in each episode of ON was recorded, and the findings were analyzed.

RESULTS:

Forty-seven patients met the inclusion criteria. In the MS group, all episodes of ON recurred on the same side in 15 of the 29 patients (51.7%), accounting for 32 of the total 78 episodes (41%).In the NMSOD group, all episodes of ON recurred on the same side in 2 of the 12 patients (16.6%), accounting for 6 of the total 49 episodes (12.5%).In the MOG-positive group, all episodes of ON recurred on the same side in 1 out of 6 patients (16.6%), accounting for 2 of 21 episodes (9.5%).The between-group difference in the rate of recurrences affecting the ipsilateral side was statistically significant (p = .0007 and p = .0085 for the MS-NMOSD and MS-MOG groups, respectively).

CONCLUSIONS:

The pattern of recurrent ON differs significantly between MS and NMOSD and MOG-positive recurrent ON. This finding suggests that in MS recurrences may be provoked by previous tissue damage, disruption of the blood-brain barrier, and other local factors while in NMOSD and MOG-antibody disease attacks are indeed due to localization of the auto antigen.


There once lived a disorder called optico-spinal MS, who's origin was Asian by distinction, but a decade on its existence in Western MS was sought, and went by the name of Devic's.

However, that's where the similarities end. Unlike MS, Devic's or NMO spectrum disorders (NMSOD) and MOG-MS disorders as they're now known have well- defined antibody targets; namely aquaporin 4 and MOG (myelin oligodendrocyte glycoprotein), respectively. They're also more severe in their relapses, with longitudinally extensive cord lesions and long optic nerve lesions. Unlike MS, however, a majority are OCB (oligoclonal band) negative.

Lotan et al's. aim was to investigate to what extent the localization of recurrent attacks of optic neuritis (ON) were similar between the disorders. Until this study, no one has paid any attention to this in MS. Whereas, in NMSOD the optic neuritis is predominantly posterior/or chiasm predominant, whilst in MOG ON they tended to involve the whole nerve/anterior predominant. As all the disorders essentially involve a pathogenic attack on antigens (although MS is believed to target more than one), there is no reason why the recurrent ON episodes should not occur at random in each eye, whether it be MS or NMSOD or MOG-MS.

The study involved MS  (n=29), NMSOD (n=12), MOG-MS (n=6) with two or more attacks of ON. They found that in the MS group that recurrent ON was on the same side in 51.7%, accounting for 41% of the events (see figure on the left for the breakdown). In the NMSOD group, 16.6% had ON affecting the same eye, accounting for 12.5% of the events. In MOG-MS group 16.6% had ON affecting the same eye, accounting for 9.5% of the attacks. The difference between the ipsilateral location of recurrent ON attacks in MS vs NMSOD and MS vs MOG-MS was statistically significant.

So why is MS-ON different from NMSOD and MOG-MS? Is it because the recurrent attacks become a response to previously damaged tissue? The latter may serve as inference for attacks elsewhere in the body. This work, fortunately/unfortunately, if replicated by others raises more questions about MS than we have answers for at the moment.

Monday, 1 October 2018

Guest Post: MS and Alcohol: Friend or Foe? Prof G responds… as do MSers


By now, we all know the lifestyle drill.
Exercise = good
Smoking = bad
Alcohol = possibly, maybe?

ProfG's MS-related Twitter Activity (24th-30th Sep)



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 ActiveMSers.org 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.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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: http://multiple-sclerosis-research.blogspot.com/2015/04/risk-sharing-scheme.html.

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).


Why? 

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.

Background:

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.

Methods:

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.

Results:

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.

Conclusions:

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.