Wednesday, 22 November 2017

Results of Rumble in the Jungle 2

As you are aware Prof. Baker (Proud Yorkshireman / Englishman) took on Prof. Heinz Weindl (Proud German) in a dramatic debate. Who won?

Imaging B cells

B cells are becoming increasingly seen as an important subset of cells and they have been implicated as drivers of progressive MS. 

There will be an increasing number of B cell therapies arriving and so being able to assess whether they get rid of B cells in the brain is an important step. 

This study reports on the production of an imaging tool.  They use rituximab to image B cells in EAE. They show an increased disease. I was excited

Monday, 20 November 2017

Rumble in the Jungle Part II

The "Rumble in le Jungle" at ECTRIMS2017 turned into a "Bumble in the Immunological jungle" as the Heavyweight clash turned into a love-fest. 

UPDATE: Slides added

Sunday, 19 November 2017

Have you been involved in shared-decision making?

A recent study published in the British Medical Journal (BMJ) proposes a simple three talk model for shared-decision making in the clinic. 

Have you been involved in a shared-decision making process, or have you simply been told what is best for you? 

Please have your say.


Saturday, 18 November 2017

The good, the bands, and the ugly: do oligoclonal bands mean more brain shrinkage?


Oligoclonal bands (OCBs) are now back in the diagnostic criteria for MS - they can be used to support a diagnosis. If someone has a clinically-isolated syndrome - an episode of symptoms or signs due to demyelination without any evidence of previous events - the presence of OCBs makes it much more likely that they will go on to develop clinically-definite MS

Friday, 17 November 2017

Guest Post: Self-catheterisation

Note: This is a no-nonsense and detailed post on self-catheterisation.

As MS progresses we often have to self-catheterise. This presents few problems for some. Others, like me, aren’t so lucky.



Thursday, 16 November 2017

Latest natalizumab PML risk update

The latest PML risk figures from Biogen. If you are on natalizumab and are JCV seropositive this post is for you.

Why does smoking increase your risk of MS?

We don’t understand yet why people get MS. The accepted view is that there is an interaction between risk genes and environmental factors like EBV, smoking, and vitamin D status. Epidemiological studies have helped to identify these risk factors for developing MS, but it is unclear how these factors actually contribute to disease evolution and progression.




Wednesday, 15 November 2017

LDN does not affect MS

"Low dose naltrexone (LDN) has become a popular off-label therapy for multiple sclerosis (MS). A few small, randomized studies indicate that LDN may have beneficial effects in MS and other autoimmune diseases. If proven efficacious, it would be a cheap and safe alternative to the expensive treatments currently recommended for MS. We investigated whether a sudden increase in LDN use in Norway in 2013 was followed by changes in dispensing of other medications used to treat MS."

Tuesday, 14 November 2017

HSCT in MS - what have we learnt?

More and more HSCT procedures (aka bone marrow transplants) are being performed for MS around the world than ever before. Currently, we lack convincing data on the conditioning regimen that best balances efficacy and safety. Patient selection is key and HSCT should be considered as an early option in aggressive cases of inflammatory MS, rather than as salvage therapy in later disease. 


Monday, 13 November 2017

Translocator protein: useful to see, useful to target?

Translocator protein (TSPO) is found on the outer mitochondrial membrane (in other words, on the outside of the powerhouse of the cell). It is thought to be involved in regulation of several cellular processes but its actual function is still up for debate. 


Sunday, 12 November 2017

Seizures, epilepsy, and MS

Any type of injury to the brain - whether focal or diffuse - can increase your risk of developing epileptic seizures. pwMS who have lots of lesions or significant atrophy are probably more at risk of developing epilepsy. The exact risk of epilepsy in MS has been a bit variable in reported studies. Because the absolute numbers of pwMS who also develop epilepsy is quite low, you need a really big cohort to see if there is any increased risk compared to people without MS. 

Saturday, 11 November 2017

Guest Post: Dr Rune. Høglund A potential pathological mechanism for memory B cells

A potential pathological mechanism for memory B cells

Bio: RAH is a Norwegian MD, currently a PhD candidate in the MS section of the Clinical Neuroscience group at Akershus University Hospital. Previous work includes examining the many effects of glatiramer acetate on the immune system. Our current work is focusing on B cells in particular, and their potential pathological collaboration with T cells in pwMS.



Friday, 10 November 2017

Ocrelizumab news: finally two eagles have landed

Landmark decision by the CHMP; ocrelizumab gets licensed for both relapsing and primary progressive MS.




The season of MS: Glandular fever may not be linked to time of year

Vitamin D (as measured by time of year) and glandular fever are not linked. Should we be surprised?

I guess it boils down to how you think it is all working. 

Thursday, 9 November 2017

#MS News. NICE being Nice for a change. Oral Cladribine now available on NHS in England

Imaging Microglia

Although this won't make me popular with the "imagers", here you have it from the horse's mouth "magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression".

Wednesday, 8 November 2017

Will Biogen walk-the-talk and do another natalizumab SPMS trial?

At #MSParis207 I presented a new analysis of the data of the ASCEND trial (natalizumab in SPMS) that shows natalizumab is very effective in protecting upper limb function, and to a lesser extent lower limb function, in people with more advanced MS (majority needing walking aids). 

Tuesday, 7 November 2017

The turn of the fungi

Fungal infections have not been widely studied in MS, many lines of evidence are consistent with a fungal etiology.

Sunday, 5 November 2017

Guest post: will the COMBAT-MS study disrupt the MS market?

You may be aware that people living with MS in resource-poor environments are often not treated with disease-modifying therapies. To address this we have been promoting a Barts-MS Essential Off-label list of DMTsThe problem with this list is that it is often not backed by a so-called 'class 1 evidence'. 

To address this lack of evidence, trials such as COMBAT-MS are being performed to provide data from real-life practice to support off-label prescribing. We are therefore privileged to have a guest post from the team running the COMBAT-MS trial explaining what the trial is about.

Saturday, 4 November 2017

Can blood neurofilaments be used to monitor disease activity?

Are we ready for a simple blood test to monitor MS disease activity?

Unrelated Comments & Questions - November 2017

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

Friday, 3 November 2017

A BAFFling tale: how does fingolimod affect B cells?

Fingolimod is an effective DMT which binds to the sphingosine-1-phosphate receptor on white blood cells. We don’t fully understand why it works in MS, but the most popular theory is that it traps lymphocytes inside the lymph nodes, preventing them from entering the blood and therefore from penetrating into the CNS. It may also have direct anti-inflammatory effects, protect the integrity of the blood-brain barrier, and (possibly) act directly in the CNS as a neuroprotective agent.

Thursday, 2 November 2017

Cognition: to measure routinely or not?

At ECTRIMS I gave a short TED-type talk on why I think we need to measure cognition in people with MS in routine clinical practice. Do you agree?


Podcast




Wednesday, 1 November 2017

News: daclizumab handcuffed by the EMA

After a second person with early RRMS died from fulminant liver failure whilst being treated with daclizumab the EMA are restricting daclizumab's use. 

Tuesday, 31 October 2017

Monday, 30 October 2017

Are you what you eat?

Circumstantial evidence has suggested an association between diet and MS, but hard evidence proving a causal link has been lacking. 

A new multicentre, prospective, longitudinal cohort study from the USA tried to crack this problem. They recruited children with MS from 11 centres. 

Friday, 27 October 2017

Are we on the cusp of a self-monitoring revolution?

Self-monitoring and the socialisation of web-based apps is the revolution waiting to happen in MS care.


Today at ECTRIMS: Barts MS Google Hangout

This afternoon Mouse Doctor and Neuro Doc Gnanapavan broadcast live from the MS Paris ECTRIMS ACTRIMS conference for a one hour Google Hangout. This was your opportunity to listen to the summary of what they've seen but also respond to questions posted by readers of this blog.

Wednesday, 25 October 2017

Cell lysis and anti-trafficking treatments in MS

My first presentation from Paris. A talk on DMTs that target cell trafficking and cell lysis mechanisms. 

Tuesday, 24 October 2017

ECTRIMS2017 Is Here! What do you want us to report on?




The Programme (UK)/Program (US) is online (CLICK HERE) The abstracts are now live



Come and see us at the Google Hangout 15.45-16.45 Central European Summer Time = GMT + 2 h) with NDG and ProfB your hosts to answer your questions and to report on what's "Hot" and What's "Not"....OK, they won't waste their time, and your time, with the what's not :-).

If you miss the Hangout some of us can be found on the ClinicSpeak and DigestingScience stands. 

Prof G and Barts MS win healthcare awards

The Barts MS team will go to ECTRIMS this week with a spring in our step. On Saturday night, we attended the Zenith Global Healthcare awards and won a Team Recognition award. Not only this, but Professor Giovannoni was awarded with a Lifetime achievement award. 

JCV index in Natalizumabers - does anyone really understand this?

Are you on natalizumab? This paper will be of interest to you. 

Monday, 23 October 2017

MS in the news today

You may have seen this BBC news article today about two pwMS. One of which had a well-planned trip to Switzerland to end his life. After meeting a local woman with MS he appears to have a new outlook and has postponed his trip to Switzerland indefinitely.

(Image is a screen shot of the article on the BBC website)

Programmed Death 1 disappears and leaves EBV to trigger Activity

Now that we know what PD-1 is, it's time to look at this paper

Sunday, 22 October 2017

What is programmed death 1?

This is about a protein expressed by the immune system. It is a protein involved in limiting the immune response.


Temperature

Twists and turns in the MS research trails


Saturday, 21 October 2017

Tackling progressive MS

Tackling Progressive MS is a priority. ECTRIMS had a meeting on this subject and they have done a special issue on this.

Here's a list of several papers on this subject.

Friday, 20 October 2017

Does MS affect peripheral nerves?

There are few things that all MSologists agree on. 

Perhaps one of the least controversial statements you can make about MS is that it is a disease of the Central Nervous System - i.e. the brain, brainstem, cerebellum, and spinal cord - and that it does not affect the peripheral nerves.


Plus ca change.



Thursday, 19 October 2017

Remyelination....a reality


Good news from repair studies! 

A few years ago Jonah Chan and his team developed a neat screening assay to show myelination (making myelin) by myelin-forming cells (oligodendrocytes). 

Monday, 16 October 2017

Barts MS at ECTRIMS 2017

In just over a week, MS researchers, Nurses and Clinicians will travel to Paris for the annual ECTRIMS conference. This is an important meeting where new research, trial results and treatment information is shared across the community. And we'd like some input from you, our readers!

Sunday, 15 October 2017

Saturday, 14 October 2017

Depletion of neutrophils after alemtuzumab

Neutrophils are your first line of defence against infection, but they express CD52 and therefore they are depleted by alemtuzumab. This will contribute to infections post treatment, but, whilst common, the level of depletion is rarely severe and long-lasting.  We have commented on this in a previous postbut you can now get a free copy of the paper.

Friday, 13 October 2017

Introducing MouseDoctor3

Hello, and thank you for reading my first post as MouseDoctor3.  Here's a brief introduction so you know my background...

Thursday, 12 October 2017

Anti-migration effect of DMF: alarms bells start ringing

This study looks at the influence of dimethyl fumarate (DMF) and its active breakdown product on control of the blood brain barrier

Wednesday, 11 October 2017

Advanced MS

Summary: Our position, as formerly stated, on more advanced (formerly know as progressive) MS. 

Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS.

Sunday, 8 October 2017

#ClinicSpeak & #ResearchSpeak: how close are we to pinning down EBV as being the cause of MS?

Causation theory is essential to frame the EBV problem in MS. #ClinicSpeak #ResearchSpeak

Summary: This post sets the scene for revisiting the Bradford-Hill criteria around EBV being the cause of MS. 


Brain Drain Pipes: A waste removal system or the immune activating pathway

As you know I have been moaning about the Late Breaking abstracts selection at ECTRIMS2017, yep sour grapes:-(...as our paper wasn't selected for a talk:-(  

We will report on how and why cladribine works 

Luckily (for them) our cladribine poster on effects on lymphocytes is not next to the company sponsored poster. Wonder what they will say?  But as my alemtuzumab poster in next to it, I'll get hear:-).

But as for the rest of the late breakers we have many where the results are announced, so if you are pressed for time you can get home early.

1. We have the Fingolimod trial in children.....It worked (CLICK HERE)

2. We have anti retro virus trial...It failed at 6 months (CLICK HERE) but then it worked at 6 months (CLICK HERE)


3. The ozanimod (Fingolimod me-too) trial.... It worked (CLICK  HERE)
4. Are neurofilaments a biomarker for trials? My guess is Yes
5. We have pathogenic antibodies to MOG, which we are not sure if this is that important to all or only a subset of MS
6. Looking forward to the MS sprint progressive trial but no announcement from Medicinova...except that enrollment was completed in Sept and results expected 2018 (CLICK). But then they say "Dr. Fox will present the top line safety, tolerability and efficacy data of ibudilast in progressive MS".
7. Then there was the last one imaging lymphatics in primates, I thought who is interested in monkey brains?

Anyway we don't have to wait for ECTRIMS and glad to see that humans are imaged and so it is clear we have drainpipes from the brain. These will take stuff into the lymph glands.

Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6. pii: e29738. doi: 10.7554/eLife.29738
.

Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent (Gadofosveset binds reversibly to serum albumin, increasing its molecular weight from 0.9 to 67 kDa. Under physiological conditions, albumin has a low transcapillary exchange rate into the interstitial compartment, estimated to be on the order of 5% per hour, which explains the propensity of gadofosveset to remain within blood vessels). The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.
So we know that there is lymphatic type drainage in rodents and the presence of glymphatics and not it is evident that there are drainage pathways from the brain. It means that proteins can move from the brain to the node.
If you are interested in reading the brain drainage system has been known for some time, so you can even read about the glymphatics

However in the study they could not prove whether lymphatic vessels drain immune cells, CSF, or other substances from the brain to deep cervical lymph nodes, nor could we assess any link with the glymphatic system
There is a neat video if you follow the link to the paper, so the next question is where does the spinal cord drain to? I suppose I can ask this at ECTRIMS2017 in a couple of weeks
    The lymphatics  of the human brain

T cell Killing anothr Idea

Peeters LM, Vanheusden M, Somers V, Van Wijmeersch B, Stinissen P, Broux B, Hellings N. Cytotoxic CD4+ T Cells Drive Multiple Sclerosis Progression. Front Immunol. 2017 Sep 20;8:1160.

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (P = 0.003, R2 = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (P = 0.005, R2 = 0.29) and with EP and EDSS after 5 years (P = 0.008, R2 = 0.42 and P = 0.003, R2 = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.

Yesterday, we had yet another post on the memory B cells and we had some cracking questions., some of which I could only give a "I don't really know yet" answer but we have been asking the same questions....but the answers need a bit more thought and a lot more reading.


But we need to ask questions and there is a killer punch we need to kill the idea and reformulate it we find the idea is wrong.

We need to listen to alternatives and here is another one. This study suggests that MS is cause by CD4 T cell that are killing machines and that they too occur in loads of different diseases.

You can read the paper as it is open access. They are expanded CD4+CD28null T cells are found in about 20% of both pwMS as well as healthy controls without obvious differences in numbers.
They are suggested to that these cells link to progression.

I would counter this by saying:

(a)  CD4 T cell depletion does not stop progression at least quickly
(b) CD4 deletion does not work in MS
(c) Histologically  there are few CD4 T cells in lesions, there are few in the nervous tissue
(d) Oligodendrocytes do not express MHC classs II, which is a recognition element targeted by CD4 T cells 
(e) Then we ask does the data  pass the "smack you in the eye test" and are the R2 values big enough, to me it says the effects cannot be explained by the CD4 T cells.

They do address the issue of CD4 monoclonal antibody and  intimate that the level of depletion wasn't big enough. We have also suggested that it may have been on the brink of not being enough based on animal studies, but alemtuzumab knocks CD4 and CD8 cells to pieces and this does not stop advanced MS. So the argument probably falls.

Saturday, 7 October 2017

How long are memory B cell depleted?. Can we learn from other conditions

#Understandingyourtreatmentsspeak

We have been making the case that memory B cells are a central player in the treatment target for all drugs in MS. 

As we saw yesterday many people don't buy this idea (see below) or perhaps don't even know about this idea because they: (a) don't read the blog; (b) Don't read papers (c) cannot assimilate knowledge  or (d) all of the above:-) or (e) I'm wrong.

Yesterday I was sad, because it confirmed what I wrote above.

So I want to put more meat on the idea

I was talking about B cells and the fact there were are more than one type of cell that make up the CD19 population.

Some didn't like my slide

You (at least one of you) said I was talking "jibberish" and it is unrelated to people with MS and it was more relevant to scientists and doctors.

I said "nonsense" because, it is important in understanding the choices that you may need to make.

Is the level pitched wrongly...the answer will be yes and perhaps no...however virtually every part of the post has been explained in the past and so look at the education posts to help you get up to speed.

If you look at alemtuzumab, the CD19 B cell population (in green below) is back to normal levels within 3 months. But alemtuzumab is still working years later...so it can't be the B cell? Can it?
This is the view if you see CD19 B cells as a single population as is usually portrayed. 

So can it be the B cell?

Yes it can, because that repopulation is occurring because of immature and then mature (also called naive B cells) cell subsets come rushing out of the bone marrow to fill the space vacated by the lymphocytes that are killed. This masks the fact that memory B cells are being depleted long-term.

See our picture from Baker et al. 2017 (below). This is the pattern you see with rituximab, and HSCT so there is nothing special going on.

The blue (Total CD19+) is a composite response of the (green, pink and the baby blue). The antibody is given at 0 and 12 months and shows percentage change from baseline (-80 = 80% depletion)

This is the default pathway for B cell repopulation and will occur for all drugs that kill B cells. However, with HSCT and alemtuzumab, this occurs in the relative absence of effective T cell regulation by CD8 T cells and maybe CD4 T regs. The default pathway of T cells is the immediate repopulation comes from expansion of the memory cells, this is seen in humans and mice. There is nothing special going on. 

Friday, 6 October 2017

The new ideas of alemtuzumab

Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10:343-359

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, pre-existing disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

This is a review and we don't report of reviews but it is perhaps good that you can get an alternative view.  If you can get access to this.

However I have been spending the day getting my poster ready for ECTRIMS 2017 and so was happy to see the state of play, 

but....reading through this makes me feel that I am am living in an alternative universe:-(. 

Apparently there are "no new safety signals" emerging so best not give a plug for the ECTRIMS poster that shows alemtuzumab can stop working

P1231. C. Eggers, K. Akgün, T. Hofer, M. Egger, T. Ziemssen
Abrogation of the lymphocyte depleting action of Alemtuzumab by neutralizing antibodies - a case report. 

Apparently there is "recent evidence on the mechanism of action of alemtuzumab" so I thought great...our ideas are gaining some traction....but then the depression sets in. 

So in addition to the mechanism of inducing depletion and repopulation of T and B lymphocytes ,we get a result in a relative increase of cells with memory and regulatory phenotypes...yeah that's T cells. 

I guess memory B are not on the radar yet.

So  the 30,000 cells per millilitre going down to 2 is still an increase in the minds of my peers?. Maybe that the 2 Treg cells are now controlling the 1 surviving CD4 T cell is the relative cell increase we need.

The new mechanism is a expansion of NKCD56 high, so it works like daclizumab too?

Have a read of this and tell me what you think.

http://multiple-sclerosis-research.blogspot.com/2017/06/looking-in-wrong-place-to-find-efficacy.html

So if we do reviews, should we regurgitate a string of facts or try and tease mechanisms from the literature...I prefer the latter but maybe I am in a minority....too much speculation. 

What do you think?

Come back tomorrow. I'll have a go.

#PoliticalSpeak: should we move to a subscription model?

Are you prepared to pay for quality online MS-related content? #PoliticalSpeak

Do you think quality web content including medical education should be free? I note that the European Charcot Foundation is moving towards a subscription model. 

Is providing free content sustainable in the long term, i.e. does quality suffer? 



I think free quality content is sustainable provided it becomes opensource and the wider community engage, join-in and provide their time/content free of charge (e.g. Wikipedia). What do you think? 


Open-source content vs. Subscription-based content

CoI: multiple

Thursday, 5 October 2017

#ClinicSpeak: DOTS or no DOTS?

Should we trust our patients to take their oral cladribine tablets or should we make them come to the hospital to observe them doing it? #ClinicSpeak

Summary:  This post addresses the issue of adherence to oral cladribine tablets as prescribed. In addition, the post addresses some of the complexities of drug pricing. 

Wikipedia: DOTS (directly observed treatment, short-course), also known as TB-DOTS, is the name given to the tuberculosis control strategy recommended by the World Health Organization. According to WHO, "The most cost-effective way to stop the spread of TB in communities with a high incidence is by curing it.

The imminent UK launch of oral cladribine tablets (Mavenclad), at a list price of £2,047.24 per tablet, stimulated a debate amongst us at Barts-MS about whether, or not, we should trust our patients taking the tablets as prescribed or we should implement DOTS (directly observed treatment, short-course). One position is to trust our patients. Why? Firstly, if we allow them to collect their own prescriptions via a community pharmacy then the NHS does not have to pay VAT on the price (value-added tax). A DOTS programme will cost NHS England 20% more per tablet. Secondly, isn't our relationship with our patients based on trust? If we don't trust them to take their medication then we have failed as educators and as HCPs. The WHO DOTS programme was developed to solve the problem of poor long-term adherence to anti-TB drugs in resource-poor environments, which was selecting for drug-resistant TB strains. I, therefore, don't think we can compare the treatment of MS with the treatment of TB. 


What would happen if one of our patients drops and loses one of the tablets? I am sure Merck would be understanding and provide a replacement tablet. You need to remember that the manufacturing price of a cladribine tablet is unlikely to be very high and hence it would be relatively cheap for Merck to provide a replacement tablet or pack. The price of pharmaceuticals is really very complex and includes intangibles such as intellectual property, the cost of the preclinical R&D, the costs of the clinical development programme, regulatory, marketing, sales, life-cycle management and the whatever else Pharma does (including paying academics to sit on steering committees, participate in advisory boards, give talks, etc.). 


Oral cladribine tablets have many advantages one of which is taking tablets, albeit for only 16-20 days over a 2 year period with the potential for the treatment effect to last years. Why would we then want patients to come to the hospital so that we can directly observe them taking their tablets? One person suggested that patients may be tempted to sell their tablets on eBay to the highest bidder? Do you think the prescribing of oral cladribine tablets will result in a secondary market? I suspect not in the UK, but I may yet be proved wrong. A potential solution to the latter is to use smart tablets, i.e. each tablet is labelled with a RIF (radio frequency identification) tag that is tracked by a wearable device, linked to your phone, to make sure each tablet is taken as prescribed. Or we can simply trust our patients. What do you think? 

CoI: multiple

A solution to MERCK pills

ProfG has been contemplating how to deliver maven clad at £2 grand a pill its more precious than gold

When DrK and I attempted to do a trial in USA & Mexico of generic cladribine, which the US funders (PECORI) and UK funders (MRC) were not interested in:-(. Rather than spend a few million on their neighbours in the South, who had organised a multi centre trial and were going to put human resource into the project, they were happy to fund two trials doing the same thing for $23,000,000 :-(.

Anyway, we discussed the issue of dosing that profG is discussing and how to get the drug delivered. 

We thought that the most sensible thing would have been to take the drug to the person, rather than the person to the drug. 

If it costs VAT (sales tax) of 20% to deliver a DOT, at £400 a pill I would drive round to deliver them. So maybe we can have a new business


 or we could have the Merck Mobile going round the community as a driving advert,and as a mobile clinic to provide the pills or a motor bike paramedic. Food for thought

Wednesday, 4 October 2017

Natalizumab (Tysabri) and PML risk: an update

Progressive Multifocal Leukoencephalopathy is a life-threatening, progressive demyelinating disease affecting the white matter tracts of the brain. It is caused by reactivation of the John Cunningham (JC) virus. Although JC virus infects 80 – 90% of the world’s population, PML is exceptionally rare and almost exclusively occurs in people who are immunosuppressed, either due to a disease such as HIV/AIDS or due to medication.

In the MS world, cases of PML have been linked to the use of natalizumab, a highly-effective disease-modifying drug which prevents entry of immune cells into the central nervous system. PML was thought to occur in around 0.5% of people treated with natalizumab. Given that there is no effective treatment for PML, it is crucial that we have a method for working out who is at risk of developing PML and who can be safely treated with natalizumab.

We knew already that the three risk factors for PML in people getting natalizumab are:
1. The presence of antibodies against the JC virus (implying prior infection)
2. Previous immunosuppressive treatment
3. Duration of natalizumab therapy

To clarify how an individual’s risk of PML depends on these factors, Chang et al did some excellent digging: they collected data from participants treated with natalizumab in 4 big studies (STRATA, STRATIFY-2,  TOP, and TYGRIS). Altogether this produced a cohort of 37,249 people treated with natalizumab.

They found that 0.4% of the cohort were diagnosed with PML. Of these people, 120 had antibody results available. 119/120 (99%) of these people tested positive for anti-JCV antibodies in the 6 months preceding PML diagnosis.  Out of 13,996 people who were negative for anti-JCV antibodies, only 1 developed PML within 6 months of the test. This shows that the presence of antibodies against JC virus is extremely sensitive for detecting PML risk. I.e. if you don’t have antibodies against the JC virus, you’re incredibly unlikely to get PML.

Among people with anti-JCV antibodies, the cumulative probability of developing PML over 6 years was 2.7% if they had had prior immunosuppression, and 1.7% if they had not. The cumulative risk was relatively stable throughout the first 2 years of treatment, but increased after year 2. This confirms what we knew, i.e. that immunosuppression and a longer duration of treatment increase the risk of PML.



Lastly, they found that the amount of anti-JCV antibody correlated with the risk of developing PML in people who had not had immunosuppression. Interestingly, the amount of anti-JCV antibody did not correlate clearly with PML risk in people who had had immunosuppression (see figure). This implies that antibody titres are not a reliable guide to PML risk in people who have been previously immunosuppressed. A possible explanation for this is that immunosuppressive drugs may ‘clear up’ antibodies in the blood but not touch antibodies in the CNS.

This study is excellent – it extends and confirms what we understood about the factors that predispose people to PML. It also provides pwMS and clinicians with a way of calculating an individual’s risk. This kind of evidence is invaluable when people are deciding with their neurologist whether to pursue treatment with natalizumab or switch to another DMT.

Abstract
Background
Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).
Methods
Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort.
Findings
156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00–0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8–4·0) in patients with previous immunosuppressant use and 1·7% (1·4–2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00–0·03) in year 1 (1–12 infusions) to 0·6 (0·0–1·5) in year 6 (61–72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0–0·2) in year 1 to 3·0 (0·2–5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0–0·5) in year 1 to 10·0 (5·6–14·4) in year 6 for those with an index of more than 1·5.
Interpretation
Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit–risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants.


Antibodies to MOG is this the answer to autoimmunity

Khare P, Challa DK, Devanaboyina SC, Velmurugan R, Hughes S, Greenberg BM, Ober RJ, Ward ES. Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model. J Autoimmun. 2017. pii: S0896-8411(17)30155-5.
Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. 

In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). 

Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

Does this work change your mind. I have been challenging DrLove to say what causes the oligodendrocyte damage in MS. 

Her response was that it was MOG (myelin oligodendrocyte glycoprotein) specific antibodies and I have said that I don't buy this. 

There is no question that antibody to MOG can cause damage in rodents. We showed this years ago, but we weren't the first to do it. It was shown that antibody that could activate complement could kill oligodendrocytes, if it could get in the brain. 

In this study they have used a genetically engineered mouse so that the antibody can more easily interact with the macrophages and other cells that have the Fc receptor that can bind to bottom end of an antibody. They say this is more important than the complement activation and so counteract numerous other studies. 

This contradiction does not worry me as we also showed that the complement fixation element was not an absolute requirement. Also mice can have defective complement systems and even they can have defective Fc receptors like the strain of mouse we work with. They find that antibodies can have greater activity via certain Fc types. This is fine but the question is how common is this activity is this the norm or the isolated case?. 

That the antibodies come from MS, says that this damaging approach can and probably does occur, so yet more evidence that autoimmunity occurs in MS. However a MOG-reactive antibodies are associated with the development of a neuromyelitis optica-like demyelinating syndrome not MS. 

So is this the cause of MS...I'll be talking with Dr Love, but people have looked for anti-MOG responses in MS and it has not been consistently found, so I may come back and try to convince you that it is the answer.

On thing that animals tell us is that each individual reacts to a different set of antigens.

If we say memory B cells are the issue, again the problem is where does the specificity for the CNS come into the equation? 

What does an EBV infected B cell see or do to trigger relapses. 

Is it alpha B crystallin? 

We know oligodendrocytes express this, 

I dont know but I am pretty convinced it is not the blood vessels...

#NeuroSpeak & #ClinicSpeak: natalizumab and lymphomas

PML is not the only complication associated with natalizumab therapy. #NeuroSpeak #ClinicSpeak

Summary: Albeit rare, natalizumab is increasingly being associated with CNS lymphoma. This is probably due to reduced immune surveillance as a result of natalizumab blocking lymphocyte trafficking into the CNS. 

Evolution designed the immune system to fight infections and to clear pre-malignant cells from the body before they cause a problem. To do this the immune system has developed surveillance systems that depends on trafficking of cells from the blood into the tissues. If you block trafficking of cells into the CNS (central nervous system) with drugs, such as natalizumab, then you increase the chances of developing malignancies in the target organ. It is therefore no surprise that we are beginning to see an increasing number of case reports of primary CNS lymphomas in pwMS on long-term natalizumab. This potential complication was predicted more than a decade ago by several insightful people in the field. Please be aware that to the best of my knowledge this complication is rare, but acts as a reminder to pwMS on natalizumab that you need to be vigilant of new symptoms that could herald CNS complications. PML is definitely not the only severe complication associated with natalizumab therapy. 


Na et al. Central nervous system lymphoma associated with natalizumab.
J Clin Neurosci. 2014 Jun;21(6):1068-70.

Patients with primary central nervous system lymphoma (PCNSL) after treatment with natalizumab have been considered co-incidental. We report another case of PCNSL in a patient where the explosive onset suggests a causal link.

Nixon et al. Natalizumab Associated Primary Central Nervous System Lymphoma. World Neurosurg. 2017 Sep 26. pii: S1878-8750(17)31647-9.

Natalizumab, a selective adhesion molecule inhibitor binding to α-4 subunit of integrin, has emerged to be an effective immuno-modulator especially in the treatment of relapsing-remitting Multiple Sclerosis and Crohn's disease. Literature documenting the development of progressive multifocal leukoencephalopathy from its use is widely available. However, only handful of reports cites the development of a more concerning pathology, primary CNS lymphoma (PCNSL) from its administration, thereby triggering a debate on a possible causal association. Considering paucity of literature and the prognostic severity of PCNSL, we herein report its development in a young woman with Crohn's disease that was previously administered Natalizumab. Additionally, we provide a comprehensive review of literature on cases of lymphoma development following Natalizumab use to re-emphasize the drug association with PCNSL, if at all.

CoI: multiple

Tuesday, 3 October 2017

#ClinicSpeak: Will MS Self-Rx become a reality?

Will I have enough hours in my day to curate the MS Tube map? #ClinicSpeak

Summary: A tentative start to curate the #ClinicSpeak posts into an MS self-management website.

I have been promising to launch a curation tool to help pwMS self-manage (self-Rx) their MS. It has been on my ToDo list for over 2-years. It comes up each year in my appraisal and gets moved to next year's ToDo list. My next appraisal is in a few week's time.

The idea is to curate all the #ClinicSpeak posts from the blog onto an easy to navigate website that can be read as you would a book and to hyperlink it to the MS Tube map with each stop on the line being linked to a particular web page or online resource. If I start now and do 2 or 3 links per day it will be completed within a few months (or years). Before proceeding can you please let me know your thoughts on this initiative? It is a very big project and I don't want to spend months doing it unless it will be used. As the map builds the stops will turn blue indicating that the stop is now linked to a completed web page.


CoI: multiple