Thursday, 30 June 2016

NewsSpeak & MSLondon: London MS Specialist Network

What should we do with the London MS group? #NewsSpeak #MSLondon #MSBlog

"I am one of the founder members of the London MS Group (LMSG), a loose network of London-based MSologists. We started the group just over 10 years ago. The aim of the group was for neurology consultants with a specialist interest in MS to meet 3-4 times a year to discuss issues in relation to the management and treatment of MS. Invitations are sent out to a list of neurologists who see people with MS at 7 regional neuroscience centres in and around London (Imperial College, St Georges Hospital, Kings College, Queen Square, Barts-MS, Royal Free and Queen's Romford) and from the regional feeder hospitals. The turnout of for the LMSG meetings has been highly variable and has becoming increasingly poor. Why? I suspect there are many reasons for this, but increasing numbers of competing commitments and meeting fatigue are the main reasons."

"We had a meeting last night and only 6 neurologists turned up; on one occasion only 3 neurologists attended. We decided last night to rejuvenate the group, change its name, expand its remit and formalise it as a registered organisation. We all agreed that London MS centres are at the vanguard of MS service development, treatment, management and research in the UK and we need a voice and a platform to promote this. As this organisation will impact on the management of close to 25,000 people with MS living in and around London it would be useful if you could tell us what you would want from this organisation. Should we include non-neurologists and other stakeholders? What about people with MS? Should we use the organisation to publish guidelines and set standards? For example, should we include the London MS-AHSCT Collaborative Group under the umbrella?"

GameSpeak & ClinicSpeak: Can we gamify MS life skills?

Can healthcare be delivered via a game? #MSBlog #GameSpeak #ClinicSpeak #BrainHealth

"Engagement and adoption is the biggest problems facing healthcare innovators, or wannabe healthcare innovators like me. We can come up with an idea very 5 minutes, but unless we can implement them, get them adopted, show that they have an impact on outcomes and are cost effective we are wasting our time and your time. On the other side of the coin getting the target population to change their behaviour is remarkably difficult. The paper below describes turning the process into a game with the hope that this will change behaviour. The downside of this is that not everyone necessarily likes games. What do you think? Could we design a game to nudge MSers to improve their lifestyles with the hope that it will improve outcomes? If you have any ideas or examples, in particular around Brain Health, I would be very interested to know about them. Please remember the game may also involve healthcare professionals."

Giunti G. Gamified Design for Health Workshop. Stud Health Technol Inform. 2016;225:605-6.

Increasing lifespans for chronic disease sufferers means a population of young patients who require lifestyle intervention from an early age. For multiple sclerosis (MS) patients, social problems begin with the decline of cognitive skills and their quality of life is affected. In this workshop, organizers will propose participants to work on different gamification design approaches to solve MS patients' engagement problem. Participants will obtain skills that can be extrapolated to other conditions that require patients change to adopt a different behavior. At the end, participants will present their proposed gamification design and discuss and comment each solution, assessing potential unintended outcomes and advantages.

Gut Microbiota is different in MS

Chen J, Chia N, Kalari KR, Yao JZ, Novotna M, Soldan MM, Luckey DH, Marietta EV, Jeraldo PR, Chen X, Weinshenker BG, Rodriguez M, Kantarci OH, Nelson H, Murray JA, Mangalam AK. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls.Sci Rep. 2016 Jun 27;6:28484. doi: 10.1038/srep28484.

Multiple sclerosis (MS) is an immune-mediated disease, the etiology of which involves both genetic and environmental factors. The exact nature of the environmental factors responsible for predisposition to MS remains elusive; however, it is hypothesized that gastrointestinal microbiota might play an important role in pathogenesis of MS. Therefore, this study was designed to investigate whether gut microbiota are altered in MS by comparing the fae
cal microbiota in relapsing remitting MS (RRMS) (n = 31) patients to that of age- and gender-matched healthy controls (n = 36). Phylotype profiles of the gut microbial populations were generated. Detailed faecal microbiome analyses revealed that MS patients had distinct microbial community profile compared to healthy controls. We observed an increased abundance of Psuedomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera in MS patients, whereas control group showed increased abundance of Parabacteroides, Adlercreutzia and Prevotella genera. Thus our study is consistent with the hypothesis that MS patients have gut microbial dysbiosis and further study is needed to better understand their role in the aetiopathogenesis of MS.

Gut bacteria is a hot topic in science as it may help shape the immune response and this study says it is diiferent in MS. This will need repeating. We will see if feacal transplants affect MS as people have this procedure done. But what happened in other studies

Tremlett H, Fadrosh DW, Faruqi AA, Zhu F, Hart J, Roalstad S, Graves J, Lynch S, Waubant E; US Network of Pediatric MS Centers. Eur J Neurol. 2016 May 13. doi: 10.1111/ene.13026. [Epub ahead of print]

"Relative to controls, MS cases had a significant enrichment in relative abundance for members of the Desulfovibrionaceae (Bilophila, Desulfovibrio and Christensenellaceae) and depletion in Lachnospiraceae and Ruminococcaceae" 

 or Bacteroidaceae, Faecalibacterium, Ruminococcus, Lactobacillaceae, Clostridium, and other Clostridiales. Compared with the other groups, untreated patients with multiple sclerosis had an increase in the Akkermansia, Faecalibacterium, and Coprococcus genera after vitamin D supplementation.

So no consistency so it is hard to know what this really means

Wednesday, 29 June 2016

GuestPost & NurseSpeak: Amy Bowen on MS Clinical Nurse Specialist Education

The clinical microsystem is where workplace motivators reside #MSTrust #MSBlog #NurseSpeak

The larger organization can be no better than the sum of its frontline units #MSTrust #MSBlog #NurseSpeak

Prof G got in touch with me last week after having received an anonymous email from an MS nurse who was really disappointed that the blog might be stopping. The nurse was pleading with Prof G not to stop because of how reliant this nurse is on the blog for an independent perspective on all things MS, especially the research data. All very positive and encouraging to the Barts team, I hear you say, and of course we know that the blog lives on, so no problem apparently.

Amy Bowen, Director of Service Development, MS Trust

But the nurse also revealed a deeper and much more worrying reason for relying on the blog. The nurse revealed that there was very little support for ongoing learning coming from either the neurologist in the team or from the NHS organisation the nurse works for. (I don’t know if this nurse is male or female but to make this easier to write and just to mess with the stereotype, let’s assume the nurse is a male. I will refer to the nurse as ’he’ from now on.)

Like multi-story carpark crime, this is wrong on so many levels (ref Tim Vine). He felt that the neurologist that he works with had no real interest in cascading the learning that she (still messing with stereotypes, so the neurologist is a woman) gains from the many educational opportunities available to medics. She keeps them essentially to herself or amongst her neurology peers and doesn’t treat that as learning that is for the benefit of the whole MS team and so should be shared widely and generously.
The NHS organisation severely restricts the nurse’s access to educational events targeted at him. He does attend the occasional pharma industry funded events, often in his own time, but with a healthy caution about the data that is being presented (the nurses’ own words). He is also struggling to get time and support to attend the MS Trust’s annual conference, the largest event of its kind in the UK.

The MS Trust has always led MS nurse education and professional development. Alongside our conference, which is regularly attended by around 300 MS health professionals we also oversee the training for all new in post MS nurses and we fully fund virtually all of the NHS nurse places. We also offer bursaries for allied health professionals. We produce competency frameworks for MS nurses and for MS AHPs. We run a user survey service free to any MS team in the UK. We run our GEMSS programme, to help teams collect evidence about the value and impact of what they do and embed an improvement mindset into the whole team. We know all the teams and will come running whenever they have a problem securing their service. All of this from a Health Professionals Programme team of six and a shoestring budget. People think it’s the NHS making MS education happen, but I can assure you it is not. There is no money, it has no priority and they don’t know enough about MS specialist practice to deliver it as well.

Why do we do it? Is it really the work of a charity? Absolutely. We believe that everyone with MS should have a skilled and supported MS specialist team because they understand the complexities and variability of MS best and they are best placed to make care better. We can make a greatest difference for the greatest number of people with MS if we work with services to make them skilled, accessible and equitable.

Recently, one of my colleagues heard Chris Ham, Chief Executive of the Kings Fund, speak at the NHS Scotland conference on quality improvement. He apparently gave a really energising talk about, amongst other things, the concept of a clinical microsystem. So much emphasis is put on whole system redesign in the NHS – shifting resources around, integrating services that have historically had discrete boundaries (like between health and social care), moving decision making power nearer to or further from clinicians. Pulling the big levers that can theoretically have the greatest structural effect. Clinical microsystems are the complete opposite.

The concept is that the closely knit front line team, with a shared mission, is actually a really powerful unit of care that can make a massive change in patient experience, safety and outcomes. If they have scope to move beyond bureaucracy, they are able to define and pursue their common objectives, work collaboratively and make changes in their culture and their processes that they know will make a difference. They know this because they are living and breathing the delivery of the service every day and are right up close to the needs of the patients they serve. The textbook on clinical microsystems Quality by Design makes this point:

The clinical microsystem is the basic building block of any health care delivery system. It is where professional identity is formed and is transformed. It is the unit in which espoused clinical policy is put into practice (clinical-policy-in-use). It is the place where good value and safe care are made. Most variables relevant to patient satisfaction are controlled here, and this is where most health professional formation occurs after initial professional preparation. The microsystem is where workplace motivators reside. The larger organization can be no better than the sum of its frontline units, or microsystems.

The point is that MS teams need to find the strength that comes from shared learning, data-driven dialogue about service improvement and a humble determination to hear what their service users are telling them about how best to deliver care. They need to take ownership of that knowledge and be prepared to work together to change their practice and their services. Knowledge is a shared asset, not a tribal secret. Neurologists need to value their nursing and allied health professional colleagues enough to make their specialist competence as important as the medics. People with MS rely on their MS nurse from information, clinical expertise and skilled management. They are the health professional they see more than anyone else. And, as for NHS Trusts, if they don’t invest in their staff, they will lose them and everyone will suffer.

1. Nelson E, Batalden P, Godfrey M. Quality by Design: A Clinical Microsystems Approach San Francisco; Wiley 2007. p.235.
2. Evidence for MS specialist services: findings from the GEMSS MSSN evaluation project. MS Trust 2015. p.36.

Use of Off label Drugs in Italian Centres

D'Amico et al. The Use of Immunosuppressant Therapy for Multiple Sclerosis in Italy: A Multicenter Retroprospective Study. PLoS One. 2016; 11(6):e0157721.

INTRODUCTION: Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS?

METHODS: We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use.

RESULTS: Out of 6,447 MS patients, 2,034 (31.6%) were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary) of the disease (RRR 5.82, 95% CI 4.14-8.16, p<0.0001), had higher EDSS (RRR 3.69, 95% CI 2.61-5.21, p<0.0001), higher assignment age (RRR 1.04, 95% CI 1.03-1.06, p<0.0001) than patients treated with only disease modifying drugs (DMDs).

CONCLUSIONS: Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population.

You can read the paper.
6,447 patients were analysed. A number of 4,413 (68.4%) were treated with DMDs (INFs or GA) and 2,034 (31.6%) with ISA. Out of 2,034 ISA treated patients, AZA was the most frequently used in monotherapy (41.4%), followed by mitoxantrone (24,4%), then cyclophophamide (7.9%) and Methotrexate (4.4%). The 21.9% of the whole group assigned to ISA treatment had used more than one single ISA drug

DrK has been banging on about use of generic cladribine, but how many neuros in UK would use off-label DMT?  

However, maybe he is wasting his time with the Brits and maybe he should be talking to his Italian Colleagues. Based on this post it is clear that neuros in Italy are willing to try off label drugs as they are prescribing Azathioprine and other unlicenced drugs. However based on results recently published it would seem that azathioprine is being used, 

Based on the data above,  azathioprine  is in the league of the interferons, so  is not going to be as good a NEDA inducing drug as cladribine. So would Italian Neuros try something that may be more active.

However when the off label drugs are being applied they are being used in people with progressive MS and so one would think they are going to have no/modest activity. 

Remember what ever you take you need to be NEDA have you read

Tuesday, 28 June 2016

NewsSpeak: ocrelizumab applications accepted by the FDA and EMA

At last the clock starts ticking for the long ocrelizumab wait #NewsSpeak #Ocrelizumab #MSBlog

"You may have heard already that Roche have finally submitted their RRMS and PPMS dossiers in relation to ocrelizumab to the FDA and EMA (see today's press release below). Ocrelizumab illustrates how long the drug development process takes.  The PPMS ocrelizumab results were made public last year at ECTRIMS and the dossier has only just been submitted approximately 9 months later. The FDA has fast-tracked ocrelizumab so PPMSers in the US should get an answer within 6 months. In Europe the EMA will take up to 12 months and then NICE will have to look at its cos-effectiveness, which typically takes 6-12 months and then post-NICE there is a 3 month delay before NHS England allows us to use it. So in the UK anyone with PPMS hoping to be started on ocrelizumab may have to wait another 2 years, that is assuming is clears all the regulatory and access hurdles. The red tape is unbelievable and then you ask us why academics don't develop drugs?"

CoI: multiple

PoliticalSpeak: MS prevention, or not?

I have finally purchased myself a pair of rose-tinted glasses; just not sure I should be wearing them. #PoliticalSpeak #MSBlog

"I was invited to at attend the MS Society's meeting on 'Developing our MS Society Research Strategy' (see PDF below) and was asked to chaired the Prevention workshop. It was a very enjoyable day and it is very clear that under the leadership of Michelle Mitchell the MS Society are doing things very differently and with focus and energy. The Prevention workshop was really and extension of the Prevention meeting we had last year at Heathrow (see report below). Interestingly when we had the feedback session yesterday afternoon there was a debate on whether or not MS is a preventable disease and whether of not we should be using the term prevention at all. I am not sure how we can avoid it when the MS community voted prevention number 2 on their list of research priorities as part of their James Lind Alliance collaboration. Stating MS is potentially a preventable disease at least allows one to formulate and test hypotheses. The corollary to this is that by stating that MS is not a preventable disease makes formulating and testing hypotheses very difficult."

Top 10 MS research priorities identified

The MS Society, in partnership with the James Lind Alliance, has identified the top 10 research questions that matter most to people affected by MS and healthcare professionals.

After a year of extensively canvassing the views of a wide range of people, over a thousand questions were narrowed down to the top 10:
  1. Which treatments are effective to slow, stop or reverse the accumulation of disability associated with MS?
  2. How can MS be prevented?
  3. Which treatments are effective for fatigue in people with MS?
  4. How can people with MS be best supported to self-manage their condition?
  5. Does early treatment with aggressive disease modifying drugs improve the prognosis for people with MS?
  6. Is Vitamin D supplementation an effective disease modifying treatment for MS?
  7. Which treatments are effective to improve mobility for people with MS?
  8. Which treatments are effective to improve cognition in people with MS?
  9. Which treatments are effective for pain in people with MS?
  10. Is physiotherapy effective in reducing disability in people with MS?

ClinicSpeak: holistic management of multiple sclerosis

New version of MS infographic using the London Underground Map #ClinicSpeak #MSBlog

"The following is the latest version of my infographic depicting MS as a journey on the London Underground. Can any of you spot the changes?"

Continued inflammation in SPMS - the role of antibodies to galectin-3

Mult Scler. 2016 Jun 23. pii: 1352458516655217. [Epub ahead of print]

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis.

Nishihara H, Shimizu F, Kitagawa T, Yamanaka N, Akada J, Kuramitsu Y, Sano Y, Takeshita Y, Maeda T, Abe M, Koga M, Nakamura K, Kanda T.



Recent studies have revealed that the disruption of the blood-brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS).


We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS).


We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity.


We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients' sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3.


Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Discworld (by Terry Pratchett 1948-2015); a large disc resting on the backs of four huge elephants, who in turn are standing on the back of an enormous turtle, the Great A'Tuin.

When it comes to understanding MS there are the known truths, the uncertain truths and the unknown truths - in the Discworld novel Terry Pratchett writes "Nothing has to be true forever. Just for long enough." Therefore, the race to link the dots is an ever consuming appetite in MS research; at the drop of a hat science shifts these truths, ideas become common knowledge and hypotheses, a reality.

In their previous work, the authors demonstrated that antibodies found in the blood of MS subjects leads to a disruption in the barrier that exists between the blood and the brain itself (called the blood brain barrier), as well as increasing the expression of VCAM-1 in the blood vessels; which aids the adhesion of immune cells and their subsequent transfer into the brain (Shimizu F et al. Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood brain barrier. PLoS ONE 2014; 9:e9872). In this work they report on a novel target (galectin-3) for these antibodies, which may be responsible for disruption in the BBB in those with SPMS (present in 10 of 11 SPMS subjects).  They also demonstrate that removal of these antibodies from the MS blood samples, decreased its effect in up regulating ICAM-1. Therefore, it's possible that anti-galectin-3 antibodies may be responsible for the persistence of BBB damage in SPMS. Of course, the work needs to be replicated in a larger group.

Why is this work interesting and why even blog on it? These and other lines of evidence point to the concept of persistent inflammation in SPMS, including BBB disruption. Immunomodulatory therapies, therefore if used appropriately should get into the brain. This may well be the biggest unknown truth in SPMS land, and now an uncertain truth.

Monday, 27 June 2016

ResearchSpeak: grey matter lesions

Shooting down the CNS plasma cell; can you help? #MSBlog #MSResearch #ResearchSpeak

"One of the hypotheses in relation to progressive MS is that after a period of time inflammation within the brain and spinal cord becomes independent of peripheral mechanisms. In other words it doesn't matter if you switch off T and B cell activation in the periphery, with potent anti-inflammatory drugs, progressive MS will continue unabated. One of the mechanisms that is hypothesised to explain this is immunoglobulin, or antibody, deposition with complement activation within the CNS. The immunoglobulin is produced by the intrathecal (within the coverings of the brain and spinal cord) B cells and plasma cells. Plasma cells in particular are hard nut to crack. They are long-lived and become independent of T cell help. The seem to live in their own niche and churn out antibody. The antibodies are what we refer to oligoclonal bands or OCBs. All the current DMTs and HSCT don't clear the spinal fluid of these antibodies. This is why our group are now exploring add-on treatments to try and get rid of the OCBs; if we get our funding for a trial we may be asking some of you to help by participating in a t rial. Getting rid of intrathecal plasma cells may be easier said that done. However, where there is a will there is a way and where there is biology there must be a mechanism to target; at least that is what we think."

"One of the ways that antibodies cause damage is that when they bind to their target they activate effector proteins called the complement cascade that then does the damage. The study below shows abundant complement activation within MS lesions. Please note that complement can be activated by other mechanisms that are not necessarily related to immunoglobulin; what we are seeing in this study can't simply be extrapolated back to the OCBs and plasma cells. However, this study and other studies provides us with a compelling case to think about additional add-on strategies for treating progressive MS."

Watkins et al. Complement is activated in progressive multiple sclerosis cortical grey matter lesions. J Neuroinflammation. 2016 Jun 22;13(1):161. doi: 10.1186/s12974-016-0611-x.

BACKGROUND: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression.

METHODS: We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls.

RESULTS: Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions.

CONCLUSIONS: Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.

Sunday, 26 June 2016

Antibodies in the CSF may be secondary to damage

Brändle SM, Obermeier B, Senel M, Bruder J, Mentele R, Khademi M, Olsson T, Tumani H, Kristoferitsch W, Lottspeich F, Wekerle H, Hohlfeld R, Dornmair K. Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci U S A. 2016 Jun 20. pii: 201522730. [Epub ahead of print]

Oligoclonal Ig bands (OCBs) of the cerebrospinal fluid are a hallmark of multiple sclerosis (MS), a disabling inflammatory disease of the central nervous system (CNS). OCBs are locally produced by clonally expanded antigen-experienced B cells and therefore are believed to hold an important clue to the pathogenesis. However, their target antigens have remained unknown, mainly because it was thus far not possible to isolate distinct OCBs against a background of polyclonal antibodies. To overcome this obstacle, we copurified disulfide-linked Ig heavy and light chains from distinct OCBs for concurrent analysis by mass spectrometry and aligned patient-specific peptides to corresponding transcriptome databases. This method revealed the full-length sequences of matching chains from distinct OCBs, allowing for antigen searches using recombinant OCB antibodies. As validation, we demonstrate that an OCB antibody from a patient with an infectious CNS disorder, neuroborreliosis, recognized a Borrelia protein. Next, we produced six recombinant antibodies from four MS patients and identified three different autoantigens. All of them are conformational epitopes of ubiquitous intracellular proteins not specific to brain tissue. Our findings indicate that the B-cell response in MS is heterogeneous and partly directed against intracellular autoantigens released during tissue destruction. In addition to helping elucidate the role of B cells in MS, our approach allows the identification of target antigens of OCB antibodies in other neuroinflammatory diseases and the production of therapeutic antibodies in infectious CNS diseases.

The inside of the cell is not normally seen by antibodies, but when a cell dies or is killed its content are liberated and then seen by the immune system and soin this study they take B cells from the CNS of some people with MS, they make the antibodies they produce and find that they are reacting to the contents of cells, suggesting that they are seconday to the disease process and not due to the cause. So not all of the antibodies in the spinal fluid may be informative. 

How do cells enter the Brain?

Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration. Lopes Pinheiro MA, Kamermans A, Garcia-Vallejo JJ, van Het Hof B, Wierts L, O'Toole T, Boeve D, Verstege M, van der Pol SM, van Kooyk Y, de Vries HE, Unger WW.Elife. 2016;5. pii: e13149. doi: 10.7554/eLife.13149. [Epub ahead of print]

Trafficking of myelin-reactive CD4+ T-cells across the brain endothelium, an essential step in the pathogenesis of multiple sclerosis (MS), is suggested to be an antigen-specific process, yet which cells provide this signal is unknown. Here we provide direct evidence that under inflammatory conditions, brain endothelial cells (BECs) stimulate the migration of myelin-reactive CD4+ T-cells by acting as non-professional antigen presenting cells through the processing and presentation of myelin-derived antigens in MHC-II. Inflamed BECs internalized myelin, which was routed to endo-lysosomal compartment for processing in a time-dependent manner. Moreover, myelin/MHC-II complexes on inflamed BECs stimulated the trans-endothelial migration of myelin-reactive Th1 and Th17 2D2 cells, while control antigen loaded BECs did not stimulate T-cell migration. Furthermore, blocking the interaction between myelin/MHC-II complexes and myelin-reactive T-cells prevented T-cell transmigration. These results demonstrate that endothelial cells derived from the brain are capable of enhancing antigen-specific T cell recruitment.

The function of the blog is to provide up-to-date research news, This paper suggests that endothelium cells in the blood vessel present myelin antigens to T cells and this is why they migrate into the central nervous system.  This would imply that evey cell in the brain recognises something in blood vessels, However, not all cells in the inflammed brain recognise the same thing based on analysis of their T cell receptors (see education),

This contrasts with a view the cells get pulled into inflammed tissues by blood vessels expressing adhesion molecules and chemokines (attractant proteins) so not all of them have to recognise anythin in the brain. If they don't, the cells can leave or die and we can make some new ones.

The other part of the blog is to publise our own work and get a few altmetics, so being ancient one can remember stuff, so have a read.

Thirty years ago it was suggested that if you express MHC class II (see education section) you can present antigen to T cells and this may be a way autoimmunity occurs. Did enothelial cells present antigens to T cells? 


Antigen presentation in brain: brain endothelial cells are poor stimulators of T-cell proliferation. Pryce G, Male D, Sedgwick J. Immunology. 1989;66(2):207-12

on't believe..... read a repeat

Endothelial cells no not express the co-stimulatory molecules as found in professional antigen presenting cells and so tend to turn off cells rather than stimulate them

But there are loads of other papers were you give endothelial cells gamma interferon and they express MHC class II antigens..I say give a wellington boot gamma interferon and they express MHC class II antigens?

But do endothelial cells actually  express MHC class II in the disease process. Have a read.

An immunoelectron microscopical study of the expression of class II major histocompatibility complex during chronic relapsing experimental allergic encephalomyelitis in Biozzi AB/H mice.
Butter C, O'Neill JK, Baker D, Gschmeissner SE, Turk JL.
J Neuroimmunol. 1991;33(1):37-42.

Is there anything else on migration

Post-arrest stalling rather than crawling favors CD8+ over CD4+ T-cell migration across the blood-brain barrier under flow in vitro.
Rudolph H, Klopstein A, Gruber I, Blatti C, Lyck R, Engelhardt B.
Eur J Immunol. 2016. doi: 10.1002/eji.201546251. [Epub ahead of print]

Although CD8+ T cells have been implied in the pathogenesis of multiple sclerosis (MS), the molecular mechanisms mediating CD8+ T-cell migration across the blood-brain barrier (BBB) into the central nervous system (CNS) are ill defined. Using in vitro live cell imaging, we directly compared the multi-step extravasation of activated CD4+ and CD8+ T cells across primary mouse brain microvascular endothelial cells (pMBMECs) as a model for the BBB under physiological flow. Significantly higher numbers of CD8+ than CD4+ T cells arrested on pMBMECs under non-inflammatory and inflammatory conditions. While CD4+ T cells crawled prior to their migration across the blood vessel (diapedesis), the majority of CD8+ T cells stalled and readily crossed the pMBMEC monolayer preferentially via a route across cells. Absence of endothelial ICAM-1 and ICAM-2 abolished increased arrest of CD8+ over CD4+ T cells and abrogated T-cell crawling, leading to the efficient reduction of CD4+ , but to a lesser degree of CD8+ , T-cell diapedesis across ICAM-1 & ICAM-2 deficient endothelia. Thus, cellular and molecular mechanisms mediating the multi-step extravasation of activated CD8+ T cells across the BBB are distinguishable from those involved for CD4+ T cells

No myelin in the system so whats the difference

Saturday, 25 June 2016

ClinicSpeak: PML without immunosuppression

PML is a complex disease with many variables to consider when assessing risk. #ClinicSpeak #MSBlog 

"The single case report on a 55-year old man with PML and no underlying risk factors highlights the the issue that PML can occur in immuno-competent individuals. This has implications for assessing risk in pwMS on DMTs and in general. Firstly, it makes it impossible to say that drug x, or drug y, is not associated with some PML risk, albeit a very small risk, of developing PML. I have often been taken to task by certain Pharma reps because of this position; they obviously want to control the messaging around their drug and I want to be honest. In short no DMT has zero risk of PML. In my career as a neurologist, I have seen three patients with PML with no apparent underlying immune disorder. All three of these patients were old, in fact they were all over 70 years of age. Presumably immuno-senescence, or an aged immune system, is a risk factor for PML. This is playing out in the MS space as well, where age is emerging as a risk factor as well. This is why we need to be wary about relatively low levels of lymphopaenia in pwMS who are over the age of 60, i.e. between 500 and 800 per mm3."

Grewal et al. Progressive multifocal leukoencephalopathy in a patient without apparent immunosuppression. Journal of NeuroVirology First online: 06 June 2016

Progressive multifocal leukoencephalopathy (PML) is a viral demyelinating disease due to the reactivation of the JC virus (JCV), which usually occurs in the context of immunosuppression in HIV infection, malignancy, or in patients on disease modifying therapy for autoimmune diseases, such as multiple sclerosis (MS) and Crohn's disease. Notably, there is growing recognition that PML can occur in patients with transient immune dysfunction. Here, we present a case of a 55-year-old man without history of immunosuppression or evidence of ICL who was diagnosed with PML on brain biopsy. We will discuss the potential etiologies of mild and transient immunosuppression that can lead to PML with non-apparent immunosuppression.

CD8 Cells after Immunological Stem Cell Reconstitutions

Arruda LC, de Azevedo JT, de Oliveira GL, Scortegagna GT, Rodrigues ES, Palma PV, Brum DG, Guerreiro CT, Marques VD, Barreira AA, Covas DT, Simões BP, Voltarelli JC, Oliveira MC, Malmegrim KC.Immunological correlates of favourable long-term clinical outcome in multiple sclerosis patients after autologous haematopoietic stem cell transplantation. Clin Immunol. 2016 pii: S1521-6616(16)30098-5.

High dose immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT) induces prolonged clinical remission inmultiple sclerosis (MS) patients. However, how patient immune profiles are associated with clinical outcomes has not yet been completely elucidated. In this study, 37 MS patients were assessed for neurological outcomes, thymic function and long-term immune reconstitution after AHSCT. Patients were followed for a mean (SD) of 68.5 (13.9) months post-transplantation and were retrospectively clustered into progression- and non-progression groups, based on Expanded Disease Status Scale (EDSS) outcomes at last visit. After AHSCT, both patient groups presented increased regulatory T-cell subset counts, early expansion of central- and effector-memory CD8+T-cells and late thymic reactivation. However, the non-progression group presented early expansion of PD-1-expressing CD8+T-cells. Here, we suggest that along with increased numbers of regulatory T-cell subsets, PD-1 inhibitory signaling is one possible immunoregulatory mechanism by which AHSCT restores immune tolerance in MS patients.

What drives MS, what controls MS?. One thing that is increasingly clear is that myoablative haematopeoitic stem cell therapy is very effective at controlling relapsing MS and it is clear that relapsing MS is a product of the immune system enetering the CNS. 

This week, I saw the data from the HALT-MS study presented (BEAM myoablation  followed by HSCT) and is high efficacy, and the way the immune system reconstituted was reported to. The authors said they would do a "guest post" on this.

However this is another study looking at immune reconstitution after the transplant. The first wave of reconstitution is the innate system and the neutrophil which has to get you some protection from infection, but which lmymphocytes appear and how does this relate to disease activity. With Alemtuzmab long-term depletion of CD4 and CD8 depletion and transient CD19 B cell depletion is associated with a good outcome for MS, not secondary B cell autoimmunities:-( 

In this study CD8 and T regulatory subsets rapidly appear, is this due to regulation or in response to viruses that lurk in our environments?, However there was a population of CD8 cells enriched in those that didnot reactivate their disease and the expressed PD-1. Programmed cell death protein 1, also known as CD279 is a cell surface receptor that binds two molecules, PD-L1 and PD-L2.

PD-1, plays an important role in down regulating the immune system 
by preventing the activation of T-cells, which in turn reduces autoimmuity and promotes self-tolerance. The inhibitory effect of PD-1 is accomplished through a dual mechanism of promoting apoptosis (programmed cell death) in antigen antigen specific T-cells, while simultaneously reducing death in regulatory T cells. 

Friday, 24 June 2016

#Cladribine4MS - effective disease modification for all, even (or particularly?) after Brexit

After oral Cladribine was dropped by Merck Serono in 2011, we identified other sources of Cladribine and developed a UK network of over 30 MS neurologists willing to try and do a head to head study with Alemtuzumb, with a view of licensing generic Cladribine.

This was not funded in 2014/15 partly on the basis of considered lack of need and the cost of the trial: Though £32,000,000 would have been saved for the NHS by doing the study our request was £2,000,000 above the ring-fenced budget that British Science (NIHR) would fund.

Since that time, with the failure of the repurposing bill, UK Government ministers have asserted that generic Cladribine can be prescribed off-label.


Based on published data, Cladribine is as effective or more effective than current MS DMTs.

It is just as safe (or safer) than current highly effective agents and not known for the development of PML or autoimmunities characteristic of other MS drugs.

It is as convenient (or more convenient) than any agent, requiring only a few cycles of administration a year, and after just over one year you monitor and wait & see whether you remain NEDA or re-dose, compared to monthly monitoring for drugs such as teriflunomide or alemtuzumab.

Cladribine is the only MS DMT that is CNS penetrant and has a mechanism of action that can work inside the CNS. It targets dividing (like beta interferon, teriflunomide, DMF) and non-dividing lymphocytes and may kill plasma cells (antibody producing cells). We know that targeting lymphocytes is beneficial in MS, because HSCT can be very effective.

This sounds like good news for Merck (Serono no more), who claim they are going back to the regulators to get their oral version licensed for relapsing MS, yet we have heard that for about 18 months now with submission still being "imminent", confirmed as recently as yesterday...

I am also told Merck might try hard to keep the price at a reasonable level should a license come their way, but is this likely I wonder?  More likely this will be priced in the region of current MS DMT, i.e. 20-30 times the cost of generic subcutaneous Cladribine, of which all gets into the body (100% bioavailability) compared to only 42% of what is ingested with the Cladribine pro-drug pill, which is converted to Cladribine after digestion.

Cladribine could be cost effective alternative for resource strapped healthcare settings, such as the UK.  Current MS drugs cost about $50,000, multiplied by 5 years thats $250,000 for most MS drugs, for some it is more. If you are NEDA after only 1 course of Cladribine that could be $350 - $1000 depending on the source. In the UK one course costs about £1600.

How about creating access to an effective DMT for the 300,000 or so pwMS on the planet whose annual income is lower than the annual cost for a DMT (and that is for the least efficacious brands)?  ECTRIMS, ACTRIMS, PACTRIMS, MSIF, MS Societies of the World - anybody interested?

That aside, Cladribine may still be a useful approach for people with progressive MS, who have slipped through the current DMT net, and this is where we can focus our energy in the UK to give people with nothing an alternative to nothing.

Please tweet the Video:

I’ve tweeted the link earlier today, so you could just retweet that if you prefer (

+++ Latest Brexit News +++ Withdrawal of video considered as according to LEAVE campaign leaders now £350 Million/week extra for NHS available +++ Apparently, The Palace considers overuling referendum due to concerns over new Scottish exit vote +++ As a result video remains available on Youtube until further notice +++

Thursday, 23 June 2016

NurseSpeak: continuing professional development or CPD

Should we run accredited CPD via the blog? Have your say. #NurseSpeak #MSBlog

"I received a very touching letter from a MS Clinical Nurse Specialist who works in the North of England stating that his/her main source of MS education is the Barts-MS Blog with an appeal for us not to close it down. They valued our 'independent interpretation' and frank discussion. 

Two things: 

(1) We may be independent, but we have conflicts of interest as declared. Conflicts may affect the way we present results and interpret them; please be aware of this. 
(2) This blog is not really being run for CPD. We have therefore shared your letter with Amy Bowen from the MS Trust who has kindly agreed to do a guest post on MS Clinical Nurse specialist CPD. May be we should run formal CPD posts with and interactive feedback via the blog. We could potentially get these accredited. We want the blog to evolve so any suggestions would be helpful on the format, frequency, etc., of CPD sessions."

BrainHealth & ClinicSpeak: Six ways to lead a brain-healthy lifestyle

The next phase of of Brain Health: Time Matters in MS! #BrainHealth #MSBlog #ClinicSpeak

"In addition to MS-specific treatments and minimising time delays we are now promoting a Brain Healthy Lifestyle for MSers."


"The simple descriptive study below shows that obesity in pwMS comes with a price; in short obesity is associated with reduced and slower mobility. The study does not address cause or effect. Does reduced mobility cause the obesity rather than the obesity being the cause of the reduced mobility. Regardless of causation, or reverse causation, if you have MS you should try an maintain a normal body weight. This is common sense and applies to the general population as well. including healthcare professionals working in the field of MS."

Kalron. Relationship of Obesity With Gait and Balance in People With Multiple Sclerosis. Am J Phys Med Rehabil. 2016 Jun 17.

OBJECTIVE: The aim of this study was to examine the relationship of obesity with walking and balance in people with multiple sclerosis.

DESIGN: This was a cross-sectional study performed at the Multiple Sclerosis Center, Sheba Medical Center, Israel. Four hundred thirty-six people with multiple sclerosis were divided into obese (n = 178) and normal-weight (n = 258) groups. Spatiotemporal parameters of gait, 2-Minute Walk test, 6-Minute Walk test, Timed Up and Go test, Timed 25-Foot Walk test, Multiple Sclerosis Walking Scale self-reported questionnaire, and posturography measures were determined.

RESULTS: Compared with normal-weight patients, obese subjects walked significantly slower [98.7 (SD, 29.2) m/s vs. 106.4 (SD, 29.2) m/s; P = 0.01], with shorter step lengths [54.8 (SD, 11.6) cm vs. 58.1 (SD, 10.7) cm; P = 0.003] and a wider step width [12.1 (SD, 3.7) cm vs. 10.9 (SD, 4.6) cm; P = 0.01]. Furthermore, the obese group walked a shorter distance on the 6-Minute Walk test [378.2 (SD, 145.5) m vs. 426.1 (SD, 129.8) m; P ≤ 0.001] and slower on the Timed 25-Foot Walk test [9.0 (SD, 8.0) seconds vs. 7.2 (SD, 2.4) seconds; P = 0.006] and the Timed Up and Go test [9.2 (SD, 6.3) seconds vs. 10.0 (SD, 6.1) seconds; P = 0.002]. No significant differences between groups were noted in the Multiple Sclerosis Walking Scale self-reported questionnaire and postural control measures.

CONCLUSION: Obesity affects walking but not postural control in people with multiple sclerosis despite the level of neurological disability.

Wednesday, 22 June 2016

ClinicSpeak: understanding trigeminal neuralgia in MS

An additional mechanism to explain trigeminal neuralgia in MSers. #ClinicSpeak #MSBlog #MSResearch 

"How many of you have had MS-related trigeminal neuralgia? If you have you will know that it was of the most debilitating complications of having MS. The pain can be so severe it makes some people suicidal. The cause in MS has always thought to be due to a MS plaque, or lesion, in the brainstem where the trigeminal nerve enters the brainstem, i.e. the so called root entry zone. This study below suggests that it may be more than a MS plaque and that a blood vessel compressing the nerve may be contributing to the problem. We call this neurovascular compression and is what is thought to be the commonest cause of trigeminal neuralgia in people without MS."

"These findings suggests that in pwMS with intractable TN we will now have to look for neurovascular compression. Why? This form of TN may benefit from a surgical procedure that gently lifts the blood vessel off the nerve and puts a soft cushion between the vessel and the nerve. The cushion is believed to prevent the pulsations of the blood vessel activating the nerve fibres and causing the brain to perceive the signals as pain."

"This study is very timely, one of my patients presented last week with TN. I have ordered an MRI expecting to see a MS plaque in the pons; I wonder if the MRI will show a vascular loop pressing on the trigeminal nerve?"

Truini et al. A dual concurrent mechanism explains trigeminal neuralgia in patients with multiple sclerosis. Neurology. 2016 May 4. pii: 10.1212/WNL.0000000000002720.

OBJECTIVE: In this clinical and neuroimaging study, we sought information on the possible role of neurovascular compression in multiple sclerosis (MS)-related trigeminal neuralgia (TN).

METHODS: After screening 1,628 consecutive patients with MS, we enrolled 28 patients with definite unilateral MS-related TN. In these patients, we acquired dedicated 3T MRI scans, identified pontine demyelinating plaques, and, using highly specific diagnostic criteria, distinguished possible neurovascular compression.

RESULTS: MRI scans in most patients showed a demyelinating plaque in the pontine trigeminal root entry zone on the affected side. The frequency of the neurovascular compression and its association with the pontine demyelinating plaque were higher on the affected than on the unaffected side (54% vs 0%; p = 0.0001).

CONCLUSIONS: Our observation that in many patients with MS-related TN a pontine demyelinating plaque and neurovascular compression coexist should prompt neurologists to seek possible neurovascular compression in patients with MS-related TN.

Tuesday, 21 June 2016

NeuroSpeak: calling all UK neurologists

Please consider attending the MS Trust Conference with your team from 6-7 November. #MSTrust #NeuroSpeak #MSBlog

"I am aware that many UK neurologists read the blog. The following is a call for you to register for the 2016 MS Trust meeting in November. In conjunction with the ABN MS Specialist Interest Group the MS Trust is including a masterclass session for MSologists. The meeting is also a good opportunity for team building."

PoliticalSpeak: health inequalities in Europe

Will staying in the EU reduce health inequality across Europe? #MSBlog #Brexit #Bremain #PoliticalSpeak

"As we approach Bremain, or Brexit, it is worth pondering the EU from the perspective of a patient. The study below highlights the inequality in prescribing of biological therapies for chronic inflammatory conditions; in the case below the example is rheumatological diseases. I always thought inequality in prescribing of expensive biological therapies was linked to per capita income. This study shows that in Eastern Europe this is not the case and based on similar data in relation to MS DMTs it is not closely linked to GDP. For example, the UK is near the bottom of most EU MS DMT league tables. Therefore inequality in prescribing, must be driven by local and cultural factors, for example the slow adoption of innovations. In the era when most people with a chronic disease have information at their fingertips via the internet it should come as no surprise that access to expensive therapies across the border is a potential incentive for EU migration. I sincerely hope after the UK votes to stay in the EU on Thursday we get the MEPs to address health inequality across our continent. If we exit the EU we will almost certainly remain at the bottom of the MS DMT league tables. A commitment to improve the lives of people with chronic diseases, and address healthcare inequalities, including MS, is something I would expect from the EU. I doubt these issues would be a major priority outside the EU."

Background: Biological agents revolutionised the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) as well as Crohn's disease (CD), ulcerative colitis (UC) and psoriasis. RA studies highlighted that uptake of biologic drugs varies strongly across Europe and the income of a country is considered as a major determinant factor for usage. It has been found that access to biologics in RA—expressed as a composite score of availability, affordability and acceptability—showed a strong positive correlation with gross domestic product (GDP)/capita (r=0.86) in Europe. Much less is known on this topic in AS, PsA and the other three inflammatory diseases.

Methods: We analysed real-world biologic usage data and their relationships with GDP/capita in the six inflammatory conditions in Bulgaria, the Czech Republic, Hungary, Poland, Romania and Slovakia. According to our previous literature search, there is no precise and comparable country-specific prevalence data in this region.Therefore, we estimated the biologic treatment rates per 100 000 inhabitants.

Results: Considering the total of six diagnoses, we found only moderate positive correlation (r=0.34, p=0.506) between biologic usage and GDP/capita levels. An approximately eightfold difference in treatment rate was observed between Hungary and Poland despite their almost identical GDP/capita. Similar treatment rates were found in Romania and the Czech Republic, in contrast to the over twice as high GDP/capita of the latter.

Conclusions: Overall, inequity in access to biologics is apparent and can be observed in rheumatology. Although our analyses were performed in Central and Eastern Europe, we assume that similar inequities might occur in other European regions as well.

Elementary, switch or escalate, my dear Watson?

J Neurol. 2016 Jun 17. [Epub ahead of print]

Lateral and escalation therapy in relapsing-remitting multiple sclerosis: a comparative study.

D'Amico E, Leone C, Zanghì A, Fermo SL, Patti F.


Performing a therapeutic switch in MS is still a matter of debate. Objective of our study is to compare switching to another first-line therapy with switching to a second-line therapy in persons with relapsing-remitting multiple sclerosis (pwRRMS). A retrospective analysis of data prospectively collected was performed. PwRRMS experiencing on-treatment disease activity were included. No clinical relapse, no sustained disability progression by the Expanded Disability Status Scale (EDSS), and no radiological activity (new T2 and/or gadolinium-enhanced brain lesions) were used as indicators of no disease activity (NEDA 3). Time to reach the first relapse after switch and time to reach an EDSS of 4.0 were also evaluated. Ninety-one pwRRMS were enrolled. Forty-eight (52.7 %) were on lateral switch, and 43 (47.3 %) on escalation switch. At baseline, the two groups differed for T2 and T1 brain lesions number (higher in the escalation group, p < 0.005). The proportion of pwRRMS who were NEDA 3 after 24 months from the switch was similar in the two groups (20.8 % in lateral group and 18.6 % in escalation group). No difference in timing to reach the first relapse after switch and an EDSS of 4.0 were found. Therefore, in selected pwRRMS, lateral and escalation strategies showed similar efficacy in delaying MS progression.

Few know that  Arthur Conan Doyle's famous detective Sherlock Holmes didn't in fact utter "Elementary, my dear Watson" in any of the original 56 short stories or 4 novels in which he stars. We assume, as it's well known, then it must be true. Rarely do we test ourselves or pay credence to the lack of supporting evidence. Issac Asimov once said that "Your assumptions are your windows on the world. Scrub them off every once in a while, or the light won't come in". We assume that escalation treatment is more effective than simply a lateral switch to another equally effective treatment. But this article tells us that evidence, at least with regard to this, may not be wholly on our side.

The predominant practice is to escalate treatments in those who fail first-line treatments - i.e. the injectables interferons (IFN) and glatiramer acetate (GA), and oral therapies teriflunomide (TF) and dimethyl fumarate (DMF). The evidence presented in this article originates from a single center only, non-randomized (i.e. not allocated to treatment based on chance alone), but prospectively collected evidence. The study spans 7 years (2005-2012), and therefore will not have data on alemtuzumab or ocrelizumab. However, it would appear that performing a lateral or an escalation switch in RRMS led to similar efficacy in outcomes (relapse activity, MRI activity, EDSS progression, and NEDA - no evidence of disease activity) over 24 months (see Figure 1 below).

As this was not a random allocation, it did mean that those who switched to the escalation treatment had more MRI disease activity (T1 and T2 lesions), which influenced the clinicians to offer more aggressive treatments. Therefore, what this data tells me is that it may be reasonable to perform a lateral switch in RRMS in those experiencing tolerability, adherence or safety issues, it doesn't however, tell me whether lateral switch is on par with escalation treatment when it comes to treatment failure! Worryingly, this real life evidence also points to more MRI activity by 24 months relative to 12 months independent of the type of switch (the relative size of the whole study is under 100, so this needs to be looked at in more larger groups).

In light of this work, the RRMS treatment algorithm is thrown into further doubt. This touches on another dilemma which is NEDA or the treat early approach. Evidence from clinical trails and real-world studies do not address these questions clearly. The difficulty is that we don't what is appropriate for the individual patient; taking into account each drugs risk-benefit profile, as well as compliance to treatment which can also greatly skew the evidence. STAMPEDE (Cancer Research UK) is a systematic trial for evaluating drug efficacy in advanced prostate cancer. It uses a multi-arm (more than one therapy) strategy to evaluate and pursue efficacious treatments - combination by the way, as well as drop treatments which do not work, at the same time as adding arms from newly introduced treatments. We need something like this in MS.

Figure 1a Proportion of patients on lateral switch with and without magnetic resonance imaging (MRI) or clinical disease activity at 12 and 24 Months. Positive indicates disease activity; negative indicates no disease activity. b Proportion of patients on escalation switch with and without magnetic resonance imaging (MRI) or clinical disease activity at 12 and 24 Months.

Monday, 20 June 2016

ResearchSpeak: Does interferon-beta still have a role in the treatment of MS?

Is interferon-beta dead, or not? #ResearchSpeak #MSBlog #MSResearch

"On our last Barts-MS Preceptorship one of the delegates asked if I thought there was still a place for interferon-beta in the treatment of MS? I answered yes. Firstly, if  you are on an interferon and you are NEDA, and are tolerating the therapy well, why would you want to change? Maybe NEDA is not sufficient and you would want to know if you had smouldering MS or not. If we had done serial MRI studies on you, and were able to show that over a 3-4 year period your rate of brain volume loss was within the normal range, and your spinal fluid analysis showed normal neurofilament levels, would you be satisfied? You need to remember that interferon-beta is a safe drug and is not associated with any major long-term risks so if you happen to be in the 20-40% of pwMS who respond why change? Remember that being a responder to interferon-beta does not necessarily mean you will respond to another class of DMT."
"What about naive patients, would I ever start interferon-beta in someone who has active MS? Yes, I would if that is what they choose when given the choice the available 1st-line therapies available on the NHS. In addition to interferon beta the other options are glatiramer acetate, terflunomide, dimethyl fumarate, alemtuzumab and shortly daclizumab. In price sensitive markets interferon-beta is still being widely prescribed; local guidelines state that you have to fail an injectable DMT first to be able to access one of the newer DMTs. Another factor is the emergence of cheaper biosimilars; these are forcing payers to demand that they be used first-line."

"Another factor that may drive the ongoing use of interferon-beta may be the re-emergence of the so-called induction-maintenance paradigm. This is when interferon-beta is used after an induction therapy; orginally interferon-beta was used in this way after mitoxantrone. May be using interferon-beta after an initial course of alemtuzumab, cladribine or HSCT may re-emerge as a viable and safe long-term treatment option. However, we would need data to support this."
"Finally, we are in discussion with one of the interferon-beta manufacturers of making their product available in resource-poor settings, on humanitarian grounds, to help treat pwMS who can't afford to pay for commercial product. We hope to start by running a pilot scheme so as to address all the local regulatory and logistical issues about making this happen. I was surprised at how difficult it is to provide a biological therapy in resource poor settings. However, I am confident we will be able to make this happen; where there is a will there is a way."

"Please note the study below showing that relapses and MRI activity on interferon-beta predicted failure in terms of disease progression on the EDSS. I note they set their threshold on 3 or more new T2 lesions for predicting failure on treatment. I don't buy into the concept of MEDA (minimal evident disease activity). Why would you allow some inflammation (MEDA) in your brain when you could have none (NEDA as measured using MRI)? I will need to analyse this paper in more detail to see if the investigators had enough power to assess whether or not patients with zero new T2 lesions did better than patients with one, or more, new T2 lesions. In the past when I attempted this I calculated that thousands of study participants would be needed to address this question."

"One final point. If you have been reading this blog for some time you will be aware that relapses and MRI activity in natural history studies, or on placebo drug, don't predict long-term disease outcome in MS. In contrast, relapse and MRI activity on a DMT do predict disease outcome. These observations tell us that relapses and MRI activity are not the disease. If they were the disease they would predict disease outcome regardless of whether you were on a treatment or not! Please think about these observations carefully. These observations challenge the current dogma about what is causing MS. Based on these insights alone it is important to find-out how interferon-beta changes the natural history of MS. Therefore there is another reason why we need to continue to use interferon-beta to treat MS, to pin down the cause of the disease."

Epub: Sormani et al. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology. 2016. pii: 10.1212/WNL.0000000000002830.

OBJECTIVE: To provide new insights into the role of markers of response to interferon-β therapy in multiple sclerosis (MS) in a multicenter setting, focusing on the relevance of MRI lesions in combination with clinical variables.

METHODS: A large multicenter clinical dataset was collected within the Magnetic Resonance Imaging in MS (MAGNIMS) network. This included a large cohort of patients with relapsing-remitting MS on interferon-β treatment, MRI and clinical assessments during the first year of treatment, and clinical follow-up of at least 2 additional years. Heterogeneity among centers was assessed before pooling the data. The association of 1-year MRI or clinical relapses with the risk of treatment failure (defined as Expanded Disability Status Scale [EDSS] worsening or treatment switch for inefficacy) and of EDSS worsening alone was evaluated using multivariate Cox models.

RESULTS: A pooled dataset of 1,280 patients with relapsing-remitting MS from 9 MAGNIMS centers was analyzed. The risk of failure had a relevant increase with 1 relapse (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.39-2.44, p < 0.001) and ≥3 new T2 lesions (HR 1.55, 95% CI 0.92-2.60, p = 0.09). In patients without relapses and less than 3 new T2 lesions, the 3-year risk of failure and EDSS worsening were 17% and 15%; in patients with 1 relapse or ≥3 new T2 lesions, the risks were 27% and 22%; in patients with both conditions or more than 1 relapse, the risks were 48% (p < 0.001) and 29% (p < 0.001).

CONCLUSIONS: Substantial MRI activity, particularly if in combination with clinical relapses, during the first year of treatment with interferon-β indicates significant risk of treatment failure and EDSS worsening in the short term.

CoI: multiple