Saturday, 24 June 2017

The ProfG's need a kick up the backside. Publish trials

Stefaniak JD, Lam TCH, Sim NE, Al-Shahi Salman R, Breen DP. Discontinuation and non-publication of neurodegenerative disease trials: a cross-sectional analysis. Eur J Neurol. 2017. doi: 10.1111/ene.13336. [Epub ahead of print]

BACKGROUND AND PURPOSE:Trial discontinuation and non-publication represent major sources of research waste in clinical medicine. No previous studies have investigated non-dissemination bias in clinical trials of neurodegenerative diseases.
METHODS: was searched for all randomized, interventional, phase II-IV trials that were registered between 1 January 2000 and 31 December 2009 and included adults with Alzheimer's disease, motor neurone disease, multiple sclerosis or Parkinson's disease. Publications from these trials were identified by extensive online searching and contact with authors, and multiple logistic regression analysis was performed to identify characteristics associated with trial discontinuation and non-publication.
RESULTS: In all, 362 eligible trials were identified, of which 12% (42/362) were discontinued. 28% (91/320) of completed trials remained unpublished after 5 years. 

Trial discontinuation was independently associated with number of patients (P = 0.015; more likely in trials with ≤100 patients; odds ratio 2.65, 95% confidence interval 1.21-5.78) and phase of trial (P = 0.009; more likely in phase IV than phase III trials; odds ratio 3.90, 95% confidence interval 1.41-10.83). 

Trial non-publication was independently associated with blinding status (P = 0.005; more likely in single-blind than double-blind trials; odds ratio 5.63, 95% confidence interval 1.70-18.71), number of centres (P = 0.010; more likely in single-centre than multi-centre trials; odds ratio 2.49, 95% confidence interval 1.25-4.99), phase of trial (P = 0.041; more likely in phase II than phase IV trials; odds ratio 2.88, 95% confidence interval 1.04-7.93) and sponsor category (P = 0.001; more likely in industry-sponsored than university-sponsored trials; odds ratio 5.05, 95% confidence interval 1.87-13.63).
CONCLUSIONS: There is evidence of non-dissemination bias in randomized trials of interventions for neurodegenerative diseases. Associations with trial discontinuation and non-publication were similar to findings in other diseases. These biases may distort the therapeutic information available to inform clinical practice

Last week we reported a discontinued Cambridge trial, where the results have not been reported yet (Only at least 15 months from termination), we have mentioned the Ely Lilly Trial that has yet to be reported..

This paper has spotted that loads of  trials don't get finished and loads don't reported. I can see that recruiting for trials is a problem, the PROXIMUS is eighteen months late but now fully recruited, the Canbex trail is very late too but almost there

However before having a rant, you've said "kettle and black"...

You are right we have to hold our hands up and say yes we need to give ourselves a bit of a kick or should I say I need to give the Profs a good kicking 

We (you and I ) know, but the rest of the World don't... that the INSPIRE trial has expired, but a failure is no reason not to publish. 

I heard a "a negative trial can tell us as much as a positive trial"...rubbish....negative trials always leave us with two questions.

It may not always tell us about biology but it may tell us that we do some poorly designed or executed trials. If we aspire to negative trials we have lost before we start. 

I have said that many of our good ideas have been killed off because of bad trials. Not popular with the Neuros and Funders of the trials, but I will stick to my guns on this one. 

I have been saying until I am blue in the face, if you don't have a trial that can work, it doesn't matter which drug you try, it won't work. 

Until beta interferon came along we didn't know how to do relapsing trials not it is easy to work out if an agent is active of not. For progressive trials we are not sure if we are using good outcomes or maybe the trials aren't long enough. 

Our idea of cannabinoids controlling nerve loss is supported by more biology that you can shake a stick at, but the trial failed. 

Speaking to one of the investigators this week. 
They said, the placebo arm just did not progress as expected
(if you are in a trial you do better even if you are on placebo) , so if tyou don't get worse in the placebo arm how can you ever find a positive result of stopping people getting worse. 
It took 6 years to learn this lesson. 

Maybe if the trial was loaded with people who could respond and in people who may get worse if they don't get treated, then we would see something

If you have evidence that your disease is worsening in may be easier to get on to trials or to get access to drugs.

So are you monitoring? 

Do you have a 9 hole peg test, do you know your time for a 25m walk. Because to get into trials or to get access to drugs you may have to show that you have documented worsening

Anyway, we need to come clean, the ProfGs needs to put pen to paper, because until they do that we can't give anyone a roasting,

Oh I forgot ProfG the CLARITY extension is also only about 3 years late so still time:-)....Yeah I know the third reviewer;-)

We collect so many metrics, maybe the number of trials reported has to be a good one when deciding who is funded to do more trials. 

People are risking a lot to participate in the studies, they have a right to know what happened. 

Friday, 23 June 2017

July comes Early

I came across this clock many months ago ticking away in French and English after I stumbled on a Norwegian Website

I nearly made a post for April the first..... so July comes early

Maybe the name will be a grower, but cladding does not have a good reputation in the UK at the moment :-) Don't understand Click

Well done, Prof G, DrK & Merck.

The Tortoise gets there in the end. Will it beat the Hare?

#NewsSpeak: another eagle has landed only this time it is a maven

Oral cladribine finally gets licensed for the treatment of relapsing MS #NewsSpeak #MavenClad

I was invited to a meeting to advice Serono in 2002 whether, or not, they should in-license an oral formulation of cladribine. We advised yes and today the CHMP have recommended that the EU give Merck a marketing authorisation for oral cladribine. The process took 15 years. Who said MS drug development was fast? 

The oral formulation of cladribine, Mavenclad, is the first oral selective immune reconstitution therapy (SIRT)* for treating patients with active relapsing MS. 

*Please note SIRT is a new term to describe the class of drugs that work via immune depletion, which can be non-selective or selective, followed by immune reconstitution. 

CoI: multiple  

#NeuroSpeak: reclaiming MS as one disease

Redefining what is a relapse and making MS one disease? #1-disease-not-2-or-3-diseases #NeuroSpeak

I was reminded at a meeting last night why it is important to publish consensus statements. Barts-MS hosted a UK NEDA meeting in 2014. As a group of UK MSologists we reached a consensus that we would stop referring to new MRI activity as 'MRI activity' and start to refer to it as a 'subclinical relapse'. In other words we all agreed to change our working definition of a what constitutes a relapse. This is not new. I was involved in another consensus meeting in 2010, held by the CMSC, during which we came to the same conclusion and published our recommendations in 2013. The problem is we didn't publish our meetings conclusions. I will now harass the chair of the meeting to get typing. 

We also did a survey on this topic in 2014 and you the community who read this blog agreed with us. 

Changing the definition of what constitutes a relapse has implications for how we use DMTs in clinical practice and challenges the older NICE guidance on not being able to escalate DMTs on MRI criteria alone. To escalate from a platform, or a 1st-line, DMT you need to have clinical attacks. However, the newer NICE guidance allows alemtuzumab to be prescribed to pwMS with active MS defined either clinically or on MRI and to retreat on MRI activity . The latest guidelines therefore recognise that clinical attacks and MRI activity mean the same thing biologically; i.e. that MS is active. This position statement is also in keeping with the new 2013 Lublin criteria of classifying MS disease activity. 

One of the consequences of this change is that pwPPMS who have active scans will be reclassified as having relapsing MS. This is not a bad thing because it starts to bring MS back under one umbrella. This also become less relevant with the emergence of effective DMTs for PPMS. Ocrelizumab now has a US label for relapsing forms of MS and PPMS. Is there a population of people with MS that is not covered by this label? Yes, patients with inactive MS defined clinically and on MRI. The latter is disease course agnostic. 

All this supports our campaign that MS #1-disease-not-2-or-3-diseases.

Cook et al. Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course: A Report from an International CMSC Consensus Conference, March 5-7, 2010. Int J MS Care. 2012 Fall;14(3):105-14.

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

You can be EBV negative and still have MS

Some one asked if we were too embarrassed to discuss the paper below. ProfG argues that EBV is the cause of multiple sclerosis, so EBV negative individuals would burst the bubble

Dobson R, Kuhle J, Middeldorp J, Giovannoni G. Epstein-Barr-negative MS: a true phenomenon? Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e318. Epstein-Barr virus (EBV) infection is associated with MS; up to 3.3% people with MS are EBV nuclear antigen-1 (EBNA1)-seronegative compared with 6.0% controls. EBV serology is complex, and multiple antigens are required to assess seropositive status.We examined a cohort of seemingly EBV-negative patients with clinically isolated syndrome (CIS). The size of the population enrolled in the International CIS study allowed us to examine the largest population of seemingly EBV-negative patients with CIS gathered to date.

Yesterday someone mentioned this paper and implied we were frightened to bring it up.

There are EBV negative pwMS. Does this mean the idea is wrong. 

In fact only 1 of 1,047 pwMS (<0.01%) was truly EBV-negative. Those that were negative were more likely to not make oligoclonal bands.

I haven't seen ProfG crying in his soup, so I am guessing that he can live with the occasional negative pwMS.

Detection is only as good as you look, they tried a few ways but didn't succeed to detect EBV in everyone

JC virus causes PML so if you are JC virus negative and taking natalizumab. Why is the risk of PML 1 in 10,000 and not never?

One suggestion is EBV is a transactivator and it make HERV (endogenous retro virus) to become active as the target. We all have HERV its 7% of our genome.

Thursday, 22 June 2017

Myelin Autoimmunity in T cells. Time to say schtop!. MS lesions are EBV killing zones

van Nierop GP, van Luijn MM, Michels SS, Melief MJ, Janssen M, Langerak AW, Ouwendijk WJD, Hintzen RQ, Verjans GMGM. Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients.  Acta Neuropathol. 2017 doi: 10.1007/s00401-017-1744-4. [Epub ahead of print]

T cells are considered pivotal in the pathology of multiple sclerosis (MS), but their function and antigen specificity are unknown. To unravel the role of T cells in MS pathology, we performed a comprehensive analysis on T cells recovered from paired blood, cerebrospinal fluid (CSF), normal-appearing white matter (NAWM) and white matter lesions (WM L) from 27 MS patients with advanced disease shortly after death. The differentiation status of T cells in these compartments was determined by ex vivo flow cytometry and immunohistochemistry.

T-cell reactivity in short-term T-cell lines (TCL), generated by non-specific stimulation of T cells recovered from the same compartments, was determined by intracellular cytokine flow cytometry. Central memory T cells predominated in CSF and effector memory T cells were enriched in NAWM and WM Lesion. WM Lesion-derived CD8+ T cells represent chronically activated T cells expressing a cytotoxic effector phenotype (CD95L and granzyme B) indicative for local antigenic stimulation (CD137). The same lesions also contained higher CD8+ T-cell frequencies expressing co-inhibitory (TIM3 and PD1) and co-stimulatory (ICOS) T-cell receptors, yet no evidence for T-cell senescence (CD57) was observed.

The oligoclonal T-cell receptor (TCR) repertoire, particularly among CD8+ T cells, correlated between TCL generated from anatomically separated WM Lesions of the same MS patient, but not between paired NAWM and WM Lesion. Whereas no substantial T-cell reactivity was detected towards seven candidate human MS-associated autoantigens (cMSAg), brisk CD8+ T-cell reactivity was detected in multiple WM Lesions-derived TCL towards autologous Epstein-Barr virus (EBV) infected B cells (autoBLCL).

Collectively, the data suggest the involvement of effector memory cytotoxic T cells recognizing antigens expressed by autoBLCL, but not the assayed human cMSAg, in WML of MS patients.

What does this study suggest? 

Advanced Disease is associated with active inflammatory lesions, so maybe not too late for a DMT.

Is it time for the card-carrying  CD4 T cell immunologists to pack up their bags and work on a different condition.

Is it time to say no more CD4, Th17 immunology in lab mice.

There is no autoimmunity to myelin basic protein or myelin oligodendrocyte glycoprotein, Kir 4.1 (potassium channel)

Cells in active lesions recognized Epstein Barr Virus, cells in normal appearing white matter did not.

You don't want your therapeutic drug to increase CD45RO, CCR7- effector memory cells..

The data suggests that CD8 T cells cause the active lesions or are associated with the active lesions and they are killing EBV infected B cells.

How does this fit with the B memory cell idea. It fits perfectly. 
If you get rid of the B memory cells you get rid of the EBV, so nothing to get the CD8 T cells going. It may suggest that blocking CD8 would stop the attack, but it wouldn't remove the problem.

This supports the approach developed by Prof Pender in Oz...
What ever happened to ProfGs hope to be involved with this?

Why MS?

It maybe has something to do with the formation of the B cell follicles creating a steady stream of CNS B cells ripe for attack, if you get follicles in the joint you get arthritis.

However do we find T cell reactivity to EBV because we are looking for reactivity to EBV

Nice study from our mates in the Netherlands

Wednesday, 21 June 2017

A NEWsletter for families affected by MS and those who support them.

Digesting Science has sent out the first monthly email newsletter to families affected by MS and those who support them. I'd love to know what you think of our first offering, sent out yesterday. 

We want to update you on project news and tell you about Digesting Science as the kits travel the country (and the world!). We have top tips for families living with MS, written by families living with MS. And we have research news in Plain English.

Reading this blog, I see a lot of comments that suggest most of you are au fait with scientific language and medical jargon. But for those who aren't, reading up about MS research can be confusing and even overwhelming. We really think research news should be accessible for EVERYONE who wants to know more about their condition. And we want to empower people to see beyond the often (shamefully) misleading headlines some media outlets propagate in response to big announcements in the research world. We hope that the Digesting Science newsletter will provide research news that doesn't oversimplify the message, but doesn't obfuscate it with technical words either.

If you'd like to subscribe to the new email, then you can do so here.

And don't forget to let me know what you think of this one!

B cell dependent EAE

Sefia E, Pryce G, Meier UC, Giovannoni G, Baker D. Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. Mult Scler Relat Disord. 2017 May;14:46-50. doi: 10.1016/j.msard.2017.03.013.

This paper warns about the value of using mice to understand B cell activity in MS. It looks at a few published studies or mouse studies and asks you to think.

If we look in the abstract in the paper below , the work is now done in a B cell- and antibody-dependent mouse model of MS. 

Is this the beginning of the airbrushing to make EAE into a B cell disease, this current paper says stop it simply isn't a B cell disease, it is a T cell disease, where B cells and B cell products can influence the T cell mediated disease.

So what is this B cell dependent disease. It is MP4-induced EAE in C57BL/6 mice. Kuerten S, Pauly R, Rottlaender A, Rodi M, Gruppe TL, Addicks K, Tary-Lehmann M, Lehmann PV. Myelin-reactive antibodies mediate the pathology of MBP-PLP fusion protein MP4-induced EAE.Clin Immunol. 2011;140:54-62. 

This model only develops when you have antigen presenting B cells. First, how representative is this very artificial system. (left) 

The C57BL/6 is amongst the most EAE resistant mouse strain and it was thought to be resistant to myelin basic protein and spinal cord disease until myelin oligodendrocyte glycoprotein came around. MP4 is a synthetic protein of myelin basic protein and water-soluble peptides of proteolipid protein, which are both not expressed on the surface of myelin and so difficult to target for antibodies. (Although antibodies may bind to epitopes outside and inside the myelin). So it was found that a disease resistant strain, could not develop disease with a weak antigen in that strain, unless it has a full complement of antigen presenting cells. 

Nothing has been done to show the issues are really different from any other T cell dependent EAE. If you add myelin antibodies to T cell EAE, this it makes the disease worse, usually, but that does not make it only B cell dependent. The antibodies also appear to be detected after the clinical disease (figure right).

Do we base our ideas on an outer extreme? 

Do we follow it without question, I suspect I can guess how people will treat this (this from one of the guys that gave us epitope spread). I have heard the view from ProfG, enjoy. 

Is this why natalizumab work's in Crohns too?

Of course not....but had you thinking:-)
(P.S. In the gut cells home using alpha4 beta 7 integrin rather than the brain which use alpha 4 beta 1 integrin. natalizumab block alpha4 integrin

MS in the guts

Wunsch M, Jabari S, Voussen B, Enders M, Srinivasan S, Cossais F, Wedel T, Boettner M, Schwarz A, Weyer L, Göcer O, Schroeter M, Maeurer M, Woenckhaus M, Pollok K, Radbruch H, Klotz L, Scholz CJ, Nickel J, Friebe A, Addicks K, Ergün S, Lehmann PV, Kuerten S. The enteric nervous system is a potential autoimmune target in multiple sclerosis. Acta Neuropathol. 2017. doi: 10.1007/s00401-017-1742-6. [Epub ahead of print]

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socio-economic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.

The opening line of the abstract gives a different twist usual science rag, it says that MS makes you poor. It gets weirder from there.

First we had the microbiota and the nervous system. 

Did you spot the possible link between the microbiome and autoimmunity after alemtuzumab in our recent paper this week, yes there are hidden gems in there. 

It is still free to download and read if you want click and follow the links.

Now we are being told it is the enteric (gut) nervous system that's a problem. We would agree that with time that there are clearly problems with the gut in mice with EAE, and believe it or not we did a project looking at constipation, so in this case we can definitely say the chicken led to the egg. That the gut problems come after the autoimmunity of the CNS.

However, in this study they imply that the gut autoimmunity comes first. They report gut problems before there is evidence of autoimmunity in the CNS in an animal model.  There was significantly less gut motility.

So should we make some students or MD2 count and weigh mouse poohs. It would not be surprising in mice with neurological EAE that there pooh count will be affected, as they eat and drink less when they are neurologically affected, but being a recipient of quite a few mouse number 2's in my time when holding a mouse, they maintain this function early in the disease course.  

They found antibodies that targeted the gut in mice, which were present in some people with MS and there was some gut pathology with MS. If they had made the suggestion that MS was secondary to autoimmunity in lung tissue would this have been found? 

But how does this disprove the possibility that lesions in the CNS has led to de-innervation of gut pathways and the effect is secondary to this. You are not going to get an answer against this from studying post-mortem MS years after disease onset.

But you are going to get support that there are gut changes in MS

Moser AM, et al. Mucosal biopsy shows immunologic changes of the colon in patients with early MS. Neurology, N2.

Objective: To investigate immune cells of the colonic mucosa and faecal short-chain fatty acids (SCFAs) in treatment-naive patients with a clinically isolated syndrome (CIS) or early relapsing MS.
Methods: In this cross-sectional proof-of-concept study, we obtained mucosal specimens during ileocolonoscopy from 15 untreated patients with CIS/MS and 10 controls. Mucosal immune cells were analyzed by FACS, and gas chromatography-mass spectrometry measurements of stool samples served to determine SCFA.
Results: The number of total dendritic cells (DCs), CD103+ tolerogenic DCs, and CD4+25+127–regulatory T cells (Tregs) was significantly reduced in the distal colon of patients with CIS/MS compared with controls, whereas we found no differences in the proximal colon. The patients' faecal samples also showed a substantially lower content of SCFA and especially lower levels of butyrate and acetate.
Conclusions: Our findings indicate a disturbed homeostasis of colonic DCs and Tregs in patients with MS which could be associated with colonic SCFA depletion. Although not implying causality, these findings confirm parallel abnormalities of the gut in MS and warrant further research if modulation of the colonic SCFA profile or the colonic Treg pool can serve to modify the course of MS.

#NeuroSpeak & #BrainHealth: walking the talk

How competitive is your group when it comes to the health of your brain? #BrainHealth #NeuroSpeak

We have been promoting 'the holistic management of MS' and 'brain health' for sometime now, hoping that the wider MS community will take the message seriously. If you repeat things enough people may start to notice and say, yes I should do this.

Interestingly, I was made aware yesterday of a Novartis funded site ( to educate pwMS about brain health. Has anyone used the site? If yes, how did you find it? 

People with MS who exercise more and have higher self-rated health had lower levels of functional limitations 11 years later. Is this chicken or egg? Did the exercise result in better outcomes or did those pwMS who were doing well simply able to exercise more? Is this observation an association or is it causal? For this we need to do randomised trials or look to animal models and other data to make the case that exercise is actually good for you. It is clear that exercise is more than just a manifestation of being physically able; exercise has biological effects that change the way the brain functions. 

Based on these and other observations exercise should be classified as a DMT (disease-modifying treatment) for MS and that everyone with MS should be enrolled on an ongoing exercise programme of some description. It doesn't matter how disabled you are there is always a form of exercise that you will be able to perform. 

If you don't have MS and are reading this post, for example you may be a HCP, Scientist or Pharma Executive, you should also be doing regular exercise. The data linking regular exercise to a reduced risk of developing dementia, or age-related cognitive impairment, is overwhelming. The problem we face is that as our society gets more sedentary how do we get people to do more exercise? This is a big public health challenge. It is time to formalise our Barts-MS Brain Health Challenge into something more concrete? 

Jodi Haartsen, a MS Nurse Practitioner, from Australia contacted me over 2 years ago about setting up a platform so that Australian MS Healthcare professionals could compete against UK MS HCPs & pwMS. We can now make this happen. How?

Virgin Pulse an organisation that is trying to transform the cultures of the world's leading organisations and improve the health and performance of employees, launched the Global Challenge (formerly known as GCC). Virgin Pulse provides a technology solutions that promote employee engagement and well-being. The next Global Challenge starts 6th September 2017.

I am going to suggest that as many MS Units and Pharma teams take-up the challenge and compete with each other. We are prepared to curate a list of competing centres and groups. If you are prepared to join please register via the Google form below and register at Virgin Pulse.

When we surveyed readers when we raised the challenge, most of you were up to doing it. I hope nothing has changed.

Stuifbergen et al. Selected health behaviors moderate the progression of functional limitations in persons withmultiple sclerosis: Eleven years of annual follow-up. Disabil Health J. 2016 Jan 28. pii: S1936-6574(16)00008-X.

BACKGROUND: Multiple sclerosis (MS), a chronic neurological disease typically diagnosed in young adulthood, presents with a wide variety of symptoms, impairments and functional limitations. Given the chronic, unpredictable and long-term nature of this disease, preserving function is essential.

OBJECTIVE: The purpose of this study was to identify psychosocial and behavioral factors that might influence the trajectory of functional limitation through eleven years of longitudinal follow-up of a sample of persons with MS.

METHODS: Participants (N = 606) completed measures of health behaviors, related constructs and functional limitations annually over eleven years. Longitudinal measures of functional limitations were analyzed using random-effects regression that allows for study of individual differences in the trajectories of a measure. Using the best fitting quadratic growth model, we tested the within and between-person effects of Nutrition, Interpersonal Relationships, Exercise, Stress Management, Health Responsibilities, Spiritual Growth, Self-rated Health and Barriers, controlling for Age, Year since Diagnosis and Year of Dropout, on Functional Limitations in the 11th year.

RESULTS: After adjusting for covariates, higher mean scores for Exercise and Self-rated Health were related to lower levels of Functional Limitations in Year 11. Higher mean scores for Stress Management, Health Responsibilities and Barriers were related to higher levels of Functional Limitations in Year 11. Higher mean Exercise scores and lower mean Health Responsibilities scores were related to slower rates of progression of functional limitations in Year 11.

CONCLUSION: Findings suggest that the highly variable trajectory of functional limitations in MS may be extended and shaped through health behavior strategies.

Tuesday, 20 June 2017

If you want to make a real difference in this world, it's a lot harder than it seems

As I watched Larissa Sansour's short exhibition entitled "In the Future, They Ate From the Finest Porcelain" at the Barbican today, it dawned on me that science, medicine, and new discoveries all create alternative realities. A reality that cannot be predicted precisely by historians or politicians come to that. In essence, the work becomes a historical intervention - a de facto truth of the future, and not the past.

"We are depositing facts in the ground for future archaeologists to evacuate. These facts will confirm the existence of this people we are positing.
So only in the future will people learn that the civilization ate from the finest porcelain?
Yes, only then.
Very few raptures are instantaneous."

In practice I have often used the PRISMS-15 study (see below for the abstract, 15y outcome of the original RRMS trial in PwMS receiving interferon beta-1a, 44ug or 22ug, three times a week compared to placebo) as evidence that higher dose exposure and longer time on treatment, improves clinical outcomes. The proportion of individuals with EDSS≽4 in the high dose group (31.8%) was almost half that in the low dose group (60.7%), while the proportion with EDSS≽6 was a quarter in the high dose (13.9%) of that seen in the low dose group (52.1%). Around half of the low dose group (52.1%) converted to secondary progressive MS compared to a fifth in the high dose group (20.8%). The 15 year analysis also revealed that change in EDSS from start of the trial to 24 months and medication possession ratio (calculated as 100 x time [in days] on treatment from the start to the 15y visit) predicted secondary progressive MS conversion, suggesting that early treatment and adherence to treatment were important factors in obtaining good clinical outcomes. 

This real-world data is very informative; information that would not have been known back in 1998 when the original study was published. My hope is that more clinicians and PwMS adopt these principles when managing MS rather than living in the past.

J Neurol Neurosurg Psychiatry. 2015 Nov;86(11):1202-7. doi: 10.1136/jnnp-2014-310024. Epub 2015 Sep 15.

Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.

Kappos L, Kuhle J, Multanen J, Kremenchutzky M, Verdun di Cantogno E, Cornelisse P, Lehr L, Casset-Semanaz F, Issard D, Uitdehaag BM.



An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) β-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS).


Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN β-1a dose groups, and according to total time receiving sc IFN β-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed.


Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years.


These findings suggest that higher cumulative exposure to sc IFN β-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

Monday, 19 June 2017

#ResearchSpeak: derisking alemtuzumab

Making alemtuzumab, or the son of alemtuzumab, safer; is it too late? #MSBlog #ResearchSpeak

It has been ~5 years since I approached Genzyme with a hypothesis to derisk alemtuzumab. I first posted on the topic of derisking alemtuzumab on the blog in 2014. I discussed derisking infusion reactions and secondary autoimmunity.
To reiterate my position is that once oral cladribine and ocrelizumab are launched most thinking pwMS and neurologists will have a hard time justifying taking the risks of alemtuzumab. Why? You get similar efficacy from ocrelizumab, a maintenance treatment, and if you want to go the PIRT (pulsed immune reconstitution therapy; previously referred to as an induction therapy) route cladribine is much safer than alemtuzumab. With cladribine you get no secondary autoimmunity, no infusion reactions and much fewer infections because cladribine doesn't take-out innate immunity or deplete T-cells to the same degree as alemtuzumab. Cladribine also has the advantage of being oral and its monitoring requirements are so much less arduous. The bottom line is would you go into a randomised trial of alemtuzumab vs. alemtuzumab plus a second agent to try and prevent secondary autoimmunity or would you choose ocrelizumab or oral cladribine? I suspect you would choose one of the latter two options. This means we will have lost equipoise and our proposed trial(s) will be unethical.

The immune system has many mechanisms in place to prevent autoimmunity. When you learn how the immune system works it is really quite surprising that autoimmunity is so uncommon. What the immunologists tell us is that there must be a series of underlying biological processes that are causing secondary autoimmunity and if we can work out what these are we can intervene and prevent this complication. This is what the Professor Alasdair Coles, and Dr Joanne Jones, have been trying to do in Cambridge. They think that because the immune system reboots itself from peripheral memory cells it is more likely to result in an aberrant autoimmune responses. They have done a trial to encourage rebooting of the immune system using more naïve cells from the thymus. They have treated MSers after alemtuzumab with a hormone called, Palifermin, that stimulates the thymus to produce more naïve T-cells. The study is called the Cam-Thy study.

We have a different take on what is responsible for the secondary autoimmunity and wanted to test a different strategy; we hypothesised several years ago that it was due to B-cell hyperproliferation. Based on our hypothesis Palifermin should exacerbate the problem; increasing reconstitution with naive cells without regulation will increase secondary autoimmunity.

Importantly, when you compare cladribine, another immune system rebooter, with alemtuzumab you can’t help but notice that the B-cell reconstitution profiles are very different. With alemtuzumab they come back very quickly and overshoot their baseline values. We have hypothesised that if you changed the profile of the B cell reconstitution with a small dose of the B cell depleting antibody rituximab you may be able to prevent this secondary autoimmunity. We are really talking about a very small dose of rituximab, i.e. 50-100mg, just enough to allow to delay B cell reconstitution by 4-6 months. This is the concept trial that Genzyme rejected several years ago.

In response to the challenge above the Mouse Doctor and DrK have analysed the alemtuzumab reconstitution data in more detail and the analysis strongly supports this hypothesis. Where to from here? I think we could still do a proof-of-concept trial, but focusing on anti-drug antibodies, i.e. anti-alemtuzumab antibodies as the readout. Alemtuzumab is a humanised antibody and the incidence of anti-drug antibodies should be very low. Alemtuzumab appears to break immune tolerance and the mechanisms that underlie anti-drug antibodies may be the same as  those that underlie secondary autoimmunity. 

Baker et al. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017 Jun 12. doi: 10.1001/jamaneurol.2017.0676.

IMPORTANCE: Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.

OBJECTIVE: To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.

DESIGN, SETTING, AND PARTICIPANTS: Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.

MAIN OUTCOMES AND MEASURES: Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.

RESULTS: Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (-80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.

CONCLUSIONS AND RELEVANCE: Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell-depleting agents. 

CoI: multiple

Sunday, 18 June 2017

#ClinicSpeak & #ThinkHand: ability to cut your own toenails correlates with EDSS

Why do we continue to treat hand function as a secondary outcome in clinical trials? #ClinicSpeak #ToeArt #ThinkHand

When  we launched our #ThinkHand campaign last year one of the hand functions that pwMS wanted to preserve was the ability to cut their toenails. This hand function item is pretty obvious. Since then I have started inspecting the state of my patients toenails in clinic and noticed that poor toenail maintenance was clearly linked to disability (EDSS) and deprivation or social isolation. In other words if you can't cut your own toenails and you don't have a partner or family member to do your toenails get neglected. I then did a survey on this topic and of 45 respondents with analysable results there was a clear correlation between EDSS and the ability to cut toenails, which was highly significant.

DfSum SqMean SqF valuePr(>F)
Model177.86877.86823.021< 0.0001

There are too few respondents to the survey to draw a box-and-whisker for the 'No' respondents, but you can see that the median EDSS for this group was 6.5, compared to 6.0 and 3.0 for this who could cut their toenails with some help or independently, respectively. 

Interestingly, 50% of respondents had difficulty cutting their own toenails. The reasons given for not being able to cut their own toenails are linked to disability, i.e. weakness, inco-ordination, reduced sensation and poor vision. For these reasons I have started asking all my patients if they can cut their own toenails, I inspect their toenails in clinic and if their toenails are in a state of disrepair I offer them a referral to the podiatry clinic. 

To raise awareness of the toenail issue, which is really a hand issue, I launched an 'art project' to collate a series of pictures of the toenails of pwMS and to relate them to levels of physical disability. Pictures are so much better at telling a story. 

The slideshow below represents renditions of pictures of first nine pwMS who have sent in photographs of their toes. I need more pictures to make this project a success. To participate please send me pictures of your toes, with some brief details about your MS and yourself. The pictures will be 'anonymised' and will used as part of our #ThinkHand campaign. 

Please send the following information with your picture to

Sex: M/F
Disease duration:
EDSS: (if you don't know your EDSS you can estimate it using our online calculator)
Are you able to cut your own toenails?:
  • 5 - Yes, easily without help
  • 4 - Yes, independently, but it takes longer than in the past 
  • 3 - Yes, independently, but it takes too long so I often get them cut by someone else
  • 2 - Yes, but I need help
  • 1 - No, I can't cut my in toenails
  • 0 - N/A, I have always had someone else cut my own toenails
Biography: (this is optional please keep this brief)

CoI: ProfG, the Cheerleader for #ThinkHand

Cortical demyelination in Animals

Ücal M, Haindl MT, Adzemovic MZ, Strasser J, Theisl L, Zeitelhofer M, Kraitsy K, Ropele S, Schäfer U, Fazekas F, Hochmeister S. Widespread cortical demyelination of both hemispheres can be induced by injection of pro-inflammatory cytokines via an implanted catheter in the cortex of MOG-immunized rats. Exp Neurol. 2017. pii: S0014-4886(17)30107-3.

Cortical demyelination is a common finding in patients with chronic multiple sclerosis (MS) and contributes to disease progression and overall disability. The exact pathomechanism that leads to cortical lesions is not clear. Research is limited by the fact that standard animal models of multiple sclerosis do not commonly affect the cortex, or if they do in some variants, the cortical demyelination is rather sparse and already remyelinated within a few days. In an attempt to overcome these limitations we implanted a tissue-compatible catheter into the cortex of Dark Agouti rats. After 14 days the rats were immunized with 5μg myelin oligodendrocyte glycoprotein (MOG) in incomplete Freund's Adjuvant, which did not cause any clinical signs but animals developed a stable anti-MOG antibody titre. Then the animals received an injection of proinflammatory cytokines through the catheter. This lead to a demyelination of cortical and subcortical areas starting from day 1 in a cone-like pattern spreading from the catheter area towards the subarachnoid space. On day 3 cortical demyelination already expanded to the contralateral hemisphere and reached its peak between days 9-15 after cytokine injection with a widespread demyelination of cortical and subcortical areas of both hemispheres. Clinically the animals showed only discrete signs of fatigue and recovered completely after day 15. Even on day 30 we still were able to detect demyelination in subpial and intracortical areas along with areas of partial and complete remyelination. Loss of cortical myelin was accompanied with marked microglia activation. A second injection of cytokines through the catheter on day 30 led to a second demyelination phase with the same symptoms, but again no detectable motor dysfunction. Suffering of the animals appeared minor compared to standard Experimental Autoimmune Encephalomyelitis and therefore, even long-term observation and repeated demyelination phases seem ethically acceptable.

Cortical demyelination occurs frequently in MS can this be modelled in rats

The Lisbon Trilogy Slides

This week we have had a lot of interest in our paper with over 3,000 views as the final part of the Lisbon trilogy.

What's the Lisbon Trilogy

Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, 
Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol, Neuroimmunol Neuroinflam
4:e360; doi:10.1212/NXI.0000000000000360: 2332-7812

Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017 Jun 12. doi: 10.1001/jamaneurol.2017.0676.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017;16:41-50. doi: 10.1016/j.ebiom.2017.01.042

and to counter the animal experiments that could follow

Sefia E, Pryce G, Meier UC, Giovannoni G, Baker D Depletion of CD20 B cells fails to inhibit relapsing mouse experimental autoimmune encephalomyelitis. Mult scleros is and related disorders DOI:

ProfG was asked to give a talk on the mechanisms of Action of Antibodies in MS to a group of Antibody Engineers.

ProfG could not attend so he asked me to do it, gave me his 75 slides for a 30min talk.....No chance. 

I had a few weeks to construct a story and plan my slides

So I thought, could I explain how natalizumab, daclizumab, alemtuzumab and ocrelizumab work?

Starting with daclizumab as the odd one out and having the details of of the alemtuzumab and cladribine to hand this is what the audience got.

There was one Neurologist in the Room. 

Saturday, 17 June 2017

#ToeArt: who is more or less disabled?

What can the toes tell us about the lives of people living with MS? #ToeArt #ThinkHand

To find out what these art pieces are about you need to read my earlier post on #ToeArt.

#ClinicSpeak: chemobrain in MS

HSCT or BMT accelerates brain atrophy rates and disability worsening in SPMS. #ClinicSpeak #MSBlog #MSResearch

I am revisiting this old paper to make it a Saturday trilogy of posts on HSCT.

HSCT (hemopoetic stem cell transplantation) or BMT (bone marrow transplantation) requires chemotherapy to ablate or wipe-out your immune system to allow the stem cell transplantation. The chemotherapy drugs that are used are neurotoxic, i.e. they damage the brain.

PwMS who already have pre-existing damage to their brain and spinal cords are particularly susceptible to the neurotoxic effects of chemotherapy. This is also driven by age; the older you are the worse you handle chemotherapy. The oncologists refer to this observation as chemobrain, which is particularly prevalent in the elderly. 

The following study below in which I was involved with shows that when pwMS are given chemotherapy they undergo increased neuronal loss, which is associated with worsening of their EDSS and greater brain atrophy. The data speaks for itself. The picture below is what we call a survival curve of EDSS worsening; you can see that the pwMS who had high blood levels of neurofilaments were much more likely to worsen than those who did not have raised neurofilament levels. Similarly, brain atrophy rates in pwMS were in the order of 2.1% per year in those who had a HSCT compared to only 1.2% per year in pwSPMS who did not have HSCT; the upper limit of normal for brain atrophy in healthy adults is generally accepted to be 0.4% per year. The bottom line is that if you have SPMS HSCT is likely to accelerate your disease worsening. As a result of these and similar observations most units have stopped doing HSCT in people with more advanced MS. However, with the advent of highly-effective DMTs such as alemtuzumab, natalizumab, fingolimod, daclizumab, ocrelizumab and cladribine the number of pwMS needing to be referred for HSCT should be small. 

OBJECTIVE: Chronic neurotoxicity is a recognized long-term complication following chemotherapy in a range of diseases. Neurotoxicity adversely affects patients' quality of life. The objective of this study is to examine whether there is evidence of acute neurotoxicity.

METHODS: This prospective study included MSers with secondary progressive multiple sclerosis (SPMS-BMT, n = 14) and hematological malignancies (HM-BMT, n = 17) receiving chemotherapy as preconditioning for bone marrow transplant. The control groups included SPMSers matched for demographic and clinical data (SPMS-PL, n = 14) and healthy controls (n = 14). Neurodegeneration was assessed at baseline and longitudinally (months 1, 2, 3, 6, 9, 12, 24, and 36), combining a clinical scale for disability (Expanded Disability Status Scale [EDSS]), a serum protein biomarker for neurodegeneration (neurofilaments, NfH-SMI35), and brain atrophy measures (magnetic resonance imaging).

RESULTS: Disability progression was significantly more acute and severe following chemotherapy compared to placebo. Immediately after starting chemotherapy, serum NfH-SMI35 levels increased in 79% (p < 0.0001) of SPMS-BMT MSers and 41% (p < 0.01) of HM-BMT patients compared to 0% of SPMS-PL MSers or healthy controls. In SPMS-BMT serum NfH-SMI35 levels were > 100-fold higher 1 month after chemotherapy (29.73ng/ml) compared to baseline (0.28ng/ml, p < 0.0001). High serum NfH-SMI35 levels persisting for at least 3 months were associated with sustained disability progression on the EDSS (p < 0.05). Brain atrophy rates increased acutely in SPMS-BMT (-2.09) compared to SPMS-PL (-1.18, p < 0.05).

INTERPRETATION: Neurotoxicity is an unwanted acute side effect of aggressive chemotherapy.

CoI: Prof. G was a co-author on this study.

HSCT putting brain loss down to aging

Lee H, Nakamura K, Narayanan S, Brown R, Chen J, Atkins HL, Freedman MS, Arnold DL. Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.Mult Scler. 2017 Jun 1:1352458517715811.

BACKGROUND:Immunoablation and autologous hematopoietic stem cell transplantation (HSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration.
OBJECTIVE:To model GM and WM volume changes after HSCT to further understand the effects seen on WB atrophy.
METHODS: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with HSCT.
RESULTS: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively.
CONCLUSION:Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.

This study  looks at the effect of HSCT on brain atrophy. There appears to be an initial problem of early brain volume lost and although this could be because of loss of inflammation but as profG showed many years ago the drugs used are neurotoxic and cause some nerve damage and this can be seen by neurofilaments (bits of nerves) being found. However with time it looks like brain volume lost is reduced to the level associated with normal aging. This has been seen with alemtuzumab.