Tuesday, 30 June 2015

Can we rebuild a damaged knight

Maybe prostheticsRus comes to the rescue and we can live and fight for another day.

N.B. This post is unrelated to the use of bionic limbs for pwMS

Alemtuzumab, here I come: Top line results of the Ocrelizumab in relapsing MS studies

This morning, Roche announced the headline results of their Ocrelizumab in relapsing MS program (OPERA I and II).   Here is their press release:

Numerous posts on this blog have highlighted the potential of this humanized version of Rituximab (check the "BartsMS essential off-label DMT list" in the left upper corner), an established drug to treat people with B cell lymphoma, for the treatment of people with MS. Ocrelizumab appears to be significantly better compared to interferon beta, however is it as good as alemtuzumab but without the significant risk of autoimmunity?

Vitamin D in Optic Neuritis Trial fails

Salari M, Janghorbani M, Etemadifar M, Dehghani A, Razmjoo H, Naderian G.Effects of vitamin D on retinal nerve fiber layer in vitamin D deficient patients with optic neuritis: Preliminary findings of a randomized, placebo-controlled trial.
J Res Med Sci. 2015;20(4):372-8

BACKGROUND:There is accumulating evidence for a possible protective role of vitamin D in the development and disease course of multiple sclerosis. Whether vitamin D is also effective in treating patients with optic neuritis (ON) is not known. The aim of this study was to evaluate the effect of oral vitamin D on the thickness of retinal nerve fiber layer (RNFL) in vitamin D deficient patients with ON by optical coherence tomography.
MATERIALS AND METHODS: A Phase II placebo-controlled randomized clinical trial conducted between July 2011 and November 2012 included 52 patients with confirmed unilateral ON aged 15-38 years and low serum 25-hydroxyvitamin D levels. The main outcome measures were changes in thickness of RNFL and macula 6 months after treatment. Patients were randomly allocated to receive 6 months of treatment with adding either 50,000 IU/week vitamin D or placebo.
RESULTS: In the 27 patients treated with vitamin D, the mean (standard deviation [SD]) thickness of RNFL decreased from 111.3 (18.9) μm at baseline to 91.4 (13.3) at the end of study period (P < 0.001). Correspondingly, in the 25 patients treated with placebo, the mean (SD) thickness of RNFL decreased from 113.7 (21.5) μm at baseline to 96.1 (12.3) at the end of study period (P < 0.01). In both groups, the mean thickness of the macula did not changed (P > 0.05). Average thickness of RNFL at the end of trial did not differ between groups.
CONCLUSION: Adding vitamin D to routine disease therapy had no significant effect on the thickness of RNFL or macula in patients with ON. This trial is registered on www.clinicaltrials.gov (ID NCT01465893).
This study says that if you start taking vitamin D when you get optic neuritis, then there is no effect of saving retinal nerves and so the writing is on the wall for other CIS doing the same thing.

To me, this comes as no real surprise as I would have expected this.
OK, I accept that I could not know the answer unless the study has been done. However, I can have opinions and this is just one and may be a wrong one.

First, the treatment window from onset to drug treatment was up to one month, which is probably too long even for a drug that was going to work. Animal studies show us that damage is accumulated in the first few days and but interpolation a few weeks at most.

Next, the outcome is based on neuroprotection rather than an anti-inflammatory/immunomodulatory effect. All the rhetoric built up has been about vitamin D being an anti-inflammatory and stopping susceptibility. However, the inflammation has occurred when the optic neuritis has started.

Next, it is a nutriceutical that has few side effects....this suggests that it is not going to be a potent immunosuppressive. If it is not potent the chances of having a major effect is limited

Every MS Society will have had an application to do a trial of vitamin D and many have been funded? 

How many are looking at using vitamin D to prevent disease after it has started, compared to vitamin D as risk factor. If we think that vitamin D can have the potency of Alemtuzumab and Natalizumab then someone needs to look at our brains, as I believe we are deluding ourselves. 

We are getting an array of active drugs, but in the UK at best one can use a low efficacy drugs....maybe we should be trying to "nip it in the bud". 

The US experience of natalizumab - both very telling and very important to tell

CNS Drugs. 2015 Jun 26. [Epub ahead of print]
Platform Therapy Compared with Natalizumab for Multiple Sclerosis: Relapse Rates and Time to Relapse Among Propensity Score-Matched US Patients.
Johnson BH, Bonafede MM, Watson C.

BACKGROUND: Multiple sclerosis (MS) registry data, primarily from Europe, suggest that treatment with natalizumab delays time to relapse compared with platform therapy (interferon beta/glatiramer acetate).

OBJECTIVE:This study uses US administrative claims data and propensity score matching (PSM) to compare relapse rates and time to relapse among patients with MS using either platform therapy or natalizumab.

METHODS:Adults with MS receiving either platform therapy or natalizumab between January 1, 2009 and April 1, 2012 were identified in the Truven Health MarketScan® Research Databases. Patients were included if they had 12 months of continuous enrollment both before and after the index date (the first claim for either drug cohort) and had 12 months of claims data suggesting consistent treatment adherence during the follow-up period. Characteristics used in PSM included demographics, selected comorbidities and concomitant medications, MS severity, baseline relapse rates, and expenditures. A relapse was defined as an MS-related hospitalization or corticosteroid use.

RESULTS:A total of 882 patients were matched. Relapse occurred among significantly fewer patients in the natalizumab group (26.5 %) than platform therapy (35.5 %, p < 0.001) (hazard ratio 0.69; 95 % CI 0.59-0.82). Relapses were also significantly later for those on natalizumab (308 vs 283 days without relapse, p < 0.001).

CONCLUSION:Treatment with natalizumab was associated with a significantly lower risk and rate of MS relapse and longer MS relapse-free time compared with platform therapies.

Probability of no relapse: natalizumab vs. platform therapy

The platform therapies were IFNβ-1a (AVONEX®, REBIF®), IFNβ-1b (BETASERON®, EXTAVIA®), and glatiramer acetate (COPAXONE®). Natalizumab significantly reduced the risk of relapses both in terms of relapses (those on the platform therapy were 34% more likely to relapse) and longer relapse-free periods (nearly a month longer without a relapse). Within the 12-month post-natalizumab treatment period, those on natalizumab had significantly less steroid use and fewer MS-related inpatient admissions.

None of these findings are unexpected, the results from the Phase III AFFIRM study showed that annualized relapse rate reduced by 68% at year 1 and a 42% reduction in the risk of confirmed disability progression at 12 weeks. However, few studies have ever evaluated real life experience outside of clinical trials. And this work confirms that results from clinical trials do translate well into the real world.

There are a few important considerations. First, the disease severity of the patients in each arm, with more severe/complicated cases being channeled into natalizumab therapy in the first place, which may underestimate the impact of natalizumab on the study outcome. Secondly, the study population is limited to those with commercial health coverage or private Medicare supplemental coverage, questioning the generalizability of the findings to all MS patients.

As a general comment, I feel treatment expectations do not stop with natalizumab.

Monday, 29 June 2015

Neurologists are too blue.... ABN 2015 guidlelines

Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis Scolding N et al. Pract Neurol doi:10.1136/practneurol-2015-001139

The Association of British Neurologists (ABN) revised prescribing guidelines for the treatment of relapsing-remitting MS (RRMS) have been published. 
The whole document can be read online 

So in brief you and your neurologist, who should be an MS specialist, can come up with the right choice for you

You should be on treatment if you have relapsing disease with one of the "high" or "low" efficacy drugs, or to be more PC "moderate" efficacy drugs or if you have progressive MS you should have nothing. However, I wonder to what extent this is guided by price. On a cost effective basis then it is clear that that are not slowing progression, but it is clear that T an B cells are in the brains of progressive MSers and they should be there. If the MS drugs got in the brain, they could kill them and stop any more arriving. Maybe when generics arrive and the prices drop, this will change. 

There are only two types of drugs according to the categories, 
I am sure that the marketing departments of pharma will not be too happy that there drugs are lumped into one of two efficacy groups, when the data so clearly shows that there are differences in efficacy, convenience, safety etc.  However one in the eye for marketing.

There is a view that is expressed there is no for a reason to strive for "No evidence of Disease Activity", because there is no evidence that it is of value....However there is surely logic that does not need evidence before one attempts to do it and surely all neurologists should surely want to do it for the people in their care as "Time is your brain" not theirs, whilst they sit on the fence.

Unfortunately, the UK is ranked 25 out of 27 European countries on the proportion of people with RRMS using DMT. 

With incoming budget limitations coming from NHS England, which will have the effect of incentivising the local trusts to not prescribe expensive drugs, will the members of the ABN have their hands tied?

As ProfG says if you try and design a horse by committee you get a Camel

As many people don't read comments, here is a few arising from this post.

"If normalising atrophy is so important....given that it's one of the biggest correlates with disability.....why would you issue guidelines that a) don't even mention it and b) seemingly recommends first line treatments, for a majority of patients, which have close to zero impact on atrophy? Feels like these guidelines are going to lead to many patients committing to a path which leads to SPMS (for which you have no treatments), when there are drugs which can apparently delay (or maybe even prevent) SPMS when given early.......Really, in 2015, knowing what we know, why would a neurologist give anyone interferon beta, the lowest efficacy drug which bears almost no prospect of long term normalisation of atrophy, prevention/delay of SPMS, etc...............neurologist/the field in general needs a good kick up the arse and a reality check for being too conservative... And then you go and deliver a paper like this!

Also, "it is not yet clear whether treatment should aim for a target such as No Evidence of Disease Activity"..... WHAT???!! In what possible scenario could NEDA not be a better target than EDA?!"

"Fair enough if you are stable on injectables why change but a newly diagnosed young person starting them what?!??@& 
Its been shown aggressive treatment early in the disease can massively effect the progression and the quality of life for that person. For the life of me I don't understand why all newly diagnosed are not at least being offered alemtuzumab. Fair enough they may decide the side effects outweigh benefits but at least let them make that informed choice and then work down the scale. Neuro's are not even mentioning aggressive treatments to the newly diagnosed.... That's not their choice to make its the person living with the disease and its consequences. Ugh rant over sorry"

CoI: TeamG neuros were involved 

ClinicSpeak: destigmatizing the wheelchair

Help! We need ideas on how to destigmatize the wheelchair. #ClinicSpeak #MSBlog #MSResearch

"MS is many diseases in one. Not only does it floor you when you are diagnosed with the disease, but in those with relapse-onset disease it gets you again when you enter the secondary progressive phase of the disease; the point you realise that you have a progressive disabling disease. And again when you need a wheelchair; I did not appreciate the psychological impact it has on you when you have to migrate from using walking aids into a wheelchair."

"At Barts-MS we run regular MS Preceptorships to teach various groups about MS. Our course is based on using case studies to illustrate specific issues in relation to MS. During last week's preceptorship one of our MSers volunteers, who is struggling to stay mobile using a walker and FES (functional electrical nerve stimulation), reminded me how stigmatising using a wheelchair can be as a person with a progressive disease such as MS. Please note using a wheelchair as an MSer is very different to using a wheelchair after spinal cord injury. The paralympics have elevated spinal cord injured wheelchairers to the status of being celebrities. In MS the deficit is not fixed and gets worse over time; a very different scenario and prognosis to those with fixed deficits."

"I was making the point that using a wheelchair would improve his mobility. Instead of consuming large quantities of precious energy walking and exhausting himself, he could conserve energy for other tasks by simply using a wheelchair. It would also mean he gets from point A to B quicker and he would be able to get out more and do more. Despite the logic of my arguments this particular MSer remains determined to avoid using a wheelchair. He has tried it in the past and hated the experience. For example, when he used a wheelchair in the past he lost eye contact with people they tended to look down on him. He also noted that they tended not to talk to him, but rather directed questions and comments to his partner despite them be related to him. He was treated as an inferior being. He found the whole experience dehumanising. Why should being in a wheelchair change the way people treat you?"

"May be we should redesign the wheelchair to allow people to maintain eye contact? These sorts of wheelchairs exist already. May be the emerging field of exoskeletons will keep MSers needing wheelchairs walking? Exoskeletons are very sexy at the moment and are being developed to enhance human performance; in particular for the military. Exoskeletons will not doubt be very expensive and out of reach for the majority of MSers. What we need is a solution now! We need to allow MSers to use wheelchairs and not be stigmatised. We need to refocus our attention on the wheelchair and develop ways to communicate its benefits and to get society to accept it. I would like to start a discussion around the wheelchair and explore ways of slaying 'wheelchair stigma'!"

"If you have MS and are using a wheelchair we we would like to hear your story. In addition, we need ideas! What can we do to destigmatise the wheelchair?"

CoI: I frequently refer MSers to wheelchair clinics for assessments; sadly I rarely address the psychological impact this has on the individual being referred. 

New prescribing guidelines for multiple sclerosis

Scolding N et al. Association of British Neurologists: revised (2015) guidelines for prescribing disease-modifying treatments in multiple sclerosis Pract Neurol 2015

The Association of British Neurologists (ABN) revised prescribing guidelines for the treatment of relapsing-remitting MS (RRMS) have been published. MS charities had the opportunity to comment on the revisions and contribute the patient voice.

In the last 20 years the UK has gone from having no available treatments for RRMS to having eleven. 

The whole document can be read online but here are some extracts:

In June 1999, the ABN first published guidelines for the use of the licensed MS DMT. This 2015 revised guideline replaces former versions. It includes all newly approved or licensed treatments for MS and represents a consensus concerning their use. These guidelines will require future revision as other treatments receive approval (eg, daclizumab and ocrelizumab).

The guideline is not intended to provide a complete description of the possible complications and monitoring of disease-modifying treatments in MS.
  • In the individual patient, MS remains a fundamentally unpredictable condition. 
  • We stress the importance of shared conversations about disease activity, risk and benefit, to make the choice that is right for the individual and their circumstances.
  • The ABN believes that people with MS should be managed by neurologists with specialist experience.
  • All of the licensed disease-modifying treatments for MS - β-interferons, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, natalizumab and alemtuzumab - reduce relapse rate and MRI lesion load. 
  • We suggest that these seven agents can be divided into two broad classesdrugs of moderate efficacy (average relapse reduction in 30–50% range), including the β-interferons, glatiramer, teriflunomide, dimethyl fumarate and fingolimod; and drugs of high efficacy (average relapse reduction substantially more than 50%), alemtuzumab and natalizumab. Side effect profiles vary considerably between
  • the Mitoxantrone has significant adverse effects and is not obviously superior in efficacy to the newer drugs of high efficacy. It is not licensed for MS in the UK, but is still used
  • There is a consensus that none of the currently available disease-modifying therapies significantly modifies progressively increasing disability that is unrelated to relapses (progressive non-relapsing MS).The implication, however, is that no disease-modifying treatment is effective, or indicated, in patients with established progressive MS in the absence of relapses.
  • It is not yet clear whether treatment should aim for a target such as ‘no evidence of disease activity’—either clinical or radiological. 
  • New MRI lesions are a more sensitive index of inflammatory disease activity than clinical relapses, occurring up to 10 times more frequently than clinically eloquent relapses.
  •  Many now substitute MRI activity for clinical activity in the classification, diagnosis and management of MS. 
  • Recently, the European Medicines Agency has explicitly recognised that MS may be defined as ‘active’ on radiological or clinical evidence.
  • Meanwhile, particularly in the first years after diagnosis, it is appropriate to consider including MRI scanning during the annual review recommended by the 2014 NICE Clinical Guideline for the management of MS, both on grounds of monitoring efficacy and safety. 
  • There are now many people with relatively long-standing relapsing–remitting MS who have used β-interferons or glatiramer for perhaps several years and whose disease is stable clinically. It is unclear whether such patients would benefit from MRI monitoring.
  • Immunotherapies appear particularly helpful when given early to people with active relapsing–remitting disease, before there is fixed disability or secondary progression. 
  • MS specialist neurologists may adopt either an ‘escalation’ strategy or an ‘induction’ strategy in treating MS. The ‘escalation’ strategy involves starting with the drug that is considered the least toxic but which will control the patient's disease, and escalating to more potent therapies in the face of continued disease activity. An ‘induction’ strategy involves giving a powerful drug, with significant side effects, early in the disease.
  • As newer treatments emerge and when there is clinical equipoise agreed between clinician and patient, and there are clinical trials available for recruitment, then patients should be offered participation in relevant studies.
  • UK health systems have diverged with the devolved administrations in respect of treatment guidelines and/or restrictions. 
  • These differences render it now impossible to make treatment recommendations that are simultaneously compliant with all of the relevant advisory or statutory medicines agencies.
  • The ABN continues to support a fundamental principle of the NHS that, despite these changes, all patients have a right to access the appropriate expertise and therapy.
General management advice
  • It is important that patients and neurologists fully appreciate the risk and benefit of drugs, and of leaving the disease untreated. 
  • Patients should also discuss the risk as well as expected benefit of treatment; monitoring requirements; and work, family and other factors that are personally important, and clinicians should take account of their views in making the treatment selection.
  • MS specialist nurses play a key role in supporting patients 
  • Patients can also obtain information from patient groups, particularly the Multiple Sclerosis Trust and the Multiple Sclerosis Society, which have produced information leaflets in plain language, as well as a range of leaflets on other symptomatic, psychological and social aspects of living with MS. There are also several excellent websites particularly targeted towards patients, providing valuable information and guidance.
  • Once started on therapy, continued supervision by the specialist MS team is essential to identify side effects and assess therapeutic efficacy.
Recommendations for starting disease-modifying treatment
Eligible patients will normally be ambulant (maximum EDSS 6.5). There are no treatments licensed for use during pregnancy (but see below).

As mentioned above, the currently licensed disease-modifying treatments divide broadly into two classes:

Drugs of moderate efficacy (‘Category 1’)

  • β-interferons (including ‘pegylated’ β-interferon)
  • glatiramer acetate
  • teriflunomide
  • dimethyl fumarate
  • fingolimod
Drugs of high efficacy (‘Category 2’)
  • alemtuzumab
  • natalizumab

Relapsing–remitting MS
Patients with relapsing–remitting MS who have had two or more clinical relapses in the previous two years are considered to have ‘active’ disease that warrants consideration of disease-modifying treatments. T
he European Medicines Agency has explicitly recognised that disease activity may be established on radiological or clinical grounds.

All individuals with active relapsing–remitting MS should be considered expeditiously for treatment. 
Most are likely to start treatment with a Category 1 drug. 
  • Dimethyl-fumarate and fingolimod are the more effective drugs in this category, with the advantage of being oral agents. 
  • Some people with active disease will prefer to start dimethyl- fumarate or, if ‘highly active’, fingolimod in this group.
  • The β-interferons and glatiramer acetate have been used extensively and there is a wealth safety experience 
  • Individuals with relatively quiescent disease and/or who are more risk-averse might choose one of the β-interferons or glatiramer acetate.
  • Individuals with needle phobia may choose teriflunomide, dimethyl fumarate or, if eligible, fingolimod. 
More active relapsing–remitting MS

The formal criteria for high-disease activity are despite interferon-β or glatiramer requires one relapse in the previous year on interferon-β and either (a) ≥1 gadolinium-enhancing MRI lesions or (b) at least nine T2-hyperintensive lesions on cranial MRI.

  • We recommend that patients with more active disease use one of the Category 2 drugs, natalizumab or alemtuzumab. Indirect comparison suggests that alemtuzumab and natalizumab have similar efficacy. 
  • Although alemtuzumab's licensed indication is much less restrictive,we recommend that, given its potential adverse effects, it should be mainly confined to patients with more active disease.
  • Alemtuzumab and natalizumab are appropriate where one is concerned to achieve high efficacy, despite the more complex safety profile compared to Category 1 drugs.
  • Some people who have experienced relapses despite using a Category 1 agent may be particularly risk-averse or had occasional minor relapses. In such instances, it may be appropriate to change from one to another Category 1 agent.
  • Switching between Category 1 agents because of continued disease activity may be justified on the basis of MRI-proven disease activity alone.
  • Switching from a Category 1 agent to a Category 2 monoclonal antibody is probably justifiable only when there is clinical evidence of high-disease activity despite treatment.
Clinically isolated syndrome
Various disease-modifying treatments can delay the diagnosis of MS in patients with a clinically isolated syndrome
  • Currently, only the β-interferons and glatiramer are licensed for clinically isolated syndrome.
People with MS aged under 18 years of age
We believe that minors aged between 16 and 18 years should be treated according to the above guidelines. 

Children with MS aged <16 should consult with paediatric neurologists with a particular interest in MS.

Primary or secondary progressive MS
None of the current disease-modifying treatments is recommended in non-relapsing secondary progressive MS or in primary progressive MS. Some people with relapsing progressive MS may benefit from disease-modifying treatment.

Recommendations for stopping disease-modifying treatment
Decisions to start or stop treatment should recognise the central importance of patient choice.

We believe it is not feasible to have mandatory stopping criteria that apply in all cases.

Clinicians should consider stopping disease-modifying treatment in the following scenarios:
  • Significant side effects specific to any individual agent should trigger withdrawal of that agent and consideration of an alternative treatment.
  • Development of non-relapsing secondary progressive MS.
  • During pregnancy, disease-modifying treatments should normally be stopped. 
  • We recommend that women stop disease-modifying treatments while trying to conceive unless, the woman's clinical condition requires treatment.
  • Given the increased risk of relapse, treatment should be restarted early after delivery, depending on discussions concerning breast feeding.

This is a consensus guideline and so not every neurologist will agree with the contents of this !

CoI: Prof G and I are co-authors of these guidelines (and neither of us agrees with every paragraph).

Brain lymphatics are like buses wait fifty years and two papers come all in a short space of time

Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 . pii: jem.20142290. [Epub ahead of print]

The central nervous system (CNS) is considered an organ devoid of lymphatic vasculature. Yet, part of the cerebrospinal fluid (CSF) drains into the cervical lymph nodes (LNs). The mechanism of CSF entry into the LNs has been unclear. Here we report the surprising finding of a lymphatic vessel network in the dura mater of the mouse brain. We show that dural lymphatic vessels absorb CSF from the adjacent subarachnoid space and brain interstitial fluid (ISF) via the glymphatic system. Dural lymphatic vessels transport fluid into deep cervical LNs (dcLNs) via foramina at the base of the skull. In a transgenic mouse model expressing a VEGF-C/D trap and displaying complete aplasia of the dural lymphatic vessels, macromolecule clearance from the brain was attenuated and transport from the subarachnoid space into dcLNs was abrogated. Surprisingly, brain ISF pressure and water content were unaffected. Overall, these findings indicate that the mechanism of CSF flow into the dcLNs is directly via an adjacent dural lymphatic network, which may be important for the clearance of macromolecules from the brain. Importantly, these results call for a reexamination of the role of the lymphatic system in CNS physiology and disease.

So here we have another paper in a similar vein to the recent paper in Nature. Louveau et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jun 1. doi: 10.1038/nature14432. That was discussed previously (click

It was originally proposed that the brain had no lymphatics so that antigens couldn't be taken to lymph glands to start an immune response. However, we have known so many years that this is not quite right because we could see brain antigens in lymph glands. Lymphatic vessels were proposed and have been found and will contribute to the glymphatic system of the brain.

Lymphatic vessels are collapsed structures between the meninges (outside of cover of the brain), and if one does not know how to look, they cannot be found. These two groups worked out how to look.

This has nothing to do with CCSVI, which is going round the MS conspiracy theory circuit, and if textbooks need to be updated to include these discoveries they are not going to talking about CCSVI. 

Furthermore the brain still has relative immune privileged as the experimental results are not going to be wrong, just the explanation needs addressing and it is still clear that the brain has many features that are down regulated when it comes to immune function.

However, one has to be clear that once the immune response has become activated against brain antigens there is no immune privilege in the brain

The question is; if MS does contain an element of autoimmunity,where does it start in the brain (inside-out) or the lymph glands (outside-in)? 

The likely place has always been in the lymph glands because this is the place where the body has evolved structures for that to happen and even if the first event happens in the brain then the targets will be transported into the lymph glands for this to happen.    

MS Frontiers 2015

This is the biennial Science meeting 
on behalf of the MS Society in the UK.
This is held at Heathrow Airport. 

However, if you want to see what's going on

Follow on twitter #MSfroniters

                                          The Debate: 
           Are Stem Cells the Next Frontier in MS treatment?
                            Prof Siddharthan Chandran, University of Edinburgh
                            Prof Gianvito Martino, San Raffaele Hospital, Milan
                            Prof Gavin Giovannoni, Barts andThe London School of Medicine and Dentistry
                            Prof Alasdair Coles, University of Cambridge

                        Will it be a Real Debate or a Love-In?

Sunday, 28 June 2015

MS Frontiers 2015

Are you coming to the MS Frontiers Meeting at Heathrow tomorrow? #MSBlog #MSResearch

"The following is the programme for the biennial MS Frontiers meeting. One person in Barts-MS complained to me the programme lacks energy and is simply 'the same-old' people on the platform. This person wants 'youth' and 'new ideas'. The primary purpose of this meeting is bring together researchers in the UK who are funded by the MS Society to present their work. I haven't analysed the programme in detail, but this is its aim. Someone else raised the question about whether or not there is a correlation between the number of presentations/abstracts of the various UK research groups, at the Frontiers meeting, and their MS Society grant spend? I can't answer this question as I don't have the relevant data at my fingertips; maybe someone from the MS Society could do this for us and present it at the meeting? The level of engagement with this meeting should be high, after all this meeting is being held to showcase the MS Society's investment in MS Research."

"I am going to try something new at this meeting and broadcast/record my talks as a Google Hangout for you to view asynchronously. We will also keep you updated using the following Twitter hashtag #MSFrontiers."

NF kappa B signalling...a key to controlling inflammation

Housley WJ, Fernandez SD, Vera K, Murikinati SR, Grutzendler J, Cuerdon N, Glick L, De Jager PL, Mitrovic M, Cotsapas C, Hafler DA.Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Sci Transl Med. 2015;7(291):291ra93

The transcription factor nuclear factor κB (NFκB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines,free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory, and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
In brief, NF-κB can be understood to be a protein responsible for cytokine production and cell survival.

It has been suggested that laquinimod works by affecting NFκB are there people that give better responses to laquinimod than others?

CD40 reduction in MS

Field J, Shahijanian F, Schibeci S; Australia and New Zealand MS Genetics Consortium (ANZgene), Johnson L, Gresle M, Laverick L, Parnell G, Stewart G, McKay F, Kilpatrick T, Butzkueven H, Booth D. The MS Risk Allele of CD40 Is Associated with Reduced Cell-Membrane Bound Expression in Antigen Presenting Cells: Implications for Gene Function. PLoS One. 2015 Jun 11;10(6):e0127080

Human genetic and animal studies have implicated the costimulatory molecule CD40 in the development of multiple sclerosis (MS). We investigated the cell specific gene and protein expression variation controlled by the CD40 genetic variant(s) associated with MS, i.e. the T-allele at rs1883832. Previously we had shown that the risk allele is expressed at a lower level in whole blood, especially in people with MS. Here, we have defined the immune cell subsets responsible for genotype and disease effects on CD40 expression at the mRNA and protein level. In cell subsets in which CD40 is most highly expressed, B lymphocytes and dendritic cells, the MS-associated risk variant is associated with reduced CD40 cell-surface protein expression. In monocytes and dendritic cells, the risk allele additionally reduces the ratio of expression of full-length versus truncated CD40 mRNA, the latter encoding secreted CD40. We additionally show that MS patients, regardless of genotype, express significantly lower levels of CD40 cell-surface protein compared to unaffected controls in B lymphocytes. Thus, both genotype-dependent and independent down-regulation of cell-surface CD40 is a feature of MS. Lower expression of a co-stimulator of T cell activation, CD40, is therefore associated with increased MS risk despite the same CD40 variant being associated with reduced risk of other inflammatory autoimmune diseases. Our results highlight the complexity and likely individuality of autoimmune pathogenesis, and could be consistent with antiviral and/or immunoregulatory functions of CD40 playing an important role in protection from MS.

CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects and this is an MS risk gene. This is associated with reduced CD40 expression ,which happens in MSers. Indeed this low level of CD40 happens in MSers irrespective of whether they have the gene or not. What does it mean? It will result in a reduced immune influence somewhere in
the disease process.

Saturday, 27 June 2015

Not monetising the blog

We are not going to monetise the blog #MSBlog #MSResearch 

"Thank you for your swift response and wise counsel. It is good to see that we are like minded."

"I will feedback the results of the survey to the healthcare services company who asked me if we had ever considered allowing sponsored posts on our blog. They had proposed us using a format similar to Google's for sponsored search links."

"We want our blog to be organic and free of commercial bias. On the other hand we need resource to support the blog. In particular, we need to employ a blog administrator to help curate the site and to expand our guest blogging programme; the editorial process of inviting guest posters and collating all their information, i.e. their mugshots, biographical sketches and disclosures, takes time."

"Further suggestions on how we can evolve the blog would  be welcome. I have left the poll open if you didn't get to vote on the issue yesterday."

Another deficit in the immune response of MSers

Dhaeze T, Peelen E, Hombrouck A, Peeters L, Van Wijmeersch B, Lemkens N, Lemkens P, Somers V, Lucas S, Broux B, Stinissen P, Hellings N. Circulating Follicular Regulatory T Cells Are Defective in Multiple Sclerosis. J Immunol. 2015 Jun 12. pii: 1500759. [Epub ahead of print]

Follicular regulatory T cells (TFR) have been extensively characterized in mice and participate in germinal center responses by regulating the maturation of B cells and production of (auto)antibodies. We report that circulating TFR are phenotypically distinct from tonsil-derived TFR in humans. They have a lower expression of follicular markers, and display a memory phenotype and lack of high expression of B cell lymphoma 6 and ICOS. However, the suppressive function, expression of regulatory markers, and FOXP3 methylation status of blood TFR is comparable with tonsil-derived TFR. Moreover, we show that circulating TFR frequencies increase after influenza vaccination and correlate with anti-flu Ab responses, indicating a fully functional population. Multiple sclerosis (MS) was used as a model for autoimmune disease to investigate alterations in circulating TFR. MS patients had a significantly lower frequency of circulating TFR compared with healthy control subjects. Furthermore, the circulating TFR compartment of MS patients displayed an increased proportion of Th17-like TFR. Finally, TFR of MS patients had a strongly reduced suppressive function compared with healthy control subjects. We conclude that circulating TFR are a circulating memory population derived from lymphoid resident TFR, making them a valid alternative to investigate alterations in germinal center responses in the context of autoimmune diseases, and TFR impairment is prominent in MS.

Follicles are where B cells are produced in lymph glands an there are T cells found in these follicles in this study they look at regulatory T cells that reside in such follicles an find that there are fewer of them in the blood of MSers and that they are also less effective at regulating. So another T reg population to target.

Friday, 26 June 2015

Monetising the blog

Should we change the blog? #MSBlog #MSResearch 

"Last week I was contacted by a healthcare services company asking me if we had ever considered allowing sponsored posts on our blog. They proposed us using a format similar to Google's for sponsored search links. They are representing a client who is interested in using our blog to disseminate information. Their proposal was for us to identify sponsored posts with a disclaimer and with a different colour to allow the reader to know that the posts were sponsored and by whom."

"We have always wanted our blog to be organic and free of commercial bias. On the other hand we could do with resource to support the blog. In particular, we want to employ a blog administrator to help curate the site and to expand our guest blogging programme; simply inviting guest posters and collating all their information, i.e. their mugshots, biographical sketches and disclosures, takes time and needs resource."

"We have said no, but I wanted to test your opinion on whether or not we should consider changing our model to allow the blog to evolve. Any ideas and suggestions would be much appreciated."

Heart Rate on Fingolimod

Simula S, Laitinen T, Laitinen TM, Tarkiainen T, Hartikainen JE, Hartikainen P. Effects of Three Months Fingolimod Therapy on Heart Rate. J Neuroimmune Pharmacol. 2015. [Epub ahead of print]

Fingolimod is a novel disease-modifying drug for relapsing-remitting multiple sclerosis (RRMS). Fingolimod initiation associates with a decrease in heart rate (HR). However, the long-term effects of fingolimod on HR are not known. The aim of this study was prospectively investigate the effect of 3-month fingolimod therapy on HR. Twenty-seven RRMS patients underwent 24-h ambulatory electrocardiogram recording 20 ± 16 days before (baseline) and at the day of fingolimod initiation (1 day). Twenty-four patients completed 3 months follow-up (3 months). The average HR over 24-h and the average HR for day-time and night-time were assessed at baseline, 1 day and 3 months. Fingolimod initiation resulted in slowing of HR from 82 ± 11 1/min at baseline to 63 ± 9.5 1/min at 5 h after the initiation of the therapy. The average HR during 24-h was lower at 1d (66 ± 7.8 1/min;p < 0.001) and also at 3 months (69 ± 8.3 1/min;p < 0.001) as compared to baseline (74 ± 10 1/min). The average daytime HR at 1 day (68 ± 8.4 1/min) was lower as compared to baseline (78 ± 11 1/min, p < 0.001), whereas no difference was found between the average daytime HR at baseline and at 3 months (79 ± 10 1/min). The average night-time HR at 1 day (59 ± 8.8 1/min;p < 0.001) and at 3 months (60 ± 9.2 1/min;p < 0.05) both were lower than at baseline (64 ± 9.9 1/min). In conclusion, fingolimod resulted in HR decrease reaching the nadir at 5 h after the first dose. HR remained lower after 3 months fingolimod treatment as compared to baseline. Particularly, HR at daytime recovered whereas the night-time HR showed not recovery as compared to the day of fingolimod. initiation.

Fingolimod can drop you heart rate and this is why you get your first dose in hospital.In this study they found that heart rate at night remained low although your day rate returned.

Thursday, 25 June 2015

ClinicSpeak: more on herpes infection and fingolimod

Please be vigilant about herpes infections on fingolimod. #ClinicSpeak #MSResearch #MSBlog

"Just received an email query from an MSer about stopping fingolimod after an episode of ophthalmic herpes zoster. They appear to have had a torrid time and may now need a corneal transplant. The bottom line is herpes zoster or shingles is about 2.6x more common in fingolimod treated MSers compared to those treated with placebo. This figure is from the 2-year blinded period of the trials and hence may be much higher than this if the period of observation could be extended beyond 2 years. In other words the cumulative incidence of herpes infections in MSers on fingolimod may turn-out to be very high. Unfortunately, I don't have a simple answer to the herpes problem. Fingolimod is an immunosuppressive drug and is associated with opportunistic infections, reactivation of herpes viruses, including the Varicella-Zoster virus, and possibly other recurrent herpes infections. As herpes infections can be treated, my approach to the problem is vigilance and early treatment. I look after one patient with recurrent genital herpes that I am managing with continuous prophylactic famciclovir. I prefer famciclovir to aciclovir, or valaciclovir, as it has a longer intracellular half-life and is probably a better anti-herpes drug. The decision to stay on fingolimod is a personal one and depends on how active the MS was before starting the treatment, how well MS disease activity has been suppressed (NEDA-3) and the individual factors that includes other side effects and adverse events, planned pregnancy and aversion to risk. Therefore there is no simple answer to this question."

Arvin et al. Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management. JAMA Neurol. 2015 Jan;72(1):31-9. doi: 10.1001/jamaneurol.2014.3065.

IMPORTANCE: Varicella-zoster virus (VZV) infections increasingly are reported in MSers and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity.

OBJECTIVE: To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated MSers and provide recommendations for prevention and management.

DESIGN, SETTING, AND PARTICIPANTS: Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated.

INTERVENTIONS: In clinical trials, MSers received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all MSers received fingolimod, 0.5 mg/d (total exposure of 54,000 patient-years at the time of analysis).

MAIN OUTCOMES AND MEASURES: Calculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting.

RESULTS: Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for MSers receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation.

CONCLUSIONS AND RELEVANCE: Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the MSers' VZV immune status before initiating fingolimod therapy and immunization for MSers susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.

CoI: multiple

One more clinical Meeting

Each year we have the annual meetings of  ECTRIMS/ACTRIMS and then the other big news day is the American Academy of Neurology (AAN) meeting...not to be out done this week, we had the first European Academy of Neurology meeting in Berlin. 

So another opportunity for pharma to break their trial data and a trip for the 25,000 European Neuros footed by Pharma ...Hoorah

Will neuros stop going to the USA for their updates in medicine.

Continuing medical education is a must for Docs 
             See What's Interesting and let us know (CLICK)
                There you can hear about the INSPIRE study
                       and an update on the Biotin MS Trial

Fampridine is not good for every one

Yapundich R, Applebee A, Bethoux F, Goldman MD, Hutton GJ, Mass M, Pardo G, Klingler M, Henney HR 3rd, Blight AR, Carrazana EJ. Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial. Int J MS Care. 2015;17(3):138-45. doi: 10.7224/1537-2073.2014-040

BACKGROUND:Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg.
METHODS:Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test.
RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported.

CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.
In this study they looked at differing doses of fampridine an did not find improvements in walking speed in the trial. However we know that not everyone will benefit from this drug, some don't in fact the majority don't. So if you do not enrich your trials with responders it is probably the case of "garbage-in" (not the right data analysed) "garbage out" (failed study). The recommended dose worked best

CoI: None

Wednesday, 24 June 2015

ClinicSpeak: the uberization of health care

How quickly can we uberize the management of MS? #ClinicSpeak #MSBlog #MSResearch

"At the EAN in Berlin I gave a short talk at an Innovation Exchange about the future of tracking and assessing MS using mobile technology. I presented the concept of the uberization of healthcare; i.e. the provision of healthcare by rapid access eMedicine apps supported by concierge type service where neurologists, or robots, come to your home or place of work to examine you. In other words your neurologist, or a neurologist, will be available at very short notice. In addition, with this type eMedicine service there would be no geographic boundaries, in other words a neurologist physically based in Paris could be managing someone with MS in Quebec City. I deliberately chose these cities as they are both French speaking, but with new simultaneous, real-time, translation services emerging language need not be a barrier. I got real pushback from the audience who think I was presenting a science fiction vision of healthcare. I really don't think so, this type of service is a reality already. I get one or two email requests for neurological advice per day. Due to time and legal constraints I say no. But there are already many fee-for-service email, skype, or eMedicine portals that charge for advice of this nature. In some parts of the US this is supported by a rapid access concierge service where a neurologist is prepared to visit you in your home to examine you. This all costs money and it is hard at present to envision this business model being transferred to a socialist healthcare system. I say why not? There is a massive push in the NHS to take services into the community so why not into the home? The latter may be prove to be cost effective if it prevents MSers being admitted to hospital and improves outcome in general. We already do this with nursing and palliative care services so why not other specialist services?"

"When I was planning to do an eMedicine test run, using Microsoft Healthvault, last year I contacted my insurance company for clearance. They stated that I would be not covered for an eMedicine service if the patients were not resident in the UK. I argued that if someone in the US got an airplane and travelled to London and was seen by me in private practice that would be fine, but giving advice via the internet to someone in the US would not? They still haven't gotten back to me on this; clearly the insurance industry needs to catch-up with technology. There are clearly solutions to this as many eMedicine services in the US take all-comers regardless of where they live."

"How do you feel about your MS being managed using eMedicine?"

CoI: The innovation exchange was run and funded by Novartis.

Discriminating claims about discriminating forms of MS

Plasma biomarkers discriminate clinical forms of multiple sclerosis.Tejera-Alhambra M, Casrouge A, de Andrés C, Seyfferth A, Ramos-Medina R, Alonso B, Vega J, Fernández-Paredes L, Albert ML, Sánchez-Ramón S.PLoS One. 2015 Jun 3;10(6):e0128952. doi: 10.1371/journal.pone.0128952. eCollection 2015.

Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology-based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1β/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients.

This study looked at cytokines in different stages of MS some when up in progressive MS

Some went down

What is evident that if you took the results of any individual you would be hard pressed to know if they were RRMS or PMS because there is so much over lap and this is a common problem of many so-called biomarkers reported. On a whole group analysis you can see differences but on an individual level it is hard to make a call. In this study they report if you look at 4 cytokines it helps to discriminate, but the question is.....Would you base a treatment decision on this? I wouldn't, as there is not enough sensitivity and specificity in the system maybe NDG as a view