Friday, 30 September 2016

NewsSpeak & PoliticalSpeak: NICED twice in one week

NICE turns down daclizumab for MSers on the NHS. #NewsSpeak #PoliticalSpeak #MSBlog

NICE have just published their appraisal consultation document for daclizumab and have not recommended it on the NHS within its marketing authorisation for treating relapsing forms of multiple sclerosis in adults. This is depressing news and is not in the interests of MSers in England. I would not have expected daclizumab to be widely prescribed, but there is definitely an unmet need for its use in a well-defined cohort of patients. As I have said many times before daclizumab is not overtly immunosuppressive and therefore is an ideal switching drug for patients at high risk of PML on natalizumab. There are also a significant number of patients with highly-active disease, who have failed platform therapies, in whom fingolimod is contraindicated, who would benefit from daclizumab. These patients will now have little option, but to be treated with alemtuzumab. What about alemtuzumab failures? If NHS England don't allow us to give third and fourth courses of alemtuzumab this will be a relatively large population of patients. I have even argued in the past that patients with highly active disease or rapidly evolving severe MS who are JCV-positive may choose daclizumab over alemtuzumab first-line. Daclizumab has some attributes that will make it more appealing to some patients than alemtuzumab, i.e. it is self-administered and is not immunosuppressive. 

What now? I sincerely hope Biogen and Abbvie appeal this decision and that we the wider MS community let NICE know that we disagree with their assessment. At the end of the day having choice makes implementing personalised medicine in MS more a reality. Not being able to prescribe one of the licensed MS therapies simply disadvantages people with MS living in England. The cynic in me, however, thinks that NICE is simply asking for a big discount in the price of daclizumab for the NHS, relative to its listed price. This 'game of cat-and-mouse' is well tried and tested and is one of the reasons why the NHS gets high-cost drugs cheaper than other developed countries and why most other countries are putting in place their own versions of NICE.


CoI: multiple

ClinicSpeak: not so NICE - alemtuzumab vs. cladribine

NICE is not so NICE; alemtuzumab is too expensive to use properly. #ClinicSpeak #MSBlog #MSResearch

Could oral cladribine steal alemtuzumab's thunder? #ClinicSpeak #MSBlog #MSResearch

I naively discovered yesterday that NHS England will only be allowing us to use two courses of alemtuzumb in our patients with active relapsing MS. If these patients breakthrough and need a third, fourth or additional course of alemtuzumab we will have to apply for additional funding via an IFR (individual funding request). The problem with the latter is that as soon as there are more than 5 patients in England requiring an IFR for the same indication this triggers the requirement for a business case. Making a business case stack-up for additional courses of alemtuzumab, when it costs so much, will be difficult outside of formal NICE guidance. At present ~40-50% of patients treated with alemtuzumab will require additional courses. Based on my previous experience with NHS England, and their dire financial predicament, I suspect getting a green-light for additional courses of alemtuzumab is going to be an uphill battle. In short we have been truly NICED. The question is whether or not Genzyme-Sanofi will come to the table with additional courses at a lowered price? If not we are going to need a plan B. What DMT will we use in patients who breakthrough post-alemtuzumab?"


I am now going to have to take this information into account when counselling patients. I suspect that this may turn many patients off alemtuzumab as a treatment option. Does this also mean we should be routinely be offering our patients, who want an induction therapy, off-label cladribine or in those with highly-active disease HSCT? This new information also means that if oral cladribine gets a license it is going to disrupt alemtuzumab's market. The following is my ECTRIMS poster showing you the effect of oral cladribine. The difference with oral cladribine is that we have access to the much cheaper generic oncology version that could be used for subsequent courses if NICE, and NHS England, say no to additional courses of cladribine. Unfortunately, at present we don't have this option with alemtuzumab.


CoI: multiple

Location, location, location: MS pathology preferentially affects the edges of the brain

The Paper

Objective To assess the association between proximity to the inner (ventricular and aqueductal) and outer (pial) surfaces of the brain and the distribution of normal appearing white matter (NAWM) and grey matter (GM) abnormalities, and white matter (WM) lesions, in multiple sclerosis (MS).

Methods 67 people with relapse-onset MS and 30 healthy controls were included in the study. Volumetric T1 images and high-resolution (1 mm3) magnetisation transfer ratio (MTR) images were acquired and segmented into 12 bands between the inner and outer surfaces of the brain. The first and last bands were discarded to limit partial volume effects with cerebrospinal fluid. MTR values were computed for all bands in supratentorial NAWM, cerebellar NAWM and brainstem NA tissue, and deep and cortical GM. Band WM lesion volumes were also measured.

Results Proximity to the ventricular surfaces was associated with progressively lower MTR values in the MS group but not in controls in supratentorial and cerebellar NAWM, brainstem NA and in deep and cortical GM. The density of WM lesions was associated with proximity to the ventricles only in the supratentorial compartment, and no link was found with distance from the pial surfaces.

Conclusions In MS, MTR abnormalities in NAWM and GM are related to distance from the inner and outer surfaces of the brain, and this suggests that there is a common factor underlying their spatial distribution. A similar pattern was not found for WM lesions, raising the possibility that different factors promote their formation.


The Interpretation

In Multiple Sclerosis (MS), there are two broad kinds of damage done to the brain. There are focal lesions – inflammatory scars - which accumulate over time and are associated with relapses, and there is a diffuse neurodegenerative process which is more associated with the progression of disability. Lesions in MS affect both the grey matter – where nerve cell bodies reside – and the white matter, which consists of nerve cell projections (axons) to distant brain regions.

Interestingly, lesions in MS are more likely to appear in some parts of the brain than others. Post-mortem studies have demonstrated that white matter lesions have a predilection for the outer and inner surfaces of the brain. This predilection for particular sites is important because, amongst other reasons, it sheds light on the processes that initiate and perpetuate MS. For instance, it has been proposed that as MS lesions are most likely to occur in places close to cerebrospinal fluid (CSF) – the fluid that bathes and encases the brain – there may be a ‘toxic’ factor of some description that is involved in triggering and/or perpetuating MS.

It is therefore important that we understand exactly where in the brain is most vulnerable to developing lesions and non-lesional pathology in MS. This nice new paper from Declan Chard and pals uses a funky imaging method to find out the spatial distribution of grey and white matter pathology in people with MS.
The authors used Magnetisation Transfer Ratio (MTR) – a variant of MRI which can show subtle disturbances of brain tissue integrity quite well. MTR is used frequently in studies of MS because it is particularly good at detecting non-lesional pathology. We don’t know exactly what features of brain tissue affect MTR, but we do know that demyelination and axonal loss – which are both common in MS – do affect the MTR image.

This study recruited 30 healthy controls and 67 people with MS, of whom 41 had relapsing-remitting (RRMS) disease, and 26 had secondary progressive MS (SPMS). The authors used MTR to image these participants’ brains. They then took the images and divided each one into 12 bands based on the distance from the edge of the brain.

In normal-appearing white matter of both the cerebellum and the cerebral cortex, MTR values were reduced in MS, with the bands nearest the ventricles – the inside of the brain – most affected. This was also the case for the deep grey matter. The amount of lesioned white matter was also highest nearest the ventricles, and showed a clear relationship with distance from the ventricles. In addition there was a small, if slightly less convincing, reduction in MTR in MS related to distance from the outside edge of the brain (the pia).

These findings are cool but need to be interpreted with a bit of caution. For one, as mentioned, we do not fully understand what MTR imaging is actually measuring, and so some of the imaging abnormalities noted in this paper may not reflect pathological changes that are relevant to MS. Another problem is that some people with MS have slightly smaller brains than control subjects due to atrophy (i.e. degenerative changes) over time – this means that each ‘band’ on their brain images is smaller, and so there is more space for random variability to affect their results. Furthermore, MTR is bad at detecting grey matter lesions, and so it is tricky to say whether the grey matter abnormalities they describe are due to lesions, effects around lesions, or unrelated to lesions altogether. This is important because, as I’ve said, the processes driving lesions and the processes driving neurodegeneration are not the same – if we are trying to use studies like this to discover more about these processes then it is important to be able to distinguish lesional from non-lesional areas. A final gripe is that the control participants weren’t that well matched – the people with MS were mainly women, while the controls were split 50:50 between men and women.

But putting these concerns to one side, this paper does definitely add to our understanding of ‘selective vulnerability’ in MS – it shows that distance from the ventricles – the CSF-filled spaces which abut the inner face of the brain – and to some extent from the pia, is a key determinant of MS grey matter and white matter pathology. We will obviously need further work to determine exactly what MTR is measuring, whether these gradients in MS pathology hold up in bigger studies and to clarify what these gradients actually tell us about the disease processes in MS. Further work will also need to clarify the relationship between MS pathology and proximity to the pia, as this was not entirely clear from this study in my opinion.

In short, this work adds to previous imaging and post-mortem studies by showing that MS pathology selectively affects regions nearest the outer and inner surfaces of the brain.




Thursday, 29 September 2016

How does laquinimod block attacks

Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, Amit-Romach E, Caballero IS, Towfic F, Ator MA, Rubinstein E, Laifenfeld D, Orbach A, Shinar D, Marantz Y, Grossman I, Knappertz V, Hayden MR, Laufer R. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A. 2016. pii: 201607843. [Epub ahead of print].

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.

Laquinimod is a pretty rubbish DMT when you look at its effect on inhibiting relapse, but when you looked at MRI, the results looked more promising a slowing nerve damage suggesting that it may be neuroprotective.

How does it work?

In this current paper, it is reported that Laquinimod acts via the aryl hydrocarbon receptor (AHR). The aryl hydrocarbon receptor is a ligand-activated transcription factor involved in the regulation of biological responses to planar aromatic (aryl) hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450.

The aryl hydrocarbon receptor is a member of the family of basic helix-loop-helix transcription factors. AHR binds several exogenous ligands such as natural plant flavonoids, polyphenolics and indoles, as well as synthetic polycyclic aromatic hydrocarbons and dioxin-like compounds. AhR is a cytosolic transcription factor that is normally inactive, bound to several co-chaperones. Upon ligand binding to chemicals, the chaperones dissociate resulting in AhR translocating into the nucleus and dimerizing with ARNT (AhR nuclear translocator), leading to changes in gene transcription.

In this study they report that if they removed the AhR from mice and it stops laquinimod from blocking the immune attack which was shown earlier by Berg J, Mahmoudjanlou Y, Duscha A, Massa MG, Thöne J, Esser C, Gold R, Haghikia A. The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor. J Neuroimmunol. 2016 Sep 15;298:9-15. They reported that  the AhR pathway is crucial for the immunomodulatory, but not neuroprotective, efficacy of laquinimod in EAE.

Likewise in the current study, they show that it when removed from white blood cells it blocks the action of laquinimod in EAE but if you remove it from the brain then it doesn't do much to EAE.

So the interestering question remains how is the potential neuroprotective effect mediated. The other question is. Is there a neuroprotective effect? Will Laquinimod be developed?

The 1.2mg dosing was stopped because of heart issues but will people believe that the 0.6mg dose is safe.

Wednesday, 28 September 2016

#GuestPost #ThinkHand, #ECTRIMS2016: Professor Coyle's motion at the "Burning Debate"

Last week I posted my slides in favour of the motion that pwMS in wheelchairs should be included in DMT trials. You were asking to learn more about the motion against, and my opponent during the 'burning debate' at ECTRIMS 2016, Patricia Coyle, kindly agreed to share her slides and some key points of her argument for this Guestpost.


Patricia K. Coyle, MD, FAAN, FANA, is Professor and Vice Chair (Clinical Affairs) of Neurology, and Director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University Medical Center, Stony Brook, New York.  She received a BS degree with highest honors from Fordham University, Bronx, New York, and an MD degree from the Johns Hopkins School of Medicine, where she was elected to Alpha Omega Alpha.  While at the Johns Hopkins School of Medicine, she completed a residency and chief residency in neurology, followed by a two-year fellowship in neuroimmunology and neurovirology.  She then went on to establish a successful research laboratory in addition to building a busy clinical practice at the Stony Brook University Medical Center.  Dr. Coyle is the author of numerous articles on clinical and basic research aspects of multiple sclerosis (MS) and neurologic infections and she is recognized as a leading expert on MS and neurologic infections.  Her areas of expertise include Lyme disease and neurologic infections, cerebrospinal fluid, therapeutics, and neuroimmunology.  Her research has been supported by the National Institutes of Health and other organizations.  She is currently involved in a number of therapeutic trials testing new immunotherapies for MS, as well as studies addressing neurologic aspects of Lyme disease.  In addition to her busy clinical and research careers, she has held active leadership positions in a number of national and international organizations and academic societies, including the American Academy of Neurology, American Neurological Association, National MS Society, and the American Board of Psychiatry and Neurology, and has been a member of the FDA CNS and PNS Drugs Advisory Panel. She lectures widely on MS and neurologic infections to national and international audiences.



Professor Coyle's key points:
  • People with MS in wheelchairs can and should participate in many types of clinical trials (testing CNS repair strategies, symptom management, rehabilitation techniques, national history studies) 
  • People with MS in wheelchairs have been and are currently routinely excluded from pivotal trials testing progressive MS DMTs
  • This exclusion is not based on discrimination; it is done to give the pivotal trial the best chance to be successful
  • In such pivotal trials you typically enter much more restricted “idealized” populations to avoid bias of failing to see a treatment effect
  • The primary outcome in such trials remains a clinical one, which documents that a drug can slow progression over a short (typically two year) period
  • People with MS in wheelchairs are not ideal to show such a time-related change for multiple reasons:
  • They typically have had bad MS for a long time, have accumulated a lot of CNS damage, and have the least CNS reserve
  • They do not have EDSS in the walking part of the scale, which is where changes are most commonly seen quickly; they are in the EDSS ≥7 range, where EDSS changes slowly if at all
  • They have more confounding comorbidities, more symptoms that are not as well managed, less physical exercise tolerance, all of which can interfere with their evaluation
  • The two current successful phase III PPMS and SPMS progressive trials both excluded people with MS in wheelchairs
  • Once approved, progressive MS DMTs should and in fact must be made available to people with MS in wheelchairs
  • Bottom line: for the ultimate higher good, to provide the best chance for critical pivotal progressive treatment trials to be positive, people with MS in wheelchairs must continue to be excluded (but not from the right to be treated)
What do you think?



CoI: PKC has served in a consultancy capacity for Accordant, Bayer, Biogen, Genentech/Roche, Mallinckrodt, Novartis, Sanofi Genzyme, Merck Serono and Teva, and has received research support  from Actelion, Genentech/Roche, Novartis and Opexa.

Making Microglia

Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, Bakiasi G, Tsai LH, Aubourg P, Ransohoff RM, Jaenisch R. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016. doi: 10.1038/nm.4189. [Epub ahead of print]

Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer's, Parkinson's and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions. These in vitro pluripotent stem cell-derived microglia-like cells (termed pMGLs) faithfully recapitulate the expected ontogeny and characteristics of their in vivo counterparts, and they resemble primary foetal human and mouse microglia. We generated these cells from multiple disease-specific cell lines . We further describe a platform to study the integration and live behaviour of pMGLs in organotypic 3D cultures. This modular differentiation system allows for the study of microglia in highly defined conditions as they mature in response to developmentally relevant cues, and it provides a framework in which to study the long-term interactions of microglia residing in a tissue-like environment.

Anyone that works on living animals in the UK has to have ethical approval to justify their work and each year they have to supply numbers of animals used as part of the national statistic.

The UK Government have wanted to get the number of animals used down, but their was a problem with the development of transgenic animals, as this caused the number of animals used to increase.

Many of the transgenic animals do not develop any harms as consequence to their genetic modification, but they are recorded because they are genetically modified, yet one can get a so called "normal" mouse and not record it yet some of the bog standard lab mice have mutations that affect function such as vision and hearing loss that go un-noticed. 

It seems that a fudge is being created to limit the problem of normal transgenic mice and rather that being reported as "mild", "moderate" or "severe" they are being reported as being "sub threshold", which sounds like something below the need to report:-(

However, worst fudges that have been around to that mask the number of animals actually used and this is the use of normal animals, that are killed and tissues used to make cell cultures.

These typically don't count in the statistics and so probably thousands upon thousands of animals don't show up on the records.

I believe they should and likewise people who use animals to kill them for tissues should have to go through the same hoops that people who use living animals. I would suspect that if they had to have the same level of ethical scrutiny and licences required then some of the animal work done may not get done. 

Most notably how do you justify the use of animal cells when you can use human cells instead? 

I think it is more and more difficult to use this argument because it is becoming easier and easier to make human cells and one of these ways is via use and diffentiation of  stem cells. One of the stem cells approach is called induced pluripotent stem cells (iPS cells) 

Here you take a cell like a skin cell and give it growth factors so that it becomes a stem cell capable of growing into any other cell type if you know how to give the right differentiation clues.

In this current study they have found a way to make human microglial-like cells from iPS cells, so you should not need to use rodent cells to study microglia. So a way forward to save our furry friends

Microglia are thought by many to be central to the generation of progressive disease and so the capacity to make human microglia is going to be of value in the search for treatments of progressive MS.


#ClinicSpeak & #ThinkHand: Can I buy a 9-HPT?

How do you feel about paying for the cardboard 9-HPT? #ThinkHand #MSBlog #ClinicSpeak


‘Now that I can’t walk, my hands and arms have become my legs….’
a person with MS


Since ECTRIMS our #ThinkHand campaign seems to be going viral. I am getting a steady stream of requests for the 9-HPT. I have had requests from organisations in the US and Ireland for large numbers of tests to be distributed to their members for self-monitoring.

Some of my colleagues have expressed their reservations about MSers monitoring their own disease. I am not sure why. It is clear that if ocrelizumab and spinonimod get through the development pipeline for progressive MS their use will be restricted, at least in the NHS, to the subgroup of progressive MSers who were studied in the phase 3 clinical trials. One of the requirements will be for MSers, and their HCPs, to demonstrate that they have actively progressing disease. This will require objective evidence of worsening disability over the last 12-24 months; not too dissimilar to the requirement of showing RRMSers have active disease (relapses and/or MRI activity). We have previously shown, mainly due to time constraints, that most neurologists in the UK don't do an EDSS, or other monitoring assessments, as part of routine clinical practice.

By activating you to monitor your own disease will allow you to collect objective evidence that your disease is getting worse and this may be sufficient to show that you are eligible for treatments and/or inclusion into clinical trials. This is one of the reasons why we have developed, and validated, the online web-EDSS calculator and will be adding the 9-HPT to the mix. Shortly we will also be adding the self-measured 25-foot timed walk and walking distance to the mix.

Please be aware that self-monitoring is not for everyone. In our survey a third of subjects were unsure of, or didn't want to, engage in self-monitoring. I have no problem with this, like all voluntary activities it has to be a personal choice. If you do self-monitor your MS-related disability and you show that you are stable and/or improving over time then this is surely good news? However, if you show that you are getting worse you can arm yourself with this information and ask your neurologist what can be done about it. Are their any DMTs for me, if not can I participate in clinical trials? Knowing that you are getting worse may motivate you to adapt your lifestyle and look after your general health better. Evidence is appearing that there are other things, apart from DMTs, that can be done to slow down the progression of MS. I personally feel that knowing about something, i.e. having objectively measured it, will empower you to do something about it.

We still have about 1,000 9-HPT tests left to distribute from our first production run and are now receiving requests from across the world for the 9-HPT. To deliver a responsive, and reliable, service for distributing these tests we need to hire an online vendor to do the work for us. This means that we will have to charge for the service. We anticipate that a price of ~£10 per test will allow us to cover future manufacturing, IT and distribution charges. Do you think this is a reasonable price (see survey below)? In addition to this we will be supplying you with instructions on how to make your own 9-HPT, i.e. so called DIY versions. In addition to the wood version I have been playing around with self-drying artist clay and lego blocks all of which can be used to make a functioning 9-HPT. The other option is to purchase the plastic version online, which costs $99.99 via Amazon.




We have now validated the cardboard-9-HPT, against the current plastic version. Our data shows that the cardboard 9-HPT is as good as, if not better, than the plastic version that is currently used in trials. Users found the wooden pegs easier to grasp and manipulate and the cardboard tray easier to use. There is a tendency for users to displace the pegs from the bowl in the plastic version, which slows down the performance of the test. The other advantages of the cardboard 9-HPT is that it is environmentally friendly, cheap and much easier to pack and post to people with MS. In other words it has been designed better.

Cardboard 9-HPT
Why is the 9-HPT such a good test of hand and arm function? To perform the 9-HPT you need (1) upper limb strength to move the hand, (2) vision to locate the pegs, (3) depth perception to accurately judge picking-up and placing the pegs, (4) sensation to feel and grasp the pegs and (5) coordination to complete the movements smoothly. All these neurological functions can be affected by MS, therefore the 9-HPT is a good integrator of neurological function. The 9-HPT has de facto become the EDSS of the upper limb, which is why we will be using it our clinical trial that will include wheelchair users.

Plastic 9-HPT

Acknowledgement & COI: we would like to thank Biogen UK for an unrestricted research grant that was used to design, test and manufacture the cardboard 9-HPT.

Tuesday, 27 September 2016

ClinicSpeak & NeuroSpeak: inviting MSers to ECTRIMS

It is essential that we start to invite MSers to attend ECTRIMS #ECTRIMS2016 #MSBlog #ClinicSpeak #NeuroSpeak

"Last week I took flak from suggesting we should allow MSers to attend ECTRIMS so that they can attend scientific sessions, hold their own parallel sessions and submit posters. This is not a new idea and there are several well established precedents in many other disease areas. One critic suggested the ECTRIMS ban was to comply with ABPI, and other, guidelines on how pharma interact with patients. I think this argument sucks; if MSers attended ECTRIMS pharma would have to clean up their act and it may result in Pharma becoming more socially responsible and to stop spending vast sums on marketing their brands. I have commented many times before on how ECTRIMS has become a marketing fest; the marketing warfare that plays out at ECTRIMS each year is like an arms race or in evolutionary terms the 'Red Queen Effect'."


Oct 2, 2013 ... "As this blog had a large number of new readers (>100,000 hits last month) I will take this opportunity to remind you of the red queen effect."

How many MSers can you spot?

"The paper and editorial below in this week's BMJ are very timely and put these arguments into sharp focus. I really think the MS community needs to ask themselves if is there a better way we can do things."


EDITORIAL


Fiona Godlee. At your next conference ask where the patients are. BMJ 2016;354:i5123

Excerpts: 

..... It may not feel like it just now, but what we have is doctor centred care. Perhaps also institution, manager, and nurse centred care. What we don’t yet have is patient centred care, despite this being obviously what healthcare should be. But things are slowly shifting in the right direction, and The BMJ aims to help keep up the momentum......

....... An editorial last week summarised where we’ve got to with The BMJ’s patient partnership strategy, and there’s good progress to report. We now have patients as peer reviewers of research articles and contributing to education articles; we require authors to state how patients were involved in their research or in creating an article; and we are publishing a rich array of patients’ commentaries.....

....... It’s now 25 years since the International Aids Conference first included patients in its discussions, but as Larry Chu and colleagues point out, involvement of patients in medical conferences remains the exception rather than the norm.....

....... So, what does doing it well look like, and how can organisers overcome the barriers to patient involvement? With five years’ experience of running a large academic medical conference in which patients play a central part, Chu and colleagues are well placed to advise.... 

..... It’s not enough, though essential, to have patients on the steering and programme committees from the start, they say. Organisers need also to encourage patients to attend, comment, and speak. This means making sure that patient delegates are properly looked after and supported so they can contribute on an equal footing to other participants....

...... This is not window dressing and must not be tokenistic. Crucially, it brings patients “closer to the conversations driving the future of healthcare".

ANALYSIS

Chu et al. “Nothing about us without us”—patient partnership in medical conferences. BMJ 2016;354:i3883

Key messages: 

  1. Involving patients in medical conferences can help delegates to understand problems that matter most to patients and their caregivers
  2. Involving patients can spark collaborations with patients in healthcare design, education, research, and clinical care improvements
  3. Patient should be included in the creation of conference programmes and selection of speaker
  4. Requirements of attending patients, such as facilities for self care and travel expenses, should be considered when planning conference
Excerpts:

..... The expression “nothing about us without us” was first coined by disability rights activists to convey the idea that no policy should be reached without full participation of representatives of all stakeholders. More recently, it has been adopted by patient communities seeking broader involvement with the healthcare system. Although the drive for patient involvement has come from patients, the medical community has much to gain.....

...... Patient involvement in health policy, clinical care, and research has gained momentum in recent years.....

..... Despite this progress, the role of patients in academic medical conferences has been poorly defined, discussed, and implemented.....

What patient involvement can achieve

...... Medical conferences are convened to spark innovation in healthcare by creating networks of experts, sharing knowledge, forming collaborations, and thoughtful challenging of conventional thinking. Patients can make important contributions in all of these areas by helping everyone understand the problems that matter most to patients, caregivers, and their families......

Making it work

...... While most medical conferences that have included patients report modest numbers of patient participants, a few have reported substantial patient inclusion (10% or more of total delegates) and even patient partnership in cocreating programming in their meetings. The degree of involvement, integration, and accommodation made for patients varies greatly.... 

...... Since 2002, patients have been engaged as collaborative partners in the biannual Outcome Measures in Rheumatology (OMERACT) conference. About 10% of participants of OMERACT are patients. Patient partnership was facilitated by strong commitment from the organisational leadership, adequate patient selection criteria, inclusive conference design, and support for patients attending the event. Evaluation shows that involving patients has helped identify new patient reported outcome measures and new domains that are important to patients and provided the patient perspective in developing core and patient reported outcome measures.....

Charters and frameworks for patient involvement
..... Recently, several organisations have created charters or frameworks for patient involvement in medical conferences. Published in May 2015 by a group of 25 individuals, comprised primarily of patients, patient advocates, and people related to the drug industry, the Patients Included charter consists of five clauses that aim to provide conference organisers “with a means of demonstrating that their events are committed to incorporating the experience of patients as experts in living with their condition while ensuring they are neither excluded nor exploited.  The European Patients’ Forum has also recently released a charter on patient empowerment for conference organisers....


Four pillars of patient involvement at academic medical conferences
  1. Accommodation: Consider the medical, nutritional, and accessibility needs and financial assistance with travel and lodging arrangements as practical. For example, include patients in designing a designated physical space such as a wellness room that provides attendees with an area to rest or attend to personal care.38 Use of social media and free live streaming should be explored to allow participation by patients unable to travel
  2. Codesign: Patients should be placed on an equal footing with programme creators to help identify core conference themes, select speakers, and evaluate abstracts that relate to patient centred issues
  3. Engagement: Meaningful numbers of patients should be included in the audience and speaking roles. Patients invited to attend or speak should be able to attend all sessions open to others attending the conference. Patient speakers might be found through local patient advocacy groups, hospital patient and family advisory committees, or targeted social media efforts
  4. Education and mentorship can help patients learn how to collaborate and partner with providers, researchers, and third party stakeholders to fulfil the mission and goals of the conference organiser, hosting society, or institution.
Measuring engagement
..... Use of social media is growing in medical conferences worldwide to disseminate information and spark discussion between delegates. Social media can also be used to study the effect of patient participation on the quantity and quality of discussions at medical conferences—for example, by counting the number of discussions using patient centred words and terms.....

Conclusion

...... Patient involvement in academic medical conferences is an important step to bring patients closer to the conversations driving the future of healthcare. Current data suggest that meaningful patient inclusion can help drive discussion and knowledge dissemination at academic medical conferences and widen research agendas to include new patient centred domains. Conference organisers should work towards patient involvement not only to foster the patient voice in academic medicine but also to realise true partnership and collaboration with patients as a means to drive truly meaningful innovation in health care....

EBV and smoking in MS: Two peas in a pod?

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study

Published online before print September 23, 2016, doi: 10.1177/1352458516671028

Kjetil Bjørnevik, Trond Riise,Inger Bostrom, llaria Casetta,Marianna Cortese,Enrico Granieri,Trygve Holmøy,Margitta T Kampman,Anne-Marie Landtblom,Sandra Magalhaes,Maura Pugliatti,Christina Wolfson,Kjell-Morten Myhr.

Abstract


Background: Results from previous studies on a possible interaction between smoking and Epstein–Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.


Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.


Methods: Within the case–control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.


Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis (p  = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66–1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): −0.98, 95% CI: −2.05–0.15, p = 0.09).


Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Smoking and EBV (the virus that leads to glandular fever) are reported risk factors for developing MS. What happens if you had both smoked and had glandular fever, is your cumulative risk higher? You would have thought so, but apparently not according to work by Bjornevik et al.

This work matches PwMS with healthy people (case-control study) in Europe (Norway, Italy, Siberia, Sweden) and Canada and whether they smoked or had glandular fever (exposures) in their early life. The problem with this is that it is susceptible to recall bias as people are asked to recall historical information. 
Nonetheless,  it is a large study and may filter out these errors.

They report that both risk factors affect the likelihood of developing MS in the absence of the other, but may compete with each other when both are present. For example, the effect estimated for EBV was lower when smoking was also present. This hints at the two exposures having a shared biological pathway in the way they operate in the development of MS. But , it is important to note that one isn't protective for the others effect, but simply that they may compete with each other (two peas...).

Monday, 26 September 2016

ResearchSpeak: ECTRIMS highlight ocrelizumab NEDA data

How important is rebaseling when assessing NEDA rates? Essential - just look at the stunning ocrelizumab NEDA data. #ECTRIMS2016 #ResearchSpeak #MSBlog

"The poster below is another one of my ECTRIMS highlights. There is little doubt that ocrelizumab is a highly effective DMT. However, how does it perform if you treat-2-target of NEDA (T2T-NEDA)? I have been saying for sometime that to implement T2T-NEDA in clinical practice you have to rebaseline your metrics after the DMT in question has had time to work. For most maintenance DMTs this is 6 months."

"The analysis below shows that if you do this with ocrelizumab, then over 80% of subjects are NEDA from 6-24 months (figure 3). To the best of my knowledge this is the best NEDA data out there after rebaselining. I have yet to see the HSCT rebaseling NEDA rates, but I suspect they will be in the same ballpark. What is also important to highlight is the remarkable observation that 57% of the IFN-beta (Rebif) treated participants were also NEDA in this epoch. Based on earlier interferon data this is much better than one would expect. It looks as if from contemporary trials that the efficacy of Rebif has improved. Why? One reason could be that the population of trial participants have included subjects with more benign MS or Rebif has gotten better. I suspect both are correct. Most subjects in the Opera studies received RNF (Rebif new formulation). We know that RNF is associated with fewer NABs (neutralizing anti-bodies), which affect its efficacy; hence there are reasons to expect that Rebif's efficacy has improved. I am sure a lot of people will jump on the Rebif NEDA data to support its continued use as an effective DMT in the 'majority' of MSers."

"It will be interesting to see how the regulators, payers and/or healthcare commissioners respond to this data. I sincerely hope the regulators give ocrelizumab a liberal label that will allow first-line use in MSers with active disease. This will then allow HCPs and their patients to decide on which DMTs they want to use. However, as always in price-sensitive markets the payers and commissioner may have a different take on things particularly if ocrelizumab is priced at a premium."



CoI: multiple

Sunday, 25 September 2016

Comparing DMT



Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M.
Mult Scler Relat Disord. 2016 Sep;9:23-30. doi: 10.1016/j.msard.2016.06.001. Epub 2016 Jun 8.
PMID:

INTRODUCTION:Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis(RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies.
OBJECTIVE:To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS.
METHODS: A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome.
RESULTS: The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome.
CONCLUSION: Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS


The CRAB drugs are low efficacy and Alemtuzumab and natalizumab appear to be amongst the most effective, at least in terms of inhibition of relapse. As to disability progression, we still struggle with the most effective outcome measure. The EDSS seems to be a gold standard that is not sensitive to change nor linear and MRI measures all have their issues. 

However, there are so many things that make up best drug, such as efficacy, convenience, cost-effectiveness, CNS activity, safety.

However, will we see head to heads to work out what is the best candidates. Well we know that the CRAB drugs loose out to the newer more effective DMT, but are companies going to do a head to head against an effective drug.?

It could be pharmaceutical suicide if the comparator does better, even percieved better would bad for marketing. Comparing against low hanging fruit is marketing to say "our drug is better".

So it is down to academics to do these studies. However can  thet afford to do it properly, I doubt it because the trials would probably need to be very large to  show superiority of one verses another

Demystifying vitamin D: new study links variants in vitamin D genes to risk of MS

Abstract
Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18–20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p 5 0.04, 95% confidence interval (CI): 0.64–0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p 5 0.03, 95% CI: 0.76–0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p 5 0.003, 95% CI: 0.76–0.94). No association was observed for age at onset or disease severity.

Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

The interpretation
The association between low levels of vitamin D and the risk of multiple sclerosis (MS) has been demonstrated in several big studies. There is clearly a correlation between vitamin D status and MS risk, but this does not imply causation. It is difficult to tell from big observational studies whether vitamin D deficiency causes MS or whether there is something else going on. This graphic depicts three possible explanations for the observed association:


Potential explanations for the observed association between vitamin D status and MS risk


This question is important because if we had unequivocal evidence that low vitamin D increased peoples’ risk of developing MS, we would have a stronger case for prescribing vitamin D as a preventative measure for selected patients.

Why is it so tricky to prove a causal relationship between vitamin D status and MS risk? In big population studies of MS, investigators do their best to measure all kinds of variables – factors that could influence risk - and they try to control for these when they analyse the data to look for causal relationships.
However, these studies cannot ever fully overcome the problem of reverse causation - the possibility that MS causes low vitamin D levels - and the problem of confounding – the possibility that other factors, such as ethnicity, sunshine exposure, or obesity predispose to MS independently of their effect on vitamin D status.

So, how can we ever work out if low vitamin D causes MS in big population studies?

Lisa Barcellos and friends have come up with a clever answer to this problem. They used a technique called Mendelian Randomisation to get around the problems of reverse causation and confounding. The approach is called Mendelian Randomisation because it relies on one of Mendel’s laws of inheritance – this states that which alleles (versions) of a gene are inherited is independent of the inheritance of other genes. Everyone in the population will therefore have a random selection of alleles affecting vitamin D status. So if you know how these alleles relate to vitamin D status, you can use the genotype (i.e. the set of alleles someone has) as a surrogate marker of vitamin D status. This obviates the problems of reverse causation and confounding.

Barcellos et al found 3 single nucleotide polymorphisms (SNPs) from published work that are closely associated with vitamin D levels. They then tried to see if these SNP alleles were associated with MS risk, age of onset, and disease severity.

This approach is neat because SNPs are encoded in the genome for life - they are not affected by lifestyle factors, environmental factors, or by MS itself. So if these SNPs provide an accurate surrogate marker of vitamin D status, they provide a simple way of determining whether low vitamin D levels actually cause MS, rather than just being correlated with it. This approach to studying associations can be thought of as a natural randomised controlled trial, whereby MS risk can be compared in people with SNPs predisposing to low vitamin D vs. those with SNPs predisposing to normal vitamin D.

This study collected data from 2 separate massive cohorts, totalling a whopping >7000 people with MS and >14000 healthy controls. The pooled odds ratio for developing MS was 0.85, meaning that the odds of developing MS are significantly reduced by having genes that predispose to normal vitamin D. There was no association between these SNPs and either age of onset or severity.


The Mendelian Randomisation method for studying the relationship between vitamin D status and MS risk


While population data is never going to be as convincing as a randomised controlled trial, this study provides quite strong evidence that vitamin D status has a causal role in determining risk of MS. These findings only apply to Caucasian people, as non-Caucasian people were excluded from the study. A key assumption of this study is that the SNPs assessed only influence MS risk via their effects on vitamin D status – while we have no evidence that this assumption is wrong, we do not know what the exact function of these SNPs is, and so it is possible that they have as yet unknown effects which influence MS risk.

We now have another important piece of evidence that low vitamin D causes a slight increase in MS risk. But it is a separate question whether supplementing vitamin D reduces the risk of developing MS. Unfortunately this can only be answered through a well-designed randomised controlled trial.







Saturday, 24 September 2016

ClinicSpeak & NeuroSpeak: MS Ireland & Brain Health

Brain Health and wellness in MS is all the rage. Good! #BrainHealth #MSBlog #ClinicSpeak

"I am in Cork at MS Ireland's annual meeting. The good news is that this year's meeting for HCPs and MSers is focusing on Brain Health and Wellness. It is very reassuring how quickly awareness on the Brain Health issue had spread across the field. I sincerely hope the 'Brain Health' policy document has something to do with it (please see our new website). The good news is that the policy document has now been published in full and can be cited via PubMed (see below). If you haven't read it yet give it a go; it is written in plain English for a wide audience."





Giovannoni et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5-S48. 

INTRODUCTION: We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families.


METHODS: Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs).

RESULTS: Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models.

CONCLUSIONS: The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

Friday, 23 September 2016

NeuroSpeak: calling all MSologists and trainees

Why haven't you registered for the MS Trust Conference with your team from 6-7 November? #MSTrust #NeuroSpeak #MSBlog

"In a pioneering spirit the MS Trust decided to launch a new initiative. They wanted to bring MS teams together at their annual MS Trust conference. The management of MS in the modern era is about multidisciplinary teams that work together to improve the outcome of people with MS. The MS Trust then approached the ABN to help design a programme that would be of interest to neurologists, neurology trainees and MSologists. The ABN MS Specialist Interest Group and the MS Trust then designed a masterclass session for neurologists. The uptake so far has been so abysmal that the MS Trust is now considering cancelling it. This saddens me; in the modern era any opportunity to bring together doctors and other HCPs should be welcomed. The days of them and us are surely over? More importantly, the meeting is also a good opportunity for team building. If you don't go yourself can you please make a plan to send one of your juniors?"

"Another trend, which is unstoppable, is the move away from face-to-face meetings toward webinars. The following is an international webinar series that I have agreed to participate in; PRIME. The good news is that it is for all HCPs, both physicians and clinical nurse specialists. The bad news is that it is not for people with MS. I dream about a day when people with the disease and their healthcare professionals will be able to attend the same teaching sessions online and/or in person."

"We tried to get MSers in wheelchairs to man our #ThinkHand stand at ECTRIMS and were told by the organisers that this was not allowed under ABPI guidelines. It is a great pity MSers are not allowed to attend ECTRIMS unless they register and keep it a secret. Do you think MSers would be shocked at the extravagance of the marketing fest?"