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."


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


..... 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".


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

..... 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.....


...... 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.


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...).