Thursday, 26 May 2016

ResearchSpeak: reflections on the ABN

My pod-casting experiment from the ABN #ResearchSpeak #ABN2016 #MSBlog 

I spent most of last week at the annual Association of British Neurologists (ABN) meeting in Brighton. I chaired two debates, presented 4 posters and was co-presenter on another 2 posters. I also networked and met many young neurologists and saw some old friends.

The debates:

Debate 1: ‘Was the NICE mandate that pwMS should have annual cognitive assessments appropriate or not?’

Professor Dawn Langdon made the case for annual cognitive assessments arguing that knowing if someone with MS had cognitive impairment would affect how you manage them. Cognitive impairment is associated with poor drug adherence and difficulties with following self-management strategies. For example, pwMS who have cognitive impairment are more likely to get recurrent urinary tract infections. I suspect that this may not be causal, but simply an association; i.e. people with cognitive impairment may simply have a greater chance of associated bladder problems. She was implying that they were less likely to follow medical advice on how to manage their bladders and adhere to their treatments. She also stressed that annual cognitive assessments does not mean full neuropsychometric testing, but could simply be done using a rapid screening battery such as BICAMS (Brief Cognitive Assessment in MS). She slipped in that BICAMS takes 15 minutes to do and needs to be done by a healthcare professional. At our centre with 1200+ MSers on our books that is 400 hours of testing per year. Dr Brenner, a good friend of mine, argued against the motion. He focused on the NHS resources it would require, and consume, implement annual cognitive assessments across the UK; resources he felt would be better used on more pressing problems. He made the point that as we have no treatment for MS-related cognitive impairment it was unethical to do the tests. Do pwMS want to know they are cognitively impaired? He assumed that pwMS wouldn’t want to know about an MS complication they could do littke about. I am not sure we can make any assumptions, this is a question that needs to be answered by you people with MS.

There were too few voters to really assess which way this debate went, but the debate generated lively discussions. I concluded that this debate needs a larger audience and should include people with the disease. I wonder if NICE asked MSers their opinion before recommending annual cognitive assessments?

Debate 2: ‘To manage MS properly we need a new MS disease activity score or DAS’

As chairman I set the scene drawing on the experience of rheumatolgists who have been using the RA DAS (disease activity scale) for decades. In RA a DAS score is used as a metric to treat-2-target. The RA-DAS semi-objectively measures how active RA is and allows rheumatologists to assess how effective their DMARDs (disease-modifying antirheumatic drugs) are at controlling RA. The RA-DAS has been instrumental the paradigm of treating-2-target that underpins what we are trying to copy and promote in MS.

Dr Leonora Fisniku, from Haywards Heath, argued for a new MS-DAS. She opened the debate by reviewing the treatment landscape and made the argument that because most of the inflammatory disease activity in MS occurs below the surface, i.e. the iceberg analogy, we need to use biomarkers (MRI) to quantify MS disease activity. She made a strong theoretical argument for a MS-DAS without actually defining what components should would include in her score. Dr Waqar Rashid, from Brighton, countered her argument with a pragmatic approach telling us to shy away from perfectionism and to use what we have already and what we have been trained to do in the clinic. He argued that there is no reason to reinvent the wheel and that we should simply use what we collect routinely in clinic to make an assessment of whether the patient is active or not. In other words the clinician's acumen. He stressed the difficulties we would face with having to validate a new MS-DAS and that it is unlikely to capture all aspects of the disease. Both debaters covered the EDSS and mentioned its failings, but neither were brave enough to confine it to history. I was surprised that the vote went against the MS-DAS. I suspect what won the day was that Dr Rashid managed to exploit neurologists fears of a new unvalidated MS-DAS consuming valuable clinic time and forcing neurologists to change the way they practice clinical neurology. Neurologists don’t like change; they have been examining the nervous system the same way for over 100 years, why change the way we do things with better tools? This debate generated a lot of discussion from the floor, a lot of which focused on a prognostic scoring systems rather than the issue at hand.

I am of the opinion that a new MS-DAS is essential; we need it to get wide adoption of the treat-2-target approach of NEDA. Its development would clearly need careful consideration and multi-stakeholder input if it had any chance of being adopted. I personally would argue for it to include a PROM (patient-related outcome measure). A PROM will at least get the individual with MS engaged with the process of monitoring their own disease activity. The latter aspect may be why the RA-DAS has been so successful as a change agent in the management of RA. As I have said before patient-engagement is a no-brainer and one of the most underused therapeutic interventions we have. A MS-DAS could also be used as a driver of quality. If your neurologist refused to use the MS-DAS you may be tempted to find another neurologist who did. Now wouldn’t that be something worth talking about? I am aware from comments on this blog that some of you have done this already and moved neurologists simply to get annual MRI scans.

The posters:

Although the posters were up for most of the meeting we had just over an hour to stand by the posters to field questions from the attendees. This caused me problems although I had three posters in a row the fourth poster was in another location so I had to split my time between the two locations. It was a pity because the data in all my posters was worth talking about. The isolated poster showed that disability improvement on alemtuzumab occurs across most functional systems of the EDSS and is not simply limited to one functional system. On reflections isn’t amazing that with the more effective DMTs we can now expect disability improvement? Interestingly, we are seeing disability improvement occurring in years 3 and 4 and not just in year 1 and 2 post-alemtuzumab. This challenges the dogma about recovery mechanisms in the central nervous system and finally buries the dogma that the EDSS progression is a one-way street. Disability improvement, or the promise of disability improvement, is in itself proof of how far we have come with the treatment of MS. For the cynics and nihilists out there ‘eat your hat’.

Another ground-shifting poster was the ORATORIO study results (ocrelizumab in PPMS). This study is the first study to show a DMT slowing the rate of disability progression in PPMS. This is has to be one of the most significant things to happen in the field of MS in the last 10 years. Despite this I am concerned that NICE may not view ocrelizumab as a treatment for PPMS very favourably. NICE always assesses cost-effectiveness using an incremental cost model. For PPMS the cost-effectiveness of ocrelizumab will be compared to what is out there already, i.e. best supportive care. The latter will cause problems because ocrelizumab will presumably be licensed for RRMS where the comparison will be with existing DMTs that are high-cost. So the cost per QALY for treating RRMS will command a higher price than that for PPMS. Will this be the opportunity for NICE to demand differential pricing? Will the NHS pay less for ocrelizumab in PPMS compared to RRMS? Differential pricing of this nature is called value-based pricing whereby healthcare payers pay for what they get. In reality this is the system that airlines use for booking flights and what Uber use in the APP with surge pricing. Why shouldn't we bring value-based, or surge, pricing to the field of MS? Comments; I am particularly interested to hear Pharma’s perspective on this.

I also presented two posters on daclizumab. One was on NEDA rates in the phase 3 study and the other the effectiveness of daclizumab in study subjects in the extension study of the phase 2b, SELECT-SELECTION, study, appropriately called the SELECTED study. Please note that although I sat on the steering committee of the SELECT and SELECTION studies I had nothing to do with their names. There is a whole field dedicated to the naming of clinical trials; if you get the acronym right the study develops a life of its own. Not unexpectedly in the phase 3 ??? study the chances of NEDA were higher on daclizumab than interferon-beta. In the extension, or SELECTED, study the relapse rate appeared to continue to go down, hinting that the efficacy of daclizumab may increase with time. We actually saw the evidence for the ramping up of efficacy in the original SELECT study on MRI. Despite the daclizumab efficacy data, I spent most of my time at the daclizumab posters enthusing over daclizumab’s mode of action or MOA. Dac’s MOA challenges the core immunological dogma around the pathogenesis of MS. As I have said many times before daclizumab is not an immunosuppressive drug and it works by subtly changing the IL2 (interleukin 2) signaling pathways diverting IL2 away from activated T cells and T-reg cells towards the CD56-bright NK cell population. The expansion of this latter cell population seems to be closely linked to Dac’s efficacy. What is more the number of T-reg cells go down; this contrary to what we have been told by immunologists that MS is a immune mediated disease that is linked to abnormally regulated T-cells. An interesting discussion will be where Dac fits into the current treatment paradigm; I have thoughts on this but this will be a discussion for another time. 

My ABN highlight:

The real highlight of the meeting was Prof. Compston’s ABN gold medal acceptance speech. It was about his medical life from the time he entered medical school up until the present and his current retirement plans writing historical books. He summarised his career as a neurologist covering his research into the genetics and treatment of MS, his time as an editor of Brain (one of the premier neurology journals, or argubly the premier neurology journal) and his legacy - a large number of his trainees now head-up neurology departments across the UK. He voice broke a few times during his talk as it was clearly very emotional speech. Getting to an end of such a glittering career and reflecting on it must be very nostalgic. I personally find nostalgia one of the most powerful of emotions; it is not necessarily a sad, or happy, emotion, but it somehow brings tears to my eyes. At the end of the talk he was given a standing ovation; the first time I have experienced this at an ABN gold medal ceremony.

Some reflections after the meeting:

Many times we the community are criticised for not making progress in MS research. The problem is we tend to look at what happens from year to year. When you look at it from Professor Compston’s perspective and take a 40-year view of the field you realise that so much has changed. It is simply quite incredible what has happened to MS in the last 40 years. We now have treatments that render MSers with NEDA, i.e. putting some of them into long-term remission with the promise of a cure in a proportion of them. With ocrelizumab we now have a DMT that has been shown to be effective in PPMS. We have refined our diagnostic criteria and are better at excluding MS mimics from being inappropriately diagnosed as having MS. We know so much more about the causal pathway of MS and are beginning to use this knowledge to discuss and design MS prevention studies. Are there really some humbugs out there who still think we have made so little progress in MS research? If there are I suggest they take a 40 year helicopter view of the field rather than a very short-sighted one, or two, year view of the field. Another option who be to spend an afternoon discussing MS research with Professor Compston.

CoI: multiple

Wednesday, 25 May 2016

Clinical trials from three different perspectives

This post coincides with International Clinical Trials Day which is celebrated each year around the world, on or around the 20 May to commemorate the day that James Lind started his famous trial. This week, across the Barts Health NHS Trust site a number of activities are taking place to educate, raising awareness and celebrate some of the brilliant research going on in our area. Our contribution to this shares the experience of taking part in a clinical trial either as a person with MS, an MS researcher and a MSologist.


The patient perspective:

"Like many people when first diagnosed with MS there is the inevitable "why me" but also a realisation of helplessness due to a lack of drugs to fight, slow down or even just simply delay PPMS. The only thing I could do was to lose some weight and keep myself fit and with that in mind I started immediately and continue now weekly physiotherapy sessions, but I was keen to do more. This lead me to look at drug trials to fight back - take the war to the enemy!

Since then I have been involved in 3 drugs trials over a number of years and given that I have few if any allergies, no needle fears (important believe me, given the number of times that you need to give blood!) and time on my hands I guess I am a reasonably good trials patient. In addition to this there is also an altruistic motive, I am keen to help develop drugs for all pwMS and also ensure that that those clever people developing drugs get the opportunity to trial them. In return I get regular health check ups and access to the medical staff at the Royal London, which I consider to be a plus factor and I also am now on very good terms with most of Prof G's team! Additionally you also have the opportunity to maybe get a drug ahead of the general population and test its efficacy.

There are of course occasions when you really do not want to spend time in a hospital and some trials have been a little more demanding than I would necessarily wish, but overall I would suggest to all pwMS to sign up for a trial if it convenient for them to do so - you never know what might come of it.”


The researchers perspective:

"I am Lucia and I work in the Lab to test the trial samples - this helps to determine if the trial drug is effective. I also take care of all associated paperwork, as everything in a trial needs to be documented: this is important for the participants’ safety as well as for the reliability of the results.

The vast majority of trials nowadays are testing a new drug against the best current one and not against a placebo: this eliminates the risk of going without treatment for the duration of the trial. To enrol in a trial the clinician must give you full knowledge of the possible risks and benefits; your agreement is given by signing an ‘Informed Consent’ form. Moreover, you can withdraw from a trial at any time without the need to give a reason.

To run a trial we have to adhere to national and international regulation and must have the approval of an independent ethical committee; Lab and documentation are also regularly inspected by regulatory bodies. As much as it is sometimes exhausting and frustrating for me to keep on top of all these piles of paperwork I feel all of this is essential to ensure the trial participants’ wellbeing is the first priority. It is also important to safeguard the scientific value of the trial - in other words, there must be strong scientific data to prove the drug is indeed effective.

What from outside might look like a lot of unnecessary red tape it is in my opinion a guarantee only really improved and beneficial treatments will reach the clinic. I enjoying working in clinical trials as the results of the analysis I perform on samples could lead to better therapies being available to people with MS."


The clinicians perspective:

"As a clinician, doing a neurological diagnosis is usually challenging but always rewarding. Unfortunately the lack of effective treatments for neurological patients could be a huge problem. Therefore, it is important to seek for innovative and more effective therapies to allow patients affected with neurological disorders to improve their lives on a day-to-day basis.

Clinical research, especially clinical trials, has taught me the importance of searching for new and more effective therapies for people suffering from devastating neurological disorders such as MS. Being part of clinical research projects is one of the most rewarding activities I have experienced in my medical career. As a clinical research fellow, I am involved in developing research objectives, projects and proposals, helping in the conduction of internal and collaborative research projects, and disseminating research findings through scientific publications and conferences. The objective of our clinical research is to find more effective therapies for people with multiple sclerosis.

Apart from the technical work we have to do, I always try to have some time to chat with people with MS and hear their necessities, this is priceless as patients have little time during the normal NHS appointments to talk about more general problems that are important during the time of designing research projects. Besides, some patients are opened to share some personal gifts they have, like Sam who shared with me poetry he writes in his blog:

“I try daily to always be happy, I know life is hard but it's best to go throw it with sum1 so lively…” Sam*

This is very gratifying!


You can find out more information about the different events taking part across Barts Health here. We are also working to update our trials tab on this blog.

PoliticalSpeak: Saving Good Sams

Save the Good Samaritan; help Barts-MS mobilise support. #MSBlog #PoliticalSpeak #GoodSams

"This is a post and a call for all the MSers who are under our care at the 'Royal London Hospital'. This post is blatantly political but it is relevant to the care of people with MS who attend the MS service at the Royal London Hospital. The Pub, or Public House, is quintessential English. The pub is not just a place to drink beer, wine, cider or even something a little bit stronger, it is a unique social centre, it is usually the focus of community life in villages, towns and cities throughout the length and breadth of the country."

"In our little patch, between our research Institute and the hospital, there is pub called the 'Good Samaritan' or 'Good Sams'. We love 'Good Sams' it is the one institution that makes our patch social. Closing it down would destroy 'social capital', which is worth so much more than 'capital'. We meet in 'Good Sams' to celebrate promotions, successful PhD vivas, the passing of exams, birthdays, births, etc. We chew the cud in Good Sams and many an MS research hypothesis has been born in Good Sams. 'Good Sams' is where our medical and dental student celebrate the completion of their end of year exams. In short 'Good Sams' is the heart and soul of Barts and The London Medical and Dental School and The Royal London Hospital."

"Good Sams was established in around 1785 and rebuilt in its present form in 1937. It is one of the last remaining pubs for those who live nearby; work for and visit The Royal London Hospital. Unfortunately, it is under threat of closure. I assume this relates to money. To the current owners: if this simply about making money this is a mistake. Please think about all the fond memories and nostalgic tears that are yet to me made and shed in 'Good Sams'. Life is so much more than pounds, pence, shekels and dimes. Whenever I enter Good Sams I feel happy and content; it enriches the quality of life of all of us her work on the Whitechapel campus and for those who come to be looked after and cared for at the Royal London Hospital. Some concerned locals have set-up a petition in an attempt to save 'Good Sams'. Barts-MS supports this petition and if you agree with us we would encourage you to support the campaign. This is not only about us, but about many an MSer who has stopped for a pint after clinic."

CoI: we work around the corner from Good Sams, chances are if you come to visit us we will treat you to a pint at 'Good Sams'."

Tuesday, 24 May 2016

Tracing your lesions through the MR Myelinoscope - news from the imaging department

Longitudinal Observation of Individual Multiple Sclerosis White Matter Lesions Using Quantitative Myelin Imaging
Kitzler HH, Köhler C, Wahl H, Eisele JC, Deoni SC; Rutt BK, Ziemssen T, Linn J. 
Poster # 1282, 24th annual meeting of ISMRM

One of you recently asked the question whether lesions on MRI can disappear, and I said yes they can, and that this has to do with several factors including lesion severity (lots of axonal loss or not), subsequent lesion repair, and the tools & techniques used to detect them (or not).  Now I just returned from Singapore after attending the International Society for Magnetic Resonance in Medicine (ISMRM), where I saw this work using an MRI technique optimised for detecting the myelin content in lesions (let's call it an "MR Myelinoscope").  It nicely shows that whilst lesions may look the same on our standard workhorse MRI, they may be quite in different "states" when looking through the MR Myelinoscope.

The panel above shows that over 12 months lesions on FLAIR (standard workhorse technique, top row) don't change very much, however the Myelinoscope (bottom row) shows dynamic change over time (see arrows): A lesion hardly visible at month 0 is largest at month 3 (demyelination), and then smaller (suggesting remyelination).

Panel showing 4 different lesion "states" (differences in myelination status over 12 months) using the MR Myelinoscope whilst standard FLAIR doesn't change.

Nice work indicating how crude our current standard MRI techniques are in monitoring the severity and dynamics of tissue changes within MS lesions.

Whilst the MR Myelinoscope technique is quite complex to implement, and therefore not available at many centres, it could be useful in trials of potentially remyelinating drugs where only a limited number of centres would be involved.

CoI: none

We're redefining our Mojo

Anyone for a Mojito cocktail? That was one recommendation. #MSBlog #MSResearch #Mojo

We’re back! Following one week of painful – albeit self-inflicted – soul searching we’ve now discussed the positioning of the blog. Thank you for all the feedback (positive and not-so positive) whilst the blog was suspended. We reviewed ALL of your comments, and felt very much encouraged to resume blogging. There are things we can improve, and below are some of our action points moving forward:

  • Posting Schedule: We drafted a posting schedule that will hopefully free up some time for the contributors. This is obviously not set in stone and won't stop us responding to current events, TV programmes, News articles in relation to MS as they come out.
  • New faces and guest posts: We will continue to invite researchers and clinicians to write guest posts, however will also offer the opportunity to people with MS, their family members, friends, and people involved in charity work. Please get in touch if you would like to contribute, however note this is a platform for MS research not for advertising.
  • Barts MS Charity: We will set up the ‘BartsMS Charity’ to support our research, maintaining the blog, and off-label prescribing initiatives, particularly in resource-poor health care environments. More information about this coming soon.
  • Better social media coverage: 
  • New ideas
    • Legibility: The blog home page will now show 5 posts at a time. What do you think? 
    • We plan to update the “Trials and Studies” section of the blog. 
    • We’re planning to extract all the clinical advice and information from previous and future posts to create an information resource that is easily searchable. 
    • Prof G promised to be more diligent with producing the case studies and hopes to get some back-room help. 
    • What about podcasting and vlogging? Do you think we need to go multimedia? 
As always, we are interested to hear your thoughts on the above and beyond. It seems as if a lot of you don't like the use of anonymous comments. It would be nice to know if many of you are repeat commentators; who knows you may take on Dr Dre at his/her own game! Can we suggest you take on a pseudonym if you don't want to let the world know who you are?

Photo credit: Dolly Clew