Self-monitoring and the socialisation of web-based apps is the revolution waiting to happen in MS care.
The following is my ‘Hot Topics’ talk on web-based PROMS (patient-related outcome measures). The presentation should be self-explanatory but if you have any questions please feel free to ask.
Summary: Our position, as formerly stated, on more advanced (formerly know as progressive) MS.
Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS. The neuroaxonal loss – the underlying element of ‘advanced MS’ – is there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled. Do you agree?
MS is one disease and not two or three diseases. As we have said before, the division of MS into several diseases is not backed up by science. This false division of MS into several diseases has become counter-productive to the field of MS. The division of MS into multiple diseases was Pharma-led to get MS defined as an orphan disease. This helped in that it allowed interferon-beta-1b to get a licence based on the results of one pivotal phase 3 study.
Similarly, we believe the division between SPMS and PPMS is false. There are no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, propose doing trials in both populations simultaneously.
To slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a part in advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.
Reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we have referred to this as therapeutic-lag. These observations are explained by MS being a length-dependent axonopath. i.e. the longer nerve fibres, (to the legs) are more likely to be affected than shorter fibres, (those to the hands and arms). This means that we will need to focus more on arm-&-hand function as a primary outcome measure in clinical trials, in particular in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).
We need to challenge the current view that once someone has lost lower limb function and is a wheelchair user that their disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign and plans to a trial in wheelchairs users (#Chariot-MS).
I think we also have to accept that we will need to use combination therapies to make a real difference to more advanced MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective or remyelination therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms – for example, laquinimod which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.
Is it time to ditch the EDSS. The whole MS community, or almost, knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more patient-related outcome measures in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development; these need to be validated and used in clinical trials.
We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma don’t like adaptive designs nor do the regulators. We need to include two phases in trials of more advanced MS. For example, the standard head-to-head phase with a robust primary outcome, say the 9-HPT, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).
We also need more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and/or blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We are in the final stages of the PROXIMUS trial and we have learnt a lot in the process. The PROXIMUS trial is an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’.
We also need to push for political change. We need true incentives for the repurposing of off-patent drugs. We have discussed this on this blog before and have written a paper on the so called ‘Big Pharma Alternative’ in which we propose potential solutions.
Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue. I don’t. If we do a trial and provide compelling data that a specific drug in combination with another drug delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies. This is not rocket science and happens all the time in other disease areas, like cancer.
More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU health economic study that costs soar as pwMS lose arm function. Are you surprised? When you lose arm function you lose your independence.
We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing from reduced brain, and cognitive, reserve drives worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.
We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes . To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote recovery mechanism (axonal sprouting, synaptogenesis and plasticity) to restore function.
As you can see at Barts0MS we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS. Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.
P.S. DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded. Thank you.
Causation theory is essential to frame the EBV problem in MS. #ClinicSpeak #ResearchSpeak Summary: This post sets the scene for revisiting the Bradford-Hill criteria around EBV being the cause of MS.
Are we any closer to proving EBV is the cause of MS? I have posted on this topic many times before, but one of the Bradford-Hill criteria we use for establishing causation is ‘Coherence with Biological Background and Previous Knowledge’. We now have at least nine classes of DMTs that have been shown to work in MS. Over the last few months, we have been making the case that they work via B-cells in particular memory B-cells. It may be a coincidence that the memory B cell is the main cell where EBV resides in a latent state. The challenge now is how to work this knowledge into what we know about the pathogenesis of MS and the other factors that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure, female sex and the genetic pathways identified from the whole genome association studies. We have so much to do and so little time. Regardless of this work, we need to start our proposed infectious mononucleosis and EBV vaccination studies sooner than later. Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS. The British Statistician, Sir Austin Bradford-Hill, has formulated more general and appropriate criteria of causation; the following are the Bradford-Hill criteria:
Bradford-Hill’s criteria have been modified to apply them to the problem of MS. I coauthored the following paper over 10 years ago. I think it is time to update it with new knowledge that has been acquired since then. The case now is more compelling than ever.
Are you prepared to pay for quality online MS-related content? #PoliticalSpeak Do you think quality web content including medical education should be free? I note that the European Charcot Foundation is moving towards a subscription model.
Is providing free content sustainable in the long term, i.e. does quality suffer?
I think free quality content is sustainable provided it becomes opensource and the wider community engage, join-in and provide their time/content free of charge (e.g. Wikipedia). What do you think?
Open-source content vs. Subscription-based content
Should we trust our patients to take their oral cladribine tablets or should we make them come to the hospital to observe them doing it? #ClinicSpeak
Summary: This post addresses the issue of adherence to oral cladribine tablets as prescribed. In addition, the post addresses some of the complexities of drug pricing.
The imminent UK launch of oral cladribine tablets (Mavenclad), at a list price of £2,047.24 per tablet, stimulated a debate amongst us at Barts-MS about whether, or not, we should trust our patients taking the tablets as prescribed or we should implement DOTS (directly observed treatment, short-course). One position is to trust our patients. Why? Firstly, if we allow them to collect their own prescriptions via a community pharmacy then the NHS does not have to pay VAT on the price (value-added tax). A DOTS programme will cost NHS England 20% more per tablet. Secondly, isn’t our relationship with our patients based on trust? If we don’t trust them to take their medication then we have failed as educators and as HCPs. The WHO DOTS programme was developed to solve the problem of poor long-term adherence to anti-TB drugs in resource-poor environments, which was selecting for drug-resistant TB strains. I, therefore, don’t think we can compare the treatment of MS with the treatment of TB.
What would happen if one of our patients drops and loses one of the tablets? I am sure Merck would be understanding and provide a replacement tablet. You need to remember that the manufacturing price of a cladribine tablet is unlikely to be very high and hence it would be relatively cheap for Merck to provide a replacement tablet or pack. The price of pharmaceuticals is really very complex and includes intangibles such as intellectual property, the cost of the preclinical R&D, the costs of the clinical development programme, regulatory, marketing, sales, life-cycle management and the whatever else Pharma does (including paying academics to sit on steering committees, participate in advisory boards, give talks, etc.).
Oral cladribine tablets have many advantages one of which is taking tablets, albeit for only 16-20 days over a 2 year period with the potential for the treatment effect to last years. Why would we then want patients to come to the hospital so that we can directly observe them taking their tablets? One person suggested that patients may be tempted to sell their tablets on eBay to the highest bidder? Do you think the prescribing of oral cladribine tablets will result in a secondary market? I suspect not in the UK, but I may yet be proved wrong. A potential solution to the latter is to use smart tablets, i.e. each tablet is labelled with a RIF (radio frequency identification) tag that is tracked by a wearable device, linked to your phone, to make sure each tablet is taken as prescribed. Or we can simply trust our patients. What do you think?
PML is not the only complication associated with natalizumab therapy. #NeuroSpeak #ClinicSpeak
Summary: Albeit rare, natalizumab is increasingly being associated with CNS lymphoma. This is probably due to reduced immune surveillance as a result of natalizumab blocking lymphocyte trafficking into the CNS.
Evolution designed the immune system to fight infections and to clear pre-malignant cells from the body before they cause a problem. To do this the immune system has developed surveillance systems that depends on trafficking of cells from the blood into the tissues. If you block trafficking of cells into the CNS (central nervous system) with drugs, such as natalizumab, then you increase the chances of developing malignancies in the target organ. It is therefore no surprise that we are beginning to see an increasing number of case reports of primary CNS lymphomas in pwMS on long-term natalizumab. This potential complication was predicted more than a decade ago by several insightful people in the field. Please be aware that to the best of my knowledge this complication is rare, but acts as a reminder to pwMS on natalizumab that you need to be vigilant of new symptoms that could herald CNS complications. PML is definitely not the only severe complication associated with natalizumab therapy.
Patients with primary central nervous system lymphoma (PCNSL) after treatment with natalizumab have been considered co-incidental. We report another case of PCNSL in a patient where the explosive onset suggests a causal link.
Natalizumab, a selective adhesion molecule inhibitor binding to α-4 subunit of integrin, has emerged to be an effective immuno-modulator especially in the treatment of relapsing-remitting Multiple Sclerosis and Crohn’s disease. Literature documenting the development of progressive multifocal leukoencephalopathy from its use is widely available. However, only handful of reports cites the development of a more concerning pathology, primary CNS lymphoma (PCNSL) from its administration, thereby triggering a debate on a possible causal association. Considering paucity of literature and the prognostic severity of PCNSL, we herein report its development in a young woman with Crohn’s disease that was previously administered Natalizumab. Additionally, we provide a comprehensive review of literature on cases of lymphoma development following Natalizumab use to re-emphasize the drug association with PCNSL, if at all.
Will I have enough hours in my day to curate the MS Tube map? #ClinicSpeak
Summary: A tentative start to curate the #ClinicSpeak posts into an MS self-management website.
I have been promising to launch a curation tool to help pwMS self-manage (self-Rx) their MS. It has been on my ToDo list for over 2-years. It comes up each year in my appraisal and gets moved to next year’s ToDo list. My next appraisal is in a few week’s time.
The idea is to curate all the #ClinicSpeak posts from the blog onto an easy to navigate website that can be read as you would a book and to hyperlink it to the MS Tube map with each stop on the line being linked to a particular web page or online resource. If I start now and do 2 or 3 links per day it will be completed within a few months (or years). Before proceeding can you please let me know your thoughts on this initiative? It is a very big project and I don’t want to spend months doing it unless it will be used. As the map builds the stops will turn blue indicating that the stop is now linked to a completed web page.
The impact of reducing social isolation cannot be under-estimated. It may prevent the need for assisted suicide. #ClinicSpeak
My wife was travelling back from a conference in Bath yesterday and she listened to the following programme about a man with PPMS who had made a decision to end his life at a clinic in Switzerland, I assume Dignitas. However, a fellow MSer decided to befriend him and try and help. As a result of her intervention, Colin went from being socially isolated to having a friend and being welcomed into her family. In short, he had someone who cared about him. As a result of their friendship, he has postponed suicide as an option to dealing with his life with primary progressive MS.
This is social capital at work. If you increase your social capital, i.e your network of friends and family, then your life becomes worthwhile.
It has recently come to my attention that our patients with MS who engage with our patient and public involvement initiatives (PPI) seem to be doing much better than those who don’t. Engagers are better informed, have improved quality of life and seem to have a renewed purpose. They get more out of meeting other people with MS and sharing experiences than they do out of the actual PPI activity. This could all be an association, i.e. the kind of pwMS who engage with PPI projects are self-selecting and will do better than those who don’t engage.
I hypothesise that it is causal, i.e. PPI is acting as a catalyst and is increasing their social capital and hence their outcomes. I am not sure if anyone has studied or documented this observation, but it would be great to have the evidence at hand.
In the first programme of this series, Hardeep is in his native Scotland to cook lunch for Inverness based friends Colin Campbell and Rona Tynan. Colin has lived with primary progressive multiple sclerosis since his 30s and at the age of 56 made the decision to end his life at a Swiss Clinic rather than face an unbearable, lonely decline. Hearing his plight, fellow MS patient Rona Tynan felt compelled to get in touch with him. The former London Met police officer has lived with MS for 12 years and she felt distressed that Colin wanted to end his life, especially when he was more able than her. In June this year, when Hardeep turned up at Rona’s door to make the pair of them a haggis curry, Colin still had an appointment for the Swiss Clinic in his diary.
Can the MS Society better communicate the plight of people with more advanced MS? #GuestSpeak
Some of you will have read Patrick’s older blog posts already. The following is his third post in a series about empowering people with more advanced MS to enable them to raise money for the MS Society.
On Sunday, 24 September I went to Battersea Park in London to take part in the MS society walk. I left the house at an 8:45, caught the train to Euston and arrived at the start just after 11. I had hoped to be there earlier. Getting to Battersea Park from Euston station by public transport is not easy.
It was a lovely sunny day The MS society walk started at the bandstand in Battersea Park. Maybe I’m not very good at finding things, I had to ask several people how to get there. By the time I arrived everyone else had started their walk. There was a Zumba session at the beginning which I missed and might have made the day more exciting. I only had myself to blame.
I had never been to Battersea Park before. It was full of people and their children enjoying the sunshine and fresh air. There were people running, walking or cycling on tricycles and bicycles. Many people were wearing smart and possibly expensive exercise outfits. I felt stunningly underdressed but I was on my mobility scooter.
By the time I arrived everyone had set off on their walk. Nonetheless, I was issued with a bright orange MS society T-shirt which I put on, given some water, emergency rations and a map for the 6K walk.
When I reached the end of the walk back at the bandstand I must admit I felt slightly depressed. I saw no signs of the ‘fantastic post-event celebration in Battersea Park’. There was a steel band playing when I arrived but no party atmosphere.
Over 600 people took part that day. I couldn’t help but feel that the wrong message was being given to the public. The message on the T-shirt said ‘let’s stop MS together’. I did not see any interaction between the MS society and the participants with the general public. I saw people finish the walk and leave the park on foot.
The public must assume everyone with MS can walk and does not suffer any physical disability. I asked one of the volunteers at an entrance to Battersea Park how many mobility scooters had they seen that day. They told me they had seen about five.
MS sufferers, their family and friends know how crippling this disease can be. It took me 46 minutes to walk 1 km at the beginning of September. The public at the Battersea Park did not see the real world of MS. I suspect many of the walkers were friends or family of people with MS who were unable to participate.
Why didn’t the society arrange walks of 500 m or 1 km for people like me who are unable to walk and have to use a Rollator? It’s not difficult at Battersea Park, plenty of smooth flat road to walk on. The general public would then see the real world of MS.
I think The MS society should consider arranging their next walk using the facilities provided by Parallel London in the Olympic Park. There are distances from 100 m to 10 K. I’m sure they could have their own tent there. It is completely accessible with good car parking and excellent public transport links. Westfield shopping centre is only a stone’s throw away with shops and plenty of places to eat.
I am Patrick Burke, I was diagnosed with RRMS in 1995 but I believe the symptoms started in 1972.The disease turned into SPMS in about 1999/2000. I took medical retirement in 2012 and set up the website Aid4Disabled in the same year. The website is the story of my MS since retirement and it also identifies a wide range of objects that are readily available and can improve quality of life. I am also a member of the Barts MS Advisory Group.
