Politics, campaigns and information – Page 8

Reinventing the wheel or the 4×4

We were rightly criticised last year for holding a meeting that highlighted the problem of variance in the provision of MS services, in the NHS. without a plan and vision about how to change things. I hope we have listened to you. The follow on meeting that we are hosting next month (8th-9th July) has a more ambitious agenda; it will even come with a 3-year action plan.

I have always made the argument that variance, when it comes to the provision of healthcare services, is a euphemism for inequality and that simply represents the haves and have-nots in society and the world. Why should someone with MS who lives in place B, or country Y, get a different service to someone with lives in place A or country X? On the other side of the coin, variability creates the engine for change; it is the catalyst for people to do something about the poor services they are providing or receiving; that is assuming they know about the quality of their service and are willing to do something about it.

My colleagues have told me that I shouldn’t beat myself up too much over the problems and criticisms of our first meeting; after all, it was very instructive in that it:

Brought us together as a wider MS community and allowed us to recognise and reflect on the challenges we face in addressing the variance in the NHS.
The meeting was inclusive in that there was no hierarchy in terms of the importance of the people who deliver MS services. We identified ourselves as equals, or partners, and included people with MS.
The meeting made us realise that we have cognitive biases that need to be addressed to make the community inclusive and more diverse. Diversity of ideas is going to be the catalyst for the next phase of our project.
We also realised that variance is not necessarily bad. We need some variance and ways to measure it so that the outliers at the upper end stimulate change. The next meeting is called ‘Raising the Bar’ and refers to improving services across the board.
The meeting also allowed us to get away from the NHS rat race and provided quality thinking time, i.e. time to reflect on the task at hand. This has allowed us to set priorities or specific work streams that will allow us to set key objectives for the programmes of work going forward.

As the chair of the committee, I have been asked to set out my vision for the initiative and define what success will look like for this initiative. To make it tangible I have defined targets at year 1, 2 and 3 and beyond.

YEAR 1

At the end of next year, I would expect all participating centres to actively engage in a national quality audit. This will include providing metrics on the NICE quality standards and several other new metrics that will allow us to assess how good or bad we are at achieving what we have set out to achieve.

My vision is 4×4, i.e. for 75% of patients with uncomplicated MS to be diagnosed within 4 weeks of the specialist MS team receiving a referral letter with a diagnosis of suggestive of MS and for 75% of pwMS, eligible for DMTs under the NHSE guidelines, to be have been offered, counselled and given a date for starting a DMT. Is this too much to expect? These time frames are compatible with our International Brain Health standards so why wouldn’t we aspire to meet them?

YEAR 2

At the end of year 2, all participating centres will have a patient partner programme in place to upskill pwMS on how to navigate their local MS services and how to self-monitor and self-manage their MS. This programme will be developed in partnership with patient organisations and will depend on local champions to make it happen. We are in an era in which knowledge has been democratised. Why shouldn’t people with MS participate in providing their own healthcare and contributing to their own healthcare?

YEAR 3

Participating centres will be working differently and managing MS holistically. This will include programmes to screen and manage comorbidities and to promote lifestyle interventions. Participating centres will collect data on these new activities as part of the annual national audit. As part of this holistic management of MS, there will be a ‘no patient left behind’ philosophy embedded in all MS services. This will require systems to make sure that all people with MS, who are covered by a particular service, will have access to that service. We don’t want vulnerable, less educated or less well off patients to be disadvantaged by the service.

LEADERSHIP

It was clear to us at last year’s meeting that for our vision to be realised we need a new generation of leaders to make things happen. We are therefore proposing putting in place a leadership training programme to equip people with the skills to make things happen. The leadership programme will be small and selective and will focus on doing, i.e. as part of the programme delegates will be expected to participate in and complete a national project. This will be run by Gabriele De Luca who is a shining example of what good leaders can do. Gabriele has experience from the AAN young leadership programme and is passionate about the field himself. It may be worthwhile coming to, and participating in, our meeting just to access the leadership training programme.

SHARING BEST PRACTICE

As always the wheel has usually been invented. Most ideas are not new, but how they have been tested and implemented may be new. We are proposing to use the Variance platform to share best practice. Why reinvent something if it already exists? We expect all centres to share their successes and failures so that others can learn from them. This will hopefully allow MS centres to share their materials and experiences with other centres so as to raise the bar for everyone and to create a collegiate atmosphere. The advantage the MS Academy has is that we already have the infrastructure to make sharing relatively easy.

So if you are reading this post and are attending this year’s meeting don’t be shy; please submit a poster to the meeting on something in your service that you are proud of, or even something you are not so proud of. We will select 3 or 4 posters for a platform presentation to allow wider discussion.

If you have not registered already please do so now there are a few remaining places.

Information asymmetry

Outside the field of medicine, for example in law and economics, information asymmetry deals with the study of decisions where one party has more or better information than the other. This asymmetry creates an imbalance of power in decision making and transactions, which can sometimes cause these decisions or transactions to go awry and cause a breakdown in trust or market failure as worst-case scenarios. Examples of this problem are (01) adverse selection, (2) moral hazard, and (3) monopolies of knowledge.

Information asymmetry extends to the field of medicine. For example, if a Pharma company has better information than regulators about serious adverse events of their newly licensed drug they may take covert actions to bypass new regulation. There are many examples of this and this undermines the effectiveness of regulation and the trust we have in the Pharmaceutical industry.

Another example of information asymmetry is what happens in the typical doctor-patient relationship. Doctors may have more information than their patients, which results in an imbalance of power in decision making. Unless the doctor takes steps to correct this information asymmetry as part of the consultation process this can have serious consequences if decisions go wrong or are even perceived to go wrong; the result is usually a breakdown in trust between the doctor and patient and can have other more unpleasant ramifications.

As a practising neurologist, I always try and correct any information asymmetry between myself and my patients, but this is not always possible given the time constraints placed on us within the NHS. Many other factors, in particular, cultural and language barriers, prevent you from correcting information asymmetry. It also plays both ways; in the modern era, patients often know more about their disease and are more up to date with the latest developments in their disease area, than their doctors. In this situation are the doctors prepared to take time to listen and learn?

One of the reasons for starting this blog was to correct information asymmetry and to create a platform for the dissemination of knowledge and how this knowledge impacts on clinical practice. I, therefore, read with interest a letter in this weeks BMJ from a retired GP and patient, which succinctly addresses the problem of information asymmetry. Do you agree with him? I am particularly impressed with his concluding sentence: “The big danger of a monopoly on knowledge is just that: the absence of mechanisms to challenge it.”

If you have any personal examples of how information asymmetry has affected the management of your MS please feel free to share them with us.

Can we create a platform/mechanism to allow people like Roger Weeks and yourselves to challenge this ‘monopoly of knowledge’?

Roger Weeks. A monopoly on knowledge is bad for patients. BMJ 2019;365:l2254

Patients and their doctors should be grateful to deBronkart for highlighting the lack of access to new information about illnesses. Clearly, the advice of Abigail Adams to her president and husband, John Adams, has been ignored not just in the US but worldwide. The unlimited power of academics with a monopoly on knowledge is unchanged. The delivery of such knowledge to patients (and their doctors) at their moment of need may well not be solved by the highly unlikely achievement of open access publishing (as raised in some of the rapid responses to the commentary). Information needs about diseases and their treatment are not well served by the current patient information leaflets universally found in medication packs because they relate only to the product and to conditions treatable by the product.

As a doctor, I see that comprehensive electronic information on conditions is needed. It should include all treatments and pathways, with drug and non-drug treatments (such as physical treatments including manipulation, operations, and mind and even alternative treatments), and be accessible to all on demand. These information resources need to be as global as possible to inform patients about new developments in treating their disorder and about selected drugs. The information should be based on reliable sources, including the National Institute for Health and Care Excellence, the NHS, summaries of product characteristics, patient leaflets, Food and Drug Administration labels, and selected research papers. I contribute to work on this.

As a patient with all the latest available information on my late onset eosinophilic asthma treatment, I find great difficulty in persuading specialists to provide me with a new biological agent (with a stated 60% benefit rate), even though I can demonstrate that all their reservations are based on pre-conceived ideas, not fact. The big danger of a monopoly on knowledge is just that: the absence of mechanisms to challenge it.

The Natalizumab #AttackMS Trial

We propose the very early use of natalizumab to maximise outcomes in people with very early relapsing MS.

In the European Union, natalizumab is licensed to treat adults with highly active relapsing-remitting multiple sclerosis for the following patient groups:

Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (DMT)

Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

The reason for this restrictive labelling is historical and relates to the undefined risk of developing PML prior to the implementation of JC virus serological testing to derisk PML. As a consequence of natalizumab’s restricted label, an increasingly small number of patients with MS are being treated with natalizumab.

Natalizumab’s attributes of being a very high efficacy agent, having a rapid onset of action, being relatively safe in the short-term (12 months) and having the ability to reverse its mode of action (washout or using plasma exchange) make it the ideal DMT to treat active MS acutely to prevent further damage.

There is emerging evidence that the earlier you treat MS the better the outcome. We have anecdotal evidence, from individual patients, that even short delays in starting DMTs may have consequences for individual patients with multiple sclerosis. In many parts of the world healthcare systems are not configured for the rapid diagnosis and treatment of multiple sclerosis, which results in many pwMS waiting months, and in some cases years, to be diagnosed and treated. We feel this laissez-faire approach to the management of MS is wrong and is counterintuitive to how we approach other neurological diseases in particular stroke where time matters.

We hypothesise that by treating people who are likely to have MS acutely with natalizumab we will improve outcomes, i.e. these patients will acquire less disability and may even have improved rates of disability improvement, compared to patients managed in a standard way.

We have therefore designed the #AttackMS Natalizumab trial to test these hypotheses and have approached Biogen to fund and/or sponsor this study.

The trial plans to recruit patients with clinically isolated syndromes, with an abnormal MRI (two or more lesions suggestive of demyelination), within 7 days of onset and to randomise them to being treated with natalizumab (300mg ivi 4 weekly) or placebo. Subjects will then be managed according to a protocol that will ensure they are diagnosed and considered for licensed treatments within an 8-week period. The latter has been chosen as it is within the timeframe set out by an international panel of MS experts as being an appropriate period of time for being diagnosed with MS and started on treatment (please note in most healthcare systems it takes longer than this). At 8 weeks, i.e. after their third infusion of natalizumab or placebo, subjects will be unblinded; those on natalizumab will then continue on natalizumab for another 10 infusions and those on placebo will be started on the DMT that their treating neurologist and themselves have chosen. Subjects will then be followed for a further 10 months.

The primary outcome will be an area-under-the-curve (AUC) analysis of serum neurofilament levels, a biomarker of neuroaxonal damage, performed on serial blood samples taken over the period of the study. Secondary outcome measures will include MRI, clinical and patient-related outcome measures (PROMS).

MRI metrics will include (1) new T2 lesions as a marker of focal inflammation, (2) single lesion MTR as a marker of remyelination, (3) T1 hypodensity as a marker of tissue damage. Clinical outcomes will focus on disease improvement using a composite of the EDSS, T25W, 9HPT, SDMT, and low-contrast visual acuity (LCVA). PROMS will include a fatigue scale and important symptom for pwMS that has been shown to be improved by natalizumab.

At the end of the 12 months of the study treating neurologists and participating subjects in the natalizumab arm will be informed about their JCV serostatus and a decision will be made to continue on natalizumab or switch to another DMT. Subjects will then be rolled over into an extension study to be followed for a further 12 to 24 months to collect long-term clinical and MRI outcomes. The latter is important to assess brain atrophy or brain volume loss.

What we are interested in hearing from you the MS community is this trial ethical and do you think the scientific principles underpinning it are sound?

If you work for Biogen and are reading this blog post and are wearing your commercial hat you will see this trial may be the vehicle you need to resuscitate natalizumab as a mainstream DMT and to convince the EMA to reconsider natalizumab role in the management of MS and grant it a first-line license it deserves; particularly for people who are JCV seronegative.

At Barts-MS we are so convinced that the #AttackMS treatment paradigm will improve MS outcomes for individuals with MS that we have started using it already in a few isolated patients with highly active MS. We want to take this paradigm to all our of our patients. Yes, all of our patients, because we want to maximise their outcomes.

From a political perspective, this trial may nudge the MS community to be more proactive about treating MS and cement the message that we have been promoting for several years that ‘Time is Brain’. Why should we value the MS brain any less than the stroke brain?

CoI: multiple

Why is everyone drinking anti-CD20 kool-aid?

Prof G will ocrelizumab and rituximab prevent SPMS?

Just back from the COMBAT-MS stakeholders meeting in Pasadena with the Kaiser (Kaiser Foundation Research Institute) and Swedish (Karolinska Institute) trial teams, PCORI (Patient-Centered Outcomes Research Institute) and many brave an wonderful people with MS and their families.

The COMBAT-MS study (NCT03193866) is recruiting well and is on schedule to deliver very important comparative data on the effectiveness of rituximab in real-life. The full title of the study is ‘COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient’s Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis’. In short, COMBAT-MS will be comparing Rituximab with Natalizumab, Fingolimod, Alemtuzumab, Interferon-beta, Glatiramer acetate and Dimethyl Fumarate. Because the use of alemtuzumab seems to be quite limited in Sweden, with the majority of patients going onto rituximab, the study will not have enough power to compare rituximab with alemtuzumab. This a great pity because the real question I have is how does anti-CD20 therapy compare to our top-guns, i.e. alemtuzumab and HSCT. This question is becoming a priority for me.

We had a comprehensive safety update from the COMBAT-MS trial team, which will be presented later this year. However, the safety profile of rituximab is broadly in keeping with what is seen in rheumatology, with a few interesting exceptions. However, the overall safety profile will help with the adoption of rituximab as a treatment of MS in resource-poor environments.

I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. Yes and no. It may be a secondary progressive disease, but the pathology driving smouldering MS (microglial activation, slowly expanding lesions, subpial cortical lesions, intrathecal immunoglobulin production, demyelination, mitochondrial toxicity and energy failure, oxidative damage, delayed axonal loss, synaptic pruning, premature ageing, etc.) are all present at the very earliest stages of the disease, even the asymptomatic stage of the disease, i.e. radiologically isolated syndromes. This is why I don’t think SPMS really exists and why MS is one and not two or three diseases.

The construct that MS has distinct phases, an early inflammatory and a delayed degenerative phase, is artificial and comes from the Pharma industry’s need to get interferon-beta licensed under the orphan drug act, i.e. MS had to have a prevalence of fewer than 200,000 affected people for the orphan drug act to apply. The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases, i.e. RRMS, SPMS and PPMS. Later on, a fourth category, CIS (clinically isolated syndrome) was added. However, CIS has largely disappeared as a category because of diagnostic creep and the earlier diagnosis of MS with the evolving definition of MS based on the newer versions of the McDonald criteria. Having looked hard I can find no scientific justification for making SPMS a different disease.

In my opinion, smouldering MS and the pathologies driving it do not seem to be anti-CD20 responsive. If they were then we would see a much better impact of anti-CD20 on brain volume loss, disease improvement and the slowly expanding lesion. What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS. Can I please urge you to re-read Stephen Hauser’s case report below. You may argue that one swallow doesn’t make a summer, but Stephen Hauser implied two year’s ago in a response to a question at ECTRIMS that anti-CD20 was not the panacea everyone wants it to be and that a lot of his long-term rituximab-treated patients were now secondary progressive, i.e. they had smouldering MS.

The concept of smouldering MS is a difficult one for people in the field to grasp. Why? It is because NEDA-3 has become de-facto what defines MS. We need to move beyond what we can see and measure and focus on end-organ markers of disease activity, i.e. whole brain and regional or grey matter volumes, the expanding MS lesions, neurofilament levels and more sensitive clinical outcomes. An EDSS view of the world is simply too narrow. We need to look at cognition, visual function and more sensitive functional tests of different neuronal systems. One of the attendees was horrified when I said that the best thing that could happen to the field is if we could automate the neurological examination using a validated technology platform. The idea of using a neurologist to assess eye movements and balance, when it can be done so much better with eye tracking systems and balance sensors, shocked this individual. Bring on the robots and maybe our worldview of MS, in particular, smouldering MS, would change.

I was also able to deliver good news about our WHO Essential Medicine List (EML) application that includes ocrelizumab as one of the three drugs and rituximab as a suitable replacement for ocrelizumab if access to ocrelizumab is a problem. If our EML application is successful this will allow us to pressurise governments to prioritise the treatment of MS in low prevalence countries. I explained to the group that what had started out for me as an ‘Essential Off-label DMT list’ in 2014, may become an official WHO-backed Essential DMT list in 2019. I am holding thumbs we get MS onto the EML, it needs to be there for many reasons.

I also covered in my talk alternative hypotheses, i.e. that MS may be due to a virus and that our current world-view of MS being an autoimmune disease driven by T and B-cells may be wrong. I briefly presented the B-cell-EBV hypothesis and our proposed EBV vaccination trial. I stressed that we need to use anti-CD20 as a tool to explore the EBV hypothesis and the good news is that Fredrik Piehl is going to explore EBV biomarkers as part of the COMBAT-MS study.

I used my lecture to represent my ‘marginal gains’ philosophy as it applies to treating MS and how we need to manage MS holistically and focus on the small things that may make a big difference to MS outcomes in the future. This is only the second time that I have presented this concept to my peer group, but it is something that still needs work to make it sticky.

The following are my slides from the meeting, which you can download from my slide sharing site.

I would like to thank PCORI and the Kaiser team for including me in this study and for your wonderful hospitality. I have little doubt that the COMBAT-MS study is going to help change the way the MS community treats MS globally. I would also like to thank the MSers who attended and spoke at the meeting; you are are the reason why we are doing what we do.

von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Ann Clin Transl Neurol. 2016 Dec 20;4(1):46-52.

A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.

CoI: multiple

Yin and Yang

What is your worldview of MS?

Back in 1982 when I was in 1st-year medical school I had the good fortune of being taught by Professor David Hammond-Tooke, an eccentric social anthropologist, whose task was to make us view the world from different cultural perspectives. I was living in apartheid South Africa and Wits, a liberal English speaking University, wanted its medical graduates prepared for work in a multiethnic world.

Professor Hammond-Tooke was a ‘Worldview Expert’, who had studied the role of traditional healers in Africa. He made it clear in his first lecture that the shaman, witchdoctor, sangoma or traditional healer was a very important part of African culture and African people’s lives, and that we should have nothing but respect for them and the role they play in sickness and in health.

We were taught that the traditional healer had evolved to address the psychological and physical needs of the individual, the community and society at large. Although Hammond-Tooke implied that the methods of the traditional healer were ‘non-scientific’ it was obvious when we met them and were exposed to their practices, later on in our medical training, that they practised their art using tried and tested methods, passed down from generation to generation. To be honest it wasn’t until about 70 years ago with the emergence of the ‘scientific method’ and more recently ‘evidence-based medicine’ that ‘Western doctors’ were nothing more than traditional healers, practising anecdotal medicine that today would surely be labelled as being alternative. Blood letting is the first example that springs to mind. The worldview of my predecessors was not how I view medicine and neurology today. The biological knowledge as it applied to medical practice today was very rudimentary 70+ years ago.

The traditional healers role was to help the individual and it citizens make sense of the predicaments they found themselves in. These predicaments weren’t always disease or sickness, but often personal or family misfortune. One of the qualities of being human is to seek out explanations for the unknown. Have we changed because of modern medicine? Obviously, not! Individuals still seek out answers and explanations based on their own worldviews and modern doctors need to understand that there are alternative worldviews of MS, in comparison to their own, and these worldviews can be fluid and change over time. Failure to identify with alternative worldviews may have consequences at several levels for people with MS and society at large. Recent examples are the CCSVI epidemic, alternative natural or lifestyle therapies and the role and place of HSCT in the early treatment of MS.

Another change that has occurred with the development of the internet and the web has been a democratisation of knowledge. Gone are the days when the doctor knew it all and was the only person who could make decisions. Patients and other healthcare professionals have skilled-up and know a lot about MS; in some situations patients may even know more about MS than their neurologists. This is very challenging for some neurologists who have a more traditional Western medical worldview of neurology and its practice. In other words the neurologist is now not always best placed to make decisions about their patients. The new art of medicine is to know when you are needed to make decisions or when you are only needed as a guide to help your patients make their own decisions.

This is all well and good, but what happens when there is a clash of cultures or clash of worldviews. What do we do then? How do we reconcile widely differing worldviews of a similar problem? For example, one neurologist may think his/her patient has active MS, but an overall a good prognostic profile, and they may want to start them on a moderately effective platform therapy. In comparison, the patient who is an avid researcher and a voracious reader is adamant they want HSCT. What do you do? Do you say no, knowing that that patient will find a way to be treated with HSCT at great cost and personal sacrifice abroad? Or another neurologist may want to start a patient on a highly-effective treatment because the patient’s MS is highly active with early disability and evidence of end-organ damage. However, this patient does not agree with the neurologist’s assessment of things and wants to try an alternative lifestyle approach to manage their MS. This patient is also very knowledgeable, having read widely and sort outside opinions, and has come to the opposite conclusion of the first patient in that they think these DMTs are simply too dangerous and will interfere fundamentally with their immune systems that will have unpredictable consequences and will put them at risk of developing other iatrogenic problems (problems caused by the treatment). This second patient is more accepting of the potential outcome of their MS and is prepared to become disabled if that is what is destined to happen (yes, there are pwMS who are prepared to become disabled). What is more important to these people is how they live their life and how they treat their body.

How we reconcile these extreme and disparate worldviews is difficult. One way is a negotiated settlement with compromises. For example, I will put your case forward to the multidisciplinary HSCT team and see what they say. If they refuse to accept you onto the HSCT programme because you are not eligible we could challenge their eligibility criteria or ask them to make an exception. The other option is to try one of the other high-efficacy DMTs in the interim whilst we try and get the HSCT eligibility criteria changed. We will need to ask the MS Society and other important stakeholders to help. For the second scenario, one could try the complementary medicine approach rather than the alternative medical approach. Or you may negotiate to review the disease activity after a period of time to see if the alternative approach is working. Time, patience and a negotiated position can build trust. Showing you care and are non-judgemental helps. The other is to provide cases studies of other patients who have done well and others who have not done so well with alternative therapies. It is important not to turn the advice you are giving into ‘project fear’. Explaining that MS is an unpredictable disease and that it needs personalised treatments may help. The important point is not to stop caring and to treat the patient as if they are just another one of your patients on a specific MS treatment and ask the same questions. Be it a negotiated compromise or an unchanged treatment strategy you need to be there if the patient needs help in the future. I have seen too many pwMS, who decide to go the alternative treatment route, who are discharged without regular follow-up, who are then referred back years later very disabled. In comparison, I have had many patients who change their minds when they see how MS is affecting them and are prepared to complement their lifestyle management programmes with licensed therapies. Providing these patients with a safe and caring environment to allow them to change and adapt their worldview is what is important.

As I am writing this post I am re-learning the lessons taught to me by Professor Hammond-Tooke. To understand and be accomodating of different worldviews.

To get a handle on the many different worldviews that permeate the MS space would you be prepared to share yours? We need to know who you are and to get four statements, or adjectives, that sum-up your worldview of MS? I will then put these together in the form of an online slideshow to illustrate how diverse, or similar, we are. To participate you also need a descriptor to let us know where you are coming from.

I have put together a few examples, which will hopefully stimulate you to add to the collection. Please don’t be shy you may have many different perspectives and are welcome to add additional perspectives. As the slide show grows so will our understanding of each.

Thank you.

A call to arms – the need for a citizens jury on HSCT

A few weeks ago I did a post on using a Citizens Jury, as a potential way to deal with the emotive issue of a lack of access to HSCT as a potential 1st-line treatment for active MS in the UK.

A Citizens Jury can help sort out the disconnect between the needs or implied needs, of the MS community, and the position of the NHS and/or the HCPs in relation to HSCT. A Citizens’ jury is when a group of people from the general public (not people with MS or vested interests) decide policy on behalf of pwMS and HCPs; in other words, citizens decide if the NHS and/or HCPs are right to withhold an effective treatment from pwMS based on its costs and/or safety profile. At the moment most HCPs feel HSCT is too risky to be a mainstream treatment for MS, whereas a large and increasing number of pwMS don’t.

The following is the results of our survey. I hope the MS Society, NHS England, ABN (Association of British Neurologists) and other stakeholders reflect on these results and consider putting together a Citizens Jury to deal with this thorny issue.

Playing second fiddle to the Swedes

Why can’t we use anti-CD20 therapies as immune constitution therapies?

For some years we have been promoting our Barts-MS Essential DMT list to treat people with MS (pwMS) in resource-poor environments. One of the big guns on our list has been rituximab (anti-CD20). One of the problems is that rituximab at a dose of 1g every 6 months is still too expensive to accessible for the vast majority of MSers living in these environments. The good news is that several developments have brought the price of rituximab down.

The Swedes, who are treating more than half their MS population, have data showing that 500mg every 6 months is as good as 1g every 6 months in terms of NEDA, i.e. preventing new relapses and new MR lesions from forming.
Rituximab has come off patent and several cheap biosimilars are now entering the market.
The Swedes are also testing adaptive dosing, i.e. after 2 years of 6 monthly infusions, they are extending the interval between doses to 12 months or more and/or are even beginning to redose rituximab based on peripheral memory B-cell reconstitution. At a recent meeting, I was at one Swedish neurologist is beginning to use rituximab as an IRT (immune reconstitution therapy), i.e. only redosing with rituximab if and when disease activity re-emerges.

I classify anti-CD20 therapies as both a maintenance therapy and an IRT. At the last AAN in Los Angeles, I attended a meeting of like-minded clinical scientists to set-up a trial to test anti-CD20 as a maintenance therapy vs. an IRT. The retreatment arms of the trial were to test redosing based on the reemergence of disease activity or the repopulation of memory B cells. Using anti-CD20 therapies as an IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and ability to respond to vaccines.

I am therefore very interested in seeing the results of the Swedish experiment of testing rituximab as a maintenance therapy vs. rituximab as an IRT. Just maybe we can get the price of treating MS with rituximab down to affordable levels for low-income countries.

The following is a back of envelope calculations based on the current BNF prices:

Mabthera (Roche) 500mg = £873.15 per 500mg vial
Rixathon (Sandoz) = £785.84 per 500mg vial
Truxima (Napp) = £785.84 per 500mg vial

Standard dose (1g) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £8731.50 for the first 2 years and then £3492.60 annually.
Standard dose (1g) biosimilar maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £785.84 x 5 = £7858.40 for the first 2 years and then £3143.36 annually.
Reduced dose (500mg) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £4365.75 for the first 2 years and then £1746.30 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 1g Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Adaptive dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly for 2year and then 500mg approximately every 12 months = £785.84 x 5 = £3929.20 for the first 2 years and then £785.84 annually (the latter may be lower if redosing is done using peripheral B cell reconstitution).

Please note these figures are the list price and don’t include discounts, VAT nor the infusion costs. In reality, these costs could come down with central, say NHS, purchasing power. Unfortunately, they are still too high to help pwMS in low-income countries. Just maybe getting MS and anti-CD20 therapies onto the WHO Essential Medicines List may bring down the costs by creating political pressure on the Pharma industry or innovations in making cheap biosimilars may also help.

The Caveat

There is one major caveat I have about putting up anti-CD20 as the solution for MS is that we may be getting it wrong. I personally don’t think relapses and focal MRI activity are the disease we call MS; these markers are an inflammatory response to what is causing the disease. Therefore I suspect we may be lulling ourselves into a false sense of security with anti-CD20 therapies and ignoring what is really driving the disease, i.e. what is causing the end-organ damage in MS.

Do we know what is driving the slowly expanding lesion? What is causing the extensive cortical lesions in MS, which we can’t see on conventional MRI? What is driving the progressive brain volume and grey matter loss in MS? Don’t we need to go beyond NEDA as a treatment target? I know some would argue we have done this already, which is why so many MSers want HSCT as a first-line treatment option.

Skint Britain

Did anyone watch ‘Skint Britain: friends without benefits’ on Channel 4 in the week?

‘Skint Britain: friends without benefits’ looks at the rollout and impact of the new Universal Credit scheme for British people who are unemployed or unable to work. The ‘big idea’ behind universal credit is to incentivise people who are unemployed to work or at least to be shown to be actively seeking work in order to ‘earn their benefits’. The scheme makes some basic assumptions that the people need to be literate and be able to use a web or smartphone based database to log their job seeking activities. One of the young men on the programme clearly had behavioural issues at school and was excluded from education; the result is a 21-year-old man who is unable to read and write. He has been let down by the system and the very same system is now excluding him yet again. He seemed to like animals and was using his pet dog to help him forage and catch wild moles, squirrels and rabbits, to feed himself and his girlfriend. What type of society are we living in that in 2019 we are forcing some of our citizens to forage for food? Not to mention the increasing use of food banks to survive.

Economists glibly refer to Britain as being post-industrial and in the throes of the 3rd industrial revolution, a euphemism for automation and un- or under-employment, without considering what we are doing to society. We are now a society of haves and have-nots; a society that is more divided than ever. The have-nots, who are touchingly, albeit tragically, portrayed in this Channel 4 documentary have little hope of getting out of the economic trap society has created for them.

On a personal note, I am seeing the impact of Britain’s new social policies on patients in my care. As you are aware most of my patients with MS are unemployed. As a result, a large proportion of my patients are on benefits and depend on these to survive and participate in society. A typical example is Susan, a patient of mine with MS, who I saw in clinic last week. Susan has secondary progressive MS and lives alone in a small flat in an East London tower block. Susan’s benefits were cut last year and as a result she is finding it increasingly difficult to come out each month on her meagre allowance. The person who reassessed Susan for her benefits is expecting Susan to look for and find work. Susan is semi-skilled and has an EDSS of 6.5 and is probably 12-24 months off needing a wheelchair. Any thinking, compassionate, person should know that Susan is not going be able to find and do any meaningful work; not at this stage of her MS.

Before her benefits were cut Susan was able to afford to travel and visit her daughter and two grandchildren in the Midlands every month. This visit was Susan’s highlight of the month. Susan can’t afford the train fare anymore. Susan rarely goes out anymore and is becoming increasingly isolated. Not surprisingly Susan is depressed. Simply asking Susan about her typical day was enough to reduce her to tears. Susan is also being let down by the system. What Susan needs are meaningful connections and interactions; friends and family to make her feel loved and wanted. Should the neurologist’s job extend into the social domain of their patients? I would argue yes. If we are to adopt a treatment target that maximises the lifelong brain health of our patients we can’t ignore the social determinants of health, which have a massive impact of outcomes.

To help people like Susan and our other patients we are exploring several initiatives this year to try and increase the social capital of our patients. We are not sure what our social capital programme will look like, but is quite clear that we can’t simply manage the medical side of MS and ignore the social consequences of living with this disease in modern Britain.

HSCT Citizens’ Jury

Prof G, why do you talk with a forked tongue?

I am taking stick from many readers about my stance on HSCT. I implied in a comment yesterday that I would seriously consider it as a first-line treatment if I had MS, but in reality, I don’t offer or support HSCT for my own patients with MS as first-line therapy. Some readers are accusing me of double-standards. Should I walk the talk and put my head above the parapet or keep quiet? I have a potential solution; read on …..

The issues around HSCT are complex. HSCT is not a mainstream treatment for MS but will become so when more evidence emerges about its relative efficacy and safety when compared to other licensed DMTs. To address this question we will hopefully be starting a head-2-head trial of alemtuzumab vs. non-myeloablative HSCT in the near future.

At the moment HSCT is available to pwMS under the NHS, but not as first-line therapy. Why? It positioning as a 2nd- or 3rd-line therapy was made by consensus, albeit an HCP consensus, and the current opinion is to limit NHS access to HSCT to pwMS who have failed at least one high-efficacy DMT. I personally don’t agree with this. Provided pwMS are well informed and understands the risks of HSCT and are prepared to take the risks they should be able to have HSCT. There is no doubt that it will be cost-effective; as a one-off treatment, HSCT costs between £28,000 and £30,000. When you compare this to the annual and cumulative costs of some of the other DMTs HSCT becomes very appealing. The downside as always are the risks, and some would argue the risks are too great. Who should be taking the risks; the person with the disease or the HCP? I know where my allegiances lie.

When you have a disconnect between the needs, or implied needs, of the MS community, and the position of the NHS and/or the HCPs there is a potential solution for this problem called a Citizens’ jury. This is when a group of people from the general public (not people with MS or vested interests) decide policy on behalf of pwMS and HCPs; in other words, citizens decide if the NHS and/or HCPs are right to withhold an effective treatment from pwMS based on its costs and/or safety profile. At the moment most CPs feel HSCT is too risky to be a mainstream treatment for MS.

What I am proposing is that we set up a Citizens’ jury that looks into the question of whether or not HSCT should be available for pwMS, who have active MS, as a first-, second- or third-line therapy. If the jury says ‘yes’ then the NHS should create the necessary capacity to deal with the needs of the MS community. I think the NHS may support the results of a Citizens’ jury as it is win-win for them. Firstly, they will be viewed as being proactive in supporting MSers wishes and if they have to make HSCT widely available as a treatment for MS it will save the NHS money; potentially lots of money. From a person with MS’ perspective it will also be a win-win; i.e. (1) they will have the option of being treated with potentially the most effective DMT under the NHS and (2) they won’t have to cover the private expenses of having to travel abroad to have HSCT. Accessing HSCT under the NHS will also make it more equitable. What about the HCP or neurologist? Is it a win-win for them? Or a lose-lose for them?

Interestingly there was a very well written opinion piece in last week’s BMJ on the use of Citizens’ juries. It is worth a read.

Jacqui Wise. Citizens’ juries for health policy. BMJ 2017;357:j2650

…. What is a citizens’ jury?

….. Citizens’ juries (or community juries or citizens’ assemblies) aim to give ordinary people a role in democratic decision making. They usually consist of 12-20 randomly selected and demographically representative people, but some have had as many as 100. They explore difficult policy questions for government, charities, or think tanks. They differ from focus groups in that participants should be given reliable information and time to deliberate.

…. Malcolm Oswald, director of the Citizens’ Juries community interest company, a social enterprise supported by the University of Manchester, says, “Citizens deliberate among themselves, and, as they become better informed over several days, their views often change.”

…. They are particularly helpful for considering controversial and value-laden questions. For example, the Irish parliament formed a 99 member jury to advise elected representatives on ethical and political dilemmas including abortion, climate change, and provision for an ageing population.

…. What are their strengths?

Citizens’ juries involve the public in decision making, providing diverse experiences and perspectives, and the process can be thorough.

What do you think? Should we lobby the NHS to have a citizens’ jury on the issue of HSCT as 1st-line treatment for MS?

Supporting the NHS & social medicine

Why don’t you support private prescribing and HSCT abroad?

The social media response to yesterday’s Barts-MS Hangout on HSCT has been rather mixed. A lot of commentators are being critical of us for creating too many hurdles regarding the access to HSCT and that we shouldn’t stop our patients going abroad for treatment. From my perspective, going abroad or to private units in the UK for HSCT is private healthcare at its worst. The countries who offer private HSCT, on a fee-for-service basis, are some of the countries with the largest health inequities in the world. These private HSCT units are in it for the money and hence are not that selective in whom they will treat. Can you pay? If you say yes, then you can be treated next week, but only after you put down a large deposit.

The founding principles of the NHS and other socialist healthcare systems are that healthcare is a basic human right, therefore it should be free at the point of access and it must be equitable. Private HSCT, private prescribing and even off-label prescribing undermine these principles and this worries me a lot. This is why I can’t and won’t openly support my patients travelling abroad for HSCT; you need to understand that when it comes to access to healthcare I am card-carrying socialist.

We at Barts-MS have been pushing our Essential Off-Label list to improve access to treatments in resource-poor environments. The problem with this is that adoption of off-label prescribing is patchy at best and creates pockets of prescribing in a desert of limited access. The latter creates massive variances in prescribing and inequity. This is why we decided a few years ago to hand the baton of promoting an Essential DMT List, including HSCT, which is on our list, to the MSIF (Multiple Sclerosis International Federation).

The MSIF is an umbrella organisation representing all of the MS Charities from across the world and is therefore in the best position to endorse and promote an Essential DMT list. The MSIF made the strategic decision to go via the WHO Essential Medicines List (WHO-EML). Over the last 2 years, we have actively been working on this and I have had the privilege of co-chairing the MSIF WHO-EML Taskforce with Professor Brenda Banwell. We managed to get an international consensus on three DMTs (glatiramer acetate, fingolimod and ocrelizumab) to be considered for the WHO-EML. Please note HSCT did not make the shortlist mainly because we are trying to address the unmet need in resource-poor countries. Our application is now online and we hope the wider MS community get behind our application. Our application is more than about these three DMTs, it is a political campaign to get the WHO and the world to realise that MS is a problem across the globe; MS is not just a rich world disease. For example, did you know that there are more people with MS in India than there are in the UK?

So to our critics out there, we at Barts-MS have a wider responsibility to the MS community and to support the NHS and the pwMS living in the UK by trying as best we can to uphold the founding principles of the NHS.