Author: Gavin Giovannoni

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

1st-line HSCT

If push came to shove would you really choose HSCT as a first-line treatment to treat your MS?

When asked on the blog yesterday which DMT would I choose if I had MS, I chose HSCT. One of my patients, who I have been looking after for over a decade, sent me an email stating how upset she was that I had never offered her HSCT. I clearly need to explain my position so as not to upset anyone else.

Firstly, HSCT is not on offer as a routine NHS therapy. At the moment HSCT is only considered as a 2nd or 3rd-line treatment in the most active patients. Another problem is that it is not on offer across the country. There are only a handful of MS centres that are prepared to refer their patients for HSCT. This means that access to HSCT is not equitable and explains why an increasing number of patients are having to travel abroad, at great personal cost, to receive this therapy. Inequity of care is against one of the founding principles of the NHS and is unacceptable.

The block in access to HSCT seems to be at the level of the neurologist/MSologist. NHS England guidelines for bone marrow transplant (BMT) units allows them to use up to 15% of their procedures to treat autoimmune conditions, which includes multiple sclerosis. As BMT units exist across the country access to these units would simply require a referral from a neurologist to the unit to perform HSCT on patients with MS. However, the latter is unlikely to happen unless the local MSologist champions HSCT as a procedure and gets their local haematology unit on board. It always takes a local champion to make things happen and our Barts-MS champion is Dr Ben Turner.

Another factor that has changed in the last 10 years is the strength of the evidence-base showing how effective HSCT really is as a treatment for MS. The most recent MIST trial, the first large randomised controlled trial, and several meta-analyses of HSCT, which have been extensively discussed on this blog, have confirmed that HSCT is a very effective therapy. At the same time the risks associated with HSCT have improved and the mortality in most BMT units is now below 1% for MS.  This is now tipping the scales in favour of HSCT becoming a mainstream treatment for MS. There is however resistance from the MS community about HSCT been offered as a first-line therapy. Why? I suspect because the risk:benefit profile of HSCT has yet to be compared in a head-2-head study against our most effective licensed treatment. This why we are planning to do a head-2-head study of alemtuzumab vs. HSCT in the hope of generating this evidence. We know already that HSCT will be more cost-effective than alemtuzumab, but will it be more effective and as safe? Don’t try and second guess the results of this trial; I would not be surprised if there is no difference between these two treatments in terms of efficacy.

Please remember that most of the proponents of HSCT as a treatment for MS recognise that the major benefits from treatment will only be derived if HSCT is used early in the course of the disease. This explains why most BMT units don’t offer HSCT to pwMS with more advanced, or progressive, MS.  However, this does not stop private, fee-for-service, units offering HSCT to all-comers. If you have the money and are willing to travel abroad you will be able to find a BMT unit that will treat you. I think this is wrong and will not happen in the NHS when HSCT eventually becomes widely available. We have to be honest with our patients about the risks and the benefits and why we will limit HSCT to those who benefit the most. In fact there is evidence that more advanced patients may actually be made worse by HSCT; the chemotherapy used to ablate the immune system is neurotoxic and may speed up neuronal loss. In addition, infections are common when you have HSCT and infections are well known to worsen MS disability in more advanced disease.

Please be aware that HSCT is not for the faint-hearted. It is a risky therapy with serious adverse events and quite a high mortality. Even a mortality rate of 0.3-0.5% is high when compared to other licensed DMTs. Should this stop us from offering HSCT first-line? I think not. If we are prepared to offer alemtuzumab, with its risk profile as a first-line treatment, why not HSCT? Most pwMS would agree that the decision regarding what is an acceptable risk to take should be taken by the patient and their families, and not the neurologist or other HCP. There is data showing that neurologists are much more risk-averse than pwMS. Neurologists need to acknowledge this bias, which is likely to be an unconscious bias, and let their patients make the decision.

What I am really trying to do by stating that if I had MS I would choose HSCT as my treatment is to reframe the DMT debate, particularly in relation to access to highly effective DMTs. By focusing on HSCT as a first-line treatment it should at least consider what your treatment objectives are in MS.

Framing is another a cognitive bias that was identified by Daniel Kahneman, the Nobel laureate, and his partner Amos Tversky. By moving the frame to the right, i.e to include HSCT as a 1st-line therapy, it makes it more likely for pwMS and their neurologists to choose more effective treatments. We now know that people who start on a low to moderate efficacy DMT do worse on average than those who start on a high or very high efficacy therapies do better. Despite this the majority of pwMS are not told this and are started on a low efficacy or platform DMTs without ever being given the option of a high efficacy DMT. Why? It is not due to lack of access to treatments as we now have several NICE and NHS England approved high efficacy DMTs available as first-line treatments.

So yes, if I had active MS I would want to have the full spectrum of high-efficacy DMTs available to choose from including HSCT. I would want to know about their relative efficacy and what the aim of the treatments are. I would certainly want to have a discussion about the possibility of a potential cure. Wouldn’t you?

By framing the spectrum of efficacy by having HSCT within the frame may nudge patients and their neurologists to move up the treatment ladder and choose a high efficacy DMT.

Unfortunately, HSCT as a first-line option is not going to happen any time soon, which is why I am trying to nudge the community to start debating the issue in earnest and why I want us to have a citizens jury on the issue.

Calling all vegans

As a vegan what supplements do I need to take?

I am in the process of researching the dietary landscape for people with MS and will not be ready to make any firm recommendations for some time, but I can make a recommendation of what diets to avoid. The first is a strict vegan diet without supplements.

My index patient was an Asian woman, in her mid-20s, with RRMS who referred for a second opinion about worsening MS symptoms and escalation therapy. She was on glatiramer acetate and was complaining of progressive visual disturbance and painful pins and needles in her hands and feet. When I saw her there was little doubt she had RRMS, but it was clear to me she had superimposed vitamin B12 deficiency as well. She had bilateral visual failure (6/60 vision) with large central blind spots and when I looked into the back of her eyes her optic nerve was very pale indicating she had lost a lot of nerve fibres in the eyes (optic atrophy). The clue to the diagnosis was that she was pale and had a smooth red tongue (atrophic glossitis) and she had lost sensation in her feet and her tendon reflexes were depressed (neuropathy). Other problems included excessive fatigue, shortness of breath with minimal exertion, memory loss, poor concentration and attention, irregular periods and patchy hair loss. When I asked her about her diet she volunteered to be a vegetarian for most of her life and had become a strict vegan in the last 5 years.  Apart from the intermittent use of iron supplements for anaemia, she was not taking any supplements. When I checked her blood results she had very low vB12 levels and mild anaemia with a mixed pattern due to a combination of being iron and vB12 deficient. Tragically this patient’s visual function did not recover on vB12 supplements and her peripheral neuropathy became very painful presumably as the nerve fibres started to recover in her feet they started to fire aberrantly causing pain. She is now registered legally blind; a tragedy as her visual loss was preventable.

In addition, to this patient in my 5-years of doing the physician’s clinic at Moorfields eye hospital under Professor W. Ian McDonald’s mentorship, I must have diagnosed subacute combined degeneration of the spinal cord due to dietary vB12 deficiency in at least 5 other patients who were vegans. I have also seen a remarkable case of a lady, who was a vegan, who presented with pins and needles around the mouth and a numb tongue. She was not vB12 deficient as she was taking vB12 supplements, but when I did her peripheral metabolic profile she was profoundly zinc deficient and also had low levels of selenium. Within a week of going onto zinc and selenium supplements, her symptoms resolved.

From an evolutionary medicine, perspective veganism is not natural. We evolved as omnivores, i.e. vegetable and meat eaters; our metabolism tells us this and hence a strict vegan diet is unnatural and unbalanced. If you are vegan you need to make sure you supplement your diet with the following essential nutrients and minerals:

  1. Vitamin B12
  2. Iron
  3. Zinc
  4. Iodine
  5. Calcium
  6. Essential fatty acids, in particular, omega-3 fatty acids

The following may need supplementing:

  1. Vitamin D (you can get sufficient from sunlight exposure at the correct time of the year). At Barts-MS we recommend that all our patients and first- and second-degree relatives take vD supplements according to the vD Council’s recommendations.
  2. Selenium (you can get sufficient selenium from some vegan food sources, e.g. brazil nuts, mushrooms, sunflower seeds and beans)
  3. Protein (adults can get enough protein from a vegan diet, but children and people in a catabolic state, for example with certain diseases, may need additional protein sources)

If you have children on a vegan diet you should be careful about making sure they get enough protein and the above supplements. If not they may become stunted.

The bottom line; strict veganism is not natural in health and/or disease and is deficient in several key nutrients and minerals that need to be supplemented. This is a problem for people who are on the breadline; supplements are relatively expensive and hence vegan diets put poorer people at greater risk of the health consequences of an inadequate diet.

Please note that vB12 is essential for myelin metabolism and is the reason why when you are vB12 deficient you get a mixed demyelinating and axonal nerve loss picture in the optic nerves, spinal cord and peripheral nerves. There is a body of literature showing that pwMS tend to have low vB12 levels and this may be an indication of them needing more vB12 that the average person as it is consumed as part of myelin turnover. I therefore suspect that pwMS are even more senstive to vegan diets than people without MS.

Baroni et al. Vegan Nutrition for Mothers and Children: Practical Tools for Healthcare Providers. Nutrients. 2019 Jan; 11(1): 5.

As the number of subjects choosing vegan diets increases, healthcare providers must be prepared to give the best advice to vegan patients during all stages of life. A completely plant-based diet is suitable during pregnancy, lactation, infancy, and childhood, provided that it is well-planned. Balanced vegan diets meet energy requirements on a wide variety of plant foods and pay attention to some nutrients that may be critical, such as protein, fibre, omega-3 fatty acids, iron, zinc, iodine, calcium, vitamin D, and vitamin B12. This paper contains recommendations made by a panel of experts from the Scientific Society for Vegetarian Nutrition (SSNV) after examining the available literature concerning vegan diets during pregnancy, breastfeeding, infancy, and childhood. All healthcare professionals should follow an approach based on the available evidence in regard to the issue of vegan diets, as failing to do so may compromise the nutritional status of vegan patients in these delicate periods of life.

COMBAT-MS: have your say

What are the most important outstanding research questions for people with MS?

Depending on how long you have been following this blog you may or may not be aware of the COMBAT-MS study. This is a study that is funded by the US government as part of  the Patient-Centered Outcomes Research Institute (PCORI).

COMBAT-MS is a US-Swedish initiative for a hybrid study between a traditional retrospective cohort and a structured prospective cohort study. COMBAT-MS (clinicaltrials.gov NCT03193866) aims to recruit up to 3,700 MS patients at all of Sweden´s seven university clinics (serving about 50% of the total population) who are starting their first MS therapy or switching therapies. By doing the same structured follow-up with annual disability scorings, MRIs and patient-reported QoL outcomes the COMBAT-MS study will generate high quality, real-world long-term efficacy outcomes. This will help the MS community sort out which drugs work or don’t work in a real-world setting. To address safety concerns, COMBAT-MS will obtain data from Swedish national healthcare registries, as well as from Kaiser Permanente Southern California. By combining these resources, COMBAT-MS will be able to address major risks, such as cancer, as well as transient treatable concerns like recurring bladder infections and bothersome skin rashes. So, which of the approved MS drugs will be the winner?

I will be attending the annual COMBAT-MS stakeholder meeting for an update this week and have been asked to give a talk on ‘Identifying and addressing research questions of high importance to patients’. I could simply use the MS Society’s James Lind Alliance Top 10 list (below) or ask you the Barts-MS Blog readers to add to, or critique, this list for my talk this Thursday. Please note that this list below was published in 2013 and what was a priority then may not be a priority today.

  1. Which treatments are effective to slow, stop or reverse the accumulation of disability associated with MS?
  2. How can MS be prevented?
  3. Which treatments are effective for fatigue in people with MS?
  4. How can people with MS be best supported to self-manage their condition?
  5. Does early treatment with aggressive disease modifying drugs improve the prognosis for people with MS?
  6. Is Vitamin D supplementation an effective disease modifying treatment for MS?
  7. Which treatments are effective to improve mobility for people with MS?
  8. Which treatments are effective to improve cognition in people with MS?
  9. Which treatments are effective for pain in people with MS?
  10. Is physiotherapy effective in reducing disability in people with MS?

The following is this week’s programme; any comments to help me prepare my talk would be much appreciated. I was invited onto this trial as a stakeholder because I am considered a patient advocate and for my role in formulating and promoting an ‘Essential Off-label DMT‘ list. To fulfil my role as a patient advocate I need your help. Thank you.


Katerina Akassoglou

Did you enjoy ACTRIMS?

On Thursday evening I had the privilege of being at the Barancik Prize award ceremony and lecture. Katerina Akassoglou received the award for her work on the blood-brain barrier and fibrin as a pro-inflammatory agent of the innate immune system. Her lecture was a tour de force on what a single individual with dedication and focus can achieve. Well done.

I was particularly impressed that Katerina’s group is now translating this work into the clinic and is developing a class of drugs that recognises and blocks a cryptic or hidden binding site on fibrin. Why is this important? When the blood-brain-barrier gets disrupted and fibrinogen, a clotting protein, leaks into the brain and spinal cord and gets is converted into fibrin. As fibrin this cryptic site is exposed, which stimulates a receptor on microglia, called the integrin receptor Mac-1 (also called alpha(M)beta(2) or CD11b/CD18). This receptor activates microglia and causes them to become ‘hot’ like hot chilly peppers. These chilly peppers burn the tissue around them; the activated or hot microglia produce a large number of damaging molecules including reactive oxygen species, which are not good for the brain and spinal cord and cause loss of axons and neurons.

Importantly, the antibody that Katerina has developed blocks the fribrin-microglia interaction has the potential to treat many diseases inclusing Alzheimer’s disease.

The problem I see with this treatment strategy going forward is how to test in MS. Does it get compared to placebo? Does it get added on to existing DMTs? How do you design proof of biology trials? How do you design dose-finding phase 2 trials? And finally, how do you design a phase 3 trial? Do you need to use this treatment continuously or only during the early stages of inflammation? Is it a treatment that is best targeted to progressive MS?

I suspect more CSF biomarker work looking at activated microglia and macrophages, BBB leakage and fibrin formation needs to be done to provide the tools to test this drug in MS.

Despite these challenges, the award will raise awareness of this pathway and the science underpinning it. I suspect big pharma is already all over this pathway and we may see CNS penetrant small molecule inhibitors emerging. If this work translates into clinical practice there will be many more accolades and awards for Katerina.

Well done and thank you for a very inspirational lecture.

Akassoglou et al. Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol. 2018 Nov;19(11):1212-1223.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood-brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ377-395, to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases.

Akassoglou et al. The fibrin-derived gamma377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease. J Exp Med. 2007 Mar 19;204(3):571-82.

Perivascular microglia activation is a hallmark of inflammatory demyelination in multiple sclerosis (MS), but the mechanisms underlying microglia activation and specific strategies to attenuate their activation remain elusive. Here, we identify fibrinogen as a novel regulator of microglia activation and show that targeting of the interaction of fibrinogen with the microglia integrin receptor Mac-1 (alpha(M)beta(2), CD11b/CD18) is sufficient to suppress experimental autoimmune encephalomyelitis in mice that retain full coagulation function. We show that fibrinogen, which is deposited perivascularly in MS plaques, signals through Mac-1 and induces the differentiation of microglia to phagocytes via activation of Akt and Rho. Genetic disruption of fibrinogen-Mac-1 interaction in fibrinogen-gamma(390-396A) knock-in mice or pharmacologically impeding fibrinogen-Mac-1 interaction through intranasal delivery of a fibrinogen-derived inhibitory peptide (gamma(377-395)) attenuates microglia activation and suppresses relapsing paralysis. Because blocking fibrinogen-Mac-1 interactions affects the proinflammatory but not the procoagulant properties of fibrinogen, targeting the gamma(377-395) fibrinogen epitope could represent a potential therapeutic strategy for MS and other neuroinflammatory diseases associated with blood-brain barrier disruption and microglia activation.

#AttackMS – a flipped pyramid

Why does Selma Blair’s speech sound slurred?

Whenever a celebrity gets MS and comes out of the ‘closet’ MS trends on social media. When Selma Blair attended the Oscar ceremony on Sunday night walking with a cane it caused quite a stir. You can now watch an interview with her on ABC News. You will notice that she has a slurred speech, which we call dysarthria and she is unsteady on her feet and needs the cane for balance. Her walking problem is called ataxia. It is clear from these signs that she has probably had a brainstem and/or cerebellar attack. This would be due to a so-called posterior fossa lesion, which is considered a poor prognostic sign.

In an interview in Vanity Fair, she talks about starting a monthly infusion therapy, which by inference must be natalizumab. As you are aware natalizumab is one of our most effective maintenance therapies and importantly is in the top league when it comes to disability improvement, i.e. no evident disease activity and disease improvement (NEDADI). As she appears to be quite early on in the course of her disease she has a good chance of some, or most, of her disabilities improving. However, against making a full recovery is the severity of her attack and the fact that she is now 46 an age when recovery mechanisms are known to be below par.

It is really a good sign that she is on a high-efficacy DMT (flipped pyramid) and has not being treated on a low efficacy therapy with the aim of escalating her therapy if and when necessary. Don’t forget time is brain so flipping the pyramid makes sense.

I am interested in knowing if natalizumab is being used as part of DrK’s #AttackMS paradigm (aka #BrainAttack), i.e. to get on top of the inflammation ASAP with natalizumab and to transition onto to another DMT later on if necessary, for example, if she was JCV-positive. I would also be very interested to know if an IRT (alemtuzumab or HSCT) was discussed as a potential treatment option with her?

Whatever you say it takes a brave person to come out and speak in public when you have such a potentially disabling disease and it when MS remains such a stigmatizing disease.

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.

Flipping the pyramid

Was the concept of flipping the pyramid as a treatment strategy explained to you when you were started on a DMT?

For several years I have been arguing for adopting the concept of flipping the pyramid as a treatment strategy for MS. This is a treatment strategy developed by rheumatologists for treating rheumatoid arthritis with great success. In short, flipping the pyramid is using very high efficacy treatments first line. The other treatment strategies are watchful waiting, slow escalation or rapid escalation.

I kid you not that watchful waiting is still alive and kicking, but is less common now than it was a decade or so ago. The message is finally getting through that ‘active MS’ is a modifiable disease and should be treated. Please note my emphasis on ‘active MS’, we are unable to offer people with inactive MS DMTs nor should we, therefore, watchful waiting is entirely appropriate in this situation. The debate, however, is about how to define inactive MS and how hard should we interrogate patients to exclude smouldering MS?

The slow escalation strategy uses clinical monitoring to make a decision to change treatments or not and is probably still the norm in the UK. The main reason is a lack of resources, i.e. staff and MRI scanners to implement annual MRI monitoring. Rapid escalation is probably the most common option chosen by patients and neurologists in other high-income countries, however, frequent MRI monitoring which is costly remains a barrier in many parts of the world.

By maintenance-escalation, we mean starting low and escalating up a treatment ladder using MRI monitoring to assist decision making. We know from several real-life data sets and clinical trials that on average you do better if you start on either natalizumab, fingolimod, alemtuzumab, daclizumab or more recently ocrelizumab, compared to the lower efficacy platform therapies.

It is very reassuring to see the latest real-life data set from Wales showing how much better pwMS do when they have started an ‘early intensive therapy’ compared to a ‘moderate efficacy maintenance-escalation’ approach. The evidence is now overwhelmingly in favour of the former treatment approach.

The question is whether or not neurologists and HCPs will at least register these observations and start to offer their patients a choice between these two treatment approaches?

When we designed our treat-2-target NEDA trial to compare these two approaches, several years ago, these concepts were quite new. When the trials finally got funded we at Barts-MS declined to participate because we don’t think there is clinical equipoise anymore; in other words, we don’t think it is ethical to randomise patients to a maintenance-escalation arm of a study given the emerging evidence-base.

At Barts-MS we feel strongly that our patients are educated about the above issues and actively participate in the decisions about which treatments they are started on or switched to. This does not mean that we the neurologists are not involved. In some situations, we make the decisions for our patients or limit the choices available because of extenuating factors. We also offer patients the choice of allowing us to choose or recommend a specific treatment for them. Interestingly, with the rising complexity of treatment options many more patients are opting for the latter.

Paternalistic medicine, i.e when the doctor makes the decisions, is making a comeback but only this time as an informed choice

Many of the relevant issues I discuss above were covered in my ‘Hot Topics’ talk at ECTRIMS. I am going to suggest I do a Hangout on this topic to go through these in more detail and to allow you to ask questions. In particular, I need you to understand about the cognitive bias I refer to as the Gambler’s dilemma and how you need to try and overcome it when making decisions about your treatment.

For those of you reading this post and have been started on DMTs in the last 5 years was the concept of flipping the pyramid ever explained to you and the potential consequences, to you and your brain, if you chose the slower maintenance-escalation approach?

Harding et al. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.

IMPORTANCE: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.

OBJECTIVE: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.

DESIGN, SETTING AND PARTICIPANTS: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in the analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).

EXPOSURES: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).

MAIN OUTCOMES AND MEASURES: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.

RESULTS: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

CONCLUSIONS AND RELEVANCE: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.

CoI: multiple