Category: Politics, campaigns and information

MAKING ONCOLOGISING MS A REALITY

Barts-MS rose-tinted-odometer  N/A

Yesterday’s PMSA meeting was very interesting. It is clear the field of MS is at a cross-roads and that Pharma needs the wider MS community to help them change the game. If we don’t I suspect we won’t see the next generation of treatments being developed to target the ‘real MS’ or ‘smouldering disease’.

It was clear that combination therapies are needed, but how we make them happen is another story. Regulators need to understand that we need to go beyond inflammation and treat MS as one disease. I tried to convey this message in my presentation. What I am staying is the real MS is essentially primary progressive MS or smouldering MS. Our anti-inflammatory therapies convert relapsing forms of MS into primary progressive MS and we, therefore, need to combine these groups, i.e. those who are NEDA-2 and getting worse into one group for add-on trials.

My proposal to oncologise MS and create a trials platform was presented by both Jeremy Chataway and Ludwig Kappos. It is reassuring that these two giants of the MS world are supportive of the idea. I have therefore designed the skeleton of an O’ADD-ON and DADD platform for discussion. In reality, these platforms should have been set-up yesterday.

Doing registry-type trials is now the norm in most fields of oncology. I, therefore, see no reason why we can’t steal their ideas and apply them to MS. The question which fish will bite first; Roche or Biogen? There is nothing like a bit of competition and the fear of missing out (FOMO) to get people to act.

What do you think of these platforms? I am very interested to hear if you think this is feasible or not? An ocrelizumab and/or DMF platform will at least create the base for Roche and Biogen to develop their own add-on compounds but will allow them to partner with other Pharma companies, for example, Abbvie and elezanumab, and with academia. Although these platforms will be expensive I am sure the investment will pay massive dividends down the line for pwMS, society and industry.

CoI: multiple

P.S. In response to some of the comments below. The following infographic is a crude attempt to explain what I mean when I say that current DMTs convert RRMS into PPMS or smouldering MS. PwPPMS simply have a much longer asymptomatic and prodromal phase so that when they present with symptoms and get diagnosed they have lost more brain and spinal cord. In other words, pwPPMS have more advanced MS and have less reserve compared to people with early relapse-onset MS. The latter explains why the treatment response is less in both SPMS and PPMS.

Oncologising MS

We have been beating the combination-therapy drum for so long now we have become bored with the concept. Every time we apply for grants to test the concept, be it with pharma or via other traditional funding routes, we get pushback. Either our targets are questioned or the concept of combination therapies is challenged based on the scientific principles underlying the combination being proposed. Then there is regulatory complexity of doing licensing combination trials that makes most Pharma companies put their heads in the sand.

It is obvious that if we want to achieve our aim of getting pwMS to old age so that they can age normally we are going to have to do more than simply tackle inflammation. 

Oncologise is a neologism or new word

I propose oncologising multiple sclerosis and putting in place a national NHS-funded register as part of routine practice, similar to what happens with cancer patients so that everyone can participate in add-on trials of neuroprotectants, remyelination and neurorestoration therapies and any other add-on treatments that we think may work in MS. The latter can include dietary interventions, for example, intermittent-fasting or ketogenic diets. 

Making the case for building a treatment sandwich or pyramid

If the NHS doesn’t fund this I would urge Roche and Biogen to do start with the two biggest blockbusters, i.e. ocrelizumab- and DMF-treated patients and to do this as an international initiative. The real-life trial platform could be run like the oncology platforms in that as soon as you find a combination that is better than the monotherapy (plus placebo) the combination then becomes the standard of care. We would have to implement this with more sensitive outcome measures, possibly brain volume loss, rather than the EDSS which has too many warts to survive much longer. 

Do you think we can oncologise MS? Would you be interested in participating in add-on studies as proposed above? We have ten or more compounds that we could test right now. 

The good news is that I have an ally who works in a large Pharma company who has been chewing the cud with me on this concept and is hopefully going to be able to sell it within his company. If he doesn’t do it I suspect another company may be tempted to take it on.

I gave a talk to general physicians at the Royal College of Physicians (RCP) yesterday afternoon telling them how we have transformed the management of MS. But have we really? To really transform the management of MS we need to cure the disease and then tackle the problem of post-inflammatory neurodegeneration or smouldering MS. The problem we have is that the wider MS community is not necessarily prepared to accept this position and the need for combination therapy add-on studies or the sequential therapy paradigm (induction-maintenance). 

CoI: multiple

Curing MS

How close are we to offering some people with MS a cure?

I am speaking at the Imperial College Neuroscience Society this morning on ‘how close we are to curing MS’. I think we are very close; in fact some of the longterm follow-up data of IRT (immune reconstitution therapies), in particular, alemtuzumab, non-myeloablative HSCT and myeloablative HSCT looks very promising. I suspect that when we complete our long-term follow-up of cladribine -treated patients we will find a similar story.

If you want to have any chance of potentially curing yourself of MS you have to be treated early, as early as possible, with an IRT preferably with one of the big guns. The problem you will have is finding a neurologist who agrees with this treatment strategy.

CoI: multiple

Pathways to Cures

Barts-MS rose-tinted-odometer ★★★★★ 

I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me. 

As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people. 

Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences. 

So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me! 

If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease? 

Sonia Vallabh. The Patient-Scientist’s Mandate. N Engl J Med 2020; 382:107-109.

Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.

There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease. 

My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS. 

Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with. 

In the area of MS prevention, it will take more than a  patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.

My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?

Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there. 

On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.

For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold. 

I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.

CoI: multiple

How healthy is your lifestyle?

Barts-MS rose-tinted-odometer ★★★★★ 

It is a no-brainer. A healthy lifestyle is one of the most effective preventive health interventions available. The study below shows that you can increase your chances, by a factor of over 20, of a life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 by making ensuring you maintain 4 or 5 low-risk lifestyle factors; i.e. not smoking, staying trim, doing moderate to vigorous physical activity, keeping your alcohol intake moderate and eating a quality diet. 

Although this study has implications for the general population the message is applicable to pwMS. All these lifestyle factors have been linked in some studies to MS outcomes. In other words, everyone with MS should assess their lifestyle to see if they can change things to maximise their longterm outcome. 

Another thing you can do is to ask your HCP to score themselves on these five factors. I maintain that HCPs have a responsibility to lead by example and they should be practising what they preach. This is why I am determined this year to max-out on all five of these factors so that I can look my patients in the eye and say “I am with you all the way”. 

What is not discussed in this paper is the fact that what determines your ability to live a ‘healthy life’ is often down to the social determinants of health (SDoH) and these are usually beyond the control of the individual. Education, poverty, inequality, social isolation, a poor environment, lack of self-control, a sense of helplessness, chronic stress, etc. are all factors that make adopting a healthy lifestyle almost impossible. This is why our #ThinkSocial campaign is really a political campaign. Without politicians acknowledging the importance of the SDoH little will change. 

Please let us know if you are managing to adopt and maintain a healthy lifestyle and how you have done it; success stories are more motivating than pontificating from a soap-box.

Li et al. Healthy lifestyle and life expectancy free of cancer, cardiovascular disease, and type 2 diabetes: prospective cohort study. BMJ 2020;368:l6669

Objective: To examine how a healthy lifestyle is related to life expectancy that is free from major chronic diseases.

Design: Prospective cohort study.

Setting and participants: The Nurses’ Health Study (1980-2014; n=73 196) and the Health Professionals Follow-Up Study (1986-2014; n=38 366).

Main exposures: Five low-risk lifestyle factors: never smoking, body mass index 18.5-24.9, moderate to vigorous physical activity (≥30 minutes/day), moderate alcohol intake (women: 5-15 g/day; men 5-30 g/day), and a higher diet quality score (upper 40%).

Main outcome: Life expectancy free of diabetes, cardiovascular diseases, and cancer.

Results: The life expectancy free of diabetes, cardiovascular diseases, and cancer at age 50 was 23.7 years (95% confidence interval 22.6 to 24.7) for women who adopted no low-risk lifestyle factors, in contrast to 34.4 years (33.1 to 35.5) for women who adopted four or five low-risk factors. At age 50, the life expectancy free of any of these chronic diseases was 23.5 (22.3 to 24.7) years among men who adopted no low-risk lifestyle factors and 31.1 (29.5 to 32.5) years in men who adopted four or five low-risk lifestyle factors. For current male smokers who smoked heavily (≥15 cigarettes/day) or obese men and women (body mass index ≥30), their disease-free life expectancies accounted for the lowest proportion (≤75%) of total life expectancy at age 50.

Conclusion: Adherence to a healthy lifestyle at mid-life is associated with a longer life expectancy free of major chronic diseases.

CoI: multiple

What is advanced MS?

Barts-MS rose-tinted-odometer – zero stars

Someone recently asked what is advanced MS? I suspect they have been getting frustrated with our use of this adjective without a clearer understanding of what it really means. To find out if you have advanced MS you need to put yourself through a battery of stress tests to find-out much reserve you have left to deal with MS and life in the future.

What is advanced MS is a very important topic and we at Barts-MS have tried not to define it using the EDSS as it entrenches the physically-disabling, particularly lower-limb function, worldview of MS.  

Advanced MS is really when someone has lost reserve in a particular neuronal system and they are noticing worsening in that system that is impacting on their ability to function at a personal, social or occupational level and by inference is affecting their quality of life. 

Using this definition someone can have advanced MS with very little physical disability. As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.

A software engineer with MS who depends on her cognitive skills for writing code, concentrating for prolonged periods of time and multitasking may find it very difficult-staying at the top of her game. She will notice much earlier her progressive cognitive loss based on her performance or lack of performance in her work. In comparison, a professional athlete may not necessarily notice early cognitive impairment but will be more susceptible to the effects of MS on their coordination and endurance, for example, the marathon runner with a dropped foot.

These examples are the two extremes, but they illustrate why we need stress tests of the nervous system to be able to ascertain how much reserve there is which will give us some idea how advanced MS is in a particular domain. One thing that is not done very well in MS clinics is cognition. Most MS centres don’t have the resources to monitor cognition properly. This needs to change (#ThinkCognition). 

In almost every MS clinic I do I see patients who complain of cognitive symptoms; increasing forgetfulness, difficulty multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; this was in the pre-natalizumab era.

Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had advanced (secondary progressive) MS manifesting as progressive dementia.

You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.

Until recently we the MS community used the Paced Auditory Serial Addition Test (PASAT) for monitoring cognition in clinical trials. The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. The PASAT is presented using audiotape or disk to ensure standardization in the rate of stimulus presentation. Single digits are presented every 3 seconds and you have to add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. The PASAT is very difficult and requires multitasking; it is a very good cognitive stress test. 

One of the reasons we dropped the PASAT test is because of its learning effect, when you do the PASAT test your scores improve because of so-called ‘learning’ or ‘practice’ effects. In reality this is a general phenomenon of most neurological stress tests; our nervous systems are wired for learning. 

In the FREEDOMS 1 and 2 pivotal phase 3 fingolimod trials, we showed that not being able to improve on the PASAT at baseline predicted a worse outcome. We hypothesised that pwMS who couldn’t learn, i.e. were unable to improve their PASAT scores at baseline, would do worse and this is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo. 

Not surprisingly, the poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve or resilience. In other words, they had more advanced MS. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. In reality, their MS disease activity in the past had primed their brains to continue to deteriorate despite being on a DMT; previous damage or smouldering MS was now driving their disease worsening. This is why the treatment response on DMTs drop off with ageing and disease duration. Please note this applies to all DMTs, including HSCT. 

It is important to prevent the ravages of MS by treating as early and effectively as possible. Some pwMS are luckier than others; i.e. you may present very early in the course of your MS before too much end-organ damage has accrued. In others, the asymptomatic period of the disease may be longer, during which time you acquire a lot of end-organ damage. Regardless of what group you are in, you still need to seriously consider getting on top of your MS disease activity as soon as possible to prevent any further damage.  

It is clear from several data sources that on average pwMS do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions and relapses) and those that reduce brain volume loss. In reality, these are the high and very high efficacy DMTs. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly the DMTs that ‘normalise’ brain volume loss.

This post illustrates why we should be monitoring cognition in routine MS clinical practice. Although this topic gets discussed and debated all the time most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, will change as data emerges that DMTs have positive effects on cognitive function, even in advanced MS. For example, siponimod has been shown to delay cognitive worsening compared to placebo in people with SPMS. 

At Barts-MS we will continue to run our #ThinkCogniton campaign. By shifting the MS worldview from a physical one to a cognitive one we will hopefully get the MS community to manage MS more actively. 

Maria Pia Sormani et al. Learning Ability Correlates With Brain Atrophy and Disability Progression in RRMS. J Neurol Neurosurg Psychiatry, 90 (1), 38-43 Jan 2019.

Objective: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.

Methods: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.

Results: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.

Conclusions: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

CoI: multiple

Is siponimod the first cul-de-sac DMT?

Barts-MS rose-tinted-odometer  ★

A big worry for neurologists and pwMS is the sequencing of DMTs. What DMTs can be used before and after each other and does the sequencing of DMTs change the risk profile of the individual DMTs concerned? These have been dealt with many times on this blog and I am in the final stages of completing phase 1 of my app that will address the specific issues around each DMT. 

Another issue relates to the specifics of the label and how we classify patients; this is particularly problematic when it comes to the EMA’s label for siponimod, i.e. “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity (see section 5.1)”. 

To prescribe siponimod we will have to (1) label the patient concerned as having secondary progressive MS and (2) provide evidence, at least in the UK, that the patient has active disease. The latter would be relapses and/or evidence of MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions). The latest NICE guidance, which is trying to standardise the definition states that MRI activity is “1 T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2-lesion load compared with a previous MRI”. Although we haven’t been given a specific time period it is likely to refer to the last 24 months. 

Some questions. If the relapses and MRI activity occurred prior to the diagnosis of SPMS can they still be counted? Or does the diagnosis of SPMS rebaseline patients? I think the answer should be somewhere in between these two extremes. As the diagnosis of SPMS is retrospective the baseline or clock for assessing disease activity should be set when the first objective evidence of worsening was documented. In reality, this is typically 6 or 12 months in the past depending on the frequency of follow-up appointments. The definition of SPMS requires at least 6 months of worsening disability independent of relapse activity. The problem here is that to have active SPMS you also need to have had a relapse and/or MRI activity in this period as well. So it becomes very difficult to untangle worsening from relapses from worsening independent of relapses. These definitions are a mess!

In an ideal world, all the above may make sense, but this does not take into account the reluctance of neurologists and HCPs to document or label their patients as having SPMS. In some countries, a label of SPMS means the current DMTs may need to be stopped. Also the label SPMS has other negative connotations; it is often interpreted as having a second disease, importantly a disease that is not modifiable. I know this happens a lot. When we tried to recruit study subjects for our PROXIMUS study (add-on neuroprotection with oxcarbazepine) my colleagues were reluctant to refer their patients for the trial as it required them to diagnose early SPMS and nobody wanted to do that. 

Another issue that arises is that once someone is labelled as having SPMS can you unlabel them and refer to them as having relapsing MS? Common wisdom says no. In other words, once you have transitioned (and I hate this term) to becoming SPMS you can’t go backwards. This has major implications for patients with active SPMS; once you are on siponimod it may close the door to the other DMTs as they are not licensed, at least in Europe, for SPMS. I suspect this will be one of the biggest hurdles for the widespread adoption of siponimod for active SPMS in the UK. In other words, siponimod will become the cul-de-sac or dead-end DMT until another DMT is licensed for SPMS.  I can already see NHS England making it impossible to switch someone who is failing on siponimod, can’t tolerate it, or develops adverse events that require stopping siponimod, onto another high-cost DMT that is licensed for RRMS.

I think we as an MS community need to make the argument that you can flip-flop between MS subtypes. We have evidence buried in the trial data that a subset of patient labelled as having SPMS behave as having RRMS, i.e. their EDSS scores improve despite superimposed relapses. Similarly, there is a subgroup of patients with ‘inactive’ or ‘smouldering’ SPMS who have not had a relapse for years suddenly become active. The same thing happens with PPMS; approximately 25% of pwPPMS will go onto have superimposed relapses. Surely these people have relapsing MS rather than PPMS? Calling them progressive-relapsing MS does not deal with the biology of the disease in these patients nor their treatment. Leaving them as having a form of PPMS means that are only eligible for ocrelizumab, whereas relabeling them as having RMS opens up many more treatment options for these patients.

These arguments are more than just semantics they have real-life implications for individuals with MS and how we treat their disease.

At the end of the day, we can avoid all these arguments by defining MS as one disease and not two or three diseases (#MS_is_1_not_2_or_3_diseases). Until we do this siponimod, despite the hype and hope around its anticipated launch, is likely to not to be used as much as it should be used to avoid putting patients down a treatment pathway that is a cul-de-sac.

CoI: multiple

Slip-sliding away – do I have secondary progressive MS?

Barts-MS rose-tinted-odometer – zero stars

We have been running a campaign that #MS_is_1_not_2_or_3_diseases for sometime. This is based on the biology of MS and not what we see clinically. The pathology that underpins so-called progressive MS is the loss of axons, loss of neurons and loss of synapses, which are the chemical connections between neurons. All three of these processes begin very early in the so-called asymptomatic stage of MS. What dictates whether or not we see the effects of these subtle changes depends on how much we stress the neurological system concerned and how much resilience, or reserve, this system has to handle the stress.

A good example is a marathon runner with MS who develops a dropped foot after running for about an hour at race pace. A year earlier he would only notice that symptoms towards the end of the marathon. Does this marathon runner have SPMS? If this runner had not stressed his motor pathway with vigorous competitive exercise the issue of whether or not he has SPMS would not arise. In other words, the question of SPMS would only arise when his dropped foot would impact on normal activities of daily living, for example walking, which may have only occurred in 10 years time if he had not been a runner. 

What this anecdote tells us that the diagnosis of SPMS is a moving target and depends on what system, or systems, MS has shredded, how you use that system and how much reserve is left in that system to compensate for the damage. We know progressive cognitive dysfunction is the driver of early unemployment in so-called knowledge jobs. Why aren’t these patients being labelled as having SPMS? That is because neurologists, first and foremost, view MS as a physically disabling disease rather than a cognitively disabling disease. This needs to change; #ThinkCognition. 

The diagnosis of SPMS is therefore in the eye of the beholder. In my eyes, progressive MS is present from the beginning of the disease. Trying to identify a point in time when you can be diagnosed with SPMS is futile and to discuss transitioning MS is a misnomer. Neurologists think we are smart when we classify our patients as having relapsing-remitting MS, or relapsing SPMS, or non-relapsing SPMS. Let me tell you this is a fallacy. 

For example, I am doing a relapse assessment on a patient later today who was thought to have non-relapsing SPMS. Four weeks ago she went off her legs with new-onset weakness in her good leg. Her MS nurse said this is likely to be progressive MS and asked her to sit it out. Over the last few weeks, she has been recovering function in that leg and has started to mobilise again. Based on her history it is likely she has had a relapse. I am seeing her, to document the likely relapse, to assess whether or not she needs a course of steroids and to counsel her about her future treatment options. At present, she is not on any DMT having completed two courses of off-label cladribine several years ago. 

The problem the MS community faces is that we view MS through clinical and MRI spectacles and we don’t think about the biology of the disease. If we took a biological approach to MS all MS would be labelled as being inflammatory, all MS would be active and all MS would progressive. Based on this thinking all people with MS would need to be offered treatment with a combination therapy approach and treated holistically. 

The following study below describes the development of a new HCP-completed questionnaire to support HCP-patient interactions in evaluating disease transition or progression to SPMS. Using a prompt like this in clinical practice will almost certainly lead to an earlier label change in the notes, i.e. SPMS being diagnosed earlier. Will this help the patient? In the UK once you are labelled as having SPMS you are meant to stop DMTs. Would things change if NICE approved siponimod for the treatment of active SPMS under the NHS? If siponimod was green-lighted by NICE the SPMS label had better be ‘active-SPMS’ and not ‘inactive-SPMS’. The latter label would make the patient ineligible for treatment. 

Another problem around the corner is that what happens if you now are now labelled as active-SPMS and start on siponimod and you then have to stop taking it because of lack of efficacy, poor tolerance or an adverse event?  Will we be able to relabel the patient as having relapsing MS and put them back on a DMT that is licensed for relapsing MS? I call this flip-flopping and it happens all the time in clinical practice. However, it is likely that NHS England will put in place systems to prevent this from happening. My solution is to get rid of labels and let the neurologist and the patient decide on what treatment they want. 

I think all the licensed treatment for MS, including HSCT, work in patients with active MS but have very little impact on smouldering disease. Smouldering MS is really the next frontier in the management of MS. 

I hope the above demonstrates the folly of our ways. We need to call-out MS for what it is; an inflammatory neurodegenerative disease from the outset. Our guiding treatment principle should be to diagnose and treat MS early and effectively to prevent end-organ damage. Our therapeutic aim should be to maximise brain health for the duration of our patients’ lives. Anything less would be doing them a disservice. 

Ziemssen et al. A mixed methods approach towards understanding key disease characteristics associated with the progression from RRMS to SPMS: Physicians’ and patients’ views. Mult Scler Relat Disord. 2019 Nov 18;38:101861. doi: 10.1016/j.msard.2019.101861.

OBJECTIVES: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) evolves over time and it can be challenging for physicians to identify progression early. Typically, SPMS is diagnosed retrospectively with a significant delay, based on a history of gradual worsening, independent of relapses, following an initial relapsing-remitting disease course. As such, SPMS is often associated with a considerable period of diagnostic uncertainty. This study aimed to explore and characterize key symptoms and impacts associated with transitioning from RRMS to SPMS and inform the content for a tool to support evaluation of early subtle signs suggestive of progressive disease.

METHODS: The qualitative study involved 60-min, face-to-face, concept elicitation (CE) interviews with 32 patients with MS (US = 16 and Germany = 16); and 30-min, telephone, CE interviews with 16 neurologists (US = 8 and Germany = 8). Multivariate analysis on data from a real-world observational study of 3294 MS patients assessed the differences between early-RRMS and early-SPMS, and identified factors that were significant drivers of this difference. These studies informed selection of the key variables to be included in a pilot tool. Sixteen physicians used the pilot tool, presented as a paper questionnaire, with a sample of patients whom they suspected were progressing to SPMS (n ≥ 5). Following this, the physicians participated in a 30-min cognitive debriefing (CD) interview to evaluate the relevance and usefulness of the tool. Qualitative analysis of all anonymized, verbatim transcripts was performed using thematic analysis.

RESULTS: Patients and physicians reported signs that indicated progression to SPMS including gradual worsening of symptoms, lack of clear recovery, increased severity and presence of new symptoms. No specific symptoms definitively indicated progression to SPMS, however a number of potential symptoms associated with progression were identified by SPMS patients and physicians, including worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Quality of life domains reported to be more severely impacted in SPMS than MS in general included: physical activity, work, daily activities, emotional and social functioning. Multivariate analysis of the observational study data identified several variables strongly associated with progression to SPMS including, requirement of assistance in daily living, presence of motor symptoms, presence of ataxia/coordination symptoms, and unemployment. Physicians reported that items included in the tool were easy to understand and relevant. Physicians also reported that there is an unmet need for a tool to help identify signs of SPMS progression and so the tool would be useful in clinical practice.

CONCLUSIONS: This was the first stage of development of a novel, validated, physician-completed tool to support physician-patient interactions in evaluating signs indicative of disease progression to SPMS. Qualitative and quantitative methods (involving physician and patients) were used to determine tool content. The usefulness and unmet need for such a tool in clinical practice was confirmed via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm and validate the tool so that it can be reliably implemented in clinical practice.

CoI: multiple

To smoke or not to smoke that is the question

Barts-MS rose-tinted-odometer  ★ ★ ★ ★ ★

Yawn! I am getting tired of the saying the same-old things on this blog. Is it time to retire and do something new? 

We have done some modelling work and predict that ~20% of new or incident cases of MS could be prevented if we stop the population from smoking. The question is how do we achieve this? Taxation has worked to some extent in that we are seeing a fall in the number of current smokers, but the numbers of teenagers smoking looks as if it is quite resistant to change. The solution must be education, education, education and a war against the tobacco industry. 

Public Health England

If social media is such a powerful tool to hack the brains of voters, why don’t public health departments use this technology to promote their agenda? What we need are companies like Cambridge Analytica to do some good in the world and to promote a ‘Don’t Start Smoking’ campaign. 

We did try and get some insights into why teenage girls start smoking when Amy Sankey, a work experience student, did a survey in her school for us. Despite the almost universal awareness of the harms of smoking in terms of lung cancer, most girls, however, did not know that there is a link between smoking and autoimmunity. I suspect even if they knew about the link it would be unlikely to prevent them from starting to smoke. 

We are interested in smoking as a risk factor for MS as it is telling us something about the cause of the disease. It appears that smoking must be acting via the lungs and is due to tobacco itself. Use of oral, non-smoked, tobacco is in fact associated with a reduced risk of getting MS, hence it is not tobacco exposure. Solvent exposure is also associated with an increased risk of getting MS, which supports the lung hypothesis of developing MS. 

Lung hypothesis #1 argues that damage to the lung from smoking or solvents creates a pro-inflammatory environment that is sufficient to activate pre-existing autoreactive T-cells. In comparison, lung hypothesis #2 argues that smoking damages proteins by a process called post-translational modification and that these proteins stimulate an immune response that then cross-reacts with normal antigens to set-up autoimmunity. The argument for the latter in triggering rheumatoid arthritis, an autoimmune disease of joints, is quite compelling but is less compelling when it comes to MS. We hope to study whether post-translational modification of CNS antigens is relevant in MS via an ECTRIMS fellowship we have supported.  

What is interesting is that smoking interacts with genetic risk factors for developing MS and with EBV infection suggesting that there is a critical gene-environment interaction that causes MS. Wouldn’t it be interesting to study and find out what these interactions are? We have an exceptionally bright and able young researcher, Ben Jacobs, who wants to do a PhD on this exact topic; gene-environment interactions. At the moment we are ruminating about the best approach he should take to address this question. It is not an easy experiment so if you have suggestions please feel free to contact us.

I would also like to remind you that smokers who have MS have a much poorer prognosis, which is why we recommend that you stop smoking if you can.

If you are interested in smoking and MS there is a new review that has just come out. 

Rosso &  Chitnis. Association Between Cigarette Smoking and Multiple Sclerosis: A Review. JAMA Neurol. 2019 Dec 16. doi: 10.1001/jamaneurol.2019.4271

IMPORTANCE: Cigarette smoking is a common environmental exposure and addiction, which has severe health consequences. Smoking is a risk factor for multiple sclerosis (MS); also, smoking has been associated with disease activity and overall prognosis for patients with MS.

OBSERVATIONS: Cigarette smoking is an irritative agent on the lungs, in which a proinflammatory cascade starts that culminates in autoimmunity. Inflammation may increase the risk of MS in some individuals, in a process driven by antigen cross-reactivity between lung antigens and myelin antigens. Genetics plays a central role in the individual predisposition to mounting an autoimmune reaction. Also, free radicals, cyanates, and carbon monoxide in cigarette smoke may be directly toxic to neurons. Patients with MS who smoke have higher rates of disease activity, faster rates of brain atrophy, and a greater disability burden. Some of the outcomes of smoking were found to be reversible, which makes counselling key.

CONCLUSIONS AND RELEVANCE: The pathways involved in cigarette smoking should be further analyzed to understand the mechanisms whereby smoking worsens MS prognosis. The proinflammatory and neurotoxic outcomes of cigarette smoking may be shared by other environmental exposures, such as pollution and organic solvents. From a global perspective, efforts should be made to diminish the prevalence of cigarette smoking in patients with MS.

CoI: multiple

Do no harm

Primum non-nocere is a Latin phrase that means “first, do no harm”. 

On the tube this morning I recognised one of our medical students reading Henry Marsh’ book “Do no harm”.  He is a semi-retired neurosurgeon, turned author, who uses his past patients to discuss ethical dilemmas and to criticise the NHS. His book does showcase the life of a surgeon, warts and all.  It is clear that to be a good neurosurgeon you have to be a team player. In surgery, it is critical to get the clinical decision-making correct, i.e. when and when not to operate. Surgery is also a technical speciality above all else; from the age of about 55 a surgeon’s skills deteriorate so it is best to be operated on by someone who is in their prime. In short, if you make the wrong clinical decision and you get things wrong technically then you will get a suboptimal outcome; i.e. you will do harm. 

I remember from very early on in my medical school career being told to do no harm. It is important to understand that this phrase dates back from a bygone era; an era when we hardly had any treatments that worked. 

Wikipedia: It is often said that the exact phrase “First do no harm” is a part of the original Hippocratic oath. Although the phrase does not appear in the AD 245 version of the oath, similar intentions are vowed by, “I will abstain from all intentional wrong-doing and harm”. The phrase “primum non nocere” is believed to date from the 17th century. Another equivalent phrase is found in Epidemics, Book I, of the Hippocratic school: “Practice two things in your dealings with disease: either help or do not harm the patient”. The exact phrase is believed to have originated with the 19th-century English surgeon Thomas Inman. 

In the modern era, we have to walk a tightrope of treating people to prevent future harm from a specific disease, knowing well that a small number of patients will be harmed from the side effects of the treatment. In other words, modern medicine has become a balancing act between the outcome of a population of patients at the expense of a small number of patients with adverse events. 

In the MS space, natalizumab epitomises this dilemma. Natalizumab is one of our most effective DMTs; it is very effective, easy to use and has few adverse events, which are uncommon. Unfortunately, however, in JC virus-positive individuals it may result in PML  a life-threatening infection of the brain. A lot has been done to derisk this complication, but unfortunately, there are still pwMS developing PML as a complication of natalizumab.

One industry analyst said to me that he had no idea why natalizumab was still on the market. He felt it should have been withdrawn after the PML crisis emerged. I said to this individual that he clearly hasn’t seen the impact that natalizumab has on people with MS’ lives. Natalizumab is a truly a transformative drug, which is why I refer to the treatment of MS as being represented by two eras; pre- and post-natalizumab. 

It is clear that pwMS understand that to maximise outcomes for pwMS some individuals have to pay the price of suffering adverse events. This is why it is not surprising that pwMS are prepared to take greater risks than their risk-averse neurologists (see below). I recall working with a rheumatologist who made the point that if he didn’t have a few of his patients dying each year from the complications of his treatment decisions then he was not treating his patients actively enough. The corollary is that a rheumatologist without a body count is being too conservative. 

Could the same analogy be levelled at neurologists? I think yes. I am still seeing far too many pwMS for second or third opinions who are very disabled from watchful waiting, slow escalation or sideways switching when they should have been treated with high efficacy treatments years ago. We really need to change the behaviour of MSologists from being risk-averse to becoming risk-takers. This also means pulling no punches and telling pwMS how bad MS really is and that to maximise your outcome you need to treat the disease effectively early on. 

At Barts-MS we are taking this principle to the extreme with our #AttackMS trial. As always the ideas underpinning this trial are already being adopted by our team so that by the time we get the trial funded and up and running we may not be able to do the study because we would have lost equipoise. 

Wikipedia: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial. 

I would be interested to know the MS Community’s opinions on the #AttackMS trial. 

Heesen et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010 Dec;16(12):1507-12. 

BACKGROUND: Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients’ and physicians’ risk estimates and attitudes towards natalizumab treatment.

METHODS: Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.

RESULTS: After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.

CONCLUSION: Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

CoI: multiple

%%footer%%