This week some of us with decanting to Edinburgh for the annual Association of Neurologists meeting.
From an MS perspective, we will have lots to discuss including whether or not the UK MS community has the appetite to take on one, or all of these, studies. Which one do you think is the most important?
The SALVAGE study, which is challenging NHS England’s DMT stopping criteria and saying that even if you end up in a wheelchair it is worth protecting your upper limb function.
The ADIOS study. This is questioning whether or not we need to dose ocrelizumab continuously, or can we use it as an immune reconstitution therapy (IRT), or using adaptive dosing based on peripheral memory B-cell kinetics.
The #AttackMS study to treat MS as early as possible to see if we can maximise disease outcomes for people with CIS or early MS.
Don’t be shy we need you, and the wider MS community, to get behind these studies if we are to have a chance of getting them funded.
Just arrived back from the AAN 2019 in Philadelphia. Jetlagged, which is why I am writing this at 2 am in the morning.
As always the AAN is more a meeting of meetings or networking in academic lingo. These meetings have allowed us to progress several of our ideas including (1) DrK’s #MSAttack study with natalizumab, (2) to think more deeply about our proposed ADIOS Trial (adaptive dosing ocrelizumab study), (3) support for our plasma cell and (4) social capital hypotheses and to (5) to gain a deeper understanding of the emerging new ’safety’ issues surrounding alemtuzumab.
Alemtuzumab is getting an unnecessarily rough ride. I had an opportunity to review all of the vascular events and AEs that led to the EMA triggering article 20. These are all rare events. The intracranial haemorrhages appear to be related to transient hypertension and may relate to the amount of hydration the US infusion centres use when administering alemtuzumab. It is clear that MSers develop a transient rise in blood pressure when receiving alemtuzumab, which means this rare complication can be derisked with anti-hypertensives.
When it comes to the cases of arterial dissections and arterial thromboses on alemtuzumab I was not convinced alemtuzumab is to blame. The majority of the cases had comorbidities or had had procedures that are a more likely explanation for the ischaemic events. In many of the cases, the events were poorly characterised and it was not clear if they had occurred at all; this is particularly in relation to the so-called myocardial infarctions.
It is clear that most if not all of the ‘vascular cases’ have arisen in the USA. Why? I suspect it is because alemtuzumab is being used in a much riskier and older population compared to the other parts of the world. Herein lies the problem. The fact that the EMA has now copied the FDA and made alemtuzumab a 3rd-line DMT will shift the use of alemtuzumab into a riskier older population and thereby increase the likelihood of us seeing these vascular AEs in Europe.
To be honest I am not convinced that the risk-benefit profile of alemtuzumab has changed at all. I would, therefore, appeal to the EMA to include the new AEs in the SmPC, but not to change alemtuzumab’s label. We need to be able to offer alemtuzumab to MSer with early MS when they have the most to gain from the treatment. I am sure MSers are in the best position to weigh up the risks and benefits of alemtuzumab. My big fear is that restricting access to alemtuzumab will simply increase HSCT tourism abroad.
If I needed proof that our blog is read it was in abundance at the AAN. Several people were interested in our ADIOS trial and were thinking of doing versions of their own. The one caveat was new data that Stephen Hauser presented showing that the efficacy of ocrelizumab may be linked to the level of B-cell depletion, i.e. the greater the peripheral B-cell depletion the greater the treatment effect of ocrelizumab on disability progression. There was no dose-related signal on MRI or relapses because these have a floor effect, i.e. virtually all patients are NEDA 1&2 and hence it is impossible to use these outcomes to assess a dose-effect. The one caveat is the dose effect on disability was confounded by body weight; i.e. the larger the patients the less B-cell depletion. As you know MSers with an increased BMI (body mass index) are at increased risk of comorbidities, which may explain why they do less well on ocrelizumab and the observation has nothing to do with the level of peripheral blood B-cell depletion.
The peripheral B-cell depletion data, however, needs to be taken further and tissue and CNS B-cell depletion kinetics need to be studied further. I am convinced the ADIOS trial will be a good place to start with some of these studies. Clearly, it is time to get our grant writing hats on. We need to do this study in the UK.
DrK and I had several meetings with key stakeholders in Biogen about our #MSAttack study. There is little doubt about the efficacy of natalizumab in MS, its safety even in JCV-positive MSers when used for short periods, its rapid onset of action (weeks) and it reversibility (washout) that make it the only suitable DMT for this study. We have changed our trial design slightly, but hopefully, we will be able to get this study funded in the near future. If the #MSAttack study is successful it will change the way we treat and think about active MS and may help natalizumab obtain a first-line indication, which many MSers and CISers deserve; particularly if you want to save brain and spinal cord.
NeuroDoc Gnanapavan got very excited when she saw some posters supporting the use of proteasome inhibitors as a treatment for autoimmune disease. This supports our new SIZOMUS trial (Safety of IxaZOmib targeting plasma cells in Multiple Sclerosis) to try and scrub the brain clean of plasma cells. We will be letting you know much more about this trial in the next few weeks now that we have ethics and MHRA approvals. We will be needing volunteers for this study.
Saul, or Dr Reyes to some, is now one of the pioneers in studying social capital and MS outcomes. His poster on the topic was well received. It is clear that the social determinants of health outcome are very important and have not been systematically studied in MS. Dr Reyes will be changing all that and has many activities planned as part of his ECTRIMS fellowship The poster he presented at the AAN is self-explanatory, but if you have any queries please don’t hesitate to ask.
I have a new hero or heroine; Dr Riley Bove, from UCSF. Riley has developed a telemedicine service to help people with neurological problems in resource-poor areas. The service is provided for free by the USCF residents and staff and is linked to an educational course to train the staff in these countries. The whole service is run using Zoom an online teleconferencing service. Well done Riley; if you lived in the UK I would be putting your name forward for an honours award from our Queen. And if I had more bandwidth I would join and contribute to your service; maybe something for my retirement? Could this platform be expanded to help diagnose and manage MS in resource-poor settings?
Dr Riley Bove, UCSF, AAN 2019
It is now 4:10 am and I am beginning to feel a bit groggy. So I will signoff now but will come back with some more AAN highlights in the week.
I arrived in Philadelphia on Thursday to attend the 2019 AAN annual meeting. The programme of this year continues much of what was started in 2017 and 2018 around burnout and its opposite wellness.
The AAN states: “Neurology is the only medical speciality that has both one of the highest rates of burnout and the lowest rates of work-life balance. AAN leadership is well aware of your daily challenges and how emotional exhaustion can lead to the loss of interest and enthusiasm for practising medicine. It’s important to remember that it is possible to prevent burnout as well as restore well-being. Your health matters to the AAN and we’re here to help. Each day AAN staff and member volunteers are working on your behalf to decrease regulatory hassles to make it easier to be a successful neurologist. Additionally, we’ve compiled the following resources to provide you with tips, tools, and strategies for cultivating well-being and resiliency in your life.”
After last years meeting, I penned the following which I posted on Medium. Little has changed but is clear that neurologists and clinicians, in general, are facing an existential crisis.
The most important part of attending large International conferences is the time for thought, reflection and importantly introspection. The AAN 2018 was no exception. The programme was informative, in a disturbing sort of way, in that a lot of the teaching sessions were dedicated to survival in the workplace; i.e. dealing with burnout, mentorship, work-life balance, mindfulness and meditation, giving and receiving feedback and many issues related to private practice.
When I was a trainee I was expected to be resilient; I simply had to get on with the job at hand. I was too busy to think about or identify these sorts of issues. I am not even sure if ‘burnout’ was an identified problem back in the late ’80s when I started my clinical training. For me, and most of my colleagues, internal medicine and neurology was a calling; ‘our vocation’. Being a doctor was more than simply doing a job. What has changed? My wife tells me the millennials have changed things; they are not as accepting as we were of the status quo and want something different out of life. Play and leisure define the millennials and not their work. Is this true? If yes, maybe I need to play more and work less hard?
The millennials demanding something different from life doesn’t explain it all. Something more seismic is happening to society and medicine. In the current era, often referred to as the post-industrial era, technology has democratised knowledge and the medical profession’s power base of asymmetric knowledge has been eroded. This is leading to an existential crisis for the profession. Unless you have a technical skill that you have honed over years with practice, for example, a surgical skill, our knowledge-based skills are being challenged by the crowd and algorithms. This is leaving the average neurologist frightened and bewildered; like a rabbit caught in the headlights. In the past, my colleagues used to get excited about major advances in medicine. Now what seems to excite them most are reminiscences from the past, from the era when our seniors seemed to be the masters of the universe.
Gone are the days of the clinical anecdote. Big data is now king. I heard a talk at the AAN2018 on pathogen discovery using deep nucleic acid sequencing of clinical samples (blood, spinal fluid, biopsies, etc.) and clever bioinformatics; unsurprisingly, it outperformed the clinicians. Gone are the days when an astute well-trained clinician would have the edge over their colleagues. In the current era technology and big data trump clinical skills and human knowledge.
Another example of a threat to neurology is the revolution that is happening in relation to gene therapy and RNA interference. Both are creating an unprecedented need for presymptomatic genetic diagnosis. Why waste time screening for single genes? Why not simply do whole genome sequencing on everyone at birth so that we can identify treatable genetic diseases, risk profile everyone for common diseases and then let algorithms analyse and reanalyse the genomes of the world’s populations as new information becomes available? It won’t be doctors that will be making diagnoses or treatment decisions it will be algorithms.
Neurologists still cling to the neurological examination claiming it is too complex for a machine to do and interpret. This is clearly not true. Data is emerging that the way we use our smartphones and how we interact with the web tells tech giants, such as Google and Facebook if we are depressed or have signs of early Parkinsonism. Image analysis using artificial intelligence of pictures taken of suspicious skin lesions and the retinae of diabetics are outperforming dermatologists and ophthalmologists at diagnosing skin malignancies and diabetic retinopathy. The same goes for image analysis in radiology and pathology. Why wouldn’t machines get better than us at interpreting physical function?
As we enter a world of smart wearables and other smart technologies it is only a matter of time before a robot will be able to perform and interpret a neurological examination better than we can. I have little doubt that the neurological examination will be deconstructed, improved on and ultimately performed by machines.
So how are we physicians and neurologists going to ensure our survival? Dare I suggest we redefine our role? Clearly, the part we play as diagnosticians will become less important as the algorithms take over this role. Treatment of disease will increasingly be delivered by assistants using care pathways and standardised protocols. IT systems linked to the electronic record will analyse variance. Any variance from the protocol will trigger an investigation into our practices. I am already aware of this happening in multiple sclerosis in relation to possible over- and under-prescribing of highly-effective disease-modifying therapies or DMTs.
To survive in the brave new world neurologists will need new skills, particularly in relation to sifting, curating and communicating information. We will increasingly be called upon to fight fake news and anti-science movements so as to protect our patients from harm. To be effective in this role will need to actively engage with the new media and acquire new digital skills. Neurologists will need to become better listeners and better communicators. We will need to shift the focus from a disease-centric worldview to a preventative and holistic worldview. Treating disease will become a smaller part of our work. We will need to train and support teams of assistants and nurse practitioners who will do the majority of the hands-on work. We will need to become knowledgeable and skilled in lifestyle and wellness counselling. More importantly, we are going to have to walk the talk; we are going to have to live our lives the way we want our patients to live theirs. Neurologists who lead by example will become the pioneers of a new type of neurological practice. Based on my experience at the AAN2018 I would call this Wellness Neurology.
Are you prepared to retrain as a wellness neurologist?
I am still haunted by the concluding lines from The Great Gatsby that are as relevant to me today as they were when I read them as a 16-year old: “So we beat on, boats against the current, borne back ceaselessly into the past.”
If you live in London it is impossible not to have gotten caught up in London-Marathon fever over the weekend.
Eliud Kipchoge won the London marathon in the second fastest recorded time (two hours two minutes 38 seconds). Interestingly, Kipchoge wears an electric blue band on his wrist, where four simple words are written: “No human is limited”. He has obviously not met someone with advanced MS who is disabled.
In the study below people with progressive MS used up to 2.81x times more energy on average, for simple mobility tasks, compared to control subjects. The progressive MSers in this study accumulated an oxygen deficit and experienced fatigue and exertion when repeating simple motor tasks such as rolling over in bed, moving from a lying to a sitting or a sitting to standing position, walking and climbing steps. Reasons for why MSers use more energy is complex but part of it is due to deconditioning, i.e. simply being unfit.
We don’t know how the brain perceives fatigue but a higher oxygen cost during physical activity is measured by the body and results in a greater perception of fatigue. The reason why Eliud Kipchoge can run mile after mile at a pace no man or woman has done before is that he is conditioned to do so and has trained his brain to not feel fatigue.
“The mind is what drives a human being, If you have that belief – pure belief in your heart – that you want to be successful then you can talk to your mind and your mind will control you to be successful. My mind is always free. My mind is flexible. That is why I wear this band on my wrist. I want to show the world that you can go beyond your thoughts, you can break more than you think you can break.”Eliud Kipchoge.
Lessons from elite marathon runners and the findings from this study suggest that rehabilitation interventions that increase endurance during physical tasks will help reduce fatigue in people with progressive MS. The question now is to get NHS resources allocated to setting-up a National exercise and training programme for MS-related fatigue and to get MSers to buy into the benefits of regular exercise no matter how disabled they are. I know this is easier said than done, but that is no excuse not to get it done; it needs to be done.
Please note, it is also not only about exercise, but how you live your life.
Kipchoge’s believes that “living simply sets you free”. For nearly 300 days a year, he lives and trains at a simple training centre in Kaptagat, a tiny village in the Kenyan highlands. He is known as the “boss man” by his training partners but that doesn’t stop him cleaning the toilets or doing his share of the daily chores. If you are interested in being inspired please watch ‘Breaking2’ a Nike sponsored project to see if the 2-hour barrier for the marathon could be broken. It is not that Kipchoge came so close to breaking the two-hour barrier, missing it by a mere 25 seconds, but his philosophy on how to live that is so inspiring. I am in awe!
OBJECTIVE: To compare the oxygen costs of mobility tasks between individuals with progressive MS using walking aids and matched controls and to determine whether oxygen cost predicted fatigue.
DESIGN: Cross-sectional descriptive.
SETTING: A rehabilitation research laboratory.
PARTICIPANTS: 14 adults with progressive MS (54.07+8.46 years of mean age) using walking aids and 8 age/sex-matched controls without MS.
INTERVENTIONS: Participants performed five mobility tasks (rolling in bed, lying to sitting, sitting to standing, walking and climbing steps) wearing a portable metabolic cart.
OUTCOME MEASURE(S): Oxygen consumption (V̇O2) during mobility tasks, maximal V̇O2 during graded maximal exercise test, perceived exertion and task-induced fatigue measured on a visual analogue scale before and after mobility tasks.
RESULTS: People with progressive MS had significantly higher oxygen cost in all tasks compared to controls (p<0.05): climbing steps (3.60 times more in MS), rolling in bed (3.53), walking (3.10), lying to sitting (2.50), and sitting to standing (1.82). There was a strong, positive correlation between task-induced fatigue and oxygen cost of walking, (rs(13)=0.626, p=0.022).
CONCLUSIONS: People with progressive MS used 2.81 times more energy on average for mobility tasks compared to controls. People with progressive MS experienced accumulation of oxygen cost, fatigue and exertion when repeating tasks and higher oxygen cost during walking was related to greater perception of fatigue. Our findings suggest that rehabilitation interventions that increase endurance during functional tasks could help reduce fatigue in people with progressive MS who use walking aids.
If you live in London you may have had your life interrupted over the last two weeks by the Extinction Rebellion protests. This is a serious environmental movement that wants us to act now to save the planet from environmental catastrophe.
As part of the protest, my daughters have been giving me a hard time about my carbon footprint. They want to know if I am offsetting my air miles, which I do occasionally, that is when I personally book my flights. But in general, I am sure that most of my air miles are not offset. However, there is one initiative I am proud of that is addressing climate change and that is TriMS.online.
triMS-online is a virtual online conference for people interested in MS. The original idea of triMS-online came from this blog; thank you.
The aims of triMS-online are multiple. The objective is to do punchy, short, themed MS-related conferences online that can be viewed as a live event, or asynchronously, i.e. when you have the time. This is particularly useful for people who can’t travel for family reasons, for example, you may have young children or you are a carer. Or you simply don’t have the time and/or resources to travel to large international meetings.
triMS-online is environmentally friendly; imagine how many air miles we are avoiding by not having to fly people to conferences?
The other advantage of triMS-online is that it takes high-quality MS research and education to resource-poor environments across the globe. We want a new generation of MS researchers and HCPs to have access to the latest MS research and teaching.
As founding chair of the scientific committee of triMS-online, I wanted to use the opportunity to shake things up a bit. When you go to ECTRIMS it is generally the same-old faces and KoLs on the platforms; the English refer to this as the ‘Old Farts’ syndrome, which includes me. We, therefore, invited a diverse group of ‘young’ MS academics from across the globe to run triMS-online and we made a strategic decision of having at least an equal number of women on the steering committee; in fact, 6 out of 10 of members are women.
The following is our second triMS-online programme, which addresses paediatric MS. We plan to run about 2-3 triMS.online conferences a year and have many ambitious plans for the triMS-online platform going forward. One idea is to host regional meetings on the platform, for example, a Latin American meeting in Spanish. Why not one in Polish or for that matter any other language?
I urge you to register for the next meeting and to submit posters. The platform is like a real conference with meeting rooms, social events and exhibition spaces.
We will be need feedback, including suggestions for future meetings. Don’t be shy and join the revolution, even though it may not be a rebellion.
We would encourage young academics, in particular, those who are from under-represented groups to submit posters for this next meeting.
In the past, I have made the claim that vaccinations, including vaccination with live attenuated viruses such as yellow fever, are relatively safe post-IRTs (immune reconstitution therapies) such as alemtuzumab, cladribine and HSCT.
I even have two Alemtuzumabers on my books who have both had yellow fever vaccines before travelling to Ecuador and the Galapagos Islands. who I frequently mention in talks who had no problems with the vaccine. I will have to retract that advice. HCPs have just been sent the following warning from the MHRA (Medicines and Healthcare products Regulatory Agency).
“We have recently received 2 reports of fatal adverse reactions to the yellow fever vaccine (Stamaril). Due to an increased risk of life-threatening reactions, the vaccine must not be given to anyone with a medical history of thymus dysfunction or who is immunosuppressed. In addition, extreme caution must be used and a careful risk assessment conducted before vaccination of people aged 60 years and older due to a substantially increased risk of such adverse reactions in this age group.”
This is particularly relevant to Alemtuzumabers in that there is recent data that has been presented that it damages the thymus. If you are HCP who works with MSers please read the advice on the MHRA’s website.
Below is the first case report of fulminant hepatitis owing to echovirus 25 in an MSers on ocrelizumab.
Please note continuous anti-CD20 therapy takes out your B-cells and prevents you from forming germinal centres (where B-cells get educated to make antibodies, i.e. the B-cell’s Universities) in lymph nodes and the spleen. In other words, ocrelizumab treatment causes functional splenectomy. The latter causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted.
This echovirus infection on ocrelizumab is a known-unknown; severe enteroviral infections have previously been reported after B-cell depletion, mainly in patients with haematological conditions.Meningoencephalitis is the most common manifestation, but there have been 3 other cases of fulminant hepatitis reported.
This case is a warning to be careful about infections on ocrelizumab. I predict that both the FDA and EMA will both have their say in relation to ocrelizumab’s adverse event profile in the future; maybe even an article 20 moment. The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels tells us there will be, or there are, infectious complications on ocrelizumab.
So if you are on ocrelizumab please be vigilant and take care.
….. A 44-year-old woman with RRMS received 600 mg of ocrelizumab intravenously every 24 weeks for 4.5 years as part of the OPERA II trial….
….. In July 2017, the patient and a person in close contact with her developed watery diarrhea. While the other person recovered quickly, the patient reported persistent febrile diarrhea (2 to 4 episodes/day) associated with a self-limiting maculopapular rash. For fever control, patient took 1000 mg of acetaminophen per day for 10 days. Two weeks thereafter, she was hospitalized. Blood tests showed increased alanine aminotransferase and aspartate aminotransferase levels (1847 and 2484 U/L, respectively; to convert either value to microkatals per liter, multiply by 0.0167), without cholestasis……
….. after admission, alanine and aspartate aminotransferase levels peaked to 6241 U/L and 9799 U/L, respectively, with increased bilirubin (total, 4 mg/dL; direct, 2.9 mg/dL; to convert either value to micromoles per liter, multiply by 17.104) and signs of coagulopathy (prothrombin time, 24%; international normalized ratio, 2.95). Owing to progression to liver failure, she received a liver transplant 11 days after admission……
….. In the patient’s native liver tissue, an HBV DNA test result was negative, while a test result for enterovirus RNA was positive. A phylogenetic analysis revealed that both serum and native liver samples harbored echovirus 25…..
….. ocrelizumab was permanently withdrawn, the patient did not show signs of MS activity or disability progression, possibly owing to the immunosuppressive effects of basiliximab and tacrolimus, which were given to prevent liver rejection…..
Another alemtuzumab-related post, this time in relation to alemtuzumab-associated liver injury, which has been also been included as a complication of alemtuzumab treatment in the EMA’s SmPC (summary of product characteristics).
Liver or hepatic injury can occur as part of a drug-induced injury as seen in case 2 below or as a delayed, presumably autoimmune, condition as in case 1 below. Please be aware autoimmune hepatitis has been described in association with all licensed MS DMTs including the original injectable therapies, i.e. interferon beta and glatiramer acetate. I have always considered this to be a simple association, i.e. pwMS are at risk of developing comorbid autoimmune hepatitis.
Again I think autoimmune hepatitis is a rare complication if it is a complication, of alemtuzumab treatment. You need to be vigilant of any new symptoms and get medical help immediately if you experience any of the following:
25-year-old female patient was diagnosed with RR-MS in September 2011. The patient received two courses of ATZ in November 2014 and 2015 successively. She remained stable with an EDSS score of 4 and no recurrence of disease activity on brain MRI. Eleven months following the last ATZ course, laboratory assessments revealed hyperthyroidism attributed to Grave’s disease. l-thyroxin and thiamazol were initiated.
An increase in liver enzymes occurred 1 month later, while thyroid function was normalized. Despite the interruption of thiamazol, liver dysfunction persisted.
Liver biopsy showed a diffuse, severe and mixed inflammatory infiltrate, composed of lymphocytes, eosinophils and neutrophils, infiltrating the limiting plate, surrounding the portal triad, and sparing the biliary tract. A diagnosis of type 1 autoimmune hepatitis (AIH) was made.
Standard treatment, consisting of 1 mg/kg/day of prednisolone, was initiated, with a transient episode of encephalopathy, resolving after corticosteroid dose reduction (to 0.5 mg/kg/day). 1 month later, the patient improved clinically and her laboratory abnormalities resolved; prednisolone doses were then slowly decreased, and immunosuppressive treatment with azathioprine was introduced.
This patient developed severe hepatitis within two days of starting alemtuzumab, both initially and upon rechallenge. The alanine aminotransferase peaked at 577 units per litre and 426 units per litre after the initial dose of alemtuzumab and rechallenge respectively. The patient’s liver function tests improved significantly between doses of alemtuzumab and again normalised within three months of the second dose, with no clinical manifestations of acute hepatic failure.
This post has been moved to Medium. From now on Prof G will do all personal postings on Medium. He will continue to post on this platform but will be limiting his posts on the Barts-MS blog to factual content, no random personal musings and no off-beat MS topics.
