When I started my training as an MSologist working for W. Ian McDonald at Queen Square I recall us having to see MSers with very severe and disabling relapses on a weekly basis. We always had one or two MSers on the wards; admitted to hospital to manage severe relapses, pressure sores, fractures and severe contractures. This rarely happens now. The only patients with relapses that get admitted tend to be patients coming via A&E with their first attack, i.e. their initial presentation. DMTs don’t only reduce relapses they reduce the severity of attacks. I estimate that the use of high-dose steroids to treat relapses has dropped off by over 80%. Most of our RRMSers are being treated to target and are NEDA and relatively stable. We know that prognosis for relapse-onset MS has changed. With DMTs, in particular, high-efficacy DMTs, we have revolutionised the outcome for people with the disease; fewer relapses, milder relapses, less disability, fewer people with SPMS, improved survival, better symptomatic treatments, etc.
What about PPMS? Firstly, the proportion of people being diagnosed with PPMS has fallen from about 15% of the new, or incident, cases to 5%. Why? This is because neurologists don’t label people as having PPMS so that they can offer them treatment. Even those with a diagnosis of PPMS are being treated in most countries, with either licensed DMTs or off-label treatments such as rituximab. At Barts-MS we have a cohort of our PPMSers on rituximab and an increasing number with active PPMS on off-label cladribine. I also have quite a large number of PPMSers who I still follow who I treated with mitoxantrone. We are also offering an increasing number of PPMSers HSCT. In fact, I saw one of my patients with PPMS, who had HSCT in February this year, in clinic last week. She seems to have done well; i.e. she is stable and says her fatigue levels are much better. And finally, we have ocrelizumab licensed and available to treat early, active, PPMS. Ocrelizumab delays the need for a wheelchair by about 5 years and maintains arm and hand function by about 9 years. Is this not an improvement on what was available 25 years ago? In addition, there is a lot of activity in terms of PPMS trials. We are about to start ORATORIO-HAND, the second ocrelizumab in PPMS trial, and I am aware of at least three other PPMS trials in development.
Despite the advances in the treatment of PPMS mentioned above we have done many other things. For example, we have improved the recognition and diagnosis of the condition. Also, the symptomatic treatments for PPMS have improved. There are newer antispastic agents (Sativex, intrathecal baclofen, gabapentin), drugs and devices to improve walking (fampridine, functional electric stimulators, botox, better splints), better drugs and devices for bladder and bowel dysfunction, better drugs for pain, better drugs for osteopaenia, and this list goes on. We are improving outcomes by managing MS holistically and this is why the life-expectancy of PPMSers has improved substantially and is now only 3-4 years below what is expected for the general population; 25 years ago life expectancy was about 8 years lower.
So this commentator, who is clearly a cynic, should think a little more deeply and look at the facts before commentating.
Maybe the following quote from Bill Gates’ is apt: “we always overestimate the change that will occur in the next two years and underestimate the change that will occur in the next ten. Don’t let yourself be lulled into inaction”.
So if you have been diagnosed with PPMS in the last few years your outcome is so much better than it was 25 years ago and will continue to improve over the next 25 years. Please remember that innovation is relentless, even if you have PPMS, so never give up hope!
I have just returned from the EAN in Oslo. A strange meeting of encore abstracts and talks; clearly 2nd tier for the MS community.
There were very few MSologists who attended. Why? They have all already attended either ECTRIMS and/or the AAN. All the MSologists I met at the EAN were either bused in to talk, to attend private MS meetings or to film CPD activities, but not to learn or be influenced as the abstract below suggests.
The EAN, however, is a meeting that Pharma, Big Pharma, has earmarked to get the message across to the general and other specialist neurologists that MS is an important disease, which they need to take seriously. That is (1) recognising the symptoms ASAP, (2) to diagnose the condition ASAP and (3) to refer the patient to a specialist MS unit ASAP (4) were they will be started on a high efficacy DMT ASAP.
Is this ASAP philosophy such a bad thing? No.
The whole premise underpinning our ‘Brain Health: Time Matters’ policy document is to try and activate the MS community to treat MS as a semi-emergency or an emergency. Why wait to be diagnosed, treated or treated with highly effective DMTs if time is brain (or spinal cord)?
The EAN, however, is dominated by MS marketing. I would estimate that 75% of the money spent on marketing at the EAN was MS-related without many MSologists in attendance. The scale and quality of the Pharma MS stands were impressive. Interesting or not? This is the Red Queen Effect in action.
The Red Queen Effect is a term taken from the Red Queen’s race in Lewis Carroll’s Through the Looking-Glass. The Red Queen said, ‘It takes all the running you can do, to keep in the same place.’ The marketing departments of Big Pharma are simply feeding the Red Queen as they try to compete with each other; in reality, they are simply running on the spot with the downside of reputational damage to neurology, themselves and the industry as a whole. When MSers see and hear about the marketing extravaganza that comes with conferences it is no wonder they don’t respect Pharma and neurologists. This is one of the issues that feed social phenomena such as CCSVI and HSCT and divides society. It is simply another example of the haves and have-nots.
I would like to suggest to Big Pharma that it looks at itself in the mirror and rejects the Red Queen Effect and comes up with something more sustainable that will help us regain our self-respect and more importantly the respect of the community that we serve. Note the ‘Royal We’; by participating, I am part of this jamboree.
Despite my criticisms, I suspect nothing will happen. Turkeys’ are as likely to vote for Christmas as Turkey Farmers’ are to vote for cancelling Christmas.
Despite my overt cynicism, I believe that a leader, a true leader, will emerge and slay the Red Queen. And from the ashes, a Phoenix will arise that will change the way Pharma sees and interacts with the world.
For example, why doesn’t one brave Pharma company hire a stand and keep it empty? Empty, except for maybe a few white pinboards with the publications of the peer-reviewed papers that led to the licensing of their product(s). They could also have a board or box for post-it notes for suggestions to donate the money saved on not having an expensive stand to be donated to an MS charity, to support a specific research project or provide DMTs for people living with MS in resource-poor countries. However, doing this would put the marketing teams, designers, builders, booth bunnies, hospitality and logistics staff, etc. out of business. With the latter perspective maybe the Pharma gravy train should be embraced as being a net contributor to society and the economy in general and we should support the Red Queen instead; maybe even increasing the speed of her treadmill?
I maybe a grumpy old man, but I don’t like the underbelly of conferences and what they represent. Maybe it’s time to throw in the towel?
Conferences traditionally play an important role in the ongoing medical education of healthcare professionals. We assessed the influence of attending the ECTRIMS congress on therapeutic decision-making in multiple sclerosis (MS) care. A non-interventional, cross-sectional study involving 96 neurologists was conducted. Treatment escalation when therapeutic goals were unmet and management errors related to tolerability and safety scenarios of MS therapies were tested using different case-scenarios. Attendance at ECTRIMS was associated with an increase likelihood of treatment escalation in the presence of clinical progression (cognitive decline) and radiological activity (OR 2.44; 95% CI 1.06-5.82) and lower number of management errors (OR 0.26; 95% CI 0.07-0.98). Attendance at ECTRIMS may facilitate therapeutic decisions and reduction in management errors in MS care.
I am at the European Academy of Neurology (EAN) congress in Oslo. It is quite clear that in the message of brain health and the holistic management of MS has moved center stage. Everyone is talking about #BrainHealth.
The emphasis is now on early diagnosis, early effective treatments and maximising brain health as a treatment goal. To do this we need a full toolbox of treatments, new therapies and to manage MS holistically with a focus on the individual with MS.
In terms of getting these messages across Genzyme-Sanofi have commissioned an art installation on their EAN stand; a large brain ice sculpture that is gradually melting over course of the Congress. Embedded in the ice sculpture are items that are meaningful to MSers, for example, a wedding ring to symbolise relationships, a cocktail glass for social activities, a passport for travel, a teddy bear for children and family and various other work and other activity related items. As the ice sculpture melts these items will emerge to remind us why protecting the brain for the individual with MS is so important. On the plinth of the ice sculpture, it states ‘there is no MRI for quality of life’ to remind us that behind every MRI scan is a living person with hopes and aspirations. It is also suggesting that we need a person-focused, and not an MRI-focused, view of MS.
On the stand, there is a photographer who is taking pictures of Congress attendees alongside the ice brain sculpture holding various pledges in connection with brain health in MS. I took a pledge.
My concern is that the regulators, in particular, the EMA and the FDA, don’t see it this way. The EMA is currently reviewing alemtuzumab’s risks and benefits, under an article 20 procedure, to see if it needs to change alemtuzumab’s license. At the moment it has put temporary handcuffs on alemtuzumab recommending that it is only used third-line, i.e. after MSers have failed at least two prior DMTs. The problem I have with this is that the average MSers spends about fours years on each tier of DMT, in addition to the many years lost in the asymptomatic and diagnostic phases of the disease. In other words, most MSers would have had MS for more than 10 years before they can access alemtuzumab 3rd-line. In 10 years many MSers would lose more than 10% of their brain volumes, become cognitively impaired, developed bladder dysfunction and have walking problems; not to mention the impact that undertreated MS has on their social and occupational functioning. Limiting alemtuzumab, our most effective DMT when it comes to ‘normalising’ brain volume loss in MS, to these sorts of patients is wrong and makes no sense.
So a plea to the EMA to think very carefully before taking away the option of using alemtuzumab early in the course of MS.
My interpretation is that we have found ourselves in this article 20 position because the American neurologists are having to use alemtuzumab 3rd-line and later in the course of MS; i.e. in older patients with more comorbidities. This almost certainly explains some of the vascular complications of alemtuzumab. Alemtuzumab was never tested in this population and therefore we don’t really know its risks and benefits in an older more disabled population of MSers.
I predict that if the EMA makes alemtuzumab a 3rd-line agent then we will start to see the same problems the Americans have seen with alemtuzumab. Forcing us to keep our most efficacious DMT for last flies in the face of conventional wisdom and current thinking about how to manage MS.
Another issue I have is that the EMA and FDA think they need to protect MSers from risky therapies and irresponsible neurologists and HCPs. In other words, the regulators don’t trust MSers to be able to make their own decisions about the treatment they receive. In short, the EMA is saying to you that you can’t assess what risks you are prepared to accept and as a result, you can’t choose the most effective DMT 1st-line. I would argue that this is patronising and not in keeping with the wish to empower MSers.
I am sure that if we are forced to stop offering alemtuzumab first-line more of my patients, who can afford it, will seek HSCT and other risky treatments abroad. Is this what we want? I have learnt that all decisions have unintended consequences and the EMA may in fact put more patients at risk of off-label treatments as a result of the unintended consequences of their decision(s) and they will entrench inequalities, i.e. the rich will simply travel abroad to get treated and the poor will be left to fester.
The EMA needs to understand what it is really like to be someone with MS, staring down a barrel playing Russian roulette on low efficacy DMTs, whilst their brains are being irreversibly shredded by MS. The brain is the most precious organ we have and we need to do everything we can protect it so we can have some resilience in old age.
I, therefore, call upon you the MS community to prevent the EMA from handcuffing alemtuzumab and denying neurologists and their patients the option of using alemtuzumab, our most effective DMT, early on in the course of MS. We will all be worse off for not having the option of using alemtuzumab the way we use it now.
Let’s talk about death, that is unassisted suicide.
The meta-analysis below, not surprisingly, shows that if you have MS your chances of suicide are about twice the background rate. The risk is particularly high at diagnosis compared to symptom onset. I suspect this latter is an artificial finding; if you commit suicide before you are diagnosed with MS the code ‘multiple sclerosis’ is unlikely to be recorded alongside suicide as a cause of death. Despite this, it is clear that suicide is a not such an uncommon cause of jumping from EDSS 2.0 or 3.0, at diagnosis, to EDSS 10 or death.
In my career as an MSologist, I have had two patients commit suicide. Both made me question whether or not we could have done something to prevent their deaths. In both cases, the answer was yes; I could have done much more to manage their associated depression and social isolation. HCPs working in MS need to skilled in recognising depression and suicide risk. One of the reasons why we are running our #ThinkSocial campaign is to address these issues and the social determinants of outcomes in MSers.
It is understandable why MSers resort to suicide. MS is a devastating diagnosis with major consequences for individuals. As it is a brain disease it affects your personality and hence interpersonal relationships. MSers are often anxious and depressed. It has a major impact on your life trajectory. Most MSers given sufficient time will become disabled and unemployed. The loss of income results in downward social drift, often causing poverty and in some cases severe social isolation. It is not surprising that some MSers turn to suicide as a way out.
Society doesn’t help. It rates the life of someone with MS who has lost both lower and upper limb function (EDSS>=8.5), who need 24-hour a day care, as having a quality of life worse than death. However, it doesn’t have to be this way. I suspect this negative view of MS will change as a result of earlier diagnosis and treatment of the disease to prevent end-organ damage and its consequences.
We are beginning to see a transformation in outcomes as new cohorts of MSers are being diagnosed earlier and treated effectively. The problem we have is getting the wider MS community to acknowledge that MS as a neurological emergency. When we say ‘Time Matters’ and ‘Time is Brain’ we really mean it. This is why we want to do our #AttackMS trial to try and change attitudes to treating MS.
I am aware talking about death is a taboo, but unless we do how do we expect MSers to take decisions about their treatment seriously. Yes, seriously. I often speak about the Gambler’s dilemma, a cognitive bias that affects both MSers and their HCPs.
A gambler never goes into a casino to lose money. However, the gambler knows that on average he/she will lose money. The cognitive bias that affects MSers is that they will be the lucky one that will win; they are going to be the lucky one that will turn out to have benign MS. ‘I am going to be the one that ends up with no problems in the future, therefore, I don’t need to be treated’ or ‘ No, that treatment is far too risky for me, I will take my chances with an injectable’. Chances are you will be wrong.
As I have said given sufficient time MS causes disability in the majority of people with MS. Therefore the practices of watchful waiting (a British medical tradition) and/or slow stepwise escalation of treatment comes at a cost to individuals with MS. This is why it is so important to buy into an aggressive treatment goal when you are diagnosed with MS.
The treatment targets in MS have evolved from simply reducing the frequency of relapses (NEDA-0) to becoming relapse-free (NEDA-1) to having no measurable disease activity (NEDA-3), to preventing end-organ damage (NEDA4 and NEDA-5) to finally maximising brain health to allow you to age normally.
In the future, we will want to cure you of your MS before any meaningful damage is done to your brain and spinal cord, and we will want to prevent people at risk of MS getting the disease. To achieve these targets we need a much more proactive treatment approach and we also need to manage MS holistically, which includes actively preventing and managing comorbidities and focusing on wellness and lifestyle factors.
The cynics will be poo-pooing my enthusiasm, but if we don’t aim high we will never achieve a world without MS and suicide will remain a problem.
Let’s talk about death, but focus on what needs to be done to prevent it!
BACKGROUND: Whether multiple sclerosis is associated with a higher rate of suicide remains controversial. Therefore, we aimed to evaluate the risk of suicide in multiple sclerosis patients based on a meta-analysis of previously published data.
METHODS: We searched for studies that measured the suicide risk in multiple sclerosis patients compared with the general population that were published up to 1 December 2018 in PubMed, EMBASE, and Web of Science databases. Sixteen studies fulfilled the eligibility criteria. We performed random-effects meta-analyses to calculate suicide rate ratio (SRR) and 95% confidence intervals (CIs) for patients with multiple sclerosis.
RESULTS: The association between suicide and multiple sclerosis was statistically significant with a pooled SRR 1.72 (95%CI 1.48-1.99, I-squared = 55.0%). Risk of suicide at diagnosis of multiple sclerosis (SRR 2.12, 95% CI 1.84-2.46; I-squared = 4.4%) was higher than the risk of suicide at symptom onset (SRR 1.69; 95% CI 1.43-2.00; I-squared = 0.0%). Gender may exert an influence on the impact of sex on the association between MS multiple sclerosis and suicide, but this requires is controversial and need further studies to demonstrate.
CONCLUSION: Our meta-analysis shows a significant association between suicide and multiple sclerosis, although ethnic and geographical differences were not considered. These findings should be confirmed and extended in future large studies.
Making a decision about which DMT to prescribe, or preferably to help your patients make a decision, many of my colleagues mix up their priorities. For example, some mix-up baseline prognostic profiling and disease activity, and then some of them throw disease-stage or disability progression into the mix. I think this occurs because these factors are somewhat related, but only tell part of the story.
Disease activity (DA) – Disease activity (DA) really refers to the here-and-now and what has happened in the last 12-24 months. DA does affect prognostic profiling (PP), but it is only one component of PP.
DA refers to recent focal inflammatory activity and hence is defined as relapses in the last 2 years and focal MRI activity, i.e. new or enlarging T2 lesions and Gd-enhancing lesions, in the last 12 months. More recently raised at Barts-MS we have also incorporated raised CSF neurofilament levels in the last 12 months.
In the UK/NHS we have 4 categories of DA:
Inactive
Active
Highly-active
Rapidly evolving severe
Inactive MS – If you have had no relapses in the last 24 months, and serial MRI studies covering this period show no new lesions, then your MS is defined as being inactive. This does not mean your MS is necessarily stable. I have said that you could have worsening disability as part of the progressive phase of the disease without focal inflammatory activity. If you have so-called inactive MS you need to be monitored, as inactive MS may reactivate and you could then become eligible for treatment.
Active MS – Most neurologists require evidence of disease activity in the last 24 months, with most accepting a 12-month window if there is MRI support. Our current criteria for active MS incorporates MRI into the definition, which allows us to treat so-called high-risk patients with CIS.
Highly-active MS – These are MSers with unchanged or increased relapse rate, or ongoing severe relapses compared with the previous year, despite treatment with beta interferon, or another so-called first-line DMT. Another category refers to treatment-naive MSers with two attacks in a 12 month period with MRI evidence of activity during this period.
Rapidly-evolving severe MS – Rapidly-evolving severe MS (RES) is defined as two disabling attacks in a 12 month period with MRI evidence of activity during this period.
Prognostic Profiling (PP) – Prognostic profiling (PP) really refers to baseline factors that have been linked to poor prognosis. Although several of DA metrics are associated with a poor prognosis they are a small part of the prognostic profiling metrics I personally use. The following is a list of 24 prognostic factors I tend to use in clinical practice. In general, if you have four or less you fall into the good prognostic category, five to eight the intermediate prognostic category and if nine or more the poor prognostic category.
Age of onset (<40 vs. >40 years) (1)
Sex (F vs. M) (1)
Sites: unifocal vs. multifocal onset (1)
System:
Motor: no vs. yes (1)
Cerebellar: no vs. yes (1)
Bladder: no vs. yes (1)
Cognition
Impairment: no vs. yes (1)
Learner: yes vs. no (1)
Recovery: complete vs. partial or no recovery from initial relapses (1)
Relapse rate: low/ ≤ 2 vs. high / >2 in the first 2 year (1)
Early disability: EDSS < 3.0 vs. EDSS ≥ 3.0 within 5 years (1)
Active: no Gd-enhancing vs. Gd-enhancing lesions (1)
Posterior fossa lesions: no vs. yes (1)
Spinal cord lesions: no vs. yes (1)
Brain atrophy: no vs. yes (1)
CSF
OCBs (oligoclonal IgG bands): no vs. yes (1)
Raised neurofilament levels: no vs. yes (1)
Vitamin D levels: low vs. normal (1)
Smoker: no vs. yes (1)
Comorbidities
diabetes/prediabetes: no vs. yes (1)
Hypertension: no vs. yes (1)
Hypercholesterolaemia: no vs. yes (1)
obesity: no vs. yes (1)
Total Score out of 24
Disease Stage (DS) – Disease stage (DS) simply refers to the amount of damage accumulated, i.e. how disabled you are. We tend to overlap this with disease descriptors early in the disease course, simply to help deal with treatment guidelines and to set the scene for changing our worldview of MS; i.e. away from a neurological/clinical perspective to a biological perspective (pathology). If we changed our worldview of MS we would almost certainly want to treat MS in the asymptomatic stage to prevent disability. Please note that we still live in an EDSS-centric world and hence the EDSS is used by most people to define disability.
In an ideal world, we would include other metrics, in particular, cognition, to define MS-related disability and include end-organ damage markers (brain volume loss) or other metrics that measure reserve capacity. The latter is critical in defining the resilience of your nervous system to deal with insults in the future including physiological or normal ageing.
The following is my classification system of DS:
Radiologically isolated syndrome (RIS) with no apparent disability (EDSS = 0)
Clinically isolated syndrome (CIS) with no apparent disability (EDSS = 0)
MS with no apparent disability (EDSS = 0)
MS with mild physical disability (EDSS=1.0-3.0)
MS with moderate physical disability (EDSS=3.5-5.5)
MS with severe physical disability (EDSS=6.0-6.5)
Advanced MS with profound physical disability(EDSS >=7.0)
Although DS may affect treatment decisions we need to get away for the idea that to be treated effectively, i.e. with highly-effective treatments, you need to be disabled. Our current philosophy is to treat early to prevent disability.
In the following slideshow, I try and put all these factors together in a 3D graph. Please note that the grey cubes represent an evidence-free zone and DMTs are typically not used in MSers with these attributes. We are trying to change this with our #TreatEarly, #BrainHealth, #PreventMS and #ThinkHand campaigns.
The colour scheme to denote the level of DMT by risk category is an estimate. I have included this to try an illustrate the complexity of decision making that is involved in selecting DMTs when considering only three factors. This gets even much more complex when you start to incorporate personal factors.
I predict this post will be very controversial. So let me know your thoughts.
Our microbiomes are clearly very important, but they don’t come close to explaining why you get MS and whether or not one of our microbiomes is causal in MS. Yes, there are multiple microbiomes in and on our bodies. At the moment the attention is all focused on the gut microbiome, in particular, the distal colon. Why? Because it is easy to collect poo samples. But why the colonic microbiome in MS and not another site?
If I had the time and interest I would focus on other sites, in particular, the paranasal sinuses and lungs. There is a hypothesis that infections in the paranasal sinuses are more common in MSers and can trigger MS. There is some evidence, albeit weak, that MSers are more likely to have had sinusitis than control subjects. What organisms are causing these episodes of sinusitis?
The other site is the lungs. Smoking and solvent exposure increases your risk of getting MS. It does not appear to be tobacco itself which is the risk factor because the oral use of tobacco is not associated with an increased risk of getting MS. In fact, oral tobacco use appears to lower the risk of getting MS. The overlap between smoking and solvents could be via the microbiome in the lung and/or lower respiratory tract.
For me, the most exciting data points to our internal or systemic microbiome, i.e. the viruses and bacteria that live within our bodies. EBV is an exogenous virus that lives with our bodies; in fact inside memory B-cells the major therapeutic target of our treatments. The evidence for EBV being the cause of MS is so overwhelming that we are planning an anti-EBV vaccine prevention trial and we are also exploring anti-viral strategies against EBV.
How EBV causes MS is unknown, but one hypothesis is via its induction of HERVs (human endogenous retroviruses). EBV simply wakes-up, or resurrects, these dormant viruses which then activate the immune system and trigger autoimmunity. This is why we are so keen to target HERVs with antivirals as a treatment strategy for MS.
But getting back to the gut microbiome. In my opinion, it is simply the latest research bandwagon with everyone making premature claims that by manipulating it we may be able to prevent people from getting MS in the first place. Or alternatively, once you have MS we may be able to treat your disease by manipulating the microbiome with diet or by providing you with ‘good’ bugs. This has resulted in a new generation of quacks offering vulnerable MSers faecal transplants to ‘treat’ and ‘cure’ them of having MS. There is simply zero evidence to support these claims so please avoid being hoodwinked into having a faecal transplant, which may be dangerous.
The following microbiome paper is interesting and shows that (1) daily microbiome variation is related to your food choices, but not to conventional nutrients, (2) daily microbiome variation depends on at least two days of dietary history and most importantly (3) similar foods have different effects on different people’s microbiomes. Therefore, there will be no magic bullet bacterial pill, super-poo transplant or some superfood diet that will necessarily alter your microbiome.
My advice is to eat well and eat sensibly, real-food rather than processed food, and get off the microbiome bandwagon until some class 1 evidence emerges to contrary.
Diet is a key determinant of human gut microbiome variation. However, the fine-scale relationships between daily food choices and human gut microbiome composition remain unexplored. Here, we used multivariate methods to integrate 24-h food records and fecal shotgun metagenomes from 34 healthy human subjects collected daily over 17 days. Microbiome composition depended on multiple days of dietary history and was more strongly associated with food choices than with conventional nutrient profiles, and daily microbial responses to diet were highly personalized. Data from two subjects consuming only meal replacement beverages suggest that a monotonous diet does not induce microbiome stability in humans, and instead, overall dietary diversity associates with microbiome stability. Our work provides key methodological insights for future diet-microbiome studies and suggests that food-based interventions seeking to modulate the gut microbiota may need to be tailored to the individual microbiome. Trial Registration: ClinicalTrials.gov: NCT03610477.
We need to be able to explain smouldering MS and why pwMS get worse despite having no evident disease activity (NEDA) on DMTs. One of the hypotheses is that something is occurring within the brains and spinal cords of pwMS. I have referred to this in the past as the field hypothesis and have suggested that it could be due to an active virus within the brains of pwMS. I have always made the point that the two viruses with most of the evidence behind them are EBV and HERVs, particularly HERV-W.
This study below strongly suggests that the HERV-W envelope protein may be driving smouldering MS. It would be interesting if the ENV protein is found in SELs (slowly expanding lesions). This study supports our Charcot Project and the urgent need to formally test HAART (highly active antiretroviral therapies) in MS. Our INSPIRE trial, which was negative, was not HAART as it only tested one anti-retroviral and integrase inhibitor.
Do you have the appetite for another push at getting funding for an add-on HAART trial in MS? The case for doing it is compelling both from an epidemiological and basic science perspective.
Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.
I was still wet behind the ears, in my 3-year as a neurology registrar in Johannesburg, when I first used an off-label DMT in MS.
I manage to convince Vivian Fritz, my professor of neurology, to allow us to treat one of her patients with MS with mitoxantrone. This was shortly after the first case series had emerged from Germany.
The patient concerned was a young woman with malignant MS who had one relapse after another and was in our ward for steroids and neurorehabilitation. She had just had a severe spinal cord relapse. She had an EDSS of 8.5 (bed bound with partial loss of hand and arm function). She had had MS for just 2 years. I proposed that she would likely die from her MS if we did nothing to stop her attacks. What had she, and her family, to lose by trying a course of mitoxantrone?
Viv Fritz listened and read the case series. After some reflection, she finally agreed to us trying mitoxantrone in her patient. We went ahead with a course of infusions as per the case series. The patient did so-so; i.e. we managed to stop her having more attacks, but she never got out of a wheelchair. I heard later that she sadly died about 2 years later after she developed septicaemia from an infected pressure sore.
The point I am making about this case is that as a neurology trainee in South Africa I was able to read about a potential innovation in Europe, suggest it to my Professor, argue the case and change our unit’s practice. There were other examples of OLP in SA; it was common in Johannesburg and I suspect it is still happening.
In comparison, OLP is not universal. I have just returned from a short visit to Japan where I found the culture amongst Japanese neurologists to be very similar to parts of the UK in relation to OLP. Very few Japanese neurologists are prepared to stick their heads above the parapet and prescribe off-label DMTs. Why? And what are the potential consequences of not adopting OLP for their patients?
With regards to why I think it is cultural. OLP seems to be more common in cultures that allow individuals to express themselves and challenge the status quo. Japanese neurologists are very deferential and respect their superiors. The same applies to trainees in the UK. For OLP to be widely adopted in Japan and the UK, heads of department, or the ‘neurology establishment’, will have to lead the way.
I am personally in favour of OLP as an engine of innovation. So many of our DMTs in MS have been developed from the insights and actions of individual neurologists who were brave enough, yes brave enough, to give it a go. Larry Jacobs administered intrathecal interferon-beta to his patients based on the hypothesis that MS was due to a virus. Interferons are foremost antiviral agents hence their name. Professor Jacobs saw positive results in a few of his patients and the rest is history. Interestingly, we still don’t know exactly how interferon-beta works. It may be working in MS as an antiviral agent; we just don’t know. Nobody to my mind has disproved the antiviral hypothesis of interferon-beta’s mode of action.
Professor Larry Jacobs; interferon-beta pioneer
Mauch and colleagues tried mitoxantrone, an anti-proliferative chemotherapy agent, on the basis that MS is an autoimmune disease. Mitoxantrone is cell depleting chemotherapy agent and was the first immune reconstitution therapy (IRT) to be licensed. The idea is to simply kill the autoimmune cells responsible for causing MS. It took more than a decade of wider adoption of off-label mitoxantrone prescribing and research before mitoxantrone was eventually licensed as a treatment for MS.
Cyclophosphamide was less fortunate. Cyclophosphamide had been tried in MS for similar reasons as mitoxantrone. Unfortunately, cyclophosphamide was trialled in an era when the MS community didn’t know how to do trials. Cyclophosphamide failed as it was tested in more advanced MS and all the trials were underpowered, i.e. the trials had too few patients to be definitive. I am prepared to bet that if cyclophosphamide was formally tested in early in MS and the trials were adequately powered that it would be shown to a highly-effective DMT.
A more well-known example of OLP and innovation is Professor Alastair Compston’s off-label use of alemtuzumab. It started with Prof. Compston using it in a handful of patients in the early 1990s. Alemtuzumab was being tried in MS based on the same hypothesis as that for mitoxantrone and cyclophosphamide, i.e. MS is autoimmune and that to treat it and potentially cure MS you need to reboot the immune system killing off the autoimmune cells or at least regulating them when the immune system reconstituted itself.
I recall attending my first meeting in Cambridge, in late 1993 shortly after arriving in the UK to do my PhD, when Alastair presented the results of his first two patients. At the end of the meeting Professor Newsome-Davis, a senior and well-respected neuroimmunologist said to me that he didn’t agree with this approach. I recall him saying what we really needed was a pair of molecular tweezers and not a sledgehammer to treat autoimmunity. Unfortunately, the molecular tweezers are still the holy grail and without Alastair Compston’s perseverance, alemtuzumab would have never made it to the clinic.
Another example, is Prof. Jonathan Edwards, a rheumatologist at UCLH, who was brave enough to successfully try rituximab as a potential treatment for rheumatoid arthritis (RA). This was a very counterintuitive as the whole world at the time thought RA was a T-cell mediated autoimmune disease. The success of rituximab in RA led to senior executives at Genentech drawing up a list of other autoimmune diseases to try rituximab in. This and other factors subsequently led to Anne Cross trying rituximab in MS. Without a brave clinician trying OLP of an anti-CD20 in RA, we wouldn’t have ocrelizumab and several other me-too anti-CD20s in trials for treating MS.
There are similar stories for dimethyl fumarate, daclizumab, cladribine and some of the other emerging DMTs. Innovation in MS and other areas of healthcare emerge in an environment where OLP is championed and clinicians and their patients are brave enough to test the waters. What has changed?
It seems as if Barts-MS is being criticised, by some UK neurologists, for our compassionate use of off-label subcutaneous cladribine in more advanced MS. I don’t understand this as our position is no different from that of our predecessors mentioned above. We are simply building on a hypothesis that inflammation drives MS disease progression at all stages of the disease. We don’t agree with the 2-staged disease hypothesis of MS, i.e. that MS has an inflammatory phase that is followed by a neurodegenerative phase. The data overwhelming supports the parallel hypothesis that inflammation drives neurodegeneration throughout the course of the disease.
The implications of the parallel hypothesis of MS is that MS is potentially modifiable by anti-inflammatory therapies throughout its course; this even applies to advanced MS, which is why we will be formally testing DMTs in people who are already using wheelchairs for their mobility.
Another implication of the parallel hypothesis of MS, i.e. MS is always both inflammatory and neurodegenerative, is that we need to build a sandwich with an anti-inflammatory therapy, or a combination of anti-inflammatory therapies, at the base and to then use this as a platform on which to build the layers of the sandwich, which includes add-on neuroprotective, remyelination and neuro-restorative therapies.
At the same time we need a holistic approach and to focus on all the other factors that may impact on the health of the brain of someone with MS. This is why we need to proactively manage all of the things that are potentially associated with accelerated ageing in pwMS.
For this reason, I have been proposing for some time that we adopt the marginal gains paradigm when treating MS. Dave Brailsford from the British cycling team is acknowledged as making the marginal gains approach mainstream.
“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Sir Dave Brailsford.
Small changes in many things can have a massive impact on the overall outcome. Prior to Dave Brailsford taking over as head coach of the UK cycling the team, it was in the doldrums. In 1996, prior to adopting the marginal gains philosophy, Team GB was in 12th place in the Olympic Games medal table with two bronze cycling medals. In comparison at the Beijing games in 2008 Team GB won 12 medals from 10 events; 7 gold, 3 silver and 2 bronze medals.
Why can’t we apply marginal gains to the management of MS? If you have MS, you need to ask what you need to do across your disease course to maximise your chances of having a good outcome. This means not only focusing on optimising your MS DMTs but doing all the lifestyle things you can do and more.
For the naysayers, who are criticising Barts-MS for trying to treat people with advanced MS (wheelchair users) and/or active secondary and primary progressive MS, can you imagine what it is like to be told that ‘you are beyond hope and there is no treatment that can help you’? Or ‘there is nothing I can do you for you as you have progressive MS’? This is why it is important to learn how to spread hope and to try and improve everything you possibly can for your patients with MS.
Spreading the hope is why we are doing the #CHARIOT-MS and #ORATORIO-HAND studies, why we are planning the #SALVAGE-MS study and trying to optimise our MS service, within the confines of the NHS, to adopt a marginal gains approach to managing MS.
I would also like to remind the naysayers that they seem not to have noticed that progressive MS is now modifiable? Ocrelizumab is licensed for active PPMS and Siponimod is licensed for active SPMS in the US and is likely to get an SPMS label in Europe. In addition, there are several other progressive trials underway with a high likelihood of being positive. We are now in an era where progressive MS is treatable.
If you are a naysayer, can I suggest you take off your blinkers, buy a pair of rose-tinted spectacles and smell the roses? Our compassionate use of off-label cladribine has allowed us to collect enough observational data to make the case for doing a trial of cladribine in more advanced MS. We would not have been able to get this point without OLP. For this, we would like to thank our patients and some of our colleagues for their ongoing support and to put DrK on a pedestal for his perseverance and resilience.
We won’t let the critics silence us and distract us from the job at hand; preventing MS (#PreventMS), treating MS early and effectively (#AttackMS, #ThinkCognition) and treating MS in the more advanced stages (#Proximus, #ThinkHand, #Over&Under, #ChariotMS, #OratorioHand, #SalvageMS).
As I write this post I wonder what our colleagues are going to say about our strategy of targeting the intrathecal plasma cell response with an add-on off-label therapy that is currently licensed to treat myeloma (#SIZOMUS)? I suspect the same naysayers will continue to advise their patients to stay away from our centre. At Barts-MS we are proud to practice experimental medicine. Without brave and bold scientists & clinicians and their patients, who are prepared to volunteer for clinical trials using off-label therapies, the innovation cycle, at least in the UK, will grind to halt.
Disclaimer: Please note that off-label prescribing is not a substitute for on-label prescribing unless it is the only way for people living with MS to access DMTs in resource-poor environments.
Jacobs et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science. 1981 Nov 27;214(4524):1026-8. Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.
Mauch et al. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci. 1992;242(2-3):96-102. Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.
Moreau et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994 Jul 30;344(8918):298-301. The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a “meta-analysis”, the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.
Edwards et al. B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders. Biochem Soc Trans. 2002 Aug;30(4):824-8. B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.
Recently one of my patients chastised me for telling her off for her poor diet, which consisted mainly of bread. She lives alone, which may explain why she eats so poorly. She has marmite or jam on toast for breakfast, a sandwich for lunch and if she feels hungry another piece of toast for dinner.
Interestingly, my mother used to refer to her elderly stepmother as a tea-and-toast lady and I never knew why until I became a doctor. My step-grandmother, we used to call her Aunty Betty, didn’t do marmite but stuck to marmalade. She prefered lime to orange marmalade suggesting she had at least preserved her senses of taste and smell. She lived into her late 80’s and died of frailty. For those of you who don’t know the tea-and-toast syndrome is well described. The following excerpt is from Wikipedia:
“Tea and toast syndrome is a form of malnutrition commonly experienced by elderly people who are unable to prepare meals and tend to themselves. Their diets often dwindle to tea and toast resulting in a deficiency of vitamins and other nutrients. The syndrome often manifests itself as hyponatremia, a low concentration of the electrolyte sodium in the bloodstream, due to the lack of salt in the diet.
The syndrome often occurs once children have moved away, and a partner has died or is dying. An elderly person with nobody left to cook for, or without the skills to cook, will revert to a diet of simple foods such as bread, cheese and crackers, and canned foods. According to the New York Times, as many as 60% of seniors living at home are either malnourished or at risk of becoming malnourished. In addition to the problems lack of nutrients will cause, this state also means that the complications of other illnesses, even the common cold, can be much more severe.
Factors that lead to the syndrome include social isolation, psychological issues such as depression, illness, and physical limitations. Though less of a factor than psychological issues, the increased number of medications often taken by elderly people can also affect eating habits. These medications may suppress appetite, make food taste different, or affect how nutrients are absorbed, making it even less likely seniors will get the required nutrients.Typical laboratory findings for tea and toast syndrome include a low serum osmolality (hypotonicity) with a normal urine osmolality since antidiuretic hormone levels are normal.”
Maybe I should update the Wikipedia entry to include multiple sclerosis and other socially-isolating chronic conditions as a cause of this syndrome? Interestingly, my patient is not underweight, which implies she is getting enough calories. She wants to eat other food, but simply can’t afford more nutritious meals, nor does she have the physical energy to cook because of her MS. Her story is not unique. Three years ago when we did a dietary audit of a group of our Barts-MS patients I was horrified at how poor their diets were in general. Most of our patients eat large quantities of cheap processed foods. The main reason is cost and convenience. I suspect with increasing austerity over the last few years things could have only gotten worse and may get even worse if food prices rise, as predicted, if and when Brexit goes ahead.
An editorial in last week’s British Medical Journal, by Michael Marmot, does not pull any punches. It explains why the social crisis is leading to a health crisis with knock-on effects. Marmot in his final paragraph states: ‘A stalling or reversal of long term improvements in health and increases in health inequalities are of great concern to anyone who cares about health’. This applies to me as a neurologist working in the NHS. I see the impact of austerity and the social crisis is having on my patients week after week and it is getting worse. The question is what can we do about it? Yes, we. This is not something that can be tackled by one person it is something society has to address.
Our second variance meeting in relation to MS services, called ‘Raising the Bar’, in Birmingham next month (8th & 9th July) has a workstream dedicated to the social determinants of health. At the end of year 3, we want all participating centres to be working differently and managing MS holistically. This will include programmes to screen and manage comorbidities and promote lifestyle interventions. To make sure it is not only MSers in the top echelons who benefit most from changes in service provision we want all HCPs to adopt a ‘no patient left behind’ philosophy as part of this holistic management and embed this philosophy in all MS services.
How we make this happen with fewer resources is going to require ingenuity and a different way of working. We are going to have to create disruptive new systems to make sure that all people with MS, who are covered by a particular service, have access to that service. We don’t want vulnerable, less educated, ethnic minorities or less well off patients to be disadvantaged by the service.
This is why we are reaching out to all HCPs and people with MS and their families to help us change the current and outdated ‘Victorian’ model of healthcare, which is configured around the HCP and to make the person with the disease the person who controls their care. I anticipate the changes happening gradually and incrementally; one brick at a time. By linking the changes to a national audit and the MS Academy, a platform to share best practice and resources, we will hopefully create an environment that will transform the way people with MS are managed in the NHS.
What concerns me, however, is how do we tackle the social crisis? Our patients not having enough money to buy food or access transport to attend group therapy to tackle social isolation? Surely we need more resources for the NHS and social care? Marmot politicises his Editorial by linking the social crisis to changes in government: ‘In the UK, the fact that the break in the long term rise in life expectancy began in 2011 and has been accompanied by an increase in health inequalities must lead to serious questions about whether the government elected in 2010, with its flagship austerity policies, made a difference for the worse’. This makes you worry that under the current government there will simply be no new resources for implementing our ideas. This raises many challenges and will make the task harder. We may have to mobilise a volunteer army of helpers or we are going to have to show senior NHS managers that the changes we are proposing will save the NHS money.
In a parallel editorial to Marmot’s, Rajan and Mckee remind HCPs that we have a duty to speak out. The following are a few excerpts:
…. Nothing Left in the Cupboards, by Human Rights Watch, describes a country in which tens of thousands of families lack enough food to live on. The second report, by Philip Alston, the UN special rapporteur on extreme poverty and human rights, also examines food poverty but goes much broader, covering the many ways in which successive British governments have been “dismantling the social safety net.” Neither report makes comfortable reading for the British government. The Human Rights Watch report talks of “a grim picture of the grinding reality that teachers are dealing with,” with children arriving at school hungry, without warm clothes or dry shoes. Alston describes a situation that is not just “a disgrace, but a social calamity and an economic disaster rolled into one.”…..
…… In 2002, Derek Wanless published a landmark report commissioned by Gordon Brown, then chancellor of the exchequer. It concluded that sustainable NHS funding into the future required a “fully engaged” scenario, with investment in action on the determinants of health allowing people to live longer in better health. Yet, since 2010, mortality has been stagnating and, for some groups, increasing……
……Yet the British government is currently in a state of near paralysis as it struggles with the Brexit process. And as Alston notes, “If Brexit proceeds, it is likely to have a major adverse impact on the most vulnerable.” When added to the damage that any Brexit will do to the NHS, the outlook is extremely concerning…..
…… Over 150 years ago Rudolf Virchow said that doctors are “natural advocates of the poor.” When, as Alston argues, “the government has remained determinedly in a state of denial,” it is time for all health professionals to stand up for those who are falling through the increasingly large holes in our social safety nets. We must do so not only for the individuals concerned but for the future of the NHS, which, as Wanless pointed out, cannot continue to pick up the pieces following failures by others…….
If the issues in this blog post affect you, or someone close to you, please do not hesitate to reach out to us or your local MS team. We are committed to improving the care we provide all of our patients with MS and that includes helping you with your social issues.
I am about to return from a short MS meeting in Tokyo. This was my first exposure to Japan and Japanese culture. It is everything and more than I expected.
I am beginning to get a sense of what ikigai means. Ikigai translates ‘to a reason for being, encompassing joy, a sense of purpose and meaning and a feeling of well-being’. Ikigai derives from iki, meaning life and kai, meaning the realisation of hopes and expectations.
I first learnt about ikigai from the ‘Blue Zones’, a book by Dan Buettner, on the secrets of the world’s ‘happiest places’, where people are super-agers. One of the blue zones is Okinawa, a subtropical Japanese island to the South of Japan. Some of the philosophy underpinning happiness and super-ageing is cultural and is specific to the Japanese culture.
The lessons of the blue zones are applicable to our Brain Health initiative and I would urge you to read the book. Who knows it may change the way you want to live your life regardless of whether or not you have MS.
It is clear that MS is a problem in Japan and the incidence and prevalence is rising. Why? Japan is now one of the epicentres of the global MS epidemic; i.e. an area of the world where MS has gone from a low to a medium incidence area, similar to Iran, and will quite soon become a high incidence area. The clue to this is the rapidly increasing sex ratio of females to males that is now over 3:1.
As an MS community, we need to study these epicentres to see if we can pin down the cause of MS and put in place robust prevention trials. Japan has rapidly westernised and the Japanese neurologists I spoke to think this is the reason why the incidence of MS is increasing in Japan. Not sure I buy this at face value. What is it about the Western lifestyle that is causing MS? Could it be childhood obesity? Processed carbohydrate/sugar consumption? Smoking? Change in the epidemiology of EBV infection; a different strain, later infection, more infectious mononucleosis? Less sunshine and lower vitamin D levels?
It is interesting that Japanese neurologists think MS is more benign in Japan than elsewhere. I am not sure why they think this. All the evidence I saw this weekend points to Japanese MS being identical to Western European MS. Unfortunately for Japanese MSers, they have access to fewer DMTs and there are only two highly effective DMTs licensed in Japan, i.e. fingolimod and natalizumab. There is also a much higher JCV seroprevalence rate in Japan of close to 80% with a higher proportion of people with a high anti-JCV index. This makes the risk of PML potentially much higher in Japan. For example, there have been 4 cases of non-carryover PML on fingolimod, which equates to a PML rate of about 1 in 1,000 to 1,500 per fingolimod-treated MSer. This is an order of magnitude higher than the non-carryover PML rate on fingolimod outside of Japan and clearly needs further study.
Another factor is the reluctance of Japanese neurologists to use off-label treatments, for example, subcutaneous cladribine and rituximab. The reasons for this are multiple but mainly relate to lack of reimbursement and cultural factors. It was also clear that the Japanese neurologist, similar to British neurologists, are quite conservative and prefer a step-care approach. The Japanese are particularly concerned that because of their ancestry they may respond differently to DMTs, which have been tried and tested in other populations. In other words, they need data on the safety and efficacy of specific DMTs in their own Japanese MS population. To get a drug licensed in Japan Pharma has to trials in Japan.
As a result of the JCV problem extended interval dosing of natalizumab, also referred to as EID, and PML surveillance (3-monthly MRI monitoring) is very important for natalizumab-treated Japanese MSers. In fact, Japan is the one country that the derisking of PML for natalizumab is critical. Until other high-efficacy DMT arrive the Japanese are going to have to make do with fingolimod and natalizumab. In comparison, we are spoilt for choice in the UK and other high-income countries; we have forgotten what it was like to manage MS before the avalanche of new DMTs.
I have uploaded my slides from Japan on my slideshare site; you are welcome to download them and repurpose the slides for your own uses. I presented our #AttackMS study as a way to illustrate how important time matters in MS. I am not sure the Japanese neurologists agreed with such an active approach to treating MS. Do you?
BACKGROUND AND PURPOSE: The prevalence of multiple sclerosis (MS) is considered to be lower in East Asia than in Western countries. An increasing trend has been reported globally for the prevalence of MS. We investigated the changes in the prevalence and clinical characteristics of MS in the Tokachi province of Hokkaido, northern Japan from 2001 to 2016.
METHODS: Prevalence was determined on 31 March 2016. Data-processing sheets were collected from all MS-related institutions in Tokachi province. We applied Poser’s diagnostic criteria for MS as used in our previous three studies. Cases of neuromyelitis optica spectrum disorders were excluded.
RESULTS: In 2016, the crude MS prevalence was 18.6/100 000 (95% confidence interval, 14.3-23.8) in northern Japan. Over the last 15 years, the prevalence of MS in the same area was 8.1, 12.6 and 16.2 in 2001, 2006 and 2011, respectively. The female:male ratio was 3.57, which increased from 2.63 in 2001. The ratios of primary progressive, relapsing-remitting and secondary progressive MS types were 2%, 84% and 14%, respectively.
CONCLUSION: Our results demonstrated a consistent increase in MS prevalence among the northern Japanese population, particularly in females, and relatively lower rates of progressive MS in northern Japan than in Western countries.
