We need to keep pushing the envelope and moving the goalposts in terms of our treatment targets in MS.
As MS advances innate immune activation with microglial and astrocyte activation occurs. However, the latter may be adaptive in response to damage and hence a good thing, which is why I am sceptical about treatments aimed at targeting these cells in advanced MS.
In comparison, B-cells and plasma cells are a different story. These cells are part of the adaptive immune system and are likely producing pathogenic, or damaging, antibodies. B cells and plasma cells set-up shop in the brain and spinal cords of MSers and churn out these heat-seeking missiles that are likely to be responsible for smouldering MS; i.e. the cortical lesions and the slowly expanding lesions or (SELs), which cause disease worsening even in those MSers who are NEDA (no relapses or no new or enhancing MRI lesions). The problem we have is that our current DMTs don’t appear to target these cells with the possible exception of cladribine that is a small molecule and gets into the brain and spinal cords of MSers. Konrad Rejdak and colleagues in Poland have shown that about 50% of cladribine treated MSers lose their oligoclonal IgG bands (OCBs) from their CSF and that the patients who lose their OCBs tend to be stable compared to those who don’t lose their OCBs. We need to replicate these findings and supports our hypothesis to target CNS-resident plasma cells in MS.
Please note spinal fluid OCBs and immunoglobulin free light chains are at the bottom of our treat-2-target pyramid. This is our new goalposts.
This is why we are starting two studies in parallel, and want to start more studies with additional agents, to see if we can get rid of OCBs in MSers.
Our first study will look at oral cladribine’s effect on B-cell and plasma cell activity within the brain and spinal cords of MSers. Does cladribine reduce OCBs and immunoglobulin production? This study is called the “Oral Cladribine B-cell study” or CLAD B.
The following are the inclusions criteria for CLAD B:
Patients with RRMS who are being treated with oral cladribine at Barts Health NHS Trust
Patients must be willing and able to undergo lumbar punctures
Patients who are OCB positive in their CSF (from previous diagnostic lumbar puncture)
In our second study, we are testing a myeloma drug called Ixazomib in MS. Ixazomib is a second-generation proteasome inhibitor that works against malignant plasma cells. This study is called “Safety of targeting plasma cells in Multiple Sclerosis: A phase 1b randomised, double-blind, placebo-controlled trial” or SIZOMUS.
The following are the SIZOMUS inclusion criteria:
Each participant must meet all of the following inclusion criteria to be enrolled in the SIZOMUS study:
Male and female patients 18 to 65 years old at screening.
Must have a diagnosis of MS, and:
Patients with RRMS must be on DMT
Patients with progressive MS must not be on DMT
Participants with RRMS must be on stable DMT (i.e. must not have had a relapse within 1 month prior to the screening visit)
OCB positive CSF either from a previous CSF analysis or from the screening CSF analysis
Patients must be willing and able to undergo lumbar punctures
Agree to use of effective contraception
For those interested in proteasome inhibitors there is an emerging evidence base of them working in autoimmune diseases in general, in particular with the 1st-generation drug called Bortezomib.
Do you think we are crazy? We have been working on getting these trials off the ground for over 3 years and the ideas, and hypotheses, underpinning these trials goes back more than 15 years. I originally wanted to do a thalidomide trial, targeting plasma cells, way back in 1997. However, I was advised against it by Professor W. Ian McDonald who thought it would be too risky.
If you live in London, or the home counties, and are interested in participating in these trials, and you think you are eligible, let your HCP know and they can contact us.
There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.
I have just received the following information from Roche, which is reassuring in that
As of July 3rd 2019, the Roche can confirm there have been no new carry-over cases of PML in MS patients treated with ocrelizumab since their last update in April 2019. The seventh case was reported in March 2019.
As of April 2019, over 100,000 people have been treated with ocrelizumab globally, within a combination of clinical trial and post-marketing settings.
No unconfounded cases of PML with ocrelizumab have been reported to date.
Of the seven cases of carry-over PML, none were reported as fatal at the last point of follow up (Feb 2019).
Information relating to all carry-over cases has been reported to regulatory agencies in compliance with agreed pharmacovigilance processes.
The recommendations relating to PML in the approved product labelling for ocrelizumab remain unchanged. HCPs should be vigilant for early signs and symptoms of PML, which can include any new-onset, or worsening of neurological signs or symptoms, as these can be similar to an MS relapse. If PML is suspected, withhold dosing with ocrelizumab.
Summary of carry-over PML cases to date (July 2019):
Carry-over case
Country
Reported
Setting
Carry-over from
1
Germany
May 2017
Compassionate Use programme
Natalizumab
2
Canada
April 2018
Post-marketing
Fingolimod
3
USA
May 2018
Post-marketing
Natalizumab
4
USA
June 2018
Post-marketing
Natalizumab
5
USA
July 2018
Post-marketing
Natalizumab
6
Luxembourg
September 2018
Post-marketing
Natalizumab
7
USA
February 2019
Post-marketing
Natalizumab
Roche are sharing this information for full transparency and hope you find this useful.
At our second MS Services Variance meeting, ‘Raising the Bar’, in Birmingham last week my colleague Helen Ford and I co-chaired the workstream on the social determinants of health (SDoH).
What are the SDoH?
The SDoH are life-enhancing resources, such as food supply, housing, economic and social relationships, transportation, education and health care, whose distribution across populations effectively determines length and quality of life. As MS is such a disabling disease with poor quality of life it is likely to impact on the SDoH, which in turn will feedback and make MS outcomes worse. This vicious cycle needs to be broken if we want to optimise MS outcomes; i.e. when applying the philosophy of marginal gains we can’t ignore the SDoH when managing someone with MS.
The following is a selection of slides we put together around the SDoH theme.
Do you have an example of how the SDoH can impact on a person with MS?
The study highlighted below from Sweden is an example of how MS reduces your earnings. Interestingly, the reduction in earnings even begins before MS diagnosis and clearly increases thereafter. I suspect some people who have prodromal MS have difficulty working, which impacts on the average outcome or earnings. Besides sickness absence and disability pension, educational level and type of occupation are influential determinants of earnings in pwMS. In other words, inequality plays a role in determining your earnings once you have MS. Are you surprised? I am not.
When we asked whether or not MS HCPs routinely screen for the SDoH very few hands went up in the room. The hands that went up tended to belong to occupational therapists; they clearly need to look at SDoH as part of their treatment plans. No neurologists put up their hands and therein lies a problem or a solution depending on how you look at things.
The following is a short list of some of the SDoH that may impact on MS outcomes, which we discussed.
Level of education and health literacy
Poverty (absolute or relative)
Employment / unemployment
Access to social services (personal independent payments, etc.)
Home environment (heating, cleanliness, amenities, etc.)
Local environment (safety, green spaces, amenities, etc.)
Food poverty (absolute or relative)
Transport (access and costs)
Childcare (access and costs)
Social isolation (social networks, access to the internet, mobile phone, data, etc.)
Lifestyle factors (sedentary vs. active, smoking, alcohol and other addictions)
Need to be looked after by a child (child carer) or ageing parents or other family members (aged carers)
Cognitive impairment and hidden psychiatric comorbidities (depression and anxiety)
Physical and emotional abuse
How do we address these issues in an MS clinic without upsetting our patients by being too overbearing? We did agree that there was a lot we could potentially do about some of these SDoH and that we had an obligation to at least consider these as part of our routine management of our patients and their families. Some ideas that emerged in our session include the following:
Provide information about IT solutions to help pwMS.
Start a high-risk register of patients within our service; patients on this list would need to be seen and contacted more frequently, ideally on pre-planned and regular basis.
Start a home visit programme. Most services have had to stop home visits because of resource and staffing issues.
Make sure our patients know that they can get hospital transport so they don’t go out of pocket or reimburse their travel costs.
Convert were possible physical face-2-face visits with telemedicine options.
To do a complex needs assessment similar to what is done in other disease areas to identify high-risk or vulnerable patients.
Lobby the government to waive prescription costs for pwMS and other disabilities.
Lobby government to create a healthy food voucher system for pwMS and other disabilities.
Lobby government to improve social services for pwMS and other disabilities.
Engage pwMS and include them in your service; for example, using an MS Health Champions model.
Explore social prescribing to increase social capital.
Enrol all patients into a lifestyle and wellness programme.
OBJECTIVES: To investigate earnings among people with multiple sclerosis (PwMS) before and after MS diagnosis compared with people without MS, and if identified differences were associated with educational levels and types of occupations. Furthermore, to assess the proportions on sickness absence (SA) and disability pension (DP) in both groups.
DESIGN: Population-based longitudinal cohort study, 10 years before until 5 years after MS diagnosis.
SETTING: Working-age population using microdata linked from nationwide Swedish registers.
PARTICIPANTS: Residents in Sweden in 2004 aged 30-54 years with MS diagnosed in 2003-2006 (n=2553), and references without MS (n=7584) randomly selected by stratified matching.
OUTCOME MEASURES: Quartiles of earnings were calculated for each study year prior to and following the MS diagnosis. Mean earnings, by educational level and type of occupation, before and after diagnosis were compared using t-tests. Tobit regressions investigated the associations of earnings with individual characteristics. The proportions on SA and/or DP, by educational level and type of occupation, for the diagnosis year and 5 years later were compared.
RESULTS: Differences in earnings between PwMS and references were observed beginning 1 year before diagnosis, and increased thereafter. PwMS had lower mean earnings for the diagnosis year (difference=SEK 28 000, p<0.05), and 5 years after diagnosis, this difference had more than doubled (p<0.05). These differences remained after including educational level and type of occupation. Overall, the earnings of PwMS with university education and/or more qualified occupations were most like their reference peers. The proportions on SA and DP were higher among PwMS than the references.
CONCLUSIONS: The results suggest that the PwMS’ earnings are lower than the references’ beginning shortly before MS diagnosis, with this gap increasing thereafter. Besides SA and DP, the results indicate that educational level and type of occupation are influential determinants of the large heterogeneity of PwMS’ earnings.
The WHO rejected our application to get glatiramer acetate, fingolimod and ocrelizumab/rituximab onto the Essential Medicined List. Why?
The following is the relevant section from Executive Summary:
“The Expert Committee recognized the public health need for effective and affordable treatments for multiple sclerosis (MS) but did not recommend the addition to the EML and EMLc of glatiramer acetate, fingolimod and ocrelizumab at this time. The Committee acknowledged the application’s approach to increasing access to MS treatments by prioritizing selected treatment options. However, the Committee noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). The superiority of presented medicines over other therapeutic options in the outcomes considered (benefits, harms, affordability) did not clearly emerge. The Committee would, therefore, welcome a revised application which comprehensively reviews the relative roles of relevant available medicines for MS. “
For the committee to recommend we look at azathioprine again, when the WHO themselves rejected azathioprine in 2015, is odd. To the best of my knowledge, nothing has changed in terms of new data since 2015 to change Azathioprines position as a potential off-label treatment for MS.
As for natalizumab, we did not add it to the EML application because it is still on patent, i.e. expensive, it needs to be given as a monthly infusion, which adds to its expense, and is associated with a high monitoring burden for PML. The latter is would be very difficult in resource-poor environments. At the moment the PML JCV serology assay is controlled by Biogen so when natalizumab comes off-patent, and say natalizumab biosimilars emerge, what will happen to the international JCV serology monitoring system that currently exists? Would the WHO take it over from Biogen? Would it be distributed to national labs? Will resource-poor countries be able to incorporate this into their already over-stretched systems?
We went through all these factors in our deliberations and came to the conclusion that 6-monthly ocrelizumab, and rituximab if ocrelizumab is not available, would be a better alternative to natalizumab. Another factor was that ocrelizumab is now licensed to treat PPMS. If we excluded ocrelizumab from the list what message would this send out to PPMSers in the world? In addition, the monitoring requirements for anti-CD20 therapies are much less burdensome than natalizumab.
So we take the punch on the chin, get up and start working on the next application that will be due in 2021. We are a resilient group and we owe it to people with MS all over the world to get them access to effective DMTs.
The following is the MSIF’s press release and the agenda for their meeting in London this Thursday and Friday. Instead of a celebratory mood, I suspect the atmosphere will be more sombre.
We may have lost a battle, but we have not lost the war.
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 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.
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.
We were rightly criticised last year for holding a meeting that highlighted the problem of variance in the provision of MS services, in the NHS. without a plan and vision about how to change things. I hope we have listened to you. The follow on meeting that we are hosting next month (8th-9th July) has a more ambitious agenda; it will even come with a 3-year action plan.
I have always made the argument that variance, when it comes to the provision of healthcare services, is a euphemism for inequality and that simply represents the haves and have-nots in society and the world. Why should someone with MS who lives in place B, or country Y, get a different service to someone with lives in place A or country X? On the other side of the coin, variability creates the engine for change; it is the catalyst for people to do something about the poor services they are providing or receiving; that is assuming they know about the quality of their service and are willing to do something about it.
My colleagues have told me that I shouldn’t beat myself up too much over the problems and criticisms of our first meeting; after all, it was very instructive in that it:
Brought us together as a wider MS community and allowed us to recognise and reflect on the challenges we face in addressing the variance in the NHS.
The meeting was inclusive in that there was no hierarchy in terms of the importance of the people who deliver MS services. We identified ourselves as equals, or partners, and included people with MS.
The meeting made us realise that we have cognitive biases that need to be addressed to make the community inclusive and more diverse. Diversity of ideas is going to be the catalyst for the next phase of our project.
We also realised that variance is not necessarily bad. We need some variance and ways to measure it so that the outliers at the upper end stimulate change. The next meeting is called ‘Raising the Bar’ and refers to improving services across the board.
The meeting also allowed us to get away from the NHS rat race and provided quality thinking time, i.e. time to reflect on the task at hand. This has allowed us to set priorities or specific work streams that will allow us to set key objectives for the programmes of work going forward.
As the chair of the committee, I have been asked to set out my vision for the initiative and define what success will look like for this initiative. To make it tangible I have defined targets at year 1, 2 and 3 and beyond.
YEAR 1
At the end of next year, I would expect all participating centres to actively engage in a national quality audit. This will include providing metrics on the NICE quality standards and several other new metrics that will allow us to assess how good or bad we are at achieving what we have set out to achieve.
My vision is 4×4, i.e. for 75% of patients with uncomplicated MS to be diagnosed within 4 weeks of the specialist MS team receiving a referral letter with a diagnosis of suggestive of MS and for 75% of pwMS, eligible for DMTs under the NHSE guidelines, to be have been offered, counselled and given a date for starting a DMT. Is this too much to expect? These time frames are compatible with our International Brain Health standards so why wouldn’t we aspire to meet them?
YEAR 2
At the end of year 2, all participating centres will have a patient partner programme in place to upskill pwMS on how to navigate their local MS services and how to self-monitor and self-manage their MS. This programme will be developed in partnership with patient organisations and will depend on local champions to make it happen. We are in an era in which knowledge has been democratised. Why shouldn’t people with MS participate in providing their own healthcare and contributing to their own healthcare?
YEAR 3
Participating centres will be working differently and managing MS holistically. This will include programmes to screen and manage comorbidities and to promote lifestyle interventions. Participating centres will collect data on these new activities as part of the annual national audit. As part of this holistic management of MS, there will be a ‘no patient left behind’ philosophy embedded in all MS services. This will require systems to make sure that all people with MS, who are covered by a particular service, will have access to that service. We don’t want vulnerable, less educated or less well off patients to be disadvantaged by the service.
LEADERSHIP
It was clear to us at last year’s meeting that for our vision to be realised we need a new generation of leaders to make things happen. We are therefore proposing putting in place a leadership training programme to equip people with the skills to make things happen. The leadership programme will be small and selective and will focus on doing, i.e. as part of the programme delegates will be expected to participate in and complete a national project. This will be run by Gabriele De Luca who is a shining example of what good leaders can do. Gabriele has experience from the AAN young leadership programme and is passionate about the field himself. It may be worthwhile coming to, and participating in, our meeting just to access the leadership training programme.
SHARING BEST PRACTICE
As always the wheel has usually been invented. Most ideas are not new, but how they have been tested and implemented may be new. We are proposing to use the Variance platform to share best practice. Why reinvent something if it already exists? We expect all centres to share their successes and failures so that others can learn from them. This will hopefully allow MS centres to share their materials and experiences with other centres so as to raise the bar for everyone and to create a collegiate atmosphere. The advantage the MS Academy has is that we already have the infrastructure to make sharing relatively easy.
So if you are reading this post and are attending this year’s meeting don’t be shy; please submit a poster to the meeting on something in your service that you are proud of, or even something you are not so proud of. We will select 3 or 4 posters for a platform presentation to allow wider discussion.
If you have not registered already please do so now there are a few remaining places.
As you are aware approximately 3% of people with multiple sclerosis develop their first symptoms in childhood and adolescence. As the incidence and prevalence of MS are increasing we are seeing more children and adolescents with the disease. Why?
Relative to MS in adults, most neurologists and other healthcare professionals are unfamiliar with the diagnostic evaluation, clinical course, outcome, and management of MS in children.
To remedy some of these deficiencies we are running a dedicated triMS.online meeting on Paediatric MS on Tuesday 11th, June 2019. We have an exciting programme of international speakers. As with all triMS.online meetings you don’t necessarily have to watch them live, but can log-in after the event and watch the content in your own time. You can also ask questions, which the speakers will respond to for up to 4 weeks after the event.
