Prof G's MS Blog Archive

Progressive multiple sclerosis is a misnomer

Barts-MS rose-tinted-odometer: ★

In my opinion, the term ‘progressive multiple sclerosis’ is a misnomer. In general, progression means improvement, which is one of the reasons I prefer the term ‘late-stage MS’, which not only differentiates the terminologies but captures the associated disability that comes with this phase of the disease.

It is important to stress that the pathologies that drive neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘late-stage MS’) are there from the earliest stages of MS; even when people have asymptomatic MS. This means the neurodegenerative phase of MS is present prior to pwMS becoming physically disabled.

MS is 1-disease and not 2-3-or-4-diseases. As I have said before the false division of MS into several diseases is not backed up by science, nor by philosophical arguments. This false division of MS into many diseases has become counter-productive to the field of MS. The division of MS into relapsing and progressive forms was Pharma-led to get MS defined as an orphan disease, which allowed interferon-beta-1b to get a license based on the results of one pivotal phase 3 study.

One could argue that this has been good for MS in that it has attracted a lot of Pharma investment and has supercharged drug development in MS. However, MS as three or four disease entities is now slowing down drug development and making it very expensive. We need more affordable DMTs for late-stage MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for late-stage MS need to be priced lower than those licensed for earlier or relapsing forms of MS.

Following on the point above the division between SPMS and PPMS is false. There is no pathological, genetic, imaging or other data that suggests these are different entities. We therefore should be doing trials in both late-stage MS populations simultaneously.

Slay the dogma that more late-stage MS has reduced inflammation or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a big part in driving late-stage MS. Therefore not to target more late-stage MS with an anti-inflammatory is folly.

Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve, i.e. surviving and functioning axons, are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we refer to this as therapeutic-lag. These observations are explained by the length-dependent axonopathy hypothesis. This means that we will need to focus more on arm-and-hand function as a primary outcome in pwMS who have lost too much function in their lower limbs (EDSS>=6.0).

Challenge the dogma that once someone has lost lower limb function and is a wheelchair user that the disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in late-stage MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign.

Accept that we will need to use combination therapies to make a real difference to more late-stage MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms, which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.

We need to ditch the EDSS. The whole community knows that the EDSS is not fit for purpose in more late-stage MS. We need to get the regulators to accept this. We also need to use outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more PROMS in the battery, in particular, ones that capture hand-and-arm function, cognition and quality of life.

We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma doesn’t necessarily like adaptive designs nor do the regulators. I do think we do need two phases to trials in more late-stage MS, i.e. the standard head-to-head phase with a robust primary outcome, say a multi-outcome composite, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more late-stage MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).

Acceptance of more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past.

Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and we even wrote a paper on the so called ‘Big Pharma Alternative’ to explain our thoughts on this.

Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials, newer outcome measures and combination therapy approach.

More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the health economic data that the costs associated with managing MS increase as disability advances.

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing as a result of reduced brain and cognitive reserve underpins worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in late-stage MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.

We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for us to falsely raise their hopes. To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote axonal sprouting, synaptogenesis and plasticity mechanisms to restore function.

As you can see we are passionate about tackling more late-stage MS. We have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted in the points above. We need a serious debate about these issues and get on with the job of protecting cognition, arm, hand and bulbar function in people with more late-stage MS. The good news is that we now have licensed therapies for both primary and secondary progressive disease that can act as the platform on which to build our pyramid and to tackle MS holistically to improve longterm outcomes.

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.

CoI: multiple
Twitter: @gavinGiovannoni Medium: @gavin_24211

Swiss Neurologists Challenge Lublin

Barts-MS rose-tinted-odometer: ★

I have just been chastised by someone from a Swiss Pharma company for suggesting that siponimod is a cul-de-sac DMT. Why can’t someone who is diagnosed and labelled as having SPMS who is started on siponimod be switched to any other DMT? I agree, but the absurdity of the situation arises because of the rigidity of the Lublin classification of MS (see below) and the salami-slicing of MS into multiple disease entities.

The cul-de-sac is based on the assumption that once you have progressive MS, either primary progressive or secondary progressive MS, you can’t become unprogressive and be subsequently re-diagnosed as having relapsing-remitting MS. This is explicit in the Lublin classification system that defines the clinical course of MS. According to Lublin progressive MS is a one-way street.

The reason we find ourselves in this ridiculous situation is that MS was salami-sliced up into three and four diseases in the 1990s to allow interferon-beta to get licensed under the US Orphan Drug Act. The Orphan Drug Act states that to be an orphan disease there have to be fewer than 200,000 US citizens with the disease. There are clearly more than 200,000 people with MS in the US, but there were less than 200,000 people with relapsing-remitting MS, secondary progressive MS or primary progressive MS in the 1990s. Subsequently, a fourth category was added to the classification system of clinically-isolated syndrome (CIS). Fortunately, CIS is gradually disappearing as the McDonald criteria are gradually nibbling away at this pseudo-category of MS.

Few people are aware of the history of MS becoming four diseases, but the consequences of this to the field have been enormous. For one it means that Pharma has had to do trials in all four ‘pseudo-MS disease states’ at great expense to the field. It has had major psychological effects on people with the disease. When you tell people they have SPMS it is like telling them they have a second disease that until recently was unmodifiable.

The other consequence of MS being three or four diseases is that once you have been diagnosed as having SPMS we are mandated under NHS England guidelines to stop DMTs. This is why most neurologists in the UK avoid labelling their patients as having SPMS.

The Lublin classification system is based on a clinico-radiological worldview of MS and is not underpinned by biology. If you take a biological worldview of MS, which is the correct philosophy based on our current thinking of what constitutes a disease, then MS is one disease and not three or four diseases.

Interestingly, I have been asked by the CONY Virtual Conference organisers to give a keynote plenary lecture on this exact topic, which I recorded yesterday.

The good news is that this Pharma Executive tells me that the Swiss Neurologists have decided that the Lublin classification system is incorrect and that according to the Swiss it will be fine to reverse out of the secondary-progressive cul de sac and to relabel their patients as having relapsing MS and to be able to switch their patients from siponimod to ofatumumab once it is licensed in Switzerland. I sincerely hope the Swiss neurologists publish their new classification system of MS, or MS roadmap, as the Lublin one is out-of-date. More importantly, will the Swiss neurologists be prepared to convince the NHS of their wisdom?

Lublin et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014 Jul 15;83(3):278-86.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Anti-CD20 Derisk Study

Barts-MS rose-tinted-odometer: ★★★★★

Did you watch the anti-CD20 debate on the triMS-online platform yesterday? The question that was asked was ‘Can we use anti-CD20 therapies as immune reconstitution therapies rather than maintenance therapies?’. I am not sure the debaters answered the question.

When I asked Anders Svenningsson, who is probably the world’s biggest adopter of anti-CD20 therapy as a treatment for MS, whether or not someone with MS could stay on anti-CD20 for life, he hesitated before saying ‘YES and NO’. His reason? SAFETY. He described things they were doing to try and reduce the risk of hypogammaglobulinaemia and infections in their patients on longterm anti-CD20 therapy. I am not sure it will work. Interestingly, he suggested stopping anti-CD20 therapy when pwMS get to 55-60 years of age when the risks of treatment outweigh the benefits. In other words, Anders Svenningsson is saying we can’t leave pwMS on anti-CD20 lifelong.

I have been making this exact point on this blog for several years and that is why I have proposed the ADIOS and iTeri studies as ways to derisk long-term anti-CD20 therapies. However, I have been thinking are there any other DMTs we could use after anti-CD20 that would potentially work to derisk the hypogammaglobulinaemia and tackle the cause of MS. I suspect yes. Fumarates, as monotherapy, or in combination with a neuroprotective therapy, also makes sense. The difficulty is what will be the primary outcome of such a trial and how would you do power calculations?

Maybe we could use a non-inferiority design and make safety the primary outcome. Would regulators buy that in addition to non-inferiority as a secondary outcome?

There are not many companies who have the resources, motivation and know-how to do such a study. Roche-Genentech and Novartis would not as this would eat into their franchise. In my opinion, the only company with big enough bollocks and know-how to take this on would be Biogen. Would they be interested?

This is potentially an opportunity for them to come up with a new combination pill of one of their fumarate formulations with an add-on neuroprotective. DMF will maintain MS in remission post-anti-CD20 and the neuroprotective will tackle smouldering MS, which is something anti-CD20 therapies don’t do. A fumarate-neuroprotection combination may actually not only show improved safety but superiority on end-organ damage markers (brain volume loss etc.).

The hypothesis is that if B-cells and in particular memory B-cells are driving MS then starting DMF for example before memory B-cell reconstitution occurs may actually make MS more responsive to fumarates. Add in a combination, to generate new intellectual property (Biogen need this as their fumarate patents are being challenged) and you have a new DMT.

If successful this new combination pill will probably become the most prescribed DMT in MS. Why? To quote Anders Svenningsson you can’t really remain on anti-CD20 lifelong so if you have to derisk an anti-CD20 at some stage. So why not do it before you develop hypogammaglobulinaemia? As more than 50% of MS patients will be treated with anti-CD20 therapy in the near future this combination therapy could potentially capture more than 50% of the market.

If you are on an anti-CD20 therapy (ocrelizumab, rituximab or ofatumumab) would you volunteer to participate in the DERISK study below?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: woods for the trees

Barts-MS rose-tinted-odometer: ★★★★

I am sure you know the term “I can’t see the woods (or the forest) for the trees”. This means you are unable to understand a situation clearly because you are too involved in it. I think this is what has happened to the MS community when it comes to managing multiple sclerosis during the coronavirus pandemic.

We are so fixated on the potential risks associated with DMTs and COVID-19 that we are ignoring the elephant in the room, age and comorbidities. It is now clear that moderate immunosuppression from some of the MS disease-modifying therapies (DMTs) does not increase one’s risk substantially of getting COVID-19, severe COVID-19 or dying from COVID-19. The real risk factors for getting severe COVID-19 are age, progressive or advanced disease, which is closely associated with age, and the presence of comorbidities.

I presented the ocrelizumab COVID-19 data at a satellite symposium on day-1 of our fourth triMS.online conference and it was clear to me that the risk associated with anti-CD20 therapies are trumped by age and comorbidities. It is also clear that the pharmacovigilance data for ocrelizumab has to be biased in that patients on infusion therapies and those with more severe disease needing hospitalisation, ITU admission, ventilation and sadly those who die from the infection, are more likely to be reported. People with MS who have mild or even moderate COVID-19 are clearly less likely to be reported by their HCPs. Therefore, the current data is likely to be the worst-case scenario.

Another factor that is not being captured in this data is the fact that the outcome for COVID-19 has been improving. As treatments for COVID-19 and medical know-how, for example, how to manage ventilation and thrombotic complications of SARS-CoV-2 infection, have improved the mortality from COVID-19 has almost halved.

The issue of vaccine-readiness, which also raises its head frequently, is like the greasy pig; you may be able to catch the pig but it is almost impossible to hold on to. This is why I suggest batting vaccine readiness into the long grass and addressing the issue if and when a vaccine finally arrives. It has also become apparent as the immunology of coronavirus infection has become better understood that T-cell immunity, in particular CD8+ T-cell immunity, is likely to be the dominant player in driving immunity from primary infection and reinfection. Even if people who have been infected and do not seroconvert or lose their antibodies quickly, are highly likely to be immune to reinfection. Even if they are reinfected with the SARS-CoV-2 virus that causes COVID-19 they are likely to get asymptomatics infection or mild disease. Please note reinfection rates at present are very rare and get much more air-time than is warranted.

In my talk, I concluded that MS is a bad disease and we should manage it as we would have managed it prior to COVID-19. I think untreated or under-treated multiple sclerosis is a bigger problem than COVID-19 for people with MS at present.

I also stressed that prehabilitation is really important for people with MS and remains so. If you can, you need to do everything possible, to optimise your general health so that if you get COVID-19 you give yourself the best chance of recovering without complications.

To quote from Chalie Mackesy’s bestseller “The Boy, The Mole, The Fox and The Horse”, when the boy asks the horse “What’s the best thing you have learned about storms?”. “That they end”, said the horse.

This quote not only sums up my optimism but has also made me realise that the storm clouds have lightened, the thunder and lightning have moved over the horizon, the rain is not as hard as it was at the beginning of the storm and the winds have dropped in intensity. I get a sense that the storm will pass over very soon.

I must compliment and thank Roche for releasing the ocrelizumab data to the MS community. The only other company that has attempted to do the same has been Merck in relation to their cladribine data. However, the data for cladribine is a lot less robust because of the smaller number of patients who have had cladribine and have subsequently gotten COVID-19.

The ocrelizumab and cladribine data are what they are. Having the data in the public domain, however, puts us in a much better place. We can quote the data to our patients, reassure them about the potential risks, which are small, and use it as part of the decision-making process to manage their MS as best we can during the pandemic.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Are you a super-responder?

Barts-MS rose-tinted-odometer: ★★

For every DMT there are patients who respond and there are those who don’t respond. Trying to predict who will be a responder and non-responder is not possible upfront. This is why we talk in averages, i.e. what happens to populations of patients and extrapolate backwards to the individual. If only we have individualised or personalised prediction tools.

The study below shows a cohort of glatiramer acetate super-responders who are doing as well a group of patients on fingolimod when it comes to the end-organ, i.e. losing brain volume loss. Could you imagine a world when we didn’t have to gamble with time and we could select the treatment that will do the job we want it to in terms of protecting your brain for when you get older?

In my talk at the MSVirtual2020 meeting this year I try and communicate these concepts using an actuarial approach. Is it understandable? As it is your brain what have you done?

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Honce et al. Brain Atrophy Rates for Stable Multiple Sclerosis Patients on Long-Term Fingolimod versus Glatiramer Acetate. Frontiers in Neurology 2020 Sep 23;11:1045.

Background: Clinically stable multiple sclerosis (MS) patients on long-term therapy often have negligible acute inflammation on MRI. Brain atrophy may provide insight into subclinical disease progression in such populations. Objective: This study aims to compare brain atrophy for age- and gender-matched MS patients treated for >2 years with fingolimod (FTY) or glatiramer acetate (GA), examining brain volume, cognition, and patient-reported outcomes (PROs).

Methods: Stable relapsing-MS patients, age 18-60, on FTY or GA for >2 years were followed up for 2 years. MRI brain and lesion volumes, cognitive measures, and PROs were collected at baseline and annually.

Results: Forty-four FTY and forty-three GA patients completed baseline and year 2 visits. No differences in age, gender, or education were observed. Median EDSS was 2.0GA and 2.5FTY (p = 0.22). Treatment duration was longer for GA, 6.50GA vs. 3.73FTY years (p < 0.001). Baseline geometric mean T2LV were different, GA = 1,009.29 cm3 vs. FTY = 2,404.67 cm3 (p = 0.0071). Baseline brain volumes were similar, GA = 1,508 cm3 vs. FTY = 1,489 cm3 (p = 0.2381). Annualized atrophy rates, adjusted for baseline and at mean baseline value, were GA = -0.2775% vs. FTY = -0.2967% (p = 0.7979). No differences in cognitive measures or PROs were observed.

Conclusions: Stable MS patients on long-term treatment with FTY and GA have similar brain volume loss rates. Differences in baseline disease severity may suggest patients with more aggressive disease treated with FTY may achieve similar brain volume loss rates as patients with milder baseline disease on GA.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

triMS.online: diversity and youth

Barts-MS rose-tinted-odometer: ★★★★★

What do you do you do when you realise that your baby has grown up!

Several years ago someone on this blog recommended launching OCTRIMS, i.e the Online Consortium of Treatment and Research In Multiple Sclerosis. I diligently registered the domain name and approached ECTRIMS for support and they said no they weren’t prepared to support an online offering and they asked if I would refrain from using the name. We explained to ECTRIMS that the reason we wanted to launch OCTRIMS was to address the inequality of access to information on MS research and treatment. We felt women, ethnic minorities, people from middle- and low-income countries and the next or younger generation was not able to attend ECTRIMS because of financial and other cultural barriers. It was clear that ECTRIMS and other large MS meetings were being dominated by a specific demographic profile. We, therefore, had to settle for the less catchy triMS.online (Treatment and Research in Multiple Sclerosis Online) instead; c’est la vie.

A big selling point for us was the environment, i.e. how do we deliver online content that is environmentally friendly and reach and maintain engagement with our target audience. When we designed our first meeting we tried to rethink the conference and in particular the online experience. It became clear that the long didactic lecture format would not work. To simply replicate the face-2-face conference would not work. Our model was TED and TEDx talks, i.e. short well-rehearsed talks that were themed, to the point and engaging. At the same time, we had to put together a young and diverse International steering committee to make sure triMS-online lived up to its founding principles, i.e. more diversity (more women and ethnic minorities) and the next generation (youth). This is why I am so proud of the fourth triMS.online conference that delivers on so many of our founding principles.

So if you have the time to attend the live meeting please register and even if you can’t stay online for the whole meeting you can come back at any time to watch the talks in your own time. We promise that each talk will be well planned, short, to the point and with a limited number of well-defined objectives.

Enjoy and please spread the word to your colleagues and friends. And a big thank you to you our supporters and the sponsors for making this possible.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#BlackSwan: anecdotal evidence we can’t ignore

Barts-MS rose-tinted-odometer: ★★★★★

What is a black swan event?

“The black swan theory or theory of black swan events is a metaphor that describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalised after the fact with the benefit of hindsight”. (Source Wikipedia)

The case study below is another example of a mounting number of case studies of patients with MS being treated with antivirals, with activity against EBV, doing well. We now need to do properly powered randomised controlled trials to test the EBV causation of MS hypothesis definitively.

Prof. Julian Gold and I launched the Charcot Project in 2012 to investigate the viral aeitology of MS. We tried on numerous occasions to get trials funded to test this hypothesis and have failed. We managed to test one anti-retroviral in a small proof-of-concept study, which was negative. Since then we have managed to get funding to see if famciclovir is capable of suppressing EBV shedding in the saliva. This study should have been completed by now, but we had to delay its start because of the COVID-19 pandemic.

We have also managed to show that teriflunomide is anti-EBV in that it reduces EBV viral shedding in the saliva of people with MS. I suspect this is a very relevant an important observation and underpins the iTeri study, i.e. to use a B-cell depleting agent as induction therapy and teriflunomide or related compound as a maintenance therapy to prevent EBV reinfecting B-cells during the B-cell reconstitution phase.

Life is short and I started working on EBV as a cause of MS way back in 2005 and feel like I am treading water. The evidence that EBV is the cause of MS is so overwhelming that we really can’t afford to ignore it any longer. What we need is a substantial investment from the major funding agencies, MS charities, wealthy philanthropists and Pharmaceutical companies with antiviral drugs in their portfolio to prove (or disprove) that EBV is the cause of MS.

When you apply Bradford-Hill’s causation theory to EBV being the cause of MS there is only one criterion out of nine that still needs to be ticked and that is experimental evidence. What we need are therapeutic interventional trials targeting EBV to complete the proof.

Torkildsen et al. Tenofovir as a treatment option for multiple sclerosis. Mult Scler Relat Disord 2020 Oct 7;46:102569. doi: 10.1016/j.msard.2020.102569.

Some antiretroviral medications are also inhibitors of EBV. We describe a patient with highly active MS who was infected with HIV and started HIV-treatment containing tenofovir alafenamide (TAF), a potent inhibitor of EBV lytic reactivation. Her MS was in complete remission during this treatment, and she had new radiological disease activity again after switching to tenofovir disoproxil fumarate, an HIV drug with less potent activity against EBV replication. Based on the recently detected mechanism of TDF and TAF, we suggest that further studies on these drugs in MS are warranted.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: it’s over, but it is not

Barts-MS rose-tinted-odometer: ★★★★★

I have just completed the Virtual New York City Marathon in London and have clearly survived to tell the tale. Not only did I prove many doubters wrong, I even managed to surprise myself by dipping under the 3:20 mark (3:19:07 when I clocked 42.2km on my Garmin). It was only 3 years ago, due to chronic right hip pain, that I decided my running career was over. I interpreted the pain as being due to early osteoarthritis. Despite still having some hip pain it is so much better than it was. I suspect losing weight and exercising, or using the hip, has given it a new lease of life. This for me is one of the positives of COVID-19.; it has allowed many people like me to reassess their lives and to do different things. If COVID-19 hadn’t happened I would not have just completed a virtual marathon. My experience gives credence to the saying ‘use it or lose it’.

My motivation for doing the marathon was to raise money for Dr Ruth’s and Dr Kang’s COVID-19 antibody study. The reason ‘it is not over yet’ is that we have many miles to go before we reach our target of £25,000. The good news is that we very close to raising £10,000, which is the first funding milestone, which will allow us to actually start the process of recruiting pwMS and collecting their bloodspots on Guthrie cards for our antibody assay.

Prof G after completing his NYC virtual marathon

I, therefore, want to take a moment and thank those of you who have been so generous and donated money to our study. Your support and encouragement are much appreciated. For those of you who have not donated yet please consider making a small contribution; every little bit helps and also demonstrates that this is not just our project, but a community project.

The next phase of our fundraising will involve a series of topical webinars, but more on that later. At the moment we are discussing the logistics of how we can make this happen in a way that allows everyone to have a chance of attending the webinars.

If you have other ideas for us to raise the money please let us know.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

The forgotten many: not any more

Most of you will have heard by now that NICE has green-lighted siponimod for the treatment of active secondary progressive multiple sclerosis on the NHS. As the UK member of the EXPAND trial steering committee, Novartis who market the drug asked me for a quote, which sums up my opinion about the news.

“The NICE approval of siponimod to treat secondary progressive multiple sclerosis with active disease is a landmark that promises to transform the way we view and manage MS. At last, we have a treatment that can modify the progressive pathology that underpins secondary progressive MS with active disease. The ‘Forgotten Many’ is how people with secondary progressive multiple sclerosis have described themselves; but not anymore. Our challenge is to configure our NHS services to treat patients with secondary progressive MS and to manage expectations, as not all people with secondary progressive multiple sclerosis will be eligible for siponimod. However, this is the beginning of a new era in the management of MS and should be celebrated for that.”

CoI: multiple

#MSCOVID19: one microdonation at a time

Thank you for being such kind and generous supporters for our Barts-MS COVID-19 antibody study. It is clear that Prof G running the virtual NYC marathon this weekend, or next, depending on the weather, is not going to get us to the finish line. Therefore, we are going to take your advice and launch Barts-MS webinars. The webinar idea was suggested by one of you in the comments when we launched our fund-raising campaign.

There will be a limited number of places to watch these webinars, but to be allocated a ticket we are expecting viewer’s to make a microdonation towards our fundraising efforts so that Drs Ruth & Kang can start and complete our COVID-19 or coronavirus seroprevalence study.

At the end of the antibody study we should be able to answer some of the following questions:

How many pwMS in the UK have antibodies to the SARS-CoV-2?
What type of antibodies are they, i.e. IgM, IgG or IgA, what is the titre or level of these antibodies and are they neutralising? Neutralising means they inhibit coronavirus infection of cells in culture.
How many pwMS seroconverted who had documented COVID-19, possible COVID-19 or no history of COVID-19?
What is the seroconversion rate on different DMTs?
We also hope to follow a group of pwMS longterm with repeat testing to see how long these antibodies last and to see how many seronegative pwMS convert to becoming seropositive with time.
When a coronavirus vaccine or vaccines emerges we able to use the assay to see who makes an antibody response or not and hence we plan to compare different response rates on different DMTs.

The following are some suggestions for topics for the webinars:

What are arguments for and against HSCT as a first-line treatment for MS?
What is on the horizon for treatment of advanced MS?
What will the management of MS look like in 2030?
How can we make MS prevention a reality?
What is smouldering MS and is it treatable?
How are we managing MS during the COVID-19 pandemic?
Will I be able to have a coronavirus vaccine when one arrives?
Etc …..

These topics are not fixed in stone. If you have any suggestions let us know. Do you have any problems with us running these webinars? Would you be interested in attending? How do you feel about having to donate to attend the webinars?

For those of you interested the following is Prof G’s planned marathon route and if you want to make a micro-donation towards the study please click on the link below.

CoI: multiple