#ClinicSpeak & #ThinkSpeak: ruminations and thoughts about more advanced MS

What needs to be done to tackle ‘progressive’ or more correctly ‘advanced’ MS? #ClinicSpeak #ThinkSpeak #MSBlog

I had a meeting with colleagues earlier this week to discuss what needs to be done to tackle progressive MS; i.e. from an academic perspective. The following are some of my thoughts.

  1. We all need to accept that ‘progressive MS’ is misnomer. Progression means improvement. We prefer the term ‘advanced MS’ this captures the associated disability that comes with this phase of the disease.
  2. We need to accept that the pathology that drives neuroaxonal loss, or neurodegeneration (the pathological substrate that underlies ‘advanced MS’) as being there from the beginning. This means the neurodegenerative phase of MS is present from the beginning, before pwMS become physically disabled.
  3. 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. It also allowed the company concerned to charge rather a lot of money for its product. Overall this has been good for MS in that it has attracted a lot of Pharma interest and has supercharged drug development in MS, but it is now slowing down drug development and making it very expensive. We need cheaper drugs for advanced MS; disability affects the cost-effectiveness models for reimbursement hence DMTs for advanced MS need to be priced lower than those for relapsing forms of MS.
  4. 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 populations simultaneously.
  5. Slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There is clinical, imaging and pathological data that shows inflammation plays a big part in driving advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.  
  6. Accept that reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve 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).
  7. 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 advanced 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.
  8. Accept that we will need to use combination therapies to make a real difference to more advanced 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 – for example laquinimod which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.
  9. We need to ditch the EDSS. The whole community knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of 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 a better hand-and-arm function PROM. We are aware that there are several out there and some are in development.
  10. 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 don’t like adaptive designs nor do the regulators. I do think we do need two phases to trials in more advanced 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 advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).
  11. 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. We have finally fully recruited our PROXIMUS trial and we have learnt a lot in the process. I will do a separate post in the near future on the lessons learnt from PROXIMUS. For those of you new to this blog the PROXIMUS trial was an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’.
  12. Political changes are needed to incentivise the repurposing of off-patent drugs. We have discussed this on this blog endlessly and have even written a paper on the so called ‘Big Pharma Alternative’ to explain our thoughts on this.
  13. Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue; I don’t. If we do a trial and provide compelling data that drug x in combination with drug y delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them however is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies, this is not rocket science and happens all the time in other disease areas for example oncology.
  14. 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 recent EU cost of MS study that costs soar as pwMS lose arm function.
  15. We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing from reduced brain, and cognitive, reserve drives 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 advanced 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.  
  16. 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 me 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 I am passionate about tackling more advanced MS. I personally think 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 to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS.

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

31 thoughts on “#ClinicSpeak & #ThinkSpeak: ruminations and thoughts about more advanced MS”

  1. Good to see the old Prof G back – your passion comes out in this post. The political events of the last ten months were an unwelcome distraction. Focus on what you do best – coming up with new ideas and taking action to ensure that the ideas are tested and, where effective, benefit people with MS. Thanks for all your efforts.

  2. This is a great "Advanced MS" manifesto. I have been reading this blog long enough to be totally convinced that you are right on most issues mentioned here, except for maybe nr. 4 I agree that the division between RRMS, SPMS and PPMS is like looking through different keyholes on the same thing. I think most neurologists struggle determining when it is SPMS, for example ( and rightly so, as it has severe therapeutic consequences for the patient).But I think we are going to be surprised as we look at biomarkers in the coming years – this disease is potentially different diseases in terms of underlying mechanisms/drivers.ad 15 I would try to be more specific here – because there are things that can be done, even in advanced MS at this stage.Subdivide it into sections, so that everybody reading this can see what they should be doing.Call to action, now. Cardiovascular healthObesityDiabetesSmokinglack of physical exercise to name a fewand finally, my pet peeve : bone health. Fractures in people who already have mobility problems are a disaster that either leads to even worse mobility or even death.Good luck on you mission!:-)

    1. I can only testify about what I am seeing and what makes me angry.I handle most referrals to rheuma at our hospital, also the Osteo unit with 2 DEXA scanners. And what do I see? MS patients hardly ever get referred to us from our neurologists. YOu have to be a genius to understand that a 58 year old lady with MS walking with bilateral support, with some balance problems and drop foot on one side, after a radius fracture at 55 needs something done. A year later another fracture, ortho sees the fracture and fixes the fracture. The rest is invisible to ortho :-). And so on…If a patient knows what to ask for, then the GP will either start treatment or refer to somebody who will.The truth is, we have to know how to look after ourselves. 🙂

  3. On a roll with this ProfG Superbly articulated! I so hope very many are persuaded by the rallying cry.Been a week where this site has lifted my spirits, so I will maintain the hope of no 'stuck records' across the days, weeks, months and years that I return to it – progress with disease management in all its manifestations!

  4. Advanced MS sounds like something contrived by the Government as a new exam in the national curriculum. It's too soft.Call it 'Insidious MS', or 'Pernicious MS'. It's a horrible phase of MS, therefore give it a hard-hitting label. Don't be too gentrified about it.

  5. #1 – I agree that the naming conventions of the disease are misleading. I am not so sure the term 'Advanced MS' is best choice here. Few reasons. I realize you are targeting the academic community but I also presume it would be hoped to filter into the clinical and patient community over time. If that is not the idea then the term 'advanced' will confuse people in the patient community adding additional ambiguity to existing terms.If goals are to change terminology completely academic/clinical then a term that perhaps is more definitive is in order as while I agree, it is the same disease. The course of the disease as CD20Cell notes does take on changes and possibly underlying mechanisms which is supported by DMT's minimal efficacy in said stage difference(s).While I agree the term 'progressive' can be misconstrued as 'progress' in terms of MS the patient/clinical mindset is that of 'progression of the disease' not of the patient.Clarification and alteration of the term(s) secondary/primary progressive or even RRMS which is a bit misleading as the common public considers 'remitting' a term from cancer, most I speak with MS unaware consider 'remitting' as 'to have went away.'When attempting reduce confusion and more aptly name the disease characteristics IMHO considerable thought need go into said naming conventions.Reduce ambiguity and numbers of terms towards more defined and accurate appearing courses of the disease for both sake of academics, trials, clinical, patient and public.How does said terminology reflect upon potentials for medications / trials?Whilst evidence suggests that SPMS and PPMS are the same do trials display similar efficacy? Has the handful of SPMS targeted therapies shown similar efficacy in say early onset (or dx) PPMS?If the underlying mechanisms are actually differing significantly enough to impact trial results it could be a bad thing to change naming conventions as suggested to 'advanced' if again that terminology became that of academic and clinical. 'nnn' patients a mix of spms,ppms now deemed advanced ms. The spms cohort now not known per se as such has results where the ppms cohort not?If I might suggest, perhaps a modifier is called for. Just as clinical now is often speaking "aggressive" onset MS for example.I do not know what, my head still is not on all 8 cylinders yet Prof. G. Something along two terms covering RRMS – SPMS/PPMS that helps the research processes get more bandwidth per se towards trials yet has some form of modifier where-by said bandwidth can still afford granularity for sake of BOTH trial dissemination AND clinical.

  6. Progression means improvement? We can obviously see that the progressive politics of recent years are exceptionally destructive. In Germany and Sweden the progressive politics have made it illegal to speak the truth. Progression means get worse. My brother is EDSS 8 at least and the last treatment he had was methotrexate 8 years ago. The physio told us last year that it was too dangerous to continue with his few steps a week on the parallel bar.

  7. Thank you for this! I love this place. I wish that there was something similar to this for other tricky diseases.

  8. MS Unites saidMs Unites Saturday, March 18, 2017 5:01:00 pm"#9 I agree completely, the EDSS scale is a very poor tool for assessing MS. It is no where near granular enough to be of real usage. It invokes fear in the patient populations while not serving them well. Assessment of EDSS score is an opinion and it is based on what is some respects in anecdotal information. My EDSS can skew just based on things being a overly hot day.I also like that for example OhioHealth requires MS patients to complete a questionnaire at every visit to help the physicians evaluate in a more granular fashion the patients MS.My goodness there is so much to cover in what you have written Prof. G.# 15 – I have LONG said (as you know?) that aging in MS especially as people transition towards movement of upper middle aged into geriatric (-10) needs be addressed.That is to say 50+ as things change in the body. MS not only complicates all of this in well… who knows how many ways? But CLEARLY physicians who are aware of changes in aging NEED to be in the patient and perhaps even research processes BEFORE what is considered "geriatrics."A geriatric physicians is far far more experienced with neurological, cognitive and other facets of aging than a general practitioner is. Yet, getting access is impossible unless a patient IS geriatric which in MS, too late.I literally not figuratively know the difference here. My fiance's mom at 92 see's a geriatric. I've went along. We've discussed my disease, MS and the general aspects of neurodegenerative diseases. These people NEED to be in on process MUCH earlier.If I had a star trek transporter and took some geriatric physicians and transported them into some TRIMS gatherings you would see VERY interesting data and insights / questions come forth.—-That said I would like add another number to your list! LOL :)It really doesnt fit but I feel the need to say it.There are some universities that would very much like to do work in MS and they are VERY adept and willing to do so. They however do not get funds or for that matter even approached!……"TERMINATED IN RESPONSE TO COMMENTS BY ANON…."It seems to me lots of money flys around in many places but often not into the hands of researchers where regardless of outcomes disease processes and information is learned and horse-hockey dispelled".Anonymous saidAnonymousSaturday, March 18, 2017 5:52:00 pmI am sure there are loads of places that deserve more funding, this sounds like a sales pitch. Why not TeamG?MOuseDoctor Here. I tend to agree with ANON 5:52 and perhaps not a sales pitch but sounds like a lobby. I therefore have spammed your original post, but redacted lobbying element out.If Centres want to work on MS, then they can contact relevant place that can help them achieve that aim. This is not the site to say donate all your cash to somewhere else. They can set up their own site.

    1. I understand how the comment portion may have been misconstrued. No, not a sales pitch and no, not really a lobbyist perspective.UCD has done some remarkable work w. MSC's and BDNF including introduction of modified MSC's into mice where they are not near instantly destroyed by the mice immune systems.Just as with Huntingtons which has been a focus since receiving funds from the State of California researchers I have communicated with stated to me that the research/technology is also applicable to Alzheimer's, LS and yes, MS.What I was stating or essentially attempting to state (again, I am not on all 8 cylinders yet given my recent surgery) was that MS researchers need (IMHO) as a collective consider focal funds towards targeted research that is important .vs. the manners of repetition or simply tossed away funds.Whilst I've been out of the news loop for some months you know of that which I speak.EBV research in MS need struggle for funds yet most pwMS exhibit EBV. Given the myriads of funds floating about whatall, a million dollars is a pittance.Towards BDNF / MSC's yes, research has been done however not so much so via entities who are breaking new ground, delivering results albeit perhaps slower than might be wished for by patients.Indeed, there is the commercial injectors that may rather not see such focus occur due to their financial interests (pharma). I do not know how heavily said influence's impact other funding resources.Does it not make sense to attack disease in a more methodical manner as "MS Research" towards learning than buckets of entities all sailing off in chosen directions?Perhaps I am somewhat misconstruing the term "Academic Research."I see research in two modes (logically):1. Understanding the research target towards solutions.2. Then there is commercial application which also implies #1. to obtain it.Pharma is on #2 as they are a business.Research such as EBV in MS may shed light on some critical aspects of MS be they causal of MS or not. MSC's / BDNF, same deal. Sure, as research unfolds commercial application may well arise.It just seems to me that a great deal of money floats out in the world towards MS research that is never enough funds to fully pursue a target for academic purpose. Am I wrong?I've read who knows how many research papers where the conclusion is "More research is warranted" and that seems to be the end of that.

  9. Re ProfG original postThank you, very well articulated (ever considered politics?) I love 'MS is one disease', 'slay the dogma', 'challenge the dogma'. I love this blog and thank you all for giving up your spare time to keep us all informed and updated. Just hope some neuros are reading, how is the message being received? MD2 computer analogy is worrying….Ps I don't care what we call progressive / worsening MS it's horrible and I hate it. Would a rose by any other name smell so sweet? Of course it would 😉

  10. Wow and Hallelujah. Music to many people's ears. I am going to have to be very careful when I visit my neurologist this week. Reading this blog means I now Know Too Much. STFU Dave!Having said that – feedback. But first me.SPMS, 1996 (45yo) diagnosis, EDSS 8.5, 9HPT 90sec, 0-45 UK/Canada. Now AustraliaI am conscious, as I write that, that I use terms from several of the points G made.I *always*, talking to those newly learning about MS, have to excuse the term "progressive" The debate about the word to use clearly energises and activates people (witness the "dementia" furore on this blog) but actually is not the prime point that G was making.Through use of terms like this we see arbitrary divisions arising – in prescribing, in trial design, in academic and commercial research against which the pwMS must butt their head. For example Australian prescription guidelines requiring ambulance for SPMS use of Betaferon. It's all in the words.As an aside I do, of course, realise that there is a public health economics argument for a clearly defined line in the sand. G's question is "What line?"EDSS is a score I am falling of the end of. I clearly don't want to be 10 but I look down the scale, from my 8.5 splendour (the .5 actually says it all) and envy the richness of choice lower down. It is a "walkist" scheme. It is one that clearly endorses the notion that upper limb function is barely worth the paper it's printed on.My parting word is to the Barts IT team to do the work they need to do so that the blog post emails that I save will have the post topic in the subject line. Other readers will know what I mean. I have done it for my blog and it's bliss.

    1. There is no IT Team it's a Me, him and a few others team, maybe ProfG can have a look in blogger, he's the code man, I have no clue sorry.

    2. Perhaps you could see if any of the readers are web designers and could help out. I think prof g is too important to mess with HTML.

    3. I enjoy it as well. Not sure I'd call it my R&R.My fiance' is a coder w/ C#, .NET, C++, PHP, SQL etc.At first when he started explaining it to me I was like: "Oh my gosh! Geekster!"However, I rapidly began to find not only does it become rather fascinating but additionally I found it to be therapeutic towards my MS.When I was in college moving towards my Registered Nursing degree I aced everything. I was selected to tutor much younger students in fact I'd done so well. It was my dream!MS took this from me when I was on the cusp of completing my education.Learning to code (program) has given me back quite a bit. Not only am I more capable in respect to living through each day but its given me remarkable perspective on logic, methods, reverse engineering problems and perhaps even more significant towards others MS problems.It's allowed me understand how I function. Its allowed me better understand how my MS impacts me and try solve those issues either directly or by workarounds and it can be fun too.Its like building something functional from pieces, like a scale model airplane or in the case of women say creating clothing.It can be highly therapeutic.The problem in people learning to code is it is easy to start off on the wrong foot or get overwhelmed.When I am more capable of getting back to MS Unites after my recovery it has been part of our plans to teach programming and much more to patients and HOPEFULLY draw in others, husbands, kids, friends of pwMS to build that "United" collective and do all we can to make real things happen for pwMS, researchers like you so in turn you make real things happen for us w/ MS.

  11. david stratton saidHow nice to meet a fellow traveller. Coding has been my salvation because at EDSS 8.5 almost anything else is not possible.

    1. Pleased to meet you David,My name is Cynthia, I own and created A WEBSITE (PLEASE STOP SELF-PUBLISING)The Internet in general can be a unique blessing for people enduring disability. Its unfortunate that it is often used far under its potential for people living with disability.Sure, coding can really be a fantastic outlet of creativity and purposeful growth.Most folks using the web w/ MS are not anywhere near using true potentials towards their disease. I had a long long discussion with portions of our steering folks about it and many folks do.One of the misconceptions in MS is that most pwMS use the web. They do not or should I say if they do they are not actively engaged in aspects of MS.Just as with anything there is a ying/yang to it when it comes to the Web.Most active pwMS online engage social media. I've done quite a bit of study on this. For many people it is their main outlet and support mechanism when they are enduring severe disability due to MS and other conditions.Many others who have endured MS for many years yet have not accrued significant disability work to support others with the disease. The amounts of misinformation is staggering that is often passed. Many state they have goals to raise awareness. Raising awareness just as a coded program needs to have targets and goals.In the MS community online (and offline) there is this continual wax and wane towards awareness. Twas' actually one Doc's at Barts who showed me, "There are many forms of awareness."Public awareness, research awareness, wellness awareness, awareness of others with MS, disease awareness and more.Most pwMS tend try to drive at public awareness and this is important but why? Again, targeted goals become important.I do not expect the world to become more forgiving of pwMS no more so than those with other chronic diseases. I don’t expect MS to achieve the attention of say Cancer. Cancer has countless forms and the term gets utilized in an umbrella form.I am of the mindset that 'Neurological disease' as a term would attain more public traction towards public awareness. Doesn’t happen.Further, while I do realize at your EDSS measure you are at the severe disability part of the MS spectrum others range from near none to everything in between. The DMT's existing in RRMS and RRMS encompassing what is said to be 80-85% of patients creates another set of problems unaddressed.As Prof. G states, this is one disease.Some 12 years ago few treatment options existed. Tysabri was a game changer. Since then, many DMT's have come and more are on the way.

    2. A very large concern of mine that has gone unaddressed is the partitioning occurring and lack of foresight going on. For example, newly diagnosed patients given the DMT's are far less interested in awareness. Its a different disease than it was said 12 years back and clinical has stated this. The DMT's impact. The terminology used is improper. No. This is the same disease however medications exist now to help manage it.Additionally, it use to be that being geriatric MS was rather slim. People had accrued so much disability that quality of life left became focal. The DMT's probably alter that curve, yet, geriatrics are not engaged in MS anywhere even close to say Alzheimer's or other tending late life chronic conditions.I feel it all needs be addressed now rather than seeing people fall off the end of the playfield of life like Lemmings where 5 make it towards safety and 32 when splat off a cliff.That said, this blog shows the 'power' of what can happen given the passion of Barts staff and pwMS.Documents such as Brain Health Matters. Real tangible movements towards change and real thought behind it that is actionable.You would not believe how difficult it is to get people to help and foster movement and change, or, perhaps you do.PLEASE STOP SELF-PUBLISING YOUR WEBSITE, YOUR POSTS ARE TOO LONG FOR US TO READ IN BLOGGER BEFORE LAUNCHING, SO BE WARNED THEY MAY END UP IN SPAM

  12. As a patient whose "progression" has involved hemiparesis (my right side is essentially paralyzed and wasted, my left side weakening and losing muscle seemingly by the day – my left hand becomes practically useless by the end of the day), I find this commentary both encouraging and discouraging. Encouraging for the "advanced MS" population as a whole, but discouraging for me personally as it's clear there's no silver bullet on its way to save my ass.A few questions, asked out of curiosity, no intent at confrontation.If MS is one disease, how to explain the epidemiology of PPMS, which sees males and females stricken in equal numbers, generally exhibits less incidence of O-bands, seems to do more damage with fewer lesions and is usually diagnosed later in life?If the answer is a multi-drug cocktail, say Laquinimod/Rituxamab, would this not open up patients to a scourge of opportunistic infections and other nasty side effects? Seems that the use of immunosuppressive drugs alone are worrisome, hard to imagine using these drugs in combination. Especially long-term.I've long thought that the concept of "autoimmunity" is something of a smokescreen, as it seems obvious that an immune system gone awry is a symptom of some deeper ill. Likely a combination of smoldering viruses and genetic predisposition. I know that your team is investigating EBV, as well as the role of endogenous retroviruses, and I really think that massive resources need to be thrown into this area of research, rather than finding newer and more sophisticated ways to suppress the highly evolved immune system. Unfortunately, Big Pharma is making too much money selling immunosuppressants for this to happen. So it's left to the academic/government researchers, whose funding here in the states looks like it will soon be slashed dramatically. What's needed is a Manhattan Project type effort to get to the root of these diseases and eradicate them once and for all, but the priorities of society have been turned upside down, and we've handed most mid to late stage medical research to the pharmaceutical companies. Entities that exist to generate profit aren't likely to come up with cures for the diseases that feed their bottom lines. Capitalism is a wonderful engine for creating wealth, but the marriage between capitalism and medicine is an unholy one.Thanks to the entire team at Barts and London for all the work that goes into this blog. It's an incredibly valuable resource, and we owe you a debt of gratitude.Thanks in advance for indulging my inquisitiveness and pontification…

    1. Thanks for the questions. There are several questions in this comment. I personally don't make a diagnosis of PPMS in patients who don't have an abnormal CSF, i.e. OCBs. I therefore use the original Thompson or MacDonald criteria and not the new criteria.Patients who don't have OCBs probably have another disease. You may be aware that to get into the ocrelizumab study subjects had to have an abnormal CSF. Therefore if ocrelizumab gets licensed to treat PPMS it may be licensed for patients who have an abnormal CSF.

    2. Why does the PPMS sex ratio differ from RRMS? The sex ratio in RRMS has been changing over the last 100+ years. At the turn of the 20th century the ratio of F:M was essentially 1:1 and since then it has been increasing and is now close to 3:1 in high incidence countries. In Iran it is 5:1. In comparison the sex ratio in PPMS has remained constant. The changing sex ratio is actually a proxy for rising incidence; relapse-onset MS is increasing in incidence and PPMS is not increasing. Why? PPMS has an average age of onset of 40 years, 10 years later than relapse-onset MS. I think pwPPMS actually have disease that has a long asymptomatic period probably 10+ years and are very unfortunate they don’t have a lesion in an eloquent site, which would have allowed them to be diagnosed a decade earlier. I think sex hormones play a role in how focal inflammation plays out; i.e. females hormones may result in focal lesions being larger and more inflammatory and hence more likely to cause relapses. In comparison, lesions in males may be more likely to small and smoulder and increase slowly over time.

    3. Hi Dr. G, thank you so much for your answers. Of course, they've generated a few more questions, and I hope you don't mind my picking your brain.When you say "abnormal CSF", are you referring specifically to O-bands, or are there other markers that might be used. For instance, I have no O-bands but do display high levels of fetuin-a as well as other signs of neurodegeneration/disease activity (high neuro filament levels).Also, in regards to PPMS being still driven by inflammation, how to explain the lack of efficacy of HSCT in PPMS patients and SPMS patients with more advanced disease? The recent long-term efficacy study that came out showed 46% of SPMS patients had no evidence of disease progression after five years, but the PPMS population fared much worse. I'm assuming this is because the SPMS population included people with active inflammation. As Dr. Burt at Northwestern says, when it comes to HSCT "no inflammation, no response", referring specifically to enhancing lesions. This would seem to be the best long-term study we have on PPMS, for as you so astutely note most progressive MS trials are probably too short to display efficacy. This study tracked patients for 10 years, and showed PPMS patients did much worse post HSCT then either RRMS (who generally did spectacularly) or SPMS (who fared much better than expected).Wouldn't this suggest that immunosuppression in PPMS patients (at least those with no enhancing lesions) would not be effective, as HSCT could be viewed as the most dramatic form of immunosuppression? Of course, there is more to HSCT than simply widespread suppression of the immune system…Again, much thanks in advance for your indulgence…

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